key: cord-260256-aczn39lf authors: wehrens, erik; bangura, james s.; falama, abdul m.; kamara, kelfala b.b.; dubbink, jan h.; bolkan, håkon a.; grobusch, martin p. title: primum non nocere: potential indirect adverse effects of covid-19 containment strategies in the african region date: 2020-04-29 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101727 sha: doc_id: 260256 cord_uid: aczn39lf nan dear editor: with the covid-19 pandemic spreading in sub-saharan africa [1] , governments and health authorities are stepping up containment measures. in sierra leone, measurements taken include training of healthcare professionals, establishing testing facilities, information campaigns and a partial lockdown. in many ways, there are parallels with the early phase of the west african ebola outbreak 2013-2016 -including a steep decrease in in-and outpatients across health facilities [2] . in sierra leone, which ranks amongst the countries with the highest maternal and child mortality rates worldwide, the rapid decrease of patients presenting to healthcare facilities in this evolving crisis might herald a massive indirect covid-19-related death toll. there are many well-understood reasons for healthcare avoidance in times of a massive infectious diseases outbreak [3] . measures aiming to reduce the mortality and morbidity from covid-19 needs to be weighed against their unintended adverse effects. the future course of the epidemic in africa remains uncertain, but might differ from those in hic, as the potential effects of climate, population age pyramid, and co-morbidity pattern differences are currently unknown. a 'flattening the curve' approach seems not to be a realistic option, because healthcare systems in many lmics are often overwhelmed with handling caseloads even in 'normal times'. additionally, ppe availability is limited, separation of suspect and confirmed cases and non-cases does not necessarily lead to prevention of transmission [4] , rt-pcr testing might yield false-negative results [5] , and there are essentially no treatment options in view of limited oxygen supplies and almost no facilities for mechanical ventilation. none received. none of the authors has any conflict of interest to declare. all authors have contributed to the writing process and have agreed upon the final version. covid-19 pandemic in west africa a modified case definition to facilitate essential hospital care during ebola outbreaks counting indirect crisis-related deaths in the context of a low-resilience health system: the case of maternal and neonatal health during the ebola epidemic in sierra leone asymptomatic and human-to-human transmission of sars-cov-2 in a 2-family cluster stability issues of rt-pcr testing of sars-cov-2 for hospitalized patients clinically diagnosed with covid-19 key: cord-264655-v0v7zsaw authors: kuwahara, keisuke; kuroda, ai; fukuda, yoshiharu title: covid-19: active measures to support community-dwelling older adults date: 2020-03-20 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101638 sha: doc_id: 264655 cord_uid: v0v7zsaw nan the coronavirus disease 2019 (covid-19) has rapidly spread around the world [1] , posing enormous health, economic, and social challenges to societies. as there are no proven drug and vaccine treatments [2] , non-pharmaceutical measures are essential to slow the spread of the epidemic [3] . social distancing (e.g., cancellation of large gathering, school closures) is an essential part of public health measure for infection control [3] . in line with this, many social events and activities have been cancelled or scaled-down in many countries including japan, wherein there is already a high number of reported covid-19 cases [1] . however, concerns have been raised from the community frontlines in japan following the covid-19 outbreak. first, communities may not have enough knowledge on whether maintaining, scaling-down, or cancelling social gatherings during the outbreak while minimising health risk. in addition, older adults may have higher fatality rates from covid-19. to avoid this, social gatherings can be cancelled considering the elderly, just to hedge risk. given that the impact of social distancing may depend on the transmission situation and severity of the disease [4] , social distancing should be implemented carefully. practical information should be provided to community-dwelling adults to help maintain appropriate community activity levels. in fact, some voluntary community activities were maintained owing to personal advice from health professionals. another issue is social isolation. in many countries, including japan, living alone and social isolation have been growing concerns. cancelling social gatherings and scaling down elderly care services can put community-dwelling adults, especially older adults, at an increased risk and severity of social isolation. in march 2020, an older woman in the local tokyo community said, 'lunch is not tasty; i feel a loss of appetite from eating alone owing to the loss of a gathering place during the lunch break'. thus, the isolating effects of social distancing should not be ignored, and efforts are needed to mitigate the negative psychological impact. 3 although recent technological advances may help detect and provide care for groups at high risk of social isolation, community-dwelling older adults may not have access to smartphones or internet services [5] . therefore, multiple plans and measures to maintain social ties should be prepared at the individual level (family, friends, neighbourhood, etc.), organizational or community levels, and societal levels to prevent or mitigate the negative impact of social isolation and its related problems (from the preparedness phase) on the already vulnerable among the population during an epidemic such as covid-19. no funding received. the authors declare no conflict of interest. world health organization. coronavirus disease 2019 (covid-19) situation report -50 therapeutic options for the 2019 novel coronavirus priorities for the us health community responding to covid-19 closure of schools during an influenza pandemic mental health services for older adults in china during the covid-19 outbreak we thank the community residents for sharing information about their current situations. key: cord-263968-v9sncm4l authors: ahmed, anwar e. title: incidence of coronavirus disease (covid-19) and countries affected by malarial infections date: 2020-04-22 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101693 sha: doc_id: 263968 cord_uid: v9sncm4l nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid dear editor, the city of wuhan in china -toward the end of 2019 -experienced emergence of a new coronavirus disease (covid-19), formally named severe acute respiratory syndrome coronavirus-2 (sars-cov-2) [1] . unlike other animal-to-human coronavirus diseases, this virus shows potential to spread more rapidly in certain areas or countries within the short period of a few weeks. a low incidence of novel coronavirus disease (covid-19) has been reported from countries with a high incidence of malarial infections. the author investigates whether the rapid spread of covid-19 is related to the incidence of malaria cases in countries affected by covid-19. the study utilized publicly available data on covid-19 cases by countries reporting [2] . for each country affected by covid-19, the incidence of malaria cases per 1000 population at risk in 2015 has been retrieved [3] . as of march 22, 2020, results indicate world regions that are malaria free or recorded limited malarial infections reported a large number of covid-19 cases ( the poisson regression is used to assess whether the malarial incidence rate (per 1000 population at risk) is a predictor for increased cases of covid-19. the model shows that as the malarial incidence rate (per 1000 population at risk) increased by 1, the covid-19 incidence rate tends to decrease by 8.82%. a roc curve analysis (fig. 3) indicated that the incidence of covid-19 was a good classifier (auc = 0.8115) for countries that were malaria free or recorded limited malarial infections (5 or less per 1000 population at risk). as of march 22, 2020, malarial drugs have not yet been approved by the fda as treatments for covid-19. however, the use of malarial drugs such as chloroquine and hydroxychloroquine shown great promise in treating covid-19, specifically in china [5] and in france [6] , as well as in a number of ongoing clinical trials across the world. fig. 3 . the incidence of covid-19 as a predictor for malaria-free or limited malaria infections. another study in france investigated the effectiveness of both hydroxychloroquine and azithromycin with covid-19, 97.5% of 80 patients improved clinically at day 5, except two elderly patients (2.5%) [7] . in conclusion, the spread and clinical management of the current coronavirus outbreaks may require guidelines that incorporate the use of anti-malarial drugs. future studies are needed to investigate whether a) the use of anti-malarial drugs, b) the environmental factors, and c) different strains of covid-19 reduce the incidence of covid-19 infection in countries affected by malaria. none. the study may not require irb/ethics committee approval due to utilization of publicly reported data. the contents, views or opinions expressed in this publication or presentation are those of the authors and do not necessarily reflect official policy or position of uniformed services university of the health sciences, the henry m jackson foundation for the advancement of military medicine, the department of defense (dod), or departments of the army, navy, or air force. mention of trade names, commercial products, or organizations does not imply endorsement by the u.s. government. the author has no conflict of interest to disclosure. functional assessment of cell entry and receptor usage for sars-cov-2 and other lineage b betacoronaviruses an interactive web-based dashboard to track covid-19 in real time malaria published online at ourworldindata.org chloroquine is a potent inhibitor of sars coronavirus infection and spread hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov-2 infection in vitro chloroquine and hydroxychloroquine as available weapons to fight covid-19 clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 covid-19 patients with at least a sixday follow up: a pilot observational study ahmed henry m jackson foundation for the advancement of military medicine e-mail addresses: anwar key: cord-268519-t15yvy5s authors: pothen, lucie; yildiz, halil; de greef, julien; penaloza, andrea; beauloye, christophe; belkhir, leila; yombi, jean cyr title: safety use of hydroxychloroquine and its combination with azithromycin in the context of sars-cov-2 outbreak: clinical experience in a belgian tertiary center date: 2020-06-12 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101788 sha: doc_id: 268519 cord_uid: t15yvy5s nan despite some encouraging preliminary clinical data (2,3), major concerns have been raised about the use of hcq to treat covid-19 (5), particularly regarding potential cardiac toxicity (i.e. qtc increase and risk of torsade de pointe). because hcq has been safely used for many years for various indications (e.a. connective tissue diseases) (6), we decided to follow interim belgian guidance for all eligible patients hospitalized in our covid-19 wards. moreover, we were treated by supplementation if present. repeat ecg was not systematically performed during hcq treatment, except in case of drug-drug interaction which could potentially increase qtc (see foot note of table1). the main drug-drug interaction was driven by addition of azm (n=28). in this group, qtc was controlled at day 2 of combination therapy (n=24). we observed a significant increase in mean qtc, from 418 to 433 msec (p< 0,01 with paired t-test), but none of the patients showed a qtc over 500 msec. furthermore, in our entire cohort there were no sudden deaths nor syncope requiring resuscitation or icu admission. all icu admissions (n=13) were linked to respiratory failure resulting from covid-19 pneumonia. one patient on hcq presented av nodal reentry tachycardia in parallel with respiratory failure, and was successfully treated with adenosine. all deaths in our cohort (n= 12) were attributed to covid-19 infection. in conclusion, based on our clinical experience, no safety issues were encountered with the use of hcq for the treatment of covid-19. in coherence with recent data published here (7), its association with azm also seems to be safe, despite a significant increase of qtc that should be carefully monitored. the efficacy of hcq and its combination with azithromycin on covid-19 infection needs, of course, to be strengthened with further evidence from large randomized clinical trials. however, at this point of the covid-19 pandemic, we find it relevant to share our clinical experience with this well-known, readily available compound (hcq) which has limited contraindications and may help in the fight against this outbreak. abdominal pain, diarrhea); "moderate" as clinical (fever and cough) and radiological pneumonia (infiltrates) without hypoxemia; "severe" as clinical and radiological pneumonia with hypoxemia (o 2 saturation < 93%). **other consisted in escitalopram, citalopram, fluconazole, valproate, mirtazapine and olanzapine. in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) efficacy of hydroxychloroquine in patients with covid-19: results of a randomized clinical trial. medrxiv (2020) published online clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 covid-19 patients with at least a six-day follow up: a pilot observational study online ahead of print chloroquine and hydroxychloroquine in covid-19 electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus early treatment of covid-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in marseille, france key: cord-288270-x1j0r9jk authors: daw, mohamed a. title: preliminary epidemiological analysis of suspected cases of corona virus infection in libya date: 2020-03-20 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101634 sha: doc_id: 288270 cord_uid: x1j0r9jk nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid dear editor, since december 2019, corona virus disease (covid-19), a new emerging infectious disease occurred in wuhan, has spread all over the world and who has declared that the infection is "pandemic" and no country and region can be considered safe [1] . despite that all measures has been taken and clearly illustrated by who and cdc such measure can not be easily applied and followed within the conflict areas in the world such as syria, yemen and libya which suffers mostly [2] . libya has been hampered by a major armed conflict since 2011. the country is divided and two counterattack governments were founded. this has been clearly reflected on the quality of health services all over the country and citizens suffer immensely to get the basic and emergency services [3] . influx of immigrants and fighting militias form all over the world has added extra burdens of traceability and control of emerging infectious diseases in the country [4] . few studies were carried on the impact of immigrants and military fighting on spread of infectious diseases in libya. in 2014, an outbreak of viral hemorrhagic fever composed twenty-three cases were reported in north west libya that goes in concordance with those occurred in west-africa [5] . here in we would like to report on the first suspected cases of corona virus infection in libya. eight patients arrived from different countries where corona virus infection was officially reported and critically spread including egypt (4), tunis (2), saudi arabia [1] and italy [1] . the epidemiological, demographic, clinical and laboratory data, where collected for each patient by direct communications with attending doctors and other healthcare providers. the median age of the suspected cases was 56 years and 6 (75%) of them were men. on admission, most patients had fever and/or dry cough. other different symptoms were also reported including chest pain, headache, confusion, diarrhea and constant pain as illustrated in table 1 . different hematological and biochemical marker were reported ( table 1 ) including lymphopenia occurred in 6 patients (75%), and elevated lactate dehydrogenase in 6 patients (75). platelets were below the normal range in 6 (75%) patients and above the normal range in two (25%) patients. patients also had differing degrees of liver function abnormality, with alanine aminotransferase (alt) or aspartate aminotransferase (ast) above the normal range. no other respiratory viruses in any of the patients were reported neither a significant bacteria determined. according to chest x-ray and ct, 6 (75%) patients showed bilateral pneumonia with just 3 (38%) patients showing unilateral pneumonia. two (25) patients showed multiple mottling and ground glass opacity. all patients were treated in isolation and received antiviral, antimicrobial and supportive treatment according to the international standards [1] . by march 14, 3 (38%) patients had been discharged and 2 (25%) patients had died; all other patients were still in hospital. despite the several limitations of this preliminary descriptive study has, it highlights the major concern and the consequences of the spread of this vital infection not only in libya but also southern european countries as most of immigrants come via libyan mediterranean shores. αs this unstable situation in libya continues, this will make the country at a highest vulnerable condition. hence then international efforts should be combined to encompass this pandemic. no source of funding. the author has no conflict of interest to disclosure. clinical findings in a group of patients infected with the 2019 novel coronavirus (sars-cov-2) outside of wuhan, china: retrospective case series trends and patterns of deaths, injuries and intentional disabilities within the libyan armed conflict libyan healthcare system during the armed conflict: challenges and restoration epidemiology of hepatitis c virus and genotype distribution in immigrants crossing to europe from north and sub-saharan africa viral haemorrhagic fever in north africa; an evolving emergency patients (no = 8) key: cord-273930-4asx0dq3 authors: ortiz-martínez, yeimer; cabeza-ruiz, luis daniel; vásquez-lozano, sergio humberto; villamil-gómez, wilmer e.; rodriguez-morales, alfonso j. title: pericarditis in a young internal medicine resident with covid-19 in colombia date: 2020-08-28 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101863 sha: doc_id: 273930 cord_uid: 4asx0dq3 nan patients [1, 2] , especially in developing countries such as colombia. as previously stated [1] covid-19 may also present in them with a broad and changing spectrum of clinical disease, including cardiovascular conditions, as is the case of the pericarditis. the patient, a 25-year-old male, with no past medical history, first-year internal medicine resident attending patients in the emergency department in a reference public tertiary hospital in bucaramanga, santander, northeast colombia, wearing all personal protective equipment (ppe) and complying the protection policies and procedures implemented in his hospital during the early covid-19 pandemic. on july 19, 2020, the physician presented with myalgias, arthralgias and diarrhoea (watery stools, with no blood or mucus, from five to six episodes per day). however, with no fever or respiratory symptoms, he self-medicated with paracetamol and probiotics. on july 21, he additionally presented with fever (38,6ºc) and nausea. the same day reported his clinical condition to the hospital and started home isolation, a nasopharyngeal swab for sars-cov-2 test (logix smart, ivd/ce/fda) was done at home. his initial symptoms persisted, the body temperature varied between 38 and 38.6ºc, oxygen saturation >95%, and the myalgias and with these findings, the diagnosis of acute pericarditis was made, meeting 2 of 4 criteria: pericarditic chest pain and new pericardial effusion. at that moment, treatment was started with colchicine 0.5 mg od, ibuprofen 800 mg three times daily. during his hospital course, the patient presented severe chest pain that was difficult to relieve, requiring high doses of morphine, with the subsequent change to oxycodone with clinical improvement. after that, lactate levels were normalized, electrocardiograms and serial troponin tests were performed without changes. he was discharged home in stable condition with colchicine 0.5 mg two times daily, ibuprofen 800 mg three times daily and acetaminophen plus codeine with plans for a gradual taper following complete resolution of symptoms. colombia is currently on the top ten of countries with the highest cumulative cases of covid-19, with 376,870 cases (august 8, 2020). despite the use of ppe by the hcw, including those on training, as the case described, sars-cov-2 infection risk is evident, and transmission may occur. our case also presented with, a still considered novel, clinical manifestation of covid-19. although cardiovascular conditions have been reported widely in covid-19 so far [3, 4] , there is a lack of cases presenting with pericarditis, especially without other significant complications. multiple viruses can lead to the development of pericarditis [5] . in the case of covid-19, this consequence requires more detailed studies to understand their pathophysiology, but especially their clinical course and implications. as the pandemic increases, early detection and suspicion of cases, based on broader clinical findings, would be useful, to aid diagnosis, in addition to the confirmation by the rrt-pcr [1, 6] . pericarditis is not frequent in the context of common cold and flu, then, an increase in this finding, in the covid-19 context, make this case relevant. a conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). it may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. nothing to declare. all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. none. signature (a scanned signature is acceptable, print name but each author must sign) anosmia in a healthcare worker with covid-19 in madrid, spain risk of sars-cov-2 transmission by aerosols, the rational use of masks, and protection of healthcare workers from covid-19 cardiac involvement in covid-19 patients: risk factors, predictors, and complications: a review clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis acute pericarditis secondary to covid-19 coronavirus disease 2019-covid-19 key: cord-269759-1n1oo6wc authors: villamil-gómez, wilmer e.; sánchez, álvaro; gelis, libardo; silvera, luz alba; barbosa, juliana; otero-nader, octavio; bonilla-salgado, carlos david; rodríguez-morales, alfonso j. title: fatal human coronavirus 229e (hcov-229e) and rsv–related pneumonia in an aids patient from colombia date: 2020-02-06 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101573 sha: doc_id: 269759 cord_uid: 1n1oo6wc nan we have read the article of yavarian et al. [1] , showing the prevalence of influenza and not of middle east respiratory syndrome coronavirus (mers-cov) in pilgrims and the general population. we would like to discuss the relevance of other respiratory viruses, including other cov different to mers-cov, the severe acute respiratory syndrome cov (sars-cov) and the 2019 novel cov (2019ncov) [2] in relation to a case of coinfection between hcov-229e, respiratory syncytial virus (rsv) and hiv we had in colombia. the three highly pathogenic viruses, sars-cov, mers-cov, 2019n-cov, cause severe respiratory syndrome in humans, and the other four human coronaviruses (hcov-nl63, hcov-229e, hcov-oc43 and hcov-hku1) induce only mild upper respiratory diseases in immunocompetent hosts, although some of them can cause severe infections in infants, young children and elderly individuals [3] . two years ago, a 32-year-old man admitted to the intensive care unit (icu) for acute respiratory failure, five days after hospitalization, due to continuous productive cough (yellow secretion), nasal flaring, respiratory distress, intercostal retractions, sweating, chills and mucocutaneous paleness. during this admission, the patient tested hiv positive by elisa and western-blot. his initial cd4 cell count and viral load were 20 cells/μl and 759,780 copies/ml (pcr), respectively. patient was started on combination antiretroviral treatment (art) with a regimen of abacavir, lamivudine and efavirenz. on icu admission, he had fever of 37.6°c (99.68°f) and was mildly tachypnoeic. his blood pressure was 110/60 mmhg, with a pulse rate of 128/min. a chest radiograph showed bilateral micronodular infiltrates (fig. 1) . the patient's condition deteriorated rapidly, requiring endotracheal intubation and mechanical ventilation. arterial blood gas analysis showed severe hypoxemia with pao 2 of 70 mmhg and oxygen saturation of 60%, respiratory acidosis with paco 2 of 52. fourteen days after admission to icu, and despite treatment with oseltamivir and aggressive supportive care with mechanical ventilation, fluid resuscitation, and high dose norepinephrine infusion, refractory hypoxia rapidly led to a fatal multiorgan failure. no autopsy was performed. cultures of bal fluid, blood and urine specimens remained negative for mycobacteria, and fungi. only escherichia coli from urine and proteus mirabilis from bal (both were susceptible to meropenem) were detected. there is a lack of reported cases of a human coronavirus infection in hiv infected patients from colombia and south america, confirmed by rt-pcr. hcov-229e causes common cold but occasionally it can be associated with more severe respiratory infections in children [3, 4] , elderly and persons with underlying illness [3, 5] , which would be the case of hiv infection, as seen in this report [4, 6] . the identification of coronavirus in high-risk immunocompromised patients may lead to early adoption of a specific therapeutic strategy, but, in the absence of proof of the efficacy of antiviral drugs, the treatment remains only supportive [5, 7] . evidence for a zoonotic origin of hcov (eg. involving bats, camels), have been documented extensively over the past decade, including sars-cov, mers-cov, and now the 2019n-cov, which is causing epidemic and led to the world health organization to declare it as a public health emergency of international concern (pheic) [5] . in colombia, the unique previous reference to coronaviruses was the identification of avian infectious bronchitis virus strains (an avian coronavirus, genus gammacoronavirus) in antioquia [8] , a department close to sucre, where our patient was diagnosed. the patient denied travelling recently to other regions of the country as well as internationally. this case, similar to other non-mers hcov infection cases reported [7] , is a reminder that although most infections with human coronaviruses are mild and associated with common colds, certain animal and human coronaviruses may cause severe and sometimes fatal infections in humans. influenza virus but not mers coronavirus circulation in iran, 2013-2016: comparison between pilgrims and general population the next big threat to global health? 2019 novel coronavirus (2019-ncov): what advice can we give to travellers? -interim recommendations origin and evolution of pathogenic coronaviruses clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in hiv-infected and hiv-uninfected south african children coronavirus 229e-related pneumonia in immunocompromised patients coronavirus infection in an aids patient isolation of a novel coronavirus from a man with pneumonia in saudi arabia molecular characterization of avian infectious bronchitis virus strains isolated in colombia during sincelejo, colombia doctoral program of tropical medicine to dr. ziad memish, chair, working group on zoonoses, international society for chemotherapy, for his critical review and advice for improve of the manuscript. this manuscript is dedicated to the memory of luz alba silvera, in memoriam. the authors have no reported conflicts of interest. key: cord-264127-t7w407it authors: fakhar-e-alam kulyar, muhammad; bhutta, zeeshan ahmad; shabbir, samina; akhtar, muhammad title: psychosocial impact of covid-19 outbreak on international students living in hubei province, china date: 2020-04-26 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101712 sha: doc_id: 264127 cord_uid: t7w407it nan wuhan, china has attracted widespread attention due to an outbreak caused by novel coronavirus [1] . this outbreak has revived the memory of severe acute respiratory syndrome (sars), which caused 806 deaths all over the world [2] . chinese authorities has shuttled down many cities near epicentre of hubei (wuhan). this marks the very first time in china to retaliate in such a way against any outbreak [3] . under the government policies on covid-19, universities of china especially in wuhan region issued strict rules for the foreign students to prevent the transmission of virus in university community. due to this situation a panic condition has produced in the students especially those who were living in epicentre. our aim of study was to explore that panic and influencing factors on such students. for this purpose, a cross sectional study was developed by using a questionnaire. questionnaire was filled out independently from the participants of several places in hubei especially in wuhan. we approached students through official wechat groups, which were already developed by the universities for international students. we collected 504 valid responses from international students in which male and female respondents were 288 (57.1%), and 216 (42.9%) respectively. of which 368 (73%) were married and 136 (27%) were single with 30 years (sd = 9.26) average age (fig. 1a) . respondents from wuhan were 2.12 times greater than other areas. in addition, various other demographic factors were associated with exposure. first, those who had been in china for less than three years suffered 2.19 times more than the students who had been here for one or two years. married people were 13.05 times more effected than the single people. similarly, the students who were doing bachelor and phd were more likely to be affected (odd ratio = 0.66) than the master students. also the students who were between the age of 18-24 years were more likely to be affected than > 25 years old students. a significant number of respondents reported various socio-psychological impact of covid-19 on their daily life (fig. 1b) . approximately 71.03% used to talk about virus in their regular talks, while 49.60% were unhappy due to this pandemic condition. at one point, 50.19% had their concern about virus transmission, 48.21% were much worried about their family safety and 23.21% felt helpless (fig. 1c) . whereas in the response of some open ended questions, most of the students were worried and depressed. but, it was also admirable that some students felt less helpless due to the good policies of chinese government. many respondents obeyed precautionary measures to avoid covid-19. they reduced contact with others (78.96%), decreased visits to the affected areas (71.03%), increased the frequency of washing hands (95.83%), and took more care of their room ventilation (88.88%). while attending public places also declined (94.84%) (fig. 1d) . in another two specific questions about to stay in china and the policies by chinese government, 92.85% students were satisfied with the steps took by government and 58.53% preferred to stay here in china rather than to go their home countries. this study revealed some specific socio-psychological experiences of respondents. however, it is also admirable that many of the international students were afraid during pandemic. this may be due to the fact that the respondents in affected areas paid more attention to the safety of their families [4] . secondly, students with longer stay in china reported more concerns and consequences than the students who stayed for a short period of time. this may be associated with the respondent's age and their marital status. our results are valuable for decision-makers and healthcare providers to develop effective interventions for international students. based on the findings, we suggest to create a sense of security to eliminate the helplessness. such integrative assessment can be achieved via modern communication platforms. the continuing epidemic threat of novel coronaviruses to global health-the latest novel coronavirus outbreak in wuhang, china middle east respiratory syndrome coronavirus (mers-cov): infection, immunological response, and vaccine development an investigation of transmission control measures during the first 50 days of the covid-19 epidemic in china exploratory study on psychosocial impact of the severe acute respiratory syndrome (sars) outbreak on chinese students living in japan key: cord-276839-kxfxybq4 authors: dursun, zehra beştepe; kilic, aysegul ulu-; alabay, selma; benli, ali ramazan; çelik, i̇lhami title: covid-19 among turkish citizens returning from abroad date: 2020-09-01 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101860 sha: doc_id: 276839 cord_uid: kxfxybq4 nan the first confirmed covid-19 case reported from turkey was on 11 march 2020, after a man who returned to turkey from europe. after that day, turkish citizens who are abroad were evacuated back to the country and quarantined as a part of national infection control measures (1) . the umrah pilgrims were among the quarantined being a unique cohort of people with a greater risk of acquisition viral respiratory infections due to travelling internationally and size of people performing the worship in the same place (2). in our city (kayseri, turkey), the last convoy returning from umrah was arrived on 15 th march 2020. in this study, we aimed to investigate the rate of infection among returning turkish citizens. in addition to that we examine the risk factors for severe infection among returning umrah visitors in the same convoy. nasal and pharyngeal swabs were obtained from all citizens as soon as they arrived the turkish international airports. the swabs were tested for covid-19 by reverse transcriptase polymerase chain reaction and positive results were defined as confirmed covid-19 cases. all of the citizens were questioned for the symptoms of covid-19 such as fever above 38°c, cough or sore throat, myalgia and shortness of breath. symptomatic cases were hospitalized and treated in kayseri city hospital. asymptomatic cases were also housed in a separate building and isolated for 14 days. during this period, the patients who developed symptoms compatible with covid-19 were also transferred to the kayseri city hospital. laboratory tests were performed for cases including assessment of a complete blood count, liver function tests and lactate dehydrogenase. chest radiography and computed tomography (ct) was also performed for all case patients. the confirmed cases were classified as being mild or moderate and severe. severe disease was defined as patients with a respiratory rate >30 breaths /minute, respiratory distress and oxygen saturation (spo2) <93%. mild or moderate cases were defined as less severe clinical symptoms such as low-grade fever and cough with no evidence of severe pneumoniae. a total of 264 participants were enrolled (median age, 55,6 years [range, 13-87 years]; 46% male). univariate logistic regression analysis showed that severity of the disease was significantly related with to be ≥65 years old, to have fever >37,9°c, to have myalgia and to have lower lymphocyte count. independent predictor of severity of the disease on multivariate logistic regression were only to have fever (or=4,1, p=0.04). in tomography findings, patients with severe disease had more frequently bilateral peripheral ground glass opacities (68% vs 44%), whereas focal consolidation was more frequently observed among patients with mild and moderate disease (18% vs 33%). tomography findings did not significantly differ among patients. the empirical treatment of patients was covering antimicrobials against atypical pathogens, influenza virus and covid-19 (table) . among all case patients, 7 (12,7%) were treated in intensive care unit, 4 (7,3%) received invasive mechanical ventilation. all four patients who required mechanical ventilation were died. older people are at an increased risk of acquiring covid-19 and likely to have a serious illness. the risk is higher for those people travelling in groups and worship at the holy sites without social distancing. accordingly, the umrah visits are thought to be a super-spreader event though the visitors are the older age of the people compared with the general population and higher risk of having a coexisting chronic disease (2). in this current study, about one third of the people was above 65, with a median age of 55 years among returning 252 pilgrims. during their 14 days of quarantine, was occurred in about one fifth of them. rapid action in the early phase of the epidemic and ensuring an early return to the country, might be the effective in preventing the transmission of disease to large numbers of people. the lower lymphocyte counts were also previously reported to be associated with worse prognosis. in this study, the median lymphocyte count level of severe cases found 1540, however, this level was higher than previously reported studies (3, 4) . this may be because during quarantine the patients diagnosed and treated earlier before they developed deep lymphopenia. presenting with high fever was found four times more common among patients with severe disease. the presence of a fever in the elderly is more likely to be associated with a serious viral infection than younger adults (5) . so, mass screening for fever and early recognition of severe cases may improve the prognosis especially for elderly. a small sample size of umrah visitors included to this study was the major limitation. infection control precautions should be implemented and strictly followed in travels particularly for mass movements such as umrah visit. restricting the travel of people with advanced age and chronic disease during the epidemic period, the use of masks during travel, increasing the awareness of hand hygiene and quarantine for the returning visitors for appropriate duration are among the measures that should be performed for infection control. kayseri city hospital, department of infectious diseases kayseri city hospital, department of infectious diseases ministry of health, provincial health directorate new threat: 2019 novel coronavirus infection and infection control perspective in turkey presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study key: cord-255560-c8s9f12f authors: arab-mazar, zahra; sah, ranjit; rabaan, ali a.; dhama, kuldeep; rodriguez-morales, alfonso j. title: mapping the incidence of the covid-19 hotspot in iran – implications for travellers date: 2020-03-14 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101630 sha: doc_id: 255560 cord_uid: c8s9f12f nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid after the first two months of the epidemics of coronavirus disease 2019 in the world [1, 2] , caused by the severe acute respiratory syndrome coronavirus-2 (sars-cov-2), multiple epidemiological assessments in countries from asia, pacific, europe, and north america have been published [3, 4] . nevertheless, there are countries, with a rapid increase and a high number of cases, with a lack of studies. this is the case of iran in the middle east. for these reasons, we have developed epidemiological maps of cases but also of incidence rates using official populations, by provinces, for covid-19 in iran using geographical information systems (gis). surveillance cases data from february 19 to march 9, 2020, officially reported by the iranian health authorities were used to estimate the cumulated incidence rates using reference population data on sars-cov-2 confirmed infections (cases/100,000 pop) and to develop the maps by provinces, using the gis software kosmo® 3.1. during the first 20 days of epidemics, 7161 cases of covid-19 were reported in the country, for a cumulated rate of 8.9 cases/100,000 population, reaching up to 1234 cases during march 6, 2020 ( fig. 1 ). all the provinces have been affected, and rates ranged from 0.8 (boushehr) to 61.8 cases/100,000 population (qom) (fig. 1 ). at qom, the first two cases were reported. covid-19 arrived at iran from china. the highest number of cases have been reported in tehran, 1945 ( fig. 1) , followed by qom, 712, and by mazandaran, with 633. qom is the border with markazi and semnan, provinces with rates from 27.2 to 34.9 cases/100,000 population. from the gis-based maps, it is clear that spreading in the country is occurring from north-central provinces such as tehran and qom. till march 9, 2020, there have been 237 deaths (3.31%, case fatality rate). while the number of cases seems to decrease during the last three days, this is not occurring with fatalities ( fig. 1) . iran is the third country with the highest number of reported covid-19 cases after china, and italy, up to march 16, 2020 with 14,991 cases, being the first in the middle east region, and maybe becoming a significant source of imported cases in this area, in countries such as iraq, afghanistan, and pakistan, among others. while the highest number of covid-19 cases has been reported in the capital city, using gis and estimating the incidence/attack rates per province, that one is placed as the seventh, having more cases per population at qom, semnan, and markazi, among other provinces (fig. 1) . a recent study, based on imported cases from iran, estimated that 18,300 (95% confidence interval: 3770 to 53,470) covid-19 cases would have had to occur in the country [5] , assuming an outbreak duration of 1.5 months. even if it were considered that all imported cases of iran were identified in all states with certainty, the "best case" outbreak size was substantial (1820, 95% ci: 380-5320 cases), and far higher than reported case counts in february 2020. all confirmed cases in saudi arabia are imported from iran and one from iraq and other cases are close contacts to those confirmed cases. imported cases from iran have been diagnosed at kuwait, bahrain, iraq, oman, qatar, among other asiatic countries, but also georgia, estonia, belarus, and even new zealand [6] . the capital city of khorasan razavi (3.1 cases/100,000 population), mashhad, is the second-largest holy city in the world, attracting more than 20 million tourists and pilgrims every year [7, 8] , many of whom come to pay homage to the imam reza shrine (the eighth shi'ite imam). regardless of this epidemiological scenario, the iran outbreak of covid-19 is still beginning and complex. authorities have limited travel, and schools and universities have closed, as also have occurred in italy and spain, until the start of the holiday for persian new year nowruz on march 20, 2020, as measures for spreading of this coronavirus [7] . as there are severe limitations in the medical supplies available in the iranian public health system to deal with the current sars-cov-2 outbreak, international support, additionally to be provided from the world health organization, is needed in the country to mitigate the impacts of this epidemic, and to avoid additional spreading. for the moment of the proofs correction of this article, iran reached 14,991 cases, of them 3,774 in tehran, 1,301 in esfahan, and 1,023 in qom (march 16, 2020). going global -travel and the 2019 novel coronavirus history is repeating itself, a probable zoonotic spillover as a cause of an epidemic: the case of 2019 novel coronavirus the first 2019 novel coronavirus case in nepal an interactive web-based dashboard to track covid-19 in real time estimation of covid-2019 burden and potential for international dissemination of infection from iran travelers give wings to novel coronavirus (2019-ncov) covid-19: preparing for superspreader potential among umrah pilgrims to saudi arabia covid-19 -the role of mass gatherings zahra arab-mazar infectious diseases and tropical medicine research center key: cord-292513-7mhd4wzk authors: yi-fong su, vincent; yen, yung-feng; yang, kuang-yao; su, wei-juin; chou, kun-ta; chen, yuh-min; perng, diahn-warng title: masks and medical care: two keys to taiwan's success in preventing covid-19 spread date: 2020-06-04 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101780 sha: doc_id: 292513 cord_uid: 7mhd4wzk nan despite being close to china, taiwan has stopped the covid-19 with general screening strategy and encouraging people in taiwan to wear a mask. taiwan reported the first covid-19 case on 21 january 2020. about 850 000 and 400,000 of taiwan's 23 million citizens live and work in mainland china, respectively. there were 2.71 million visitors from mainland china in taiwan in 2019 [1] . the narrowest point between taiwan and mainland china is just 130 kilometres. taiwan is one of the areas with the highest risk of the covid-19 pandemic, but it did not happen. taiwan has recorded just 438 cases and 6 deaths on may 05, 2020, including 55 local cases and 383 imported cases, respectively. in european and american countries, it is generally believed that only infected patients need to wear a mask and that wearing a mask implies an admission of disease. in asian countries, on the other hand, it is common for people to wear masks to prevent covid-19. the daily production capacity of face mask manufacturers in taiwan before the outbreak was 1.88 million face masks with a maximum production capacity of 2.44 million face masks per day. to ensure sufficient domestic resources for the prevention and control of epidemics, the government of taiwan has imposed a ban on exports of face masks on 24 january, followed by the requisition and rationing of all domestically-produced face masks (about 4 million pieces per day) by the national health command center and central epidemic command center (https://www.cdc.gov.tw/en). starting from 6 february, each person was allowed to purchase two surgical masks (priced at nt$ 5 each, equivalent to usd 0.17 each) every seven days. starting from 5 march, the purchase limit was increased to three masks for adults and five masks for children every seven days. to ensure an adequate supply of face masks, thailand, south korea, and france announced the implementation of export controls on face masks starting from 4 february, 26 february and 3 march, respectively. germany and russia also announced a ban on exports of face masks on 4 april. besides, the world health organization (who) also called for all countries to boost their production of face masks on 4 april. taiwanese people who suspect they may have been infected with covid-19 can go to the emergency department of the nearest hospital for relevant medical examinations (including sampling and testing for covid-19, blood tests, and x-ray imaging test) with out-of-pocket medical expenses of less than nt$ 600 (usd 20). people with high suspicion of covid-19 infection will be admitted to isolation wards, and those who have tested positive for covid-19 can only be discharged home after three consecutive respiratory specimens test negative for the virus. in that case, patients will have to pay less than nt$ 3,000 (usd 100) out-of-pocket for medical services. most of the medical expenses incurred by taiwanese people are covered by the national health insurance program. as of 05 may, there were a total of 438 confirmed covid-19 cases out of 65,589 screening tests under surveillance with a positive rate of 0.67%. of the confirmed cases, 6 patients died from the disease and 334 patients (76.3 %) have been released from quarantine, while the remaining patients are still hospitalised in isolation wards. on 1 april, taiwan president tsai ing-wen announced plans to donate 10 million face masks to countries that have been severely affected by the epidemic. taiwan is donating 2 million masks to the united states, 7 million masks to european countries, and 1 million masks to countries that have diplomatic relations with taiwan. taiwan is currently deliberating on epidemic prevention and control strategies, and is sharing its research outcomes with the united states, european union (eu), and the czech republic. besides, taiwan also collaborates with australia and the united states on the exchange of materials for the prevention and control of epidemics. president tsai pointed out that taiwan will definitely not stand idly by based on humanitarian considerations and will actively enhance collaborations with various countries for the prevention and control of covid-19. taiwan is willing to assist the international community in terms of face masks, medicines, and technologies. currently, taiwan is capable of producing 18 million face masks per day and will boost its production capacity to 20 million face masks per day. the purchase limit has also been revised to nine masks for adults or 10 masks for children every 14 days starting april. at present, the number of confirmed covid-19 cases has exceeded 3 million worldwide with countless medical personnel risking their lives to treat patients [2] . the united states and eu countries are greatly affected by the covid-19 epidemic. on the basis of taiwan's invaluable experience in the prevention and control of epidemics: 1. we encourage the public to wear face masks during the epidemic while keeping the price of face masks low by controlling the manufacture and sale of face masks; 2. we ensure public access to affordable comprehensive screening tests and medical care for covid-19. we believe that these two approaches are among the main factors contributing to the success of taiwan in limiting the spread of covid-19. taiwan's experience may help european countries and the united states to contain the covid-19 epidemic. jama 2020. 2. world health organization: coronavirus disease 2019 (covid-19): situation report the authors declare that they have no conflict of interest. key: cord-259106-nrg1960d authors: vasquez-chavesta, angie z.; morán-mariños, cristian; rodrigo-gallardo, paola k.; toro-huamanchumo, carlos j. title: covid-19 and dengue: pushing the peruvian health care system over the edge date: 2020-06-26 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101808 sha: doc_id: 259106 cord_uid: nrg1960d nan covid-19 and dengue: pushing the peruvian health care system over the edge dear editor, on february 25, 2020, the first case of coronavirus disease 2019 (covid-19) was reported in latin america (la). brazil was the first country. however, there was a rapid widespread throughout la due to its high transmission efficiency, lack of travel restrictions, and, in some cases, the delay (or absence) of effective health-related policy decisions [1] . in peru, the first case of covid-19 was confirmed on march 6, 2020, in a 25-year-old man with a recent travel history from europe. unfortunately, the country was already facing a nationwide state of emergency due to an outbreak of dengue fever that started in october 2019. thus, in early 2020, the ministry of health (minsa) had already reported an incidence of 7.83 cases/100,000 inhabitants [2] , and, by the end of the first trimester, the confirmed cases were above 10,000 (table 1) . simultaneously, since the first reported case, covid-19 has increased exponentially. at the end of the epidemiological week 24 (ew24), june 13, minsa reported a total of 225,132 cases, 10,342 hospitalized patients, 1113 in intensive care units (icus) and 6498 deaths. additionally, several regions in northern peru (loreto, lambayeque, piura and la libertad) not only have a considerable number of dengue cases but are also in the top 6 of covid-19 cases. it is important to mention that both diseases share some epidemiological characteristics, such as an increasing incidence and difficult control. similarly, covid-19 and dengue could be hard to distinguish because they also share some clinical and laboratory characteristics [3] . therefore, the healthcare management of patients with any of these diseases represents a real challenge (and we cannot rule out that the table 1 new and cumulative cases/deaths for dengue and covid-19, according to epidemiological week. 0 8 877 0 6267 0 4 0 15 0 9 857 0 7124 0 7 0 22 0 10 1103 6 8227 6 6 0 28 0 11 819 37 9046 43 0 0 28 0 12 629 275 9675 318 0 5 28 5 13 549 353 10,224 671 0 11 28 16 14 570 1075 10, number of dengue-related deaths is underestimated). additionally, although in peru the case fatality rate of dengue is lower than that of covid-19, some clinical manifestations such as dengue with alarm signs and severe dengue may need hospitalization and icu admission (according to peruvian guidelines [4] ). to make matters worse, the number of probable cases has followed a similar pattern to that of confirmed cases, with an approximate ratio of 2:1, which increases, even more, the demand for healthcare services and resources in the country. in peru, drastic measures have been implemented in order to achieve the mitigation of the impact of covid-19/dengue. these included the publication of two supreme decrees (n � 044-2020-pcm and n � 004-2020-sa). however, different limitations have arisen, especially since the first case of covid-19 was reported. for example, the lack of icus availability, ventilators, diagnostic and screening tests, personal protective equipment (ppe) and health workforce. similar scenarios have been reported in other la countries, such as brasil [3] and ecuador [5] . currently (16/06/20), the country is going through its fourteenth week of quarantine and covid-19 continues spreading (237,156 cases and 7056 deaths to date). at the time of submission of this manuscript, the ew24 surveillance report for dengue was still not available. although the number of deaths has not changed in the previous ew21 to ew23, the increase of dengue cases is likely to become more evident in the next weeks or months. this could add more pressure on a health system that is already being pushed to the brink of collapse. peru has been making every effort to stop the spread and mortality rate of covid-19 and we have to be optimistic. we still cannot be sure when this pandemic will end. however, when this happens, we should start by strengthening our health care system. as an old saying goes, "certain experiences mark the beginning of maturity." not applicable. not applicable. all data and materials used in this manuscript were publicly available. data sources included weekly and national surveillance reports from the center for disease control and prevention (ministry of health, peru), and daily reports published in the peruvian digital platform gob. pe. cumulative confirmed cases of dengue were obtained using the virtual dashboard of health situation (https://www.dge.gob.pe/salasit uacional/sala/index/salasit_dash/143). mortality data (daily and cumulative) for covid-19 was obtained using the health situation dashboard: covid-19 perú (https://covid19.minsa.gob.pe/sala_situacional. asp). this study was self-funded. cjth conceived the study. azvc and pkrg collected the data independently, cmm and cjth performed the cross-validation of the datasets and the quality control. all authors discussed the results, drafted the first manuscript, critically read and revised the manuscript, and gave their final approval for publication. the authors declare that they have no competing interests. covid-19 in latin america: the implications of the first confirmed case in brazil perú a la se 03-2020. lima: cdc perú covid-19 and dengue fever: a dangerous combination for the health system in brazil guía de pr� actica clínica para la atenci� on de casos de dengue en el perú. lima, perú: minsa covid-19 and dengue, co-epidemics in ecuador and other countries in latin america: pushing strained health care systems over the edge not applicable. key: cord-270684-e7xnugdd authors: iken, oluwatomi; abakporo, uzoma; ayobami, olaniyi; attoye, timothy title: covid-19: travel health and the implications for sub -saharan africa date: 2020-04-09 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101645 sha: doc_id: 270684 cord_uid: e7xnugdd nan the global health response to covid-19, coordinated by the world health organization which led to its eventual classification as a public health emergency of international concern has inadvertently affected global travel (1) . with ongoing debates for/against travel restrictions, some countries have implemented these restrictions to protect their citizens in response to the global rise in cases (2) . conversely, in countries with many confirmed cases, it appears more people are trying to travel out of those cities, whether from panic, legitimate reasons or ignorance(1). travel may be necessitated for planned, legitimate or emergency reasons which may include: conferences, family, work or vacation, which did not factor in the occurrence of a global outbreak. contacts of cases may not be self-aware of the risk they portend, especially when they are not symptomatic, putting many more people at risk. covid-19 has affected not just travelers, but also airlines, some of which have experienced dips in their revenues with the possibility of their staff being at risk and has also affected global trade/stock markets. in some countries, gatherings of over a thousand people, conferences, festivals have all been cancelled due to this outbreak which is still spreading and expected to peak in a few weeks (3) . the losses to travel agencies, families who may have delayed reunions, conference organizers, airline investors and the huge burden on the health care system, including morbidities and mortalities among health care personnel has necessitated some focus on travel health. in the response to such global outbreaks, like the covid-19, the majority of the attention is focused on building on the pre-existent preparedness measures, response, and mitigation; however, due to the ease of travel, a country that previously had no cases, can within a week begin to manage hundreds of cases. while information regarding the outbreak is being disseminated via credible public health organizations, social media and rumors in communities during this outbreak also provide sometimes, unverified and untrue information(4). this becomes more important for low-and middle-income countries, many of which are in sub-saharan africa, who may for the first time need to issue travel advisories and provide travel health services, sometimes in cities or countries where they may have been previously non-existent. the covid-19 outbreak has shown that travel health and medicine are vital in supporting the outbreak response, and more needs to be done in sub-saharan africa for capacity building and infrastructure not just for the present but in preparing for any potential outbreaks in the future. from academics to traders in the sub -region, updated, evidence -based information regarding what countries not to travel to, how to travel safely, symptoms to look out for, self-quarantine, their country embassies at the travel destination and a fair estimate of their risk if they decide to travel. knowledge regarding the disease is evolving, and citizens need to be constantly informed to make safe travels. for several reasons including limited resources for competing priorities especially across africa, travel health is not given required attention, the recent covid-19 outbreak shows this status quo is untenable. the international society of travel medicine appears to have no country in sub-saharan africa listed as a member(5), while many countries in the sub-region continue to have very few trained and licensed professionals, much less than required to address global outbreaks in the places where they are most needed. we need to re-examine the scientific basis of prescriptions around travel during communicable disease outbreak. when is travel restriction justified and to what extent? what is the minimum evidence threshold that justify travel restriction? how do we incorporate available evidence into preparedness and response in order to minimize contagion during travel in the face of infections like sars-cov2 with many unknowns? most importantly how do we get individual countries to align global health interest along with national interests for travel health decision making. furthermore, what should we be telling travelers to and from regions like africa -with limited capacityeither as a preparedness or response measure? how do we fit the communications related to travel into the overall risk communication strategies? these are relevant scientific and operational questions that will enhance global health security as it pertains to travel health. while we may not have answers to some of these questions, it is a good starting point to inform public health actions now and in the foreseeable future in a contextually relevant manner. this information can be deployed in crafting travel health information ( which can be tailored to specific demographics and disseminated via the appropriate media to those groups). covid-19 can ensure that evidence-based information reaches a wider audience across communities in sub-saharan africa. in addition, we recommend capacity building for travel health in the sub -region as this will greatly enhance the management of the current covid-19 outbreak and assist with potential outbreaks in the future. in conclusion, there is a need to enhance travel health practice and infrastructure, and its integration into all structures and processes of disease preparedness and response including risk communication. public health preparedness towards covid-19 outbreak in nigeria mustapha jo do not violate the international health regulations during the covid-19 outbreak covid-19 control in china during mass population movements at new year covid-19: real-time dissemination of scientific information to fight a public health emergency of international concern the international society of travel medicine we declare that there are none all authors contributed to the conceptualization, development, writing, editing, proofreading and approval of all the drafts that produced this document.oluwatomi iken, uzoma abakporo, olaniyi ayobami: conceptualization oluwatomi iken: writing-original draft preparation. oluwatomi iken, uzoma abakporo, olaniyi ayobami, timothy attoye: reviewing, editing, proofreading, re-writing, supervision views and opinions in this represent those of the authors writing in their personal and independent academic roles without any direction from their governments or institutions. oluwatomi iken key: cord-284477-3mspnc8q authors: kassem, issmat i. title: refugees besieged: the lurking threat of covid-19 in syrian war refugee camps date: 2020-05-05 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101736 sha: doc_id: 284477 cord_uid: 3mspnc8q nan travel medicine and infectious disease requires that all authors sign a declaration of conflicting interests. if you have nothing to declare in any of these categories then this should be stated. a conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). it may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. no funding sources. deaths, respectively, as of april 9 th [1] . this perhaps casts shadows of doubt on the absence of outbreaks or cases in the camps. indeed, there are suggestions that the refugees might not be reporting infections due to 1) lack of knowledge in regards to infection and symptoms, 2) lack of access to tests, which are already limited and insufficient for the needs of the hosting communities, and 3) fear of stigma which might lead to increasing restrictions and crackdown on the refugees. covid-19 has ignited fears in many communities and reactions to patients or potential carriers of the virus are not always charitable. furthermore, it is well known that certain hosting countries established curfews and implanted deportations of unregistered refugees even before the onset of the pandemic. therefore, tackling the spread of covid-19 in the refugee camps appears to be complicated and fraught with many complications. a quick assessment of the nature of the disease can reveal the potential scope of threat to the refugees. it is known that covid-19 is mainly transmitted via the respiratory route (spreads by close proximity), and that patients with comorbidities and those that are prone to recalcitrant and antibiotic-resistant secondary infections do not fair comparatively well. additionally, the major current approaches to control the spread of covid-19 in communities, include 1) social distancing, 2) close adherence to hygienic approaches (washing and disinfection), and 3) protective gear (such as masks and gloves), 4) frequent testing and quarantines, and 5) maintaining a good health. these measures in any community have proven difficult, but they might be even more challenging in syrian refugee camps. indeed, it is widely known that many refugee populations that witnessed catastrophic events might be immunosuppressed and can carry multidrug resistant pathogens [2] , while the camps also host elderly refugees, which are particularly susceptible to covid-19. furthermore, populations of refugees live under crowded conditions in makeshift tents that provide little protection, while camps may share common services, which render distancing very difficult. furthermore, the quality and availability of water (drinking and domestic) in many camps are insufficient; with intermittent access, shortages and documented contamination with bacterial indicators of fecal pollution and multidrug resistant pathogens [3, 4] . this obviously decreases the efficacy of hygienic practices that rely mainly on sufficient access to clean water and is more problematic in scenarios that also include shared latrines and vulnerable camp water cisterns. additionally, shortages in-and monopolization and soaring prices of protective gear, disinfectants, virus tests and nutritious food mean that these items will be even more scarcely available for the refugees, which will adversely impact the maintenance a good health. the situation is layered further with more complications and challenges. for example, lebanon, a country that hosts an estimated 1.5 million syrian refugees (distributed in makeshift camps and other dwellings) is currently facing a very severe economic crisis, civil unrest (decreased after the pandemic), and a covid-19 outbreak. lebanon is currently under a curfew in order to control the disease, and prices of food and medicine are soaring in a country that relies heavily on imports to meet its needs. the latter is becoming more difficult under restrictions imposed by the economic crisis as well as the spread of the disease. consequently, allocating resources and much needed help to the refugees might be unavailable or scarce at best. while the un refugee agency (unhcr) and other ngos are attempting to provide support and awareness to the refugees, the realty is that significant funding is required, given the various needs and the high number of refugees. in that regard, the unchr has appealed for urgent funding to combat covid-19 in refugee camps, but the results of this initiative remain to be seen [5] . in contrast, there are anecdotal reports of fears that foreign aid might withdraw from the camps due to the pandemic. the latter would have severe consequences, especially in case of an outbreak, which will leave the refugees besieged in their camps and facing a dire threat. during these challenging times, we call for global and urgent support for these disenfranchised populations. the health of refugees is intimately linked to that of their hosting communities and beyond, which is more reason to protect the camps from covid-19. consequently, an uncontrolled outbreak would result in significant morbidity and mortality that might not be confined to the camps. therefore, transparent and thorough investigations along with preemptive and inclusive control measures are urgently required to prevent and/ or control the dissemination of covid-19 in syrian and other refugee camps worldwide. the authors declare no competing interests. ethical approval: none was required. coronavirus covid-19 global cases by the center for systems science and engineering infectious disease profiles of syrian and eritrean migrants presenting in europe: a systematic review first report of the plasmid-borne colistin resistance gene (mcr-1) in proteus mirabilis isolated from domestic and sewer waters in syrian refugee camps first report on the detection of the plasmid-borne colistin resistance gene mcr-1 in multi-drug resistant e. coli isolated from domestic and sewer waters in syrian refugee camps in lebanon coronavirus emergency appeal unhcr's preparedness and response plan key: cord-254717-1hwdd7nq authors: al-tawfiq, jaffar a.; al-homoud, ali h.; memish, ziad a. title: remdesivir as a possible therapeutic option for the covid-19 date: 2020-03-05 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101615 sha: doc_id: 254717 cord_uid: 1hwdd7nq nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid remdesivir as a possible therapeutic option for the to the editor, in a recent review article, there were multiple preventive measures that were proposed for the middle east respiratory syndrome coronavirus (mers-cov) [1] . since 2002, we had witnessed the emergence of three coronaviruses with a significant impact. these are the severe acute respiratory syndrome coronavirus (sars-cov), mers-cov and the sars-cov-2, the causative agent of covid-19. sars-cov-2 emerged in wuhan, china, in december 2019, and according to the world health organization (who), the global number of confirmed cases was 80,239 as of february 25, 2020 [2] . however, there is no recommended therapy for any of these covs. remdesivir (with a development code gs-5734) is a broad-spectrum antiviral agent. this medication is an experimental drug and had not been licensed or approved at the time of writing this article. it was synthesized and developed by gilead sciences in 2017 as a treatment for ebola virus infection. it is a monophosphoramidate prodrug and is an adenosine analog. remdesivir is metabolized into its active form, gs-441524, that obscures viral rna polymerase and evades proofreading by viral exonuclease, causing a decrease in viral rna production. the antiviral mechanism of remdesivir is a delayed chain cessation of nascent viral rna . remdesivir showed antiviral activity against multiple variants of ebola virus in cell-based assays [3] as well as in a rhesus monkey model of ebola virus disease [4] . remdesivir was given on a compassionate-use basis to a british nurse who initially survived ebola virus disease and then she relapsed nine months later and had meningoencephalitis [5] . in a randomized controlled trial of ebola virus disease therapeutics, 673 participants received one of three monoclonal antibodies (zmapp, mab114 or regn-eb3) or remdesivir [6] . however, the study was stopped as an interim analysis found that individuals who received regn-eb3 or mab114 had greater survival rates than either zmapp or remdesivir [6] . in-vitro studies showed that remdesivir can inhibit coronaviruses such as sars-cov and mers-cov replication. in an in-vitro test utilizing epithelial cell cultures of a primary human airway, remdesivir was effective against bat-covs, prepandemic bat-covs, and circulating contemporary human-cov in primary human lung cells [7, 8] . one study showed that remdesiv and interferon beta were superior to lopinavir, ritonavir and interferon beta both in vitro and in a mers-cov mouse model [9] . with the emergence of the sars-cov-2, the etiologic agent of (covid-19), we are in a need for an effective antiviral agent to be able to halt the current outbreak. it had been suggested that remdesivir might be an option for the therapy of patients with covid-19 [10] . in a case report, remdisivir reatment was started intravenous on day 7 in a patient with covid-19 [11] . given the broad-spectrum anti-cov activity of remdesivir that were demonstrated in pre-clinical studies; a randomized, controlled, double blind clinical trial is planned to evaluate the efficacy and safety of remdesivir in hospitalized patients with mild or moderate covid-19 respiratory disease [12] and this trial has already involved 308 hospitalized adult patients. the participants were randomized to either placebo or remdesivir arms (remdesivir was given as 200 mg loading dose on day 1 followed by 100 mg iv once-daily for 9 days). the primary outcome was defined as the time to clinical recovery (ttcr), up to 28 days [12] . ttcr is further defined as the time (in hours) from initiation of study treatment (active or placebo) until normalization of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours [12] . another ongoing phase 3 randomized, double-blind, placebo-controlled, multicenter study is evaluating the efficacy and safety of remdesivir in 452 hospitalized adult patients with severe covid-19 respiratory disease [13] . any clinical impact of remdesivir on covid-19 remains unknown, and scientists are waiting patiently the final results of these ongoing trials. all authors have no conflicts of interest. mers-cov as an emerging respiratory illness: a review of prevention methods situation report-17 situation in numbers total and new cases in last 24 hours therapeutic efficacy of the small molecule gs-5734 against ebola virus in rhesus monkeys nucleotide prodrug gs-5734 is a broad-spectrum filovirus inhibitor that provides complete therapeutic protection against the development of ebola virus disease (evd) in infected nonhuman primates late ebola virus relapse causing meningoencephalitis: a case report a randomized, controlled trial of ebola virus disease therapeutics coronavirus susceptibility to the antiviral remdesivir (gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease broad-spectrum antiviral gs-5734 inhibits both epidemic and zoonotic coronaviruses comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-ncov first case of 2019 novel coronavirus in the united states mild/moderate 2019-ncov remdesivir rct -full text view -clinicaltrials severe 2019-ncov remdesivir rct -full text view -clinicaltrials al-tawfiq * infectious disease unit, specialty internal medicine and infection control unit, quality and patient safety key: cord-029965-bt87kai8 authors: patel, shailesh kumar; singh, rohit; rana, jigyasa; tiwari, ruchi; natesan, senthilkumar; harapan, harapan; arteaga-livias, kovy; bonilla-aldana, d. katterine; rodríguez-morales, alfonso j.; dhama, kuldeep title: the kidney and covid-19 patients – important considerations date: 2020-08-01 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101831 sha: doc_id: 29965 cord_uid: bt87kai8 nan keywords: sars-cov-2; covid-19; renal; kidney; outcomes the ongoing coronavirus disease 2019 (covid-19) pandemic, has caused substantial damage to the health system globally. the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) primarily affects the lungs, however, this virus can also affect other organs such as intestine, kidney, heart, and brain [1] [2] [3] . kidney dysfunctions are also observed in a large proportion of covid-19 patients [4] . initially, the involvement of kidneys was considered negligible, and little attention was paid to the incidence of acute kidney injury (aki) [5] . subsequently, aki incidence in covid-19 patient was found to be up to 15% in comparison to an earlier suggested range of 3% to 9% potentiating the evidence that aki is common and that the virus can specifically damage the kidneys [6, 7] . the incidence of aki could be up to 25% among critically-ill covid-19 patients with underlying comorbidities [7] . an autopsy study also showed the virus tropism to the kidney [8] . other coronaviruses such as the avian infectious bronchitis virus, are also known to cause severe kidney damage in chicken [9, 10] . the exact mechanism of sars-cov-2 associated renal damage is not fully known. studies showed that the cellular components required for virus entry such as angiotensin-converting enzyme 2 (ace2), cellular transmembrane serine protease 2 (tmprss2), and cathepsin l (ctsl) are highly expressed in kidneys [8] . expressions of ace2 rna in the small intestine, duodenum and kidneys were found much higher (around 100-fold) than the lung [4] . furthermore, the co-expression of ace2 and tmprss is reported to be relatively high in the proximal straight tubule cells and podocytes, suggesting favourable condition for localization of the sars-cov-2 in kidneys [11] . studies reporting albuminuria and haematuria in the covid-19 patients along with the detection of viral rna from the urine samples further support the potential tropism of the sars-cov-2 for the renal tissues [4, 12] . the cytokine storm associated along with the direct cytopathic effect of sars-cov-2 is suggested as the probable cause of kidney dysfunction [13] . moreover, the aki in response to cytokine storm might occur due to renal inflammation, increased vascular permeability, cardiomyopathy and volume depletion leading to cardiorenal syndrome-1 ( figure 1 ) [14] . additionally, injuries of the renal tubules related to the hypoperfusion in response to cytokine storm may also be partly responsible for the kidney injury [13] . the computed tomography of the kidneys revealed a reduction in the density suggesting the renal inflammation and oedema [4] . kidney dysfunction is characterized by elevated levels of blood urea nitrogen (bun), creatinine, uric acid and d-dimer, along with proteinuria and hematuria [4] . a study reported that 60% out of 147 covid-19 patients developed proteinuria, and 48% exhibited hematuria on hospitalization [4] . elevated levels of bun was reported in 31% of the total patients and found common in severely ill and deceased cases [4] . a study conducted on 701 consecutive hospitalized covid-19 patients revealed proteinuria and hematuria in 43.9% and 26.7%, respectively on admission. moreover, the prevalence of elevated bun and serum creatinine was reported 13.1% and 14.4% respectively, in the covid-19 patients [15] . aki was associated with higher mortality rates, especially when renal replacement therapy is required [7] . in this context, aki was reported as an independent risk factor for hospitalized covid-19 patients [4] . therefore, along with clinical management for pneumonia, potential intervention to protect the kidneys from the virus tropism and cytokine storm must be considered to minimize the mortalities associated with acute renal failure (figure 1 ). those covid-19 patients suffering from the chronic kidney disease and other comorbidities are reported to be at higher risk of a severe form of the disease and they are advised to take extra preventive measures to avoid the exposure of sars-cov-2 [16] . a higher number of comorbidities was also found to be associated with this virus tropism for kidney [8] . the covid-19 posed a new challenge in the form of renal damage directly through virus tropism and indirectly through cytokine storm and increased mortality associated with kidney damage. in this context, clinical care by monitoring and protecting the kidney functions regardless of the patient's comorbidity is utmost necessary to save the patients from unnoticed renal damage during the course of the disease. moreover, the application of effective supportive and targeted interventions to protect kidneys at the early stage of sars-cov-2 infection is highly recommended [17, 18] . clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan latin american network of coronavirus disease 2019-covid-19 research (lancovid-19). clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis pathological findings of covid-19 associated with acute respiratory distress syndrome caution on kidney dysfunctions of covid-19 patients coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from wuhan, china clinical features of patients infected with 2019 novel coronavirus in wuhan acute kidney injury in critically ill patients with covid-19 multiorgan and renal tropism of sars-cov-2 emerging and reemerging infectious diseases of livestock s1 gene sequence analysis of a nephropathogenic strain of avian infectious bronchitis virus in egypt identification of a potential mechanism of acute kidney injury during the covid-19 outbreak: a study based on single-cell transcriptome analysis zhong ns; china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china the novel coronavirus 2019 epidemic and kidneys kidney involvement in covid-19 and rationale for extracorporeal therapies kidney disease is associated with in-hospital death of patients with covid-19 chronic kidney disease is associated with severe coronavirus disease 2019 (covid-19) infection a new emerging zoonotic virus of concern: the 2019 novel coronavirus (covid-19) coronavirus disease 2019 -covid-19 dayal upadhayay pashu chikitsa vigyan vishwavidyalay evum go-anusandhan sansthan (duvasu) latin american network of coronavirus disease 2019-covid-19 research (lancovid-19) grupo de investigación bioecos, fundación universitaria autónoma de las américas grupo de investigación biomedicina, faculty of medicine, fundación universitaria autónoma de las americas e-mail: arodriguezm@utp key: cord-268971-4ue58ebz authors: virk, abinash; fischer, philip r. title: travel medicine: an american view of the australian perspective date: 2005-03-03 journal: travel med infect dis doi: 10.1016/j.tmaid.2004.11.008 sha: doc_id: 268971 cord_uid: 4ue58ebz nan peter leggat has beautifully and succinctly summarized many of the key issues in travel medicine. with humility, he claims only to have presented an australian perspective. in fact, travel medicine is a growing global domain of medicine. leggat's description is appropriately multi-national in perspective, and most of it is true beyond the specific political boundaries surrounding a particular traveler's place of origin. travelers with itineraries originating in developing countries might indeed have different risks and needs than the typical american or australian traveler. nonetheless, leggat's australian perspective provides a good description of the north american perspective on most major points. certainly, the need for good pre-travel consultation and intervention is similar between the two continents. sadly, it is also similar that too many north american travelers do not seek and/or obtain adequate pre-travel input and intervention, and the results of incomplete preventive interventions can be devastating. 1,2 leggat's discussions of immunization and malaria prevention are mostly applicable to american travel clinics as well. similarly, discussions of injury prevention, management of illness during travel, and insurance would also be part of a typical north american pre-travel consultation. despite the similarities, however, there are some noteworthy contrasts between leggat's australian perspective and the typical north american view of travel medicine. some of these relate to the medical system and the means of getting pre-travel care. others relate to details of the care provided. much pre-travel care in australia, it seems, is at the hands of general practitioners. in the united states, most generalists do not have ready access to some pre-travel vaccines (typhoid and japanese encephalitis since they would not frequently be used in a typical primary care practice, yellow fever due to certification requirements), and most pre-travel care is provided in specialty clinics mostly staffed by infectious disease physicians. 3 trained, experienced nurses provide much of the pre-travel care in some of these clinics, and they use established protocols under physician guidance to make prescriptions for medications available to travellers. 3 north american primary care providers not specifically trained in travel medicine would be more likely to limit their travel medicine advice to travelers going to settings where vaccination beyond hepatitis a is not needed. leggat also points out that there are similarities between the practices and needs of aviation medicine and travel medicine. this is true, but the two fields remain separated in north america. certification by a governmental agency (http:// www.cami.jccbi.gov/) and complex documentation are required for physicians to officially evaluate a pilot's fitness to fly, 4 and it is uncommon for an individual physician to combine travel medicine and aviation medicine. leggat also describes integrated collaboration between travel medicine providers and the travel industry. this is logical and appropriate and good for travelers. americans have much to learn from australians on this point, and it is only in very recent years that initiatives, some through the international society of travel medicine, have started to capitalize on this potential linkage in the united states. american travel medicine practitioners are often affiliated with the international society of travel medicine, as are their australian counterparts. in addition, the american committee on clinical tropical medicine and travelers, health (http:// www.astmh.org/subgroup/acctmth.asp) provides a forum for education, certification, networking, and communication for practitioners of travel medicine. the centers for disease control and prevention (cdc) (http://www.cdc.gov/travel/) also serves travel medicine providers as a high-quality resource for printed, 5 electronic, and telephone information regarding pre-travel and post-travel care. in addition, the infectious disease society of america is finalizing a statement of guidelines for the practice of travel medicine in north america which will likely be published in 2005. the us government issues travel warnings (http://travel.state.gov/travel/warnings_current. html) which guide prospective travelers in regard to safety issues in potential destination areas. the cdc website also includes special alerts about noteworthy dangers during acute situations (http://www.cdc.gov/travel/). this 'real-time' information is vitally important and helpful during outbreaks such as that of severe acute respiratory syndrome in 2003. as noted by leggat, diarrheal illness is a common problem for travelers. leggat does not discuss details of pre-travel counseling on this point, but most north american pre-travel consultations include a significant discussion of food and water hygiene as preventive interventions and of oral hydration and possibly loperamide as presumptive treatment. in addition, a prescription for an antibiotic to use in the event of bothersome travelers' diarrhea is often provided. a quinolone or azithromycin would be the most likely antibiotic used in this setting. in the united states, it is currently recommended that all infants and patients with chronic medical problems receive influenza vaccination, whether they are traveling or not. similarly, pneumococcal vaccine is routinely given to infants and is recommended for older adults. current recommendations for immunization of american children are updated regularly (accessible via http://www.aap.org/healthtopics/immunizations. cfm). a pre-travel consultation provides the opportunity to ensure that these routine vaccines have been given-even though they might not be routine in the destination country. hepatitis a vaccine is recommended for children in several american states, and it is used almost routinely for foreign travellers. 6 there is also liberal use of typhoid vaccination for travelers to higher-risk countries. officially, there are three alternative malaria chemoprophylaxis possibilities for american travelers to areas of chloroquine-resistant malaria, but primaquine is also considered to be a potential option (http://www.cdc.gov/travel/malaria-drugs2.htm). with the ready availability and side effect profile of atovaquone-proguanil, however, many travel medicine clinics are increasingly prescribing this product as the mainstay of malaria protection. concurrently, there is an emphasis on mosquito avoidance and the use of chemical repellents on exposed skin and insecticides on clothes and bednets. 'stand by' malaria treatment is not commonly recommended in the united states, and rapid displacement to a site of good medical care is advised for a traveler who might have malaria. thus, leggat's perspective is representative of most of the american practice of travel medicine. notable differences, however, center on the use of both infectious disease specialists and nurses in north american pre-travel consultations rather than primary care physicians and on the non-union of aviation medicine and travel medicine in the united states. americans' specific pre-travel interventions are also similar to those in australia, but influenza, pneumococcal, and hepatitis a vaccines are used more widely for even at-home populations in the united states. as similarities and differences are explored and documented, it is clear that while travel medicine is truly a global specialty, the specific risks and resources vary between sites, and these affect the details of a travel medicine practice. malaria deaths following inappropriate malaria chemoprophylaxis-united states malariarelated deaths among u.s. travelers a survey of travel clinics throughout the world field experience with the faa's webbased medical certification system 'amcs/diws' us department of health and human services clinical practice. prevention of hepatitis a with the hepatitis a vaccine key: cord-281551-0aj2zwx8 authors: schlagenhauf, patricia; grobusch, martin p.; maier, julian d.; gautret, philippe title: repurposing antimalarials and other drugs for covid-19 date: 2020-04-02 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101658 sha: doc_id: 281551 cord_uid: 0aj2zwx8 nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid editorial repurposing antimalarials and other drugs for covid-19 the covid-19 pandemic, caused by the coronavirus sars-cov-2, now affects countries on six continents. reported case numbers are certainly underestimates given the low rates of testing in many countries, a virus with a basic reproductive value (r 0 ) of apparently over 2.2, and evidence of viral shedding from asymptomatic infected people [1] . social distancing, hand hygiene and community mitigation measures are recommended to contain this pandemic [2] . these measures aim at 'flattening the curve' of the initial wave of infections ripping through the various countries and regions, leading to an acute overburdening of health care services. even if in part successful, many researchers are predicting a "new wave" of covid-19 infections. whilst massive efforts are underway to change this, there is currently no vaccine, no prophylaxis, few proposed specific treatments and there are to date, naturally, few data on the sequelae or longer-term outcomes of the infection. it is unknown whether or not those second waves will occur and if they do, will they occur in persons who have already been exposed to the sars-cov-2 virus or in naïve persons? all forecasts regarding herd immunity remain speculations. countries, such as china, that have passed the epidemic peak are now importing fresh cases from countries more recently affected. for health care workers (hcw) on the frontline and for patients with severe illness, the urgent search for a treatment is on. until a vaccine is available, it would also be valuable to have an option for prophylaxis of hcw enabling the protection of those on the frontline. furthermore, a therapy would expedite viral load reduction and allow hcw to return to work faster. the need for a treatment is particularly urgent, as a therapy could reduce the time spent in intensive care units and free up beds. a candidate therapy could be a single drug or substance or a combination and these candidates should preferably be repurposed drugs. some new papers have reported on therapy options. a chinese team published results of a study demonstrating that chloroquine, an antimalarial, and its hydroxyl analogue, hydroxychloroquine, inhibit sars-cov-2 in vitro with hydroxychloroquine (ec50 = 0.72%μm) found to be more potent than chloroquine (ec50 = 5.47%μm) [3] . a french paper reporting on the use of drug combinations in infected patients highlighted the possibility that hydroxychloroquine is effective in the treatment of covid-19 patients [4] particularly in combination with azithromycin. in this study, with a limited number of patients, hydroxychloroquine with azithromycin was shown to clear viral nasopharyngeal carriage of sars-cov-2 in just three to six days. these results are important because a recent paper has shown that the mean duration of viral shedding in patients suffering from covid-19 in china was up to 20 days and even 37 days for the longest duration [5] . antimalarials are potential candidates to be "repurposed" as they have been widely studied and evaluated in both the therapy and prophylaxis settings. furthermore, they have been used in a broad range of age groups and in persons with co-morbidities. there is a body of evidence available regarding drug/drug interactions, metabolic pathways, pharmacokinetics, posology and galenics. formulations are available that would suit both ambulatory and stationary settings. these include tablet forms, rectal formulations and solutions for injection. we have well controlled studies evaluating treatment and the tolerability of chemoprophylaxis [6] . there are a variety of classes of antimalarial medications, including artemisinin derivatives (derived from the plant artemisia annua), quinine and related drugs (such as mefloquine, halofantrine, lumefantrine), aminoquinolines (such as chloroquine, amodiaquine, primaquine) and a mixed group of compounds with formidable antimalarial potential (including doxycycline, atovaquone, sulfonamides). the story of the rediscovery of the sesquiterpene lactone, artemisinin in china, an active principle derived from plants described as "fever reducing" in ancient pharmacopoeia, and repurposing this class as antimalarials is a classical case of using existing treatments for new indications. the world health organisation (who) can be applauded for the launch of the solidarity study [7] that will focus on collating robust, clinical evidence on a number of potential covid-19 therapeutics. chloroquine and hydroxychloroquine are included in the panel of drugs under investigation. apart from antimalarials, some antivirals have also shown promise against the novel coronaviruses: in vitro studies have shown that the antiviral remdesivir can inhibit coronaviruses such as sars-cov and mers-cov [8] . in an in vitro test using human airway epithelial cell cultures, remdesivir was effective against other coronaviruses [9] . one study showed that remdesivir and interferon beta were superior to lopinavir, ritonavir and interferon beta both in vitro and in a mers-cov mouse model. remdesivir, administered alone or in combination with chloroquine [10] is also considered to be effective and has been used with success. major multicentre trials to systematically assess its efficacy and safety in moderate and severe covid-19 disease are currently underway (clinicaltrials.gov identifiers: nct04292899; nct04292730 and others). beside several antivirals and antimalarials, there are other pharmacological classes that must be considered for use against sars-cov-2. for instance, teicoplanin was proposed as a potential treatment in covid-19 patients and has already shown inhibitory effects on cell entry of ebola virus, sars-cov and mers-cov in the past. its in vitro activity against sars-cov-2 was reported by zhang et al. [11] . however, it has to be acknowledged that in this and other cases, it is a long, expensive and time-consuming way, even if there is an accelerated avenue to expedite promising developments, from in vitro assays indicative of antiviral effects to the initiation steps of safety and efficacy assessments in humans, finding compounds that can block the entry of the virus into the cell could be an important approach to find potential therapies for covid-19. recent research has also examined the mechanism used by sars-cov-2 for facilitating cell entry [12] . this cell entry seems to be crucial for the virus to infect the cell and uses angiotensin-converting enzyme 2 (ace2) [12] as well as the transmembrane protease, serine 2 (tmprss2), that are both expressed on human cells. this entry was already described in the past for sars-cov. sars-cov-2 binds with its own spike glycoprotein to ace2 and uses the serine protease tmprss2 for priming. this allows for easier fusion of viral and cellular membranes. ace2 is expressed in lungs, heart, kidneys and intestine and is known to convert angiotensin ii into angiotensin (1-7), thus effecting blood pressure and cardiac function. an important advantage of reviewing, evaluating and condensing evidence on available molecules, active principles or drugs is that this approach brings important key, existing medical data to the fore. it will not just be enough to have candidate drugs that work in vitro against sars-cov-2. it is essential that the identified candidate or combination of candidates have a good safety profile, have matching pharmacokinetics and, if possible, different viral targets. if antimalarials can be repurposed for covid-19, travel and tropical medicine experts can bring their expertise to the table as antimalarials are the "bread and butter" of travel medicine and there is a wealth of experience and knowledge on the use and tolerability of these drugs in all ages and in persons with co-morbidities. it is time to bring this knowledge to a new front in the war on covid-19. transmission of 2019-ncov infection from an asymptomatic contact in germany covid-19 and community mitigation strategies in a pandemic in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study tolerability of malaria chemoprophylaxis in non-immune travellers to sub-saharan africa: a multi-centre, randomised, double-blind, four-arm study systematic review of the therapeutic agents for the treatment of the middle east respiratory syndrome coronavirus (mers -cov) remdesivir as a possible therapeutic option for the covid_19 remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro teicoplanin potently blocks the cell entry of 2019-ncov sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor key: cord-277353-qilq1q7h authors: taniguchi, kiyosu; yoshida, makiko; sunagawa, tomimasa; tada, yuki; okabe, nobuhiko title: imported infectious diseases and surveillance in japan date: 2008-09-11 journal: travel med infect dis doi: 10.1016/j.tmaid.2008.07.001 sha: doc_id: 277353 cord_uid: qilq1q7h surveillance of imported infectious diseases is important because of the need for early detection of outbreaks of international concern as well as information of risk to the travelers. this paper attempts to review how the japanese surveillance system deals with imported infectious diseases and reviews the trend of these diseases. the cases of acquired infection overseas were extracted from the surveillance data in 1999–2008. the incidence and rate of imported cases of a series of infectious diseases with more than one imported case were observed by the year of diagnosis and place of acquired infection. during the period 10,030 cases that could be considered to be imported infectious diseases were identified. shigellosis ranked as the most common imported disease, followed by amebiasis, malaria, enterohemorrhagic escherichia coli infection and the acquired immunodeficiency syndrome, typhoid fever, dengue fever, hepatitis a, giardiasis, cholera, and paratyphoid fever. the annual trends of these diseases always fluctuated but not every change was investigated. the study reveals that the situation of imported infectious diseases can be identified in the current japanese surveillance system with epidemiologic features of both temporal and geographic distribution of cases of imported infectious diseases. however, further timely investigation for unusual increase in infectious diseases is needed. because of the current global travel and trade, there is no border for infectious diseases. even in japan, which belongs to a temperate climate zone many tropical infectious diseases are found in the local hospitals. but there have been several case reports describing difficulty of early diagnosis and treatment. 1e3 it is important to provide information to travelers on particular risks and to increase protection, as well as information for local clinicians on the current situation of endemicity of infections in the foreign countries in order to facilitate early diagnosis and to avoid nosocomial infection. from the viewpoint of public health, the introduction of new pathogens may result in their establishment in the country. public health surveillance is one of the essential components for infectious disease control and no doubt a starting point for control. because of current circumstances a surveillance system should be designed not only at the national level but also at the global level of infectious disease control. current national epidemiological surveillance for infectious diseases (nesid) in japan requires that all notifiable diseases should be reported with the presumptive place of infection. this report summarizes the data from the nesid from 1999 to 2008 on the situation of imported infectious diseases in japan. the national epidemiological surveillance for infectious diseases (hereafter referred to as nesid) is conducted based on the law concerning the prevention of infectious diseases and medical care for patients of infections (hereafter referred to as the infectious disease control law) enacted in april 1999. infectious disease surveillance system before then is described elsewhere. 4 infectious diseases included in this law were categorized into iev with specific means for control based upon the public health impact of each disease as shown in table 1 . all physicians must report cases of categories ieiv immediately and va within 7 days after identification to local public health centers which are the primary level institution for disease control and prevention located strategically throughout the nation. local public health centers are expected to enter data into the nationwide electronic surveillance system, which enables data to be shared throughout the system including all local public health centers, local and national governments, quarantine stations, local infectious disease surveillance center, local public health laboratory and central infectious disease surveillance center, which is the infectious disease surveillance center of national institute of infectious diseases. category vb diseases, which include sentinel reporting diseases, should be reported by designated sentinel medical institutions weekly or monthly with the number of clinical cases aggregated by sex and age groups. all reports should be compatible with the reporting criteria which were documented in detail for each disease including clinical and laboratory case definitions for categories va and vb of hospital sentinel reporting disease, and only clinical case definitions for other vb sentinel reporting diseases. 5 cases of category ieva diseases should be reported with sex, age, method of laboratory confirmation, symptoms on diagnosis (descriptive), date of onset, date of consultation, date of diagnosis, estimated date of infection, date of death (if patients died), area of permanent residence (in-country or foreign countries), presumptive place of infection (domestic or foreign countries), contact to the vectors or activities on the fields (yes or no), estimated infection route, another patients in the family members, colleagues, or neighbors (cluster or not). the presumptive place where infection was acquired should be described based on reasonable situation considering travel history and incubation period according to the interview of patients. the cases with the presumptive place of infection in a foreign country (hereafter referred to as imported cases) were extracted from the nesid data from april 1999 to march 2008. data in 1999 are only available in apriledecember because of the change of the law in april 1999 and data in 2008 are included until march. finally nine years data are reviewed. annual trend of total, imported, and domestic cases of disease containing one or more imported one are recorded and attributable events and causes are investigated with information in the line listing data and relevant epidemiological reports. incidence rates per 1,000,000 population are calculated using the 2002 census population and imported disease per 1,000,000 outbound travelers are calculated using the 2002 outbound travelers by the japan national tourist organization. in the period observed 10,030 cases that could be considered to be imported infectious diseases were identified. these include various infectious diseases as listed in table 2 with reported number of cases (imported, domestic, unknown and total), imported case rate among imported and domestic cases, incidence rate of domestic cases per year per 1,000,000 population and the incidence rate of imported cases per year per 1,000,000 outbound travelers. shigellosis ranked as the most common imported infection, followed by amebiasis, malaria, enterohemorrhagic escherichia coli (ehec) infection and the acquired immunodeficiency syndromes (aids), typhoid fever, dengue fever, hepatitis a, giardiasis, cholera, and paratyphoid fever. the rate of imported diseases of malaria, dengue fever and rabies is complete as they are not endemic in japan and over 50% in coccidioidomycosis, paratyphoid fever, typhoid fever, cholera, shigellosis and echinococcosis (echinococcus granulosus). although coccidioides is not considered to be indigenous, a domestic case is identified with no history of overseas travel. however, this case was a dealer of imported cotton and he may have acquired the infection from fungi attached to the imported cotton. 6 the annual trends of imported diseases always fluctuate because of the local situation and sometimes there is sudden increase because of cluster among the same tour groups. the amebiasis tended to increase recently both in domestic and imported cases. and cases acquired infection through sexual contact represented 50% of the total cases. 10 there were continuous reports of imported disease of aids, syphilis and hepatitis b. dengue fever is increasing year by year, but malaria is decreasing gradually. typhoid and paratyphoid fever and hepatitis a showed an increase and decrease throughout observation period. although the outbreak among group tours to endemic countries was reported to account for the increase of imported diseases, 11 investigation of attributable events or causes were not always made in a timely manner. retrospective investigation could recognize the increase of cases returning from certain countries, but it was difficult to seek further risk factors because limited information was listed on line. public health surveillance is defined by the world health organization as the ''systematic ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that action can be taken.'' the basic principle for disease control and prevention is the same no matter where it is acquired. but target groups who need to know differ. the precautionary information should be communicated to travelers with the risk assessed properly. of course rapid detection of cases can lead to rapid response and early containment and finally to prevention of indigenous transmission of exotic pathogens. in this respect, effective infectious disease surveillance is essential. in this study it was not difficult to overview the situation of imported infectious diseases because the current japanese surveillance system requires the presumptive place of infection including the specified country if possible. but there have been no studies on the evaluation of reporting rate. before april 1999 when the infectious disease control law was revised, 50e80 cases of malaria were reported annually in the framework of the old infectious disease prevention law, but the research group on chemotherapy of tropical diseases reported by their field investigation that approximately 120 patients have been confirmed with malaria annually. 12 it means that cases notified to the ministry of health and welfare were about 50% in those days. reports of malaria peaked in 2000 one year after the new law enactment and steadily decreased to the same level before 1999. on the other hand, dengue fever is increasing. it is not possible to determine whether the reporting rate of malaria has decreased recently or not, it will be necessary to evaluate the surveillance system including assessment of missed opportunity for diagnosis and treatment. it might be better to report febrile illness with travel history abroad for effective detection and evaluation. it is natural that reported imported cases of malaria, dengue fever and rabies are complete. domestic case of coccidioidomycosis is reported to be caused from imported materials. a proportion of typhoid/paratyphoid fever, cholera and shigellosis are acquired inside the country without doubt because there is no travel history abroad. as there is a report of vibrio cholerae from imported food, 13 further is required investigation of the source of infection in each cases. most of the imported cases were reported with the suspected country of infection. analysis using 2006e2008 data showed suspected countries of infection for cholera are india, philippine, and indonesia (in descending order); india, indonesia, and china for shigellosis; india, indonesia and nepal for typhoid/paratyphoid fever; philippine, thailand and india for dengue fever; papua new guinea, nigeria, india and indonesia for malaria. but it depends upon the number of travelers and the local situation in certain countries which might change year by year. more detailed analysis using country specific travelers is necessary. aids, syphilis, hepatitis b, and giardiasis are part of imported infectious diseases. as they have the unique feature as sexually transmitted diseases (std), it might be better to handle these separately. but it is important to monitor imported std because they could increase local infection rates, and to provide information for travelers. in the current study, it was noted that unusual increases of reported imported infectious disease were not fully investigated for attributable events or causes in a timely manner although several events affecting the number of reports were identified. retrospective analysis can provide the country of infection, but more timely information is necessary for travelers. the capacity of timely investigation and risk assessment should be enhanced further. the results of investigation of an outbreak among a tour group sharing common source of infection or cluster in time and of travel place of individual tourists not related each other will be reflected or involved in a local epidemic, which can be linked to international investigation and control activities. under the current circumstances of pandemic alert, the timely sharing of imported infectious disease at the global level will also be necessary. difficulty of proper diagnosis for an imported vivax malaria patient from africa plasmodium vivax malaria with clinical presentation mimicking acute type idiopathic thrombocytopenic purpura clinical characteristics of imported malaria in japan: analysis at a referral hospital overview of infectious disease surveillance system in japan case definitions for reporting in compliance with infectious disease law anonymous. imported mycoses in japan. iasr:55e6. available from anonymous. cholera 2002e2005, japan. iasr:1e2. available from iasr:61e3. available from enterohemorrhagic escherichia coli infection as of typhoid fever outbreak among group tour member to bangladesh cholera enterotoxin production in vibrio cholerae 01 strains isolated from the environment and from humans in japan the author has no conflict of interest. key: cord-259966-szkiilb1 authors: gautret, philippe; angelo, kristina m.; asgeirsson, hilmir; duvignaud, alexandre; van genderen, perry j.j.; bottieau, emmanuel; chen, lin h.; parker, salim; connor, bradley a.; barnett, elizabeth d.; libman, michael; hamer, davidson h. title: international mass gatherings and travel-associated illness: a geosentinel cross-sectional, observational study date: 2019-11-09 journal: travel med infect dis doi: 10.1016/j.tmaid.2019.101504 sha: doc_id: 259966 cord_uid: szkiilb1 background: travelers to international mass gatherings may be exposed to conditions which increase their risk of acquiring infectious diseases. most existing data come from single clinical sites seeing returning travelers, or relate to single events. methods: investigators evaluated ill travelers returning from a mass gathering, and presenting to a geosentinel site between august 2015 and april 2019, and collected data on the nature of the event and the relation between final diagnoses and the mass gathering. results: of 296 ill travelers, 51% were female and the median age was 54 years (range: 1–88). over 82% returned from a religious mass gathering, most frequently umrah or hajj. only 3% returned from the olympics in brazil or south korea. other mass gatherings included other sporting events, cultural or entertainment events, and conferences. respiratory diseases accounted for almost 80% of all diagnoses, with vaccine preventable illnesses such as influenza and pneumonia accounting for 26% and 20% of all diagnoses respectively. this was followed by gastrointestinal illnesses, accounting for 4.5%. sixty-three percent of travelers reported having a pre-travel encounter with a healthcare provider. conclusions: despite this surveillance being limited to patients presenting to geosentinel sites, our findings highlight the importance of respiratory diseases at mass gatherings, the need for pre-travel consultations before mass gatherings, and consideration of vaccination against influenza and pneumococcal disease. attendance at an international mass gathering (mg) may expose travelers to health risks related to crowded conditions, population movement, and inadequate sanitation [1, 2] . according to the world health organization, an event can be classified as a mg if the number of people attending is sufficient to strain the planning and response resources of the community, state, or nation hosting the event [2] . however, much of the available literature describes mass gatherings as those exceeding 25,000 persons. we describe demographic characteristics and diagnoses among travelers who attended a mg and presented with a travel-associated illness to a geosentinel site. august 17, 2015 , and april 30, 2019, were collected by geosentinel, a global clinicianbased surveillance network that monitors travel-related illnesses among international travelers and migrants [3] . geosentinel was established in 1995 as a collaboration between the centers for disease control and prevention and the international society of travel medicine. it consists of 68 clinical sites in 28 countries. geosentinel records ill persons' visits to network sites; well travelers are not captured. attendance at a mg is routinely recorded. during the study period, investigators were directed to enter supplemental details on the nature and location of the mg and to evaluate whether the diagnosis was likely associated with mg attendance. records were excluded if the mass gathering was likely to have < 25,000 attendees or if data were missing regarding the type of mg. geosentinel's data collection protocol has been reviewed by a human subjects advisor at cdc's national center for emerging and zoonotic infectious diseases and is classified as public health surveillance and not human subjects research. additional ethics clearance was obtained by participating sites as required by their respective institutions or national regulations. a total of 327 records of ill travelers attending a mg during international travel had surveys completed by the investigator providing their care. thirty-one records were excluded. of 296 ill travelers included, 151 (51.0%) were female and the median age was 54 years (range: 1-88; iqr: 39-64). purposes of mgs were religious (243 cases; 82.1%), cultural (e.g., music, dance, carnival) (19 cases; 6.4%), the world scout jamboree (17 cases; 5.7%), major sport events (13 cases; 4.4%), or a large conference (4 cases; 1.4%). the top three specific mgs were umrah or hajj in saudi arabia with 241 cases (81.4%), including 87 at umrah and 154 at hajj, followed by the world scout jamboree in japan with 17 cases (5.7%), and the olympics in brazil and south korea with 9 cases (3.1%) ( [17] [18] [19] [20] ). sixty-four percent of ill travelers who attended umrah or hajj were hospitalized because of their illness; one traveler who attended the world scout jamboree and no travelers who attended the olympics were hospitalized. overall, 130 of 206 (63%) ill travelers with information available reported having a pre-travel encounter with a healthcare provider. the majority (260 of 296, 87.8%) of acquired illnesses were directly associated with mg attendance, while the relation between the illness and the mg was not ascertainable for 25 travelers (8.4%), and the illness was travel-related but not linked to mg attendance for 11 travelers (3.7%). only three of nine (33.3%) diagnoses among travelers who attended the olympics were associated with attending the mg. a total of 303 diagnoses were reported among the 260 ill travelers whose illness was associated with mg attendance (table 2) . respiratory diseases were the most frequently reported disease category with 236 diagnoses (77.9%), followed by gastrointestinal diseases (14 diagnoses; 4.6%). diagnoses related to attendance at the three most common mgs -umrah or hajj, world scout jamboree, and olympics -are presented in table 1 . geosentinel sites evaluated 260 pilgrims with umrah-or hajj-related illnesses among an estimated 32 million foreign mg attendees over the study period [4] , 17 scouts among 33,628 attendees [5] and 9 olympic spectators among 7 million attendees [6, 7] . it should be noted, however, that geosentinel collects data only on ill travelers presenting to a network site and some geosentinel sites may care for more mg attendees than others, which may not be representative of all travelers attending a mg. in particular, the scouts reported to geosentinel were from a single site in sweden and were identified because of an international alert following a meningococcal outbreak (w st11 serotype) among six scottish and swedish nationals who attended this event [8] . ill mg attendees seen at a geosentinel site most frequently attended umrah or hajj, likely due to the large number of travelers to these pilgrimages. these findings are consistent with previously published literature demonstrating that outbreaks are not frequently reported during or after mgs other than umrah and hajj pilgrimages, although they sometimes occur at muslim, christian, and hindu religious events, sports events, and large-scale open-air festivals [9, 10] . its size, international recognition, unique multinational component, and yearly recurrence, likely account for the preponderance of umrah and hajj among international mgs responsible for outbreaks. our data are also consistent with previous reports regarding the older age of umrah and hajj travelers [11] , and the younger age of scout jamboree travelers. the finding that almost three-quarters of ill travelers who attended umrah or hajj were hospitalized is likely due to a recruitment bias, given that ill travelers seen at geosentinel sites may be sicker because of the specialized infectious disease or tertiary care nature of these sites; or to initial clinical suspicion for middle east respiratory syndrome, resulting in hospitalization and isolation pending testing. the paucity of reported trauma is also likely a reflection of the infectious disease specialization of most geosentinel network sites, and of the fact that trauma usually requires immediate attention and is most likely to occur during travel [12] . the predominance of respiratory tract infections reported in this analysis, including 4 cases of pneumococcal disease with one death, corroborates results obtained in saudi hospitals of pneumonia diagnoses among umrah and hajj attendees [13] as well as the high number of influenza virus infections observed among both patients in saudi hospitals and patients hospitalized on returning to their home countries from umrah and hajj [14] . crowded conditions with close proximity of large numbers of attendees at umrah and hajj are a likely explanation for the frequency of respiratory infections among pilgrims, given the transmissibility of these infections. our results confirm the importance of influenza vaccination for umrah and hajj travelers [15] . although the availability of influenza vaccine may be limited depending on the time of year hajj occurs [16] , immunization with expired influenza vaccine from the recently ended influenza season may have few associated adverse events [17] . by contrast, most illnesses among travelers attending the olympics were linked to travel, but not to attending the olympics, and these illnesses' were mild, which may be due to the physical separation of various sporting events at the olympics, the propensity to hold the olympics in high income countries, the relatively short travel duration of attendees and participants, and the relatively young age of participants. this is supported by the rarity of documented outbreaks during olympic games between 1984 and 2014 [9, 18] . our identification of respiratory tract infections, especially pneumonia, among umrah and hajj attendees suggests the need for additional research to document responsible pathogens. such data may have important consequences regarding vaccine recommendations before travel. in particular, it may be possible to validate that the influenza serotypes found are representative of strains circulating during the prior northern winter. these data also may provide justification for recommending pneumococcal vaccination for some high-risk travelers [19] [20] [21] . however, one-third of all travelers in this report did not attend a pre-travel consultation, and this will likely be a barrier to implementation of such recommendations. many countries have a staging area where umrah and hajj attendees gather before departure, or have pre-hajj classes at local mosques. leaders there could raise awareness of recommended (but not required) vaccines and personal protective measures such as carrying and routinely using hand sanitizer may lead to higher level of protective behaviors of traveling pilgrims [22] . also, primary care physicians should inquire about planned travel to mass gatherings and vaccinate travelers against meningococcus, influenza, and pneumococcus, as appropriate. given its broad international catchment, geosentinel plays a role in identifying emerging infectious diseases with epidemic potential, thus contributing to efforts to create enhanced international multidisciplinary surveillance of mg-associated illnesses, as recently recommended by experts [23] . since our surveillance was limited to patients presenting to geosentinel sites, to better understand travelassociated illnesses acquired at mgs improved global surveillance mechanisms are needed. geosentinel, the global surveillance network of the international society of travel medicine (istm), is supported by a cooperative agreement (u50ck00189) from the centers for disease control and prevention (cdc), as well as funding from the istm and the public health agency of canada. the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of cdc. global perspectives for prevention of infectious diseases associated with mass gatherings public health for mass gatherings surveillance for travel-related disease -geosentinel surveillance system japan 2015. 23 rd world scout jamboree available at available at: https:// stillmed.olympic.org/media/document%20library/olympicorg/games/summer-games/games-rio-2016-olympic-games/media-guide-for-rio-2016/ioc-marketing-report-rio-2016.pdf, accessed date olympic organizers say tickets are sold, but where are the people? meningococcal disease outbreak related to the world scout jamboree in japan communicable diseases as health risks at mass gatherings other than hajj: what is the evidence? infectious diseases and mass gatherings hajj: infectious disease surveillance and control morbidity and mortality amongst indian hajj pilgrims: a 3-year experience of indian hajj medical mission in mass-gathering medicine clinical respiratory infections and pneumonia during the hajj pilgrimage: a systematic review hajj-associated viral respiratory infections: a systematic review expected immunizations and health protection for hajj and umrah 2018 -an overview mandating influenza vaccine for hajj pilgrims notes from the field: administration of expired injectable influenza vaccines reported to the vaccine adverse event reporting system -united states enhanced surveillance at mass gatherings mismatching between circulating strains and vaccine strains of influenza: effect on hajj pilgrims from both hemispheres. hum vaccines immunother pneumococcal disease during hajj and umrah: research agenda for evidence-based vaccination policy for these events travellers and influenza: risks and prevention preparing australian pilgrims for the hajj mass gathering medicine: public health issues arisinf from mass gathering religious and sporting events key: cord-006968-1gua1abq authors: tada, yuki; okabe, nobuhiko; kimura, mikio title: travelers' risk of malaria by destination country: a study from japan date: 2008-09-23 journal: travel med infect dis doi: 10.1016/j.tmaid.2008.08.002 sha: doc_id: 6968 cord_uid: 1gua1abq background: country-specific information on the incidence of malaria in travelers provides the most reliable data on which to base the pre-travel risk assessment. some such studies have been conducted among western travelers; however, to our knowledge, there have been no reports on japanese travelers. methods: malaria cases that were diagnosed between april 1999 and december 2005 and were reported to the national infectious disease surveillance body were used as the numerators after grouped into countries of disease acquisition. the denominators, the numbers of japanese travelers visiting individual countries were derived from the recipient countries and obtained through a japanese organization. results: in addition to the well-documented high risks in sub-saharan countries, our study showed that travelers to papua new guinea were exposed to a significantly high risk of malaria. in asia, myanmar had the highest risk. generally, malaria incidence rates among japanese travelers were lower than those previously reported on western travelers. however, the rates were rather comparable to the data obtained recently. conclusions: these malaria incidence data in travelers should be taken into consideration for pre-travel risk assessment. they need to be constantly updated, and at the same time, limitations in data interpretation that are inherent in various study methodologies should also be clarified. .819 million travelers were recorded. a significant proportion of travelers visit areas of risk for malaria, yet our previous studies have shown protection against malaria to be suboptimal in japanese travelers. 1e3 in western countries, chemoprophylaxis is the mainstay of malaria preventive measures for travelers to high-risk areas. however, a high proportion of users report adverse drug events, with a predominance of neuropsychiatric adverse events among mefloquine users. 4 the benefits of chemoprophylaxis use to prevent malaria need to be carefully weighed against the risk of adverse drug events. this is particularly pertinent for travelers from japan where mefloquine is the only drug licensed for malaria prophylaxis. country-specific information on the incidence of malaria in travelers provides the most reliable data on which to base the pre-travel risk assessment. some such studies have been conducted among western travelers; however, to our knowledge, there have been no reports on japanese travelers. malaria has been a notifiable disease in japan since april 1999 under the infectious disease control law, and reports of smear-and/or polymerase chain reaction-confirmed malaria cases are recorded at the infectious disease surveillance center, national institute of infectious disease, tokyo. 5 nationality, place of birth, or details of residence are not documented on the reporting form; however, the main country of residence in the preceding several years is recorded. for the purposes of this study, japanese travelers were defined as those who had been resident in japan during the previous several years. malaria cases, diagnosed between april 1999 and december 2005, were only included if a single country could be identified as the source of infection, and these served as the numerators. the denominators were the numbers of japanese travelers visiting individual countries, and these data were obtained from the japan national tourist organization (jnto, tokyo, japan). 6 the jnto compiles data on tourism from the world tourism organization (unwto), the pacific asia travel association (pata), and the national tourism offices of individual countries. japanese nationals or those who had been resident in japan prior to travel were defined as japanese travelers by the recipient countries. most recipient countries defined the number of japanese visitors as that of arrivals at national borders, except for mali and chad, which used the number of arrivals at hotels. countries were only included if denominator data were available for at least four years of the study period (april 1999edecember 2005 . for countries where data were not available for the entire study period, the denominator was estimated, based on the numbers traveling in other years. a malaria incidence rate was calculated as the number of malaria cases per 100,000 travelers to the country. among the countries of sub-saharan africa, uganda, ghana, and mali had a malaria incidence rate greater than 100 per 100,000 travelers (see table 1 ). the rate in nigeria was two to threefold less than in these countries. high rates were noted in the central african republic and chad, however, there was only one case of malaria from each of these countries. rates could not be calculated for the west african countries of burkina faso, côte d'ivore, senegal, or cameroon due to a lack of denominator data, although cases of malaria were imported from these countries (7, 5, 5, 5 cases, respectively). the lowest rates were from south africa and kenya. plasmodium falciparum malaria accounted for all, or the majority of infections from the african countries, except for ethiopia where the infections were split almost equally between those due to p. falciparum and plasmodium vivax. incidence rates in asia were much lower than in african countries. myanmar had the highest rate, followed by india and pakistan. indonesia yielded the highest number of imported malaria cases, but with a large number of travelers to this country, the incidence rate was low. fewer malaria cases were imported from thailand and with a higher volume of travel than indonesia, the incidence rate was lower. overall, p. vivax was the dominant species, accounting for 84%, 77%, 71%, 64%, and 57% of infections from india, indonesia, thailand, myanmar, and the philippines, respectively. in oceania, papua new guinea was the only country that could be analyzed and where a high incidence rate was found, comparable to some african countries. however, unlike the african countries, p. vivax infections predominated (70%). six travelers acquired malaria in the solomon islands, two infections were due to p. falciparum and four due to p. vivax; however, denominator data for this country were incomplete. brazil was the only latin american country to be analyzed and this revealed a low incidence rate which was comparable to those in medium-risk asian countries, with the majority of cases being due to p. vivax. using different methodologies, studies have been conducted to establish malaria incidence rates among travelers of various nationalities. two longitudinal studies were published targeting returning travelers with questionnaires administered in-flight 7 or at the airport, 8 with a follow-up questionnaire mailed later. the advantage of this approach is that it captures detailed information on malaria infections, e.g., the purpose and duration of travel and chemoprophylaxis use. these data can be used to determine malaria risk in travelers, adjusting for the duration of exposure and the use of chemoprophylaxis. the volume of target population, however, is limited, and malaria incidence may be partially based on reports of malaria infection diagnosed abroad e the accuracy of which is uncertain. in other studies, malaria risk was assessed using cases of malaria reported to national surveillance bodies, with denominator data derived from various sources. some denominators were derived from home countries of the 9, 10 while others were from recipient countries with data provided by the unwto, 11, 12 as with our study. the british 13, 14 and swedish 15 studies estimated travel volume to a specific country/area using passenger surveys conducted at international airports and telephone interviews, respectively. these approaches benefited from larger sample sizes (numerator and denominator data) and greater diagnostic accuracy of malaria, as the infections were confirmed after returning home. however, illnesses that occurred abroad are not captured, and the effect of length of stay may not be evaluated due to lack of data. furthermore, the incidence rates could be greatly influenced by chemoprophylaxis use in high-risk groups, and this could not be assessed in these studies. although differences in study methodologies make it difficult to compare results across the various studies, relative infection risks between destination countries or areas could be derived from individual studies. this information is invaluable when making malaria chemoprophylaxis recommendations for travelers. this is particularly true for japanese travelers as no country-specific data have previously been acquired to assess the risk of malaria for these travelers. our results support previous findings which showed that travelers visiting sub-saharan countries are at high risk for malaria, 7e13,15 especially if travel is to west africa, 7,10,12,13 with most infections due to p. falciparum. it is also noted that our country-specific rates were generally lower than those obtained for western travelers; rates in japanese travelers to nigeria and ghana were several to 10-fold less than those of british, 13 italian, 10 and danish 11 travelers. recently, however, steffen et al. 16 showed the 10-fold decreased malaria incidence rate among travelers to tropical africa (200 per 100,000 per month of stay) than previously reported, some of whom were on chemoprophylaxis. our current results are rather comparable to those new data. the low incidence rate in kenya was unexpected and far lower than that of british travelers (8.0 per 100,000 compared with 149 per 100,000) 13 or danish travelers (245.9 per 100,000), 11 although it was similar to the rate reported among italian travelers (9.0 per 100,000). 10 this may be because japanese travelers tend to visit safari parks which may pose a lower risk than visits to coastal areas such as mombassa. in fact, visits to game parks in kenya were found to be 4.7-fold lower risk than visits to the coast and 14.3-fold lower risk than to lake victoria. 8 in line with the australian (723.5 per 100,000) 9 and us (only bars but not exact figures were shown) 12 studies, we demonstrated a high incidence rate among travelers to papua new guinea (142.3 per 100,000) e comparable to those in sub-saharan africa. the british study also showed a very high rate in oceania (4100 per 100,000), with most cases occurring after visits to papua new guinea. 13 in addition, the australian study reported even a greater risk in the solomon islands than papua new guinea. 9 in our study, however, we could not accurately assess the risk in the solomon islands as denominator data were only available for three of the study years. based on these data, an estimated 1600 travelers visited this country during the study period and six malaria cases (two p. falciparum, four p. vivax infections) were reported, giving an incidence rate of 375.0 per 100,000 travelers. we found that 70% of malaria cases acquired in papua new guinea were due to p. vivax, with 27% due to p. falciparum. even if considering the lower proportion of p. falciparum infections, chemoprophylaxis may be recommended for travelers to this region of oceania, as long as it is recommended for travel to sub-saharan africa. travel to countries in asia or brazil posed a much lower risk of malaria, with the majority of cases being due to p. vivax. limited prescribing of malaria chemoprophylaxis for travelers to the indian subcontinent 17 and latin america 18 has been proposed by european groups, because of the low incidence of malaria and low risk of travelers acquiring p. falciparum infection. our study results provide support for this recommendation. although previous studies have shown that among asian countries, the risk of malaria is high in india and the indian subcontinent, 9, 10, 12, 13, 15 our study showed the highest risk in myanmar, which may have not been previously documented. similar to previous studies, 9, 11, 12 the risk of malaria in thailand was lower than in indonesia, both being asian countries attracting an enormous number of tourists worldwide. our study results are subject to limitations in data interpretation. malaria cases that developed and were cured before returning home were not captured, the length of stay in the malaria-endemic countries or the extent of chemoprophylaxis use was not known, each of which might have had some influences on the results. nevertheless, such data on the incidence of malaria in travelers are invaluable in helping to define the risk and chemoprophylaxis recommendations. these data need to be constantly updated and at the same time, such studies should clearly outline limitations in data interpretation that are inherent in various methodologies. we declare that we have no conflicts of interest. malaria preventive measures among japanese overseas travelers. kosei no shihyo malaria prevention and stand-by emergency treatment among japanese travelers knowledge, attitudes, and practices of japanese travelers towards malaria prevention during overseas travel malaria chemoprophylaxis: when should we use it and what are the options? japan national tourist organization malaria chemoprophylaxis among european tourists in tropical africa: use, adverse reactions, and efficacy malaria incidence and prevention among european and north american travellers to kenya report of the australian malaria register for 1990 malaria epidemiological situation in italy and evaluation of malaria incidence in italian travelers the efficacy of chemoprophylaxis against malaria with chloroquine plus proguanil, mefloquine, and atovaquone plus proguanil in travelers from denmark malaria surveillance e united states risk of malaria in british residents returning from malarious areas the risk of malaria in travellers to thailand malaria risk in travelers health risks among travelers e need for regular updates malaria prophylaxis policy for travellers from europe to the indian sub continent the low and declining risk of malaria in travellers to latin america: is there still an indication for chemoprophylaxis? the authors are grateful to prof. robert steffen, university of zurich and dr. stephen toovey, bottmingen, for providing useful comments and ms. bernadette carroll, hospital for tropical diseases in london, for help with proof reading the manuscript. this study was supported by a grant-in-aid from the ministry of health, labour and welfare of japan (h17-shinkou-3). key: cord-271004-gtmo5ixs authors: al-tawfiq, jaffar a.; rabaan, ali a.; hinedi, kareem title: influenza is more common than middle east respiratory syndrome coronavirus (mers-cov) among hospitalized adult saudi patients date: 2017-10-12 journal: travel med infect dis doi: 10.1016/j.tmaid.2017.10.004 sha: doc_id: 271004 cord_uid: gtmo5ixs background: since the initial description of middle east respiratory syndrome coronavirus (mers-cov), we adopted a systematic process of screening patients admitted with community acquired pneumonia. here, we report the result of the surveillance activity in a general hospital in saudi arabia over a four year period. materials and methods: all admitted patients with community acquired pneumonia from 2012 to 2016 were tested for mers-cov. in addition, testing for influenza viruses was carried out starting april 2015. results: during the study period, a total of 2657 patients were screened for mers-cov and only 20 (0.74%) tested positive. from january 2015 to december 2016, a total of 1644 patients were tested for both mers-cov and influenza. none of the patients tested positive for mers-cov and 271 (16.4%) were positive for influenza. the detected influenza viruses were influenza a (107, 6.5%), pandemic 2009 h1n1 (n = 120, 7.3%), and influenza b (n = 44, 2.7%). pandemic h1n1 was the most common influenza in 2015 with a peak in peaked october to december and influenza a other than h1n1 was more common in 2016 with a peak in august and then october to december. conclusions: mers-cov was a rare cause of community acquired pneumonia and other viral causes including influenza were much more common. thus, admitted patients are potentially manageable with oseltamivir or zanamivir therapy. the emergence of the middle east respiratory syndrome coronavirus (mers-cov) in september 2012 had attracted international attention. the virus was initially isolated from a patient with a fatal community acquired pneumonia (cap) in saudi arabia [1] . since then, multiple hospital outbreaks occurred within [2] [3] [4] [5] [6] [7] and outside saudi arabia [8] [9] [10] [11] . as of may 1st, 2017, the world health organization reported 1952 laboratory-confirmed cases worldwide and at least 693 related deaths [12] . a wide-spectrum of mers-cov infection was described and ranges from mild to severe and fulminant infections leading to severe acute respiratory disease [2, [13] [14] [15] . in the kingdom of saudi arabia, the number of mers-cov cases was 1601 as of may 6th, 2017 [16] . since most of the cases of mers-cov in saudi arabia occurred due to intra-and inter-hospital transmissions, there was an increased amplification of the transmission [2] [3] [4] [9] [10] [11] 17] . early detection and isolation of patients with mers-cov infection remains an important factor for the control of mers-cov transmission [18, 19] . one of the goals of the surveillance of emerging respiratory viruses is the rapid and early identification and placement of control measures [20] . following the initial description of the disease [1] , the ministry of health in the kingdom of saudi arabia put in place a surveillance and screening program for patients admitted with respiratory illness [21] . similarly, we adopted universal screening of admitted patients with community acquired pneumonia. here, we report the result of the surveillance activity in a general hospital in saudi arabia over a four year period. the study was conducted at a 350-bed general hospital, which also accepts referred patients. the hospital provides medical care for about 160,000 individuals eligible for medical care. the hospital has 5 intensive care units (cardiac, medical, surgical, pediatric, and neonatal) [22] . all admitted patients with community acquired pneumonia from suspected mers-cov was an acute febrile respiratory illness (fever, cough, or dyspnea) with radiographic evidence of pneumonia [22] . we collected data for all suspected patients using a standard microsoft excel data collection sheet. both electronic and paper medical records were reviewed. we recorded the age and the date of admission and the mers-cov and influenza results. the study was approved by the johns hopkins aramco healthcare institutional review board (irb). suspected patients had either dacron-flocked nasopharyngeal swabs, or sputum testing for mers-cov. the testing was done at the saudi ministry of health mers-cov laboratory and at the main hospital. clinical samples were screened with real-time reverse-transcriptase (rt)epcr as described previously [23] . the test amplified both the upstream e protein (upe gene) and orf1a for mers-cov and if both assays were positive then the diagnosis of mers-cov was made, as described previously [14] . the influenza test was carried out at the johns hopkins aramco healthcare centre, dhahran, using the cepheid ® xpert flu assay multiplex real-time pcr. the tested influenza viruses were pandemic 2009 h1n1, influenza a (other than h1n1), and influenza b. the test was systematically carried out starting april 2015. statistical analysis was done using excel and descriptive analyses were done for demographic, results of the tests and the monthly number of cases. minitab ® (minitab inc. version 17, pa16801, usa; 2017) was used to calculate the mean age ( ± sd) of patients with influenza. during the study period from 2013 to 2016, a total of 2657 patients were screened for mers-cov and only 20 (0.74%) tested positive. during the first two years (april 2013-march 2015), a total of 1013 patients were screened for mers-cov. only 1.8% of them were positive for mers-cov (table 1 ) and unfortunately these were not systematically screened for influenza. there was an increased number of tests in november 2015-march 2016 (fig. 1) . from april 2015 to december 2016, a total of 1644 patients were tested for both mers-cov and influenza. none of the patients tested positive for mers-cov and 271 (16.4%) were positive for influenza. the detected influenza viruses were influenza a (107, 6.5%), pandemic 2009 h1n1 (n = 120, 7.3%), and influenza b (n = 44, 2.7%) ( table 1 and fig. 2 ). it is interesting to note the pattern of the influenza in 2015 and 2016 (fig. 3) . pandemic h1n1 was the most common influenza in 2015 and influenza a other than h1n1 was more common in 2016. the 2015 influenza season peaked october to december and the 2016 season had a peak in august and then october to december (fig. 3 ). there was a significant difference in the mean age ( ± sd; 95% ci) of patients with h1n1 and other influenza (fig. 4) in this study, we presented the surveillance data on mers-cov over a four year period and the surveillance for influenza over a two year period. mers-cov was only detected in 20 (0.75%) from a total of 2657 patients as detailed in previous publication [22, 24] . the earliest surveillance study from saudi arabia was done from 1 october 2012 to 30 september 2013 and tested a total of 5065 samples [21] . in that study, the mers positivity rate was 2% [21] . a second surveillance of mers-cov in saudi arabia was conducted from april 1, 2015 to february 1, 2016 and included a total of 57,363 suspected mers cases [25] . the study showed only 384 (0.7%) mers-cov positive cases [25] . in a study in the united states, two (0.4%) imported cases were detected among 490 patients-under investigation in 2013-2014 [26] . in a surveillance study of 1586 unique persons from the united arab emirates between january 1, 2013and april 17, 2014, 41 (3%) tested positive for mers-cov infection [27] . in the south korea outbreak, 184 (1%) had mers among 16,752 suspected cases [28] . in a small study from saudi arabia, mers-cov was not detected in 182 cases tested november 2013 and january 2014 (winter time) [29] . thus, the overall positivity of mers-cov among a large cohort remains low. there is a need for a better tool to identify patients with high probability of mers-cov. however, a case control study and a large cohort study did not reveal significant predictor of mers-cov infection [22, 30] . the monthly frequency of suspected mers cases that were tested showed variation with an apparent increase in the tested number during november 2015-march 2016. this apparent increase likely represented an increased activity of influenza during that time. there was no relation to the hajj season as it occurred during september 21-26, 2015 (fig. 1) . in addition at that time, there were no known outbreaks in the kingdom of saudi arabia to account for such an increase in the testing. the 2015 outbreaks occurred in al-hasa in may 2015 [31] and in riyadh in august 2015 [7, 32, 33] . previous studies had shown increased testing of patients for mers-cov during outbreaks [4] . in the current study, the 2015 season was predominated by 2009 pandemic h1n1 whereas influenza a was more common during 2016. similarly, in the united states the 2014-2015 season was predominated by pandemic h1n1 and h3n2 was more common during the 2016-2017 season [34, 35] .we found that influenza rather than mers-cov was more common among the tested patients. the findings are also consistent with other studies among travelers and pilgrims where influenza far exceeded mers [36] [37] [38] [39] [40] . similarly, in a small study in saudi arabia, influenza viruses were detected in 16% of 182 patients [29] . similarly, among a small study of 52 suspected mers cases in the united states of america, influenza was the most commonly (35%) identified respiratory agent [41] and another study found influenza a and b in 11% of 296 investigated patients [26] . thus, it is important to test for common respiratory pathogens such as influenza viruses and it should be noted that identification of a respiratory pathogen should not exclude mers-cov testing [42] . one report indicated co-infection with influenza and mers in four patients [43] . however, epidemiologic differences between different countries should remain as an important predictor of the existence of mers-cov infection. the mean age of patients with h1n1 was younger than the other influenza patients of at least 10 years (45.09 vs. 63.70 for influenza a, 55.11 for influenza b, and 61.28 for influenza negative patients (p < 0.0001). the inital cases of pandemic 2009 h1n1 were also younger than the influenza negative patients [44] . in a small study of 196 patients, influenza b patients were younger than other influenza [45] and in another study the mean age was lower for patients with influenza b (16.4 yr) than (h1n1) pdm09 influenza infection. however, these studies included children and thus are not comparable with the present study [46] . similar results were obtained in travelers returning from the middle east. these studies showed the lack of mers-cov among travelers and that influenza was more common among french travelers [47, 48] , austrian returning pilgrims [40] , british travelers [49] , german travelers [50] , and travelers to california, united states [41] . the presence of influenza infection among those travelrs stress the need for influenza vaccination in travelers, notably tfor those going for the hajj and umrah in saudi arabia. in conclusion, mers-cov was a rare cause of community acquired pneumonia (cap) and other viral causes including influenza are much more common. the epidemiology of influenza mirrored the epidemiology of influenza worldwide. the study highlights the importance of the surveillance system to elucidate the epidemiology of respiratory infections in order to formulate appropriate control measures. interhospital and intra-hospital transmission of mers-cov infection is an important element of the transmission of this virus and it is imperative to continue to have early recognition of cases and constant application of infection control measures to abort the hospital transmissions of the virus [18, 19] . isolation of a novel coronavirus from a man with pneumonia in saudi arabia hospital outbreak of middle east respiratory syndrome coronavirus mers-cov outbreak in jeddah-a link to health care facilities an observational, laboratory-based study of outbreaks of middle east respiratory syndrome coronavirus in 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saudi ministry of health c and cc. mers-cov statistics n hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description middle east respiratory syndrome coronavirus in healthcare settings middle east respiratory syndrome coronavirus infection control: the missing piece? surveillance for emerging respiratory viruses screening for middle east respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study middle east respiratory syndrome-coronavirus (mers-cov): a case-controlstudy of hospitalized patients assays for laboratory confirmation of novel human coronavirus (hcov-emc) infections. euro fig. 4. interval plot of age and 95% confidence interval of age among influenza patients hematologic, hepatic, and renal function changes in hospitalized patients with middle east respiratory syndrome coronavirus surveillance and testing for middle 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activity -united states, 2015-16 season and composition of the 2016-17 influenza vaccine cross-sectional survey and surveillance for influenza viruses and mers-cov among egyptian pilgrims returning from hajj during 2012-2015 active screening and surveillance in the united kingdom for middle east respiratory syndrome coronavirus in returning travellers and pilgrims from the middle east: a prospective descriptive study for the period 2013-2015 influenza not mers cov among returning hajj and umrah pilgrims with respiratory illness hajj-associated viral respiratory infections: a systematic review influenza a and b viruses but not mers-cov in hajj pilgrims laboratory testing for middle east respiratory syndrome coronavirus interim guidelines for clinical specimens from pui | cdc n the impact of coinfection of influenza a virus on the severity of middle east respiratory syndrome coronavirus pandemic influenza a (2009 h1n1) in hospitalized patients in a saudi arabian hospital: epidemiology and clinical comparison with h1n1-negative patients differences in clinical features between influenza a h1n1, a h3n2, and b in adult patients clinical differences between influenza a (h1n1) pdm09 & influenza b infections identified through active community surveillance in north india lack of mers coronavirus but prevalence of influenza virus in french pilgrims after infections in symptomatic travelers returning from the arabian peninsula to france: a retrospective cross-sectional study enhanced mers coronavirus surveillance of travelers from the middle east to england acute respiratory infections in travelers returning from mers-cov-affected areas all authors have no conflict of interest to declare. all authors have no funding. key: cord-287159-bjccnp7u authors: yavarian, jila; shafiei jandaghi, nazanin zahra; naseri, maryam; hemmati, peyman; dadras, mohhamadnasr; gouya, mohammad mehdi; mokhtari azad, talat title: influenza virus but not mers coronavirus circulation in iran, 2013–2016: comparison between pilgrims and general population date: 2017-10-12 journal: travel med infect dis doi: 10.1016/j.tmaid.2017.10.007 sha: doc_id: 287159 cord_uid: bjccnp7u background: the pilgrimage to mecca and karbala bring many muslims to a confined area. respiratory tract infections are the most common diseases transmitted during mass gatherings in hajj, umrah and karbala. the aim of this study was to determine and compare the prevalence of middle east respiratory syndrome coronavirus (mers-cov) and influenza virus infections among iranian general population and pilgrims with severe acute respiratory infections (sari) returning from mecca and karbala during 2013–2016. methods: during 2013–2016, a total of 42351 throat swabs were examined for presence of influenza viruses and mers-cov in iranian general population and pilgrims returning from mecca and karbala with sari by using one step rt-pcr kit. results: none of the patients had mers-cov but influenza viruses were detected in 12.7% with high circulation of influenza a/h1n1 (47.1%). conclusion: this study showed the prevalence of influenza infections among iranian pilgrims and general population and suggests continuing surveillance, infection control and appropriate vaccination especially nowadays that the risk of influenza pandemic threatens the world, meanwhile accurate screening for mers-cov is also recommended. the middle east respiratory syndrome coronavirus (mers-cov) was first identified in a patient from kingdom of saudi arabia (ksa) in june 2012 [1] . according to world health organization (who) report, until 21 september 2017, the number of laboratory-confirmed cases of mers-cov was 2081, with 722 deaths. most of the cases originated from or had a history of travel to middle-east. mecca and karbala are places in the middle-east which are visited by muslims especially during hajj, umrah and arbaeen. ksa hosts about 2.5 million muslim pilgrims from more than 180 countries during the hajj pilgrimage annually. hajj is one of the largest mass gatherings of its kind in the world. umrah is a visit to the holy sites in ksa the same as hajj but it can be occurred at any time during the year. during the hajj, respiratory tract infections are the leading cause of hospitalization in ksa [2, 3] . karbala is a holly place in iraq which muslims visit there during the year especially arbaeen. arbaeen is a shia muslim ritual that occurs forty days after the day of ashura (10th day of the month of muharram). it celebrates the death of hussein ibn ali, the grandson of prophet mohammad, who was killed on the day of ashura. arbaeen is the world largest annual pilgrimage as more than 20 millions of shia muslims gather in the city of karbala in iraq. mass gathering of people in a confined area specially hajj and arbaeen increases the risk of respiratory tract infections which are very common and responsible for most of the hospital admissions. after june 2012 global concern was about the potential for mers-cov spreading by travelers returning from the pilgrimage. for early detection of emerging respiratory viruses, the international health regulations emerging committee established a program for all countries (especially those with returning pilgrims) to strengthen their surveillance to detect and report any new cases. however ksa has been reported the majority of mers-cov cases (> 80%) since 2012, but in the 6.5 million pilgrims in hajj 2012 and 2013 no mers-cov cases were reported [4] . influenza viruses are important human respiratory pathogens with high morbidity and mortality that cause both seasonal and endemic infections. nowadays emergence of h5n1 and h7n7 is the concern for https://doi.org/10.1016/j.tmaid.2017. 10 [5, 6] but there is no published data about the prevalence of respiratory virus infections during arbaeen. among hajj pilgrims, influenza is the most common vaccine preventable virus infection, but its epidemiology is poorly understood in mass gatherings [7] . beside detection of mers-cov, we designed this study to investigate about the importance of influenza vaccination in general population and pilgrims. in iran, the influenza season starts in late november and lasts until late april, peaking in january and february. the national influenza center (nic) in iran, located at virology department, school of public health, tehran university of medical sciences, examines clinical samples from patients with severe acute respiratory infections (sari) for influenza virus surveillance throughout the year in general population and/or pilgrims. after mers detection in 2012, all suspected cases were tested in nic and the first mers case, a 52 year old woman with a history of hypertension, was confirmed in may 2014, iran [8] . with continues surveillance totally six mers cases were identified in iran which the last one was in march 2015. the study's primary aim was screening the iranian pilgrims and general population with sari for detection of mers-cov during 2013-2016. the second aim was to assess the prevalence of influenza virus infections in these patients and the final aim was to comparison of influenza and mers-cov circulation between general population and pilgrims. throat swab specimens according to ministry of health protocol were collected from a total of 42351 patients with saris. of them, 38511 specimens were collected from general population and 3840 specimens were taken from arriving pilgrims at emam khomeini airport in tehran, 2013-2016. throat swabs were collected in viral transport media and immediately transported to nic, school of public health, tehran university of medical sciences. total nucleic acids were purified from a 200 μl sample using high pure viral nucleic acid kit (roche, germany) according to the manufacturer's instructions. each sample was tested independently in a 25 μl reaction for influenza a/b and mers-cov using quantifast probe rt-pcr kit (qiagen, germany). mers-cov was tested with targeting the upstream region of the e gene (upe) for screening and the open reading frame 1b for confirmation [9] . in total 42351 patients with saris were included in this study which 3840 were returning iranian pilgrims from mecca and karbala and 38511 were patients with sari who admitted to local hospitals. iranian pilgrims had symptoms upon arrival or a week later, thereby indicating that the respiratory infections were acquired during the pilgrimage. of 3840 pilgrims, 499 (13%) were positive for influenza viruses. during the years of study in all patients, circulating influenza strains differed but the pattern was similar in both pilgrims and general population. in in 2016 just in non-pilgrim patients three dual infections of influenza a/h1n1 and a/h3n2 viruses were detected in november. during the years of this study from 3840 iranian pilgrims, 46.1% (1773/3840) returned from karbala, 35.2% (1355/3840) came from umrah and 18.7% arrived from hajj. we did not have any pilgrims returning from mecca in 2016 but just 4.8% (185/3840) came from karbala. more information about the prevalence of different influenza strains in hajj, umrah, karbala and general population are shown in table 1 . this paper showed the results of study of mers-cov and influenza virus infections among pilgrims and non-pilgrim patients with sari during 2013-2016. each year more than 5 million muslims travel from all over the world to participate in hajj and umrah. approximately more than one million pilgrims travel from iran to ksa annually. in recent years more than 10 million iranian pilgrims have been gathering during arbaeen in karbala. in this study 46.1% (1773/3840) of pilgrims returned from karbala which 13.6% were influenza positive with a/h1n1 predominance. in a study on 177 iranian pilgrims to karbala who admitted to iraqi hospitals, 3.39% suffered from respiratory infections [10] . in another study from a total of 26574 pilgrims admitted to iranian clinics in iraq, the main cause was acute respiratory infections (48%) [11] . generally performing the pilgrimage in a confined area is associated with an increased occurrence of respiratory infections in the pilgrims. transmission of different infectious diseases during mass gatherings in holly places has a global effect when pilgrims return to their country. in 1989 a meningococcal disease outbreak and its global spread during the hajj lead to this fact that meningococcal vaccine became a mandatory vaccine for all pilgrims [12] . according to the vaccination protocol in iran, all pilgrims had received meningococcal vaccination, but influenza vaccination is not mandatory and we do not have data about its vaccination in this group. however in a review by gautret et al. no remarkable effect of influenza vaccination on the influenza infection of pilgrims was found. apparently this lake of efficiency of influenza vaccine might be the result of mismatch between circulating influenza viruses with vaccine strains [2] . influenza viruses are common respiratory viruses with high mortality and morbidity especially in young children and elderly. in iran influenza viruses are circulating throughout the year with a big peak during cold months. since 2012 besides influenza virus screening nic examines clinical samples for mers-cov detection from suspected patients throughout the year in general population and/or pilgrims. we previously reported that a cluster of mers-cov was detected in kerman/iran in 2014 among nonpilgrims [8] . current study showed that among the population screened, no cases were positive for mers-cov. these results were in accordance with previous studies which have performed among pilgrims of different countries. a cohort of 5235 pilgrims attending the 2013 hajj showed the lack of mers-cov in nasal carriage [13] . in a study on 154 french hajj pilgrims in 2012, in spite of high rate of respiratory infections, mers-cov was not detected [14] . these findings suggest that mers-cov in its current form has poor interhuman transmission and may not have the pandemic potential as seen in influenza a/h1n1 in 2009. however investigation about a highly fatal human coronavirus is necessary as it is a challenge and little is known about its importance, epidemiology and zoonotic total patients 544 141 268 8321 87 366 528 6630 724 205 792 14453 185 9107 influenza positive 3 6 21 392 2 137 34 653 54 49 168 2430 19 1372 a/h1n1 -1 5 116 -73 6 125 15 16 133 1577 9 454 a/h3n2 1 3 10 173 1 8 10 272 38 5 15 432 9 717 b 2 2 6 103 1 56 18 256 1 28 20 421 1 201 transmission. in pilgrims of this study influenza b accounted for 27% (135/499) and influenza a for 71.7% (358/499) of positive influenza results in contrast to findings by balkhy et al., in 2003 , that 90% of pilgrims had influenza b and 10% had influenza a [15] . the results of a uk study with paired serum samples collected before and after the hajj using hemagglutination inhibition test, showed that 38% of uk pilgrims had influenza infection during the hajj 2003 [16] . in another study during hajj 2005, 14% of uk pilgrims with respiratory infections had influenza virus [17] . rashid et al., in 2008 performed a comparative study in symptomatic uk and saudi pilgrims which found infections in 25% and 13% of their pilgrims respectively. rhinoviruses were detected in half of uk pilgrims, followed by influenza virus but in saudi pilgrims 78.5% had influenza virus infection [18] . in 2009, alborzi et al. reported that 9.8% of iranian hajj pilgrims with respiratory infections had influenza [19] . in 2012, 305 iranian pilgrims with respiratory infections returning from hajj were assessed for detection of a/h1n1pdm which just five patients (1.69%) were positive [20] . in a survey on serum samples of 338 iranian pilgrims before and after hajj with elisa, 3.6% were influenza positive [21] . in another iranian study on serum samples of hajj pilgrims in 2004-2005, before departure and two weeks after respiratory infections, there was a 21.5% seroconversion for influenza viruses. while virus culture on their sputum was 13.3% influenza positive [22] . in a study on 275 symptomatic iranian hajj pilgrims, 25 (9.1%) were influenza positive by virus culture whereas 33 (12%) had influenza with rt-pcr test [23] . the findings of this research showed that influenza virus infection was the cause of respiratory infections in 499 of 3840 (13%) of iranian pilgrims. in a similar study in kashmir, north india during 2014-15 among returning hajj and umrah pilgrims with respiratory illness, none of the 300 participants tested positive for mers-cov; however, 33 (11%) tested positive for influenza viruses [24] . in general population, of 38511 sari patients, 4868 (12.6%) were influenza positive during the years of this study with different circulation of the subtypes as seen in other studies: timmermans et al. performed a study on 586 outpatients with influenza-like-illness in western cambodia between may 2010 and december 2012. influenza was found in 168 cases (29%). dominant influenza subtypes were a/h1n1 in 2010, influenza b in 2011 and influenza a/h3n2 in 2012 [25] . in a study by mancinelli et al. a total of 133 respiratory specimens positive for the influenza a and b viruses were subtyped during the 2012-2013 influenza season in italy. influenza b was slightly more prevalent (53.38%) than influenza a (46.62%) and the most common subtype was a/h1n1 (87.1%) while only 12.9% were a/h3n2 [26] . in a ten year (2004-2014) study of influenza surveillance in northern italy, the same as our study influenza a/h3n2 was prominent during 2013-2014 [27] . the results of this study showed similar pattern of virus circulation in pilgrims and non-pilgrims sari patients. as influenza has high morbidity and mortality, its vaccination is recommended for general population especially for high risk groups and pilgrims before going to pilgrimage. finally accurate screening and testing for 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france: distribution and timing of influenza a and b circulation we thank all staff in national influenza center, virology department, school of public health, tehran university of medical sciences. key: cord-291025-u5z8zji3 authors: karami, parisa; naghavi, maliheh; feyzi, abdolamir; aghamohammadi, mehdi; novin, mohammad sadegh; mobaien, ahmadreza; qorbanisani, mohamad; karami, aida; norooznezhad, amir hossein title: mortality of a pregnant patient diagnosed with covid-19: a case report with clinical, radiological, and histopathological findings date: 2020-04-11 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101665 sha: doc_id: 291025 cord_uid: u5z8zji3 this report highlights details on a pregnant case of covid-19 who unfortunately did not survive. this 27-year-old woman at her 30 and 3/7 weeks’ gestation was referred to our center with fever, myalgia, and cough. the laboratory investigations showed leukopenia and lymphopenia as well as increased creatinine and crp levels. the first chest x-ray (faint bilateral patchy opacities) and ct scan (some faint subpleural ground-glass opacities associated with pleural thickening) were not typical for initial covid-19 pulmonary infection, however, the treatment for covid-19 was started. due to respiratory distress, she was intubated and put under mechanical ventilation. after a while, the fetus was born with apgar score of 0 and did not react to the neonatal cardiopulmonary resuscitation protocol. finally, due to deterioration in the clinical and imaging findings, the patient was expired as a result of multi-organ failure. following the death, autopsy was performed and the histopathologic evaluations of the lungs showed evidence of viral pneumonia (viral cytopathic effect and a mild increase in alveolar wall thickness) and ards (hyaline membrane). also, reverse transcription-polymerase chain reaction (rt-pcr) confirmed sars-cov-2 infection in the lungs. to our knowledge, this is the first report of maternal death with confirmed covid-19 infection. in december 2019, an outbreak caused by a new coronavirus was started in wuhan, hubei province of china that led to a pandemic emergence according to the world health organization (who) on march 11, 2020 [1] . according to the phylogenetic studies, the pathogen was named severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and the disease was called coronavirus disease 2019 . reports have shown different signs among the patients with covid-19 among which fever and cough were most common [2] . according to the data, several clinical outcomes such as sepsis, respiratory failure, acute respiratory distress syndrome (ards), septic shock, coagulopathy, acute cardiac injury, and acute kidney injury are significantly (all p-values < 0.0001) higher in non-survivor patients compared to survivors. thus, these outcomes have been suggested to be monitored more cautiously among the admitted patients [3] . so far, few reports have provided information on the clinical and imaging follow up of pregnant patients with covid-19. although, no mortality has been reported among their patients [4] [5] [6] . herein, we report a pregnant patient diagnosed with covid-19 who, unfortunately, did not survive. this report is going to address the data from admission until after the autopsy. a 27-year-old woman at 30 and 3/7 weeks (gravida 2, para 1-0-0-1 [1 delivery, 0 premature delivery, 0 abortion, and 1 living child]) of pregnancy suffering respiratory distress was referred to our hospital https://doi.org/10.1016/j.tmaid.2020.101665 received 31 march 2020; received in revised form 4 april 2020; accepted 6 april 2020 from a maternity hospital due to fever, cough, and myalgia for 3 days. the patient had no underlying disease and declared no specific issue in her medication and family history (occupation: housekeeper). she noted no contact with anyone diagnosed with covid-19 as well as no recent travel history (inside or outside of iran) in the past two weeks. all the previous pregnancy scheduled screening tests had been performed to the date and all were normal. as mentioned in the maternity hospital summery sheet, early examinations showed respiratory rate (rr) = 34/min, heart rate (hr) = 110/min, body temperature (bt) = 39°c, blood pressure (bp) = 100/60 mmhg, o 2 saturation = 93%, and fetal heart rate (fhr) = 170/min. also, it was noted on the summery sheet that patient had received oseltamivir, azithromycin, and ceftriaxone for less than 24 h. also, results of vaginal examination and fern test stated to be normal by the maternity hospital. due to tachypnea, she was transferred to the intensive care unit (icu) and some laboratory tests were requested (table 1) . also, a chest x-ray ( fig. 1-a) was performed that showed faint bilateral patchy opacities. considering the cxr findings, azithromycin, oseltamivir, and ceftazidime were started for the patient. also, based on the cxr findings and after confirming with her gynecologist, a computed tomography (ct) scan was performed (using abdominal shield) which revealed faint subpleural ground-glass opacities as well as pleural thickening ( fig. 1-c) . according to the published data to that date, the mentioned findings were not completely in concordance with coivd-19 [3, [7] [8] [9] . however, due to the abnormal imaging findings, the patient was transferred to our center. at the first moment of arrival, she seemed ill and toxic and her examinations showed rr = 37/min, hr = 130/min, the bt = 39.5°c, bp = 135/85 mmhg, and o 2 saturation = 92% (pulse oximetry). she was immediately transferred to the icu and a full laboratory test was requested (table 1 ) which most importantly showed leukopenia and thrombocytopenia accompanied with elevated c-reactive protein (crp) and lactate dehydrogenase (ldh) levels. soon after, the fever increased up to 40°c and rr to 55/min accompanied by suprasternal and intercostal retraction. immediate blood tests showed metabolic alkalosis while the patient was under non-invasive ventilation. finally, she was intubated and put under mechanical ventilation (mode: simv(vc)+psv, fio 2 : 100%, rate 18/min, vt: 350 ml, and o 2 saturation 85%). following another portable cxr, infectious service consult, and suspicion of covid-19, oseltamivir, lopinavir/ritonavir, hydroxychloroquine, meropenem, and vancomycin were started (azithromycin and ceftazidime were discontinued in our center). the bedside trans-thoracic echocardiography was ordered which results showed severe right ventricle and atrium enlargement, severe right side systolic dysfunction, and tricuspid valve regurgitation (systolic pulmonary artery pressure = 70 mmhg), with an ejection fraction (ef) ratio of 50% (other issues were not notable). also, an hour after intubation, bp was decreased to (80/60 mmhg) for which, 5 mcg/kg/min of epinephrine drip was started until bp raised up to 100/60 mmhg. on the early morning next day, the nurses reported body movement under sedation and then following spontaneous contractions, a cyanotic fetus was delivered vaginally with apgar score of 0 (first and 5th minute of the birth). this score did not change after neonatal cardiopulmonary resuscitation (cpr). following nvd, o 2 saturation was increased up to 90%; so, another cxr was requested that showed alveolar infiltration as bilateral patchy opacities ( fig. 1-b) . following the findings of the new cxr and since the clinical status of the patient was improved, another ct scan was requested for her which illustrated bilateral central consolidation and pleural effusion as new signs. accordingly, possible ards or alveolar hemorrhages were suspected ( fig. 1-d) . however, regarding the nonspecific findings on the ct scan such as the presence of bilateral pleural effusion ( fig. 1-d) , increased cr levels and proteinuria (table 1) , thrombocytopenia (table 1) , and evidence of alveolar hemorrhage (bloody mucosal secretions, one session, in the theracheal tube 12 h after intubation, probably due to either alveolar hemorrhage or intubation trauma accompanied with coagulation disorder), our internal medicine team suspected an acute collagen vascular autoimmune disease. thus, the patient received corticosteroid pulse (methylprednisolone: 1gr) and a single session of emergent plasmapheresis with replacement of 2 l fresh frozen plasma. following these actions, both neutrophil (count) and lymphocyte (count and ratio) were increased. although, around afternoon, bp was decreased again and despite 40 mcg/kg/min epinephrine, the systolic pressure did not exceed 90-100 mmhg. after several hours, o 2 saturation was decreased (70-75%) which, despite following all ards protocols, did not reach higher than 75% and unfortunately, the patient passed away due to multi-organ failure (ards, acute kidney injury, and septic shock). based on the atypical presentations, the patient underwent sample collection for real-time reverse-transcriptase polymerase chain reaction (rt-pcr) for sars-covid-2 which was confirmative for covid-19. also, she underwent autopsy of lungs. the histologic findings of paraffin embedded lung tissue showed alveolar spaces with focal hyaline membrane, pneumocyte proliferation, and metaplastic changes. also, viral cytopathic effect including multinucleation and nuclear atypia were noted. the most inflammatory cells present in the background were mononuclear cells composed of lymphocytes and macrophages (fig. 2) . since 2000, two other outbreaks of coronaviruses have occurred other than covid-19: severe acute respiratory syndrome (sars) [10] and middle east respiratory syndrome (mers) [11] . through the evaluations performed in the previous coronavirus outbreaks (sars and mers), pregnant women have been shown to be at increased risk of mortality, spontaneous miscarriage, preterm parturition, and intrauterine growth restriction. as it has been evaluated, the fatality rate of sars and mers among pregnant patients was 25% and 40%, respectively [10, 11] . to our knowledge, this case is the first maternal death reported for pregnant patients diagnosed with covid-19 so far. however, some studies have evaluated pregnancy outcomes of covid-19. herein, we reported a case of covid-19 in her late pregnancy who expressed atypical presentations in the mentioned imaging modalities. according to the released data to that date and considering the imaging findings on covid-19 patients, results belonging to this patient were nonspecific for early stages of covid -19 pneumonia. in the first ct scan, we found some small patchy ground glass opacities with subpleural distribution. regarding the early initiation epidemic of covid-19 in iran, we decided to consider covid-19 pneumonia as the main diagnosis. however, we also noticed a bilateral pleural thickening in the ct scan. as it has been mentioned, pleural effusion or thickening might be detected in the subacute phase of the disease but not on initial investigations [9, 12] . although, regarding the clinical findings as well as patchy ground-glass opacities in ct scan, the patient received the antiviral therapy. an early study mentioned that the mean time from onset to icu admission and mechanical ventilation was about 10.5 days [13] . however, unfortunately, a rapid progression to consolidative opacities and pleural effusion occurred in our patient that only took 30 h. due to the worsening of results from clinical and imaging findings, it seems that the patient could be considered a "radiographic deterioration" as shi et al. have presented [9] . some studies have mentioned pleural effusion as a pertinent negative finding [12] ; although, in some other studies, trace amounts or mild pleural effusion in the course of the disease has been noted in some patients [9, 14, 15] . our patient, on the other hand, had moderate amount of pleural effusion which could have been attributed to the worsening of pulmonary involvement. regarding the released radiologic findings on covid-19 by the time our patient exhibited (especially about the presence of pleural effusion) and considering her fever, thrombocytopenia, proteinuria, suspicious bloody mucosal secretions, it was not easy to rule out serositis as one of the criteria of the collagen vascular disease for our internal team. an early study has evaluated the outcome of nine pregnant patients with covid-19 without any specific underlying diagnosed diseases (all gestational ages ≥36 weeks). among them, 78%, 44%, 33% and 11% had fever (on admission), cough, myalgia, and dyspnea, respectively. our patient on the other hand, presented all these symptoms at the same time. in laboratory investigations, they found that none of their patients had leukopenia while 56% of them had only lymphopenia (< 10⁹ cells/l). also, elevated crp, aspartate aminotransferase (ast)/ alanine aminotransferase (alt), and positive rt-pcr for sars-cov-2 were observed in 75%, 33%, and 100%, respectively. no iufd, stillbirth, severe neonatal asphyxia or maternal mortality was observed. however, in neonatal outcomes, 44% and 22% were preterm and had low birthweight, respectively. among the nine reported cases, 89% of them had typical signs of viral infection and only one presented "rightsided subpleural patchy consolidation". this patient was a 29-year-old woman in her 36 week of gestation with fever, caught, and myalgia for three days. in the laboratory tests, she had leukocytosis and lymphopenia at the same time. also, her crp level was stated to be missing data. she underwent a c-section and this premature delivery led to a birthweight of 2460 gr (low birthweight) [6] . another study evaluated 13 pregnant patients (two cases < and 11 cases≥ 28 week of gestation) diagnosed with covid-19. they claimed the most common presentation among them to be fever (77%). of these 13 patients, 23% were discharged before labor and they continued their pregnancy normally. on the other hand, 77% undergone cesarean section due to several reasons including fetal distress (3/10), premature rupture of the membrane or prom (1/10), and stillbirth (1/10). also, preterm labor was observed in 46% of all patients. one patient faced different complications such as multiple organ dysfunction. due to the ards, she was intubated and put under mechanical ventilation in icu. also, she was diagnosed with acute kidney injury, acute hepatic failure, and septic shock. it is noteworthy to mention that this patient also had a stillbirth and according to the authors' statement, "patient 6 was still in the support of extracorporeal membrane oxygenation" (unavailable in our center) and no further information was given on the outcome of this patient [16] . also, a study has evaluated the risk factors related to the mortality among survivor and non-survivor patients diagnosed with covid-19. authors have stated that sepsis, respiratory failure, ards, heart failure, septic shock, coagulopathy, acute cardiac injury, and acute kidney injury were significantly higher (p-values < 0.00001) in non-survivors compared to those discharged. also, they have shown that the administration of corticosteroids in non-survivors was significantly higher than in survivor group. however, some other findings in their study such as non-invasive mechanical ventilation, high-flow nasal cannula oxygen therapy, and invasive mechanical ventilation were also significantly higher in non-survivors compared to the survivors (p-values < 0.00001). it is clear that taking these actions are all necessary in critically ill patients with covid-19 and doesn't represent the worse outcome due to their action [3] . taken together, there is not enough published evidence on covid-19 (especially in pregnant patients) which help us to find the exact cause of death in this patient. although, we have discussed the prominent findings of the patient (such as leukopenia, lymphopenia, elevated crp, atypical imaging findings, and multi-organ failure) which have been known to associate with mortality in other published articles [3] . regarding the treatment plan, the only treatment which has been mentioned to relate to mortality was corticosteroids which data has been published only after our patient received this drug. although the low-dose corticosteroid therapy was a part of treatment strategy in our country, the intention beyond this treatment for the case was the clinical suspicion of a collagen-vascular disease. altogether, considering the multi-organ failure, it is difficult to identify the definite cause(s) of death in this case and it needs more investigations in such cases. as far as we know, no case of pregnancy mortality due to covid-19 has been reported to this date. this patient was referred to our center with atypical presentations of the disease in imaging modalities. this case with the mentioned clinical, imaging, and laboratory data was the first report of covid-19 pregnancy mortality. further published data have shown that the subpleural ground-glass opacity was observed in the cases with more complications [6] . however, other than this finding, the case had different other findings associated with poor maternal outcome. despite the consent form which the patient has kindly signed at the administration moment, her heirs signed a form as acceptance to use these data for publication. this report was approved by medical ethic committee of zanjan university of medical sciences. this study was not funded. authors declare no actual or potential conflict of interest related to this study. rolling updates on coronavirus disease (covid-19) clinical characteristics of coronavirus disease 2019 in china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study a case of 2019 novel coronavirus in a pregnant woman with preterm delivery an analysis of 38 pregnant women with covid-19, their newborn infants, and maternal-fetal transmission of sars-cov-2: maternal coronavirus infections and pregnancy outcomes clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records performance of radiologists in differentiating covid-19 from viral pneumonia on chest ct chest ct findings in 2019 novel coronavirus (2019-ncov) infections from wuhan, china: key points for the radiologist radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study pregnancy and perinatal outcomes of women with severe acute respiratory syndrome middle east respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from saudi arabia ct imaging features of 2019 novel coronavirus (2019-ncov) clinical features of patients infected with 2019 novel coronavirus in wuhan, china chest ct findings in coronavirus disease-19 (covid-19): relationship to duration of infection a novel coronavirus from patients with pneumonia in china clinical manifestations and outcome of sars-cov-2 infection during pregnancy travel medicine and infectious disease xxx (xxxx) xxxx key: cord-257099-8k28vkgf authors: fan, jingchun; liu, xiaodong; shao, guojun; qi, junpin; li, yi; pan, weimin; hambly, brett d.; bao, shisan title: the epidemiology of reverse transmission of covid-19 in gansu province, china date: 2020-05-12 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101741 sha: doc_id: 257099 cord_uid: 8k28vkgf background: the transmission of covid-19 is about to come under control within china, however, an emerging challenge to the chinese authorities is reverse transmission due to covid-19 patients/carriers evacuating from overseas to china. methods: we analysed the epidemiological characteristics of 311 chinese citizens evacuated from iran. all confirmed covid-19 cases amongst the returnees were displayed by the spatial distribution pattern of the extent of covid-19 infection. results: characteristics that differed significantly amongst these returnees compared to the original infected cohorts in gansu were mean age, occupation and sex. differences observed between infected patients and non-patients amongst returnees were age, sex, race, occupation, the use of facemasks, and residential situation in iran. the clinical features that were significantly related to infection were chill, shortness of breath, chest pain and nausea. spatial distribution pattern analysis indicated that infected returnees had resided within iranian provinces that had experienced high levels of covid-19. the spatial distribution of the original homes of these returnees before departure for iran demonstrated that returnees will largely return to northwest china, to regions that have only experienced low levels of infection within china. conclusion: blocking the reverse transmission of covid-19 is critical in preventing a secondary outbreak of covid-19. quarantine of the people's republic of china, now requires that a mandatory 14 days quarantine is 92 to be applied to anyone entering china from abroad from countries that have had covid-19 93 patients till further notice [12] . 94 on 2 nd march 2020, there were 978 confirmed covid-19 cases and 385 new cases in iran with the 95 mortality rate of 5.5% [13] . to provide support to chinese citizens who are currently overseas in 96 significant covid-19 outbreak regions, to minimize their risk of covid-19 infection, the chinese 97 government has sent charter planes to evacuate chinese citizens from a number of 98 covid-19-affected countries, particularly italy [14] and iran [15] to designated provinces. a total 99 of 311 overseas chinese citizens were returned from iran, arriving at lanzhou, the capital of gansu 100 province on 3 and 4 march 2020, to escape this international epicenter of covid-19, and also to 101 provide covid-19-affected patients with better medical care [15] . 102 thus, the most urgent task/challenge for the chinese quarantine authority (cdc equivalent) has 103 been to identify possible/actual covid-19 infected patients and/or people highly suspected of 104 developing a covid-19 infection, to enable quarantine of these high risk individuals, to minimise 105 possible reverse transmission of covid-19 from overseas to the chinese population. we report 106 here the epidemiological characteristics and the clinical features of 311 chinese people evacuated 107 from iran to the quarantine centre of gansu province. we aim to provide critical and objective 108 information to help control the spread of covid-19 to other provinces and countries. 109 110 5 there were a total of 311 chinese overseas citizens evacuated from iran. all of these returnees had 113 resided in provinces within iran that had experienced high levels of local covid-19 disease. none 114 of the returnees had been tested or clinically screened for covid-19 prior to their return to china. 115 these returnees were quarantined in lanzhou, gansu province upon arrival. on arrival at lanzhou 116 airport in gansu province, the returnees were isolated in a designated hotel and screened using 117 clinical tools i.e. thermometer, and questions concerning any symptoms, any history of close 118 contact with any known infected people or any persons with symptoms suggestive of covid-19. 119 all of the returnees were tested using a swab of the oral/nasopharynx for pcr testing for the 120 the statistical analysis included demographic characteristics, exposure history, clinical symptoms, 137 and pre-existing illness. median (iqr) was used to describe the ages of the returnees and 138 case-patients due to the data being not normally distributed. for categorical variables, if expected 139 cell sizes were <5, the fisher exact test was used to compare the frequency between or among 140 groups; otherwise, the χ 2 test was used. a two-sided α of less than 0.05 was considered statistically 141 significant. statistical analyses were performed using the sas software, version 9.4, unless 142 otherwise indicated. 143 this study has been approved by the ethics committee of the affiliated hospital of gansu 145 university of chinese medicine (no. 20200201). 146 7 3. results 148 there was a total of 311 overseas chinese evacuated from iran to gansu province, china, arriving 150 on 3-4 march ( figure 1 ). most of these returnees were students (82%, 255/311). their 151 demographics were: male vs female 209 vs 102, age range 3 months to 77 years, median age was 23 152 years (iqr: 20, 26). the ethnicity of the majority of these returnees (78%, 242/311) is from the hui 153 race whose religious background is islamic. there were 37 covid-19 laboratory confirmed cases 154 (12%, 37/311) among the returnees until 14 march 2020 (first 10-11 days after arrival in gansu) 155 and no more new cases up to date. most of the cohort were between 20-35 years old, because most 156 are students studying in iran, with the exception of 18 children, who were 3 months to 3 years old, 157 and 6 people who were > 50 years old. of the positive 37 cases, there were only 17 or 23 persons 158 who believed that they had no close contact with either covid-19 symptomatic persons or 159 covid-19 patients, respectively. among a total of 311 returnees, there was a significant positive 160 correlation between the incidence of covid-19 infection and male sex (χ 2 =11.615, p=0.001), 161 younger age (16-30 y) (p=0.014), hui/other races (p=0.026), or residing in a dormitory (χ 2 =4.088, 162 p=0.043) ( table 1) . paradoxically, we also observed that wearing a facemask while in iran 163 increased the risk for covid-19 infection (χ 2 =7.902, p=0.005) ( table 1) . 164 among the 37 confirmed covid-19 patients, the age ranged from 18 to 29 years, median 23 years 166 (iqr: 22, 25). there were 2 cases that developed into a critical condition (5%, 2/37 covid-19 167 cases) in the period till 21 march 2020. 168 we further analysed differences in clinical symptoms and pre-existing illnesses as a function of 169 covid-19 status between the infected patients and non-infected returnees. the clinical 170 presentations included fever, chill, cough, stuffy nose, running nose, sore throat, headache, fatigue, 171 dizziness, muscle pain, joint pain, shortness of breath, dyspnoea, chest stress, chest pain, 172 conjunctivitis, nausea, vomiting, diarrhoea, and stomach ache. significant differences were 173 observed for the following symptoms: chill (p=0.038), shortness of breath (p=0.038), chest pain 174 (p=0.038) and nausea (p=0.038), comparing the infected patients and non-infected returnees (table 175 2). pre-existing diseases amongst all the returnees included hypertension, diabetes mellitus, 176 cardiovascular diseases, asthma, chronic obstructive pulmonary disease, lung cancer, chronic renal 177 and liver diseases, and immunodeficiency diseases. however, there was no difference in the 178 presence of pre-existing disease between the infected patients and non-infected returnees. 179 the original places of residence of these 311 returnees were from 25 provinces or municipalities in 181 china, mainly within the north west of china, e.g. ningxia hui autonomous region (87, 28%), 182 gansu province (60, 19%) and henan province (48, 15%) ( figure 2 ). prior to their evacuation from 183 iran, the majority of these returnees had been living in qom province (108, 35%), tehran province 184 our data are consistent with the reports above, demonstrating that most of these returnees from iran 232 were young adult international students, who would be expected to have strong immune systems 233 and few co-morbidities. however, in the current study, the infection rate was extraordinarily high 234 among the 311 returnees, being 12% (37/311), compared to the rates in the general population in 235 gansu of 0.35 per 100,000 or < 0.001% (92/26,257,100). the 12% infection rate amongst the 236 returnees was also much higher than that of a symptomatic secondary attack rate of 0.45% (95% 237 acknowledge that the explanation for the higher infection rate among these 311 returnees may be 240 mainly due to two possible reasons: firstly, the relative lack of self-protection or, secondly, lack of 241 sanitisation during the early stages of spread during their stay in iran. 243 additionally, it is likely that the iran government has experienced difficulties scaling up its 244 response to combating the epidemic due to the economic loss and supply issues caused by the after an apparently asymptomatic infection [31] . thus, a substantial threat could occur in the 275 community if such covid-19 case(s) are misdiagnosed and these returnees are allowed to 276 eventually proceed to their final destination(s) after 14 days quarantine. although the infection rate 277 was high (12%), there was a relatively low severe/critical attack rate among these returnees from 278 iran with only 2 (5%), which was far below the results from jiangxi province (18%) [32] and gansu 279 province (17.1%) within china [7] . however, this rate is close to the age-based rate published 280 recently by imperial college london of approximately 1.2% of patients requiring hospitalisation in 281 the age range 20-29 years [33] . our explanation for such a difference might be due to most of the 282 returnees were male students, which may be mainly due to the universities preference for religious 284 study in iran [34] . interestingly, the attack rate of covid-19 amongst females was rather less than 285 male (1:4.5) in our current study, which is very different from the reports in the general population 286 there was 15% rate of covid-19 cases amongst international students, which is substantially paradoxically, our data show that the covid-19 infection rate was greater amongst those who 306 wore masks while in iran (24% infection rate) compared to those who did not wear masks (10% 307 infection rate). we speculate that this observation may be related to several factors: firstly, returnees 308 who chose to wear masks may have been involved in activities that placed them at greater risk of 309 exposure, for example, living in dormitories, attending university classes and mosques. all three of 310 these activities were identified in this study as increasing the risk of infection. by comparison, those 311 returnees who chose not to wear masks may have been largely involved in low risk activities, for 312 example, house-bound spouses engaged in domestic duties and childcare. secondly, those who 313 wore masks may have over-estimated the effectiveness of the masks in preventing infection, and 314 thus may have neglected other measures to avoid infection, such as social distancing and scrupulous 315 hygiene. thirdly, the masks may not have met p2/n95 standards for use against viral infections 316 and/or the technique for using the masks may have been inadequate, for example, touching the 317 outside of the mask after use or multiple uses of the same mask. we note that recommendations 318 concerning the mass wearing of masks remains controversial [39], and we urge caution in the 319 application of our data in relation to this issue. 320 apparently, prior to and during the evacuation, many of these returnees were not fully aware who 321 was/were covid-19 patients, particularly since a number of them (27, 9%) were asymptomatic 322 prior to their return, with their clinical presentations occurring during the current study. therefore, 12 considerable caution should be exercised in screening for covid-19 infection based only on 324 clinical presentation. 325 our data further confirm that among the reverse transmission covid-19 returnees, the clinical 326 presentations, including chill, shortness of breath, chest pain and nausea were still the typical 327 manifestations for covid-19, in comparison with presentations of covid-19 within the local 328 chinese population. furthermore, the 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people's republic of china introduction for gansu province health commission of gansu province. change of risk of new coronavirus pneumonia in 387 department of gansu province. some schools have re-opened in gansu province coronavirus disease 2019 (covid-19) situation report -63 the state council the people's republic of china. entry personnel isolation, asymptomatic 396 infection screening the xinhua news agency. a group of overseas chinese and international students from italy 402 flew to wenzhou why would an iranian charter plane fly to lanzhou the state council, the people's republic of china world health organization. coronavirus disease (covid-19) outbreak a novel approach of consultation on 2019 novel coronavirus (covid-19 the state council, the people's republic of china. premier urges resuming production of 415 major investment projects china's imported coronavirus cases rise as local infections drop again the state council, the people's republic of china. china's major industrial enterprises near full 422 production resumption mmwr)-active monitoring of persons exposed to 427 patients with confirmed covid-19 -united states covid-19 battle during the toughest sanctions 430 against iran. the lancet covid-19: coronavirus changing way muslims across world 432 worship in-flight transmission cluster of 439 covid-19: a retrospective case. medrxiv preprint national health commission of the people's republic of china. situation report-transcript of 443 the press conference on commission of gansu province. situation report-update on covid-19 in gansu up to retrospective study covid-19 in 2 persons with mild upper respiratory 452 analysis of clinical characteristics of 49 455 patients with novel coronavirus pneumonia in jiangxi province non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand trines, s. educating iran: demographics, massification, and missed opportunities transmission and epidemiological 463 characteristics of severe acute respiratory syndrome coronavirus covid-19): preliminary evidence obtained in comparison with 2003-sars. medrxiv face masks are made mandatory in wuhan ministry of education, the people's republic of china. moe party leadership group issues 469 notice for covid-2019 control and educational reforms center for disease control and prevent. steps to prevent illness wearing face masks in the community during the covid-19 476 pandemic: altruism and solidarity transmission routes of 2019-ncov and controls 478 in dental practice address for correspondence: shisan bao, discipline of pathology key: cord-286654-sox98pp3 authors: gautret, philippe; benkouiten, samir; griffiths, karolina; sridhar, shruti title: the inevitable hajj cough: surveillance data in french pilgrims, 2012–2014 date: 2015-10-03 journal: travel med infect dis doi: 10.1016/j.tmaid.2015.09.008 sha: doc_id: 286654 cord_uid: sox98pp3 background: respiratory tract infections are the most common infection affecting hajj pilgrims, and the ‘‘hajj cough’’ is considered by pilgrims almost de rigueur. methods: french pilgrims were recruited between january 2012–december 2014 and information on demographics, medical history, compliance with preventive measures and health problems during travel were collected. results: a total of 382 pilgrims were included with 39.3% aged ≥65 years and 55.1% suffering from a chronic disease, most frequently hypertension and diabetes. the prevalence of cough was 80.9% and a high proportion presented with associated sore throat (91.0%), rhinitis (78.7%) and hoarseness (63.0%). myalgia was reported in 48.3% of cases and subjective fever in 47.3%. the incubation time of respiratory symptoms was 7.7 days (range 0–25 days) and 51.9% of pilgrims presenting with a cough during their stay were still symptomatic on return. among pilgrims with a cough, 69.4% took antibiotics. the prevalence of cough was significantly higher among females than men, but age, chronic conditions and preventive measures had no significant effect. conclusions: the hajj cough is highly common, likely a result of crowded conditions at religious places. pilgrims should be advised to carry symptomatic relief for the hajj cough such as cough suppressant, soothing throat lozenges and paracetamol. use of antibiotics should be discouraged. every year around 2-3 million muslims from over 180 countries arrive in the kingdom of saudi arabia (ksa) for a pilgrimage to the holy places of islam [1] . the crowded conditions within a confined area in close contact with others leads to a high risk of pilgrims acquiring and spreading infectious diseases during their time in saudi arabia [2] . respiratory tract infections are the most common infections affecting pilgrims [3] , and the``hajj cough'' is considered by pilgrims almost de rigueur [4] . attack rates of respiratory symptoms of about 50-90% have been recorded among pilgrims from various nationalities [5] [6] [7] . early reports from the 1978 hajj season indicated that upper tract respiratory infections already formed the bulk of the work-load of medical teams attending pilgrims [8] . recent data indicate that 60% of ill pilgrims consulting at mina primary health structures suffer respiratory tract infections [9] . respiratory tract infection is the leading cause of hospitalization in saudi hospitals during the hajj, up to 57% in one study [10] . pneumonia accounts for 30-40% of hospitalizations in tertiary care structures [10, 11] and for 27% of admission in intensive care units where they are responsible for 55% of sepsis [12, 13] during the hajj. to better characterize the "hajj cough" symptoms and its outcome, this study provides a clinical description of respiratory symptoms experienced by a cohort of french hajj pilgrims during three consecutive hajj seasons. pilgrims who planned to take part in the hajj were recruited from 2012 through 2014 from a private specialized travel agency in the city of marseille, which organizes travel to mecca. participants were asked to participate in the study on a voluntary basis if they were 18 years of age or older and were able to provide consent. upon inclusion, the participants were interviewed by arabicspeaking investigators using a standardized pre-travel questionnaire that collected information on demographics and medical history. a post-travel questionnaire, that collected clinical data, vaccination status, and compliance with preventive measures, was completed during a face-to-face interview just prior to the departure for france. health problems that occurred during the pilgrims' stay were recorded by a medical doctor who traveled with them. subjective fever was defined as the pilgrim's report of feeling feverish. influenza-like illness (ili) was defined according to the presence of the triad of a cough, sore throat, and subjective fever [14] . the protocol was approved by our institutional review board. it was performed in accordance with the good clinical practices recommended by the declaration of helsinki and its amendments. all participants gave written informed consent. the pearson's chi-square test and fisher's exact test, as appropriate, were applied to analyze the categorical variables. statistical analyses were performed using spss software package version 17 (spss inc., chicago, il). p values of 0.05 or less were considered significant. a total of 382 pilgrims were included over three years (96.5% participation rate) with a sex ratio m/f of 0.61 and a mean age of 60.6 years (range 22-85 years). thirty-nine point three percent of pilgrims were aged 65 years and over. the majority was born in various countries in north africa (91.6%) and most of them were first-time pilgrims to the hajj (73.6%). a chronic disease was noted in 55.1%, including hypertension (30.2%), diabetes (27.5%), chronic cardiac disease (8.4%), chronic respiratory disease (7.6%), immune deficiency (1.3%) and chronic renal disease (0.3%). thirty-one point six percent of pilgrims declared having received the influenza vaccination in 2012 before participating in the hajj; however none received the vaccine in 2013 and 2014 as it had not been made available in france before the departure dates. 45.8% of participants reported receiving the 23-valent pneumococcal polysaccharide vaccination (ppsv23; pneumo 23 s ) in the past 5 years before participating in the hajj. fifty-three point seven percent used face masks during the hajj, 41.6% washed their hands more frequently than usual, 56.0% used hand sanitizer and 93.4% used disposable tissues. the prevalence of cough was 80.9% (ranging from 69.8% in 2014 to 86.8% in 2013). symptoms are depicted in fig. 1 . dry cough was reported by 59.6% pilgrims and productive cough by 63.8%. among pilgrims with cough (n ¼ 309) a high proportion presented with associated sore throat (91.0%), rhinitis (78.7%) and voice failure (63.0%). a proportion of 48.3% reported myalgia and 47.3% subjective fever. forty-six point 2 percent of pilgrims had ili. pilgrims with cough had associated dyspnea in 21.0% of cases; gastrointestinal symptoms were less frequently associated including diarrhea (10.0%), nausea (7.9%) and vomiting (4.2%). 11.4% of pilgrims with cough had associated conjunctivitis. the incubation time of respiratory symptoms among pilgrims with hajj cough was 7.7 days (range 0-25 days) with the majority of pilgrims having onset of symptoms during the first week of stay (58.5%) (fig. 2) . 51.9% of pilgrims presenting with cough during their stay were still symptomatic at the end of their sojourn. among pilgrims with cough, 69.4% took antibiotics and two (0.7%) were hospitalized. the prevalence of cough was significantly higher (p ¼ 0.005) among females than men (85.3% vs 73.6%, respectively). age and chronic conditions had no significant association with the prevalence of cough, pilgrims with chronic respiratory disease showed a slightly increased prevalence of cough. none of the preventive measures were effective in reducing cough prevalence with the exception of influenza vaccine, but the effect was not statistically significant (table 1) . our study has some limitations. first it was only conducted among french pilgrims and included a relatively small number of individuals so that our results cannot be extrapolated to all hajj pilgrims. second, our clinical description was only based on functional symptoms reported by pilgrims through a questionnaire. it is thus lacking information on clinical signs that could have resulted from physical examination and bias recall may have influenced our results. nevertheless, we believe that this study provides a useful basic description of the "hajj cough" which may guide health providers when preparing hajj pilgrims. our survey shows that the "hajj cough" affected a very high proportion of french pilgrims with an attack rate culminating to 86.8% in 2013. the onset of symptoms was rapid following arrival in saudi arabia and persistent symptoms were observed in one out of two pilgrims despite extensive use of antibiotics. the "hajj cough" affected all individuals independently on their age, comorbidities, vaccination status and use of individual non-pharmaceutical preventive measures against respiratory tract infections. female were more likely than men to suffer hajj cough and we have no explanation for this observation. fortunately, the disease was mild with a low rate of hospitalization and complications. microbiological studies based on pcr detection in respiratory samples were conducted among same cohorts of french pilgrims in the years 2012 and 2013 before departing from france and just prior to leaving saudi arabia [15] [16] [17] [18] [19] [20] . we observed a high rate of acquisition of viruses, notably rhinovirus, coronavirus e229 and, influenza virus a (h3n2) to a less extent and of streptococcus pneumoniae. a large study based on the same protocol was conducted in 2013 among pilgrims from different nationalities and confirmed these results. it also showed a significant acquisition of haemophilus influenzae and klebsiella pneumoniae [21] . sampling at the time of symptoms was conducted in a small subset of french pilgrims in 2012 only and included a restrictive panel of pathogens so that no strong conclusions can be drawn on the role of the respective microbes in the pathogeneses of the "hajj cough". nevertheless, both clinical and microbiological data indicate that transmission of respiratory pathogens in the context of the hajj is highly frequent, which is likely the result of overcrowding with a density of 6-8 people per square meter close in certain areas in the grand mosque [22] . it is also likely that housing conditions in large collective tents at mina encampment play a role in the transmission of respiratory viruses [23] . finally, air pollutants may play a role through their irritant effect since an increase of carbon monoxide, nitrogen dioxide and tropospheric ozone levels is observed during hajj compared to non-hajj periods [24] . physicians must be alert to the circulation of common pathogens at the hajj, which silently cause much more casualties than the newcomer like middle-east respiratory syndrome (mers) coronavirus which occupy the forefront of the stage and get all the headlines, despite only 8 umrah-associated mers cases over an estimated 20 million pilgrims who visited mecca from 2012 through 2014 [25, 26] . at the moment, none of the usual preventive measures against respiratory tract infection have been proven effective, including vaccination against influenza which is recommended for all hajj pilgrims by french authorities and vaccination against pneumococcal infections which is recommended for at risk pilgrims suffering chronic conditions and or for those aged 60 years and over [27] . the "hajj cough" seems therefore inevitable and self-treatment should be provided to pilgrims at pre-travel advice. we suggest symptomatic treatment, using cough suppressants such as dextromethorphan, decongestants to relieve nasal congestion such as phenylephrine and pseudoephedrine, with careful use among patients with hypertension, and paracetamol for symptomatic treatment of fever, myalgia and sore throat. the use of antibiotics is questionable since the respective causality of bacteria and viruses in the pathogenesis of the "hajj cough" is not fully established. nevertheless, prescription of antibiotics to hajj pilgrims suffering mild respiratory symptoms is frequent in local health care structures: 95-99% patients consulting at the ear, nose and throat clinic of a hospital in mecca were prescribed antibiotics while 85-92% presented with upper tract respiratory infection including pharyngitis and tonsillitis [28, 29] . similarly, patients consulting at various primary health care centers in mina found that 54% patients were prescribed antibiotics while 61% suffered respiratory tract infection with pharyngitis and the common cold the most frequent [9] . a cohort survey conducted among iranian pilgrims in 2007 showed that 84% experienced respiratory symptoms and that 72% took antibiotics [30] . in a cohort survey conducted among indonesian pilgrims, 63% suffered ili during their stay in the ksa, of which 94% took antibiotics that were mostly obtained over the counter [31] . a recent cohort survey showed that 35% pilgrims from australia used antibiotics during their stay, the main reason being upper respiratory tract infection. thirty percent obtained antibiotics from a local pharmacy without prescription and 48% pre-emptively carried an antibiotic with them from australia [32] . the apparent overall overuse of antibiotics by pilgrims is of concern with regards to the development of drug resistance. in this context, the development of pointof-care diagnostic tests would further enhance the ability to differentiate bacterial from viral infections and so decrease antibiotic use [33] . the hajj cough is highly common, likely a result of crowded conditions at religious places. it affects all individuals independently of their age, comorbidities, vaccination status and use of classical, individual, non-pharmaceutical preventive measures against respiratory tract infections including hand hygiene, use of face mask use and social distancing which effectiveness at the hajj has been poorly investigated [34] . clinical symptoms are non severe, with few hospitalizations necessary and symptomatic treatment should be prescribed with attempts to reduce antibiotic use in non-severe low-risk cases, unless there is evidence of bacterial infection. hajj: infectious disease surveillance and control health risks at the hajj respiratory tract infections during the annual hajj: potential risks and mitigation strategies hajj: health lessons for mass gatherings the prevalence of acute respiratory symptoms and role of protective measures among malaysian hajj pilgrims patterns of diseases and preventive measures among domestic hajjis from central, saudi arabia trend of diseases among iranian pilgrims during five consecutive years based on a syndromic surveillance system in hajj letter from abu dhabi: welfare of the hajj pattern of diseases among visitors to mina health centers during the hajj season, 1429 h (2008 g) pattern of admission to hospitals during muslim pilgrimage (hajj) causes of hospitalization of pilgrims in the hajj season of the islamic year severe sepsis and septic shock at the hajj: etiologies and outcomes clinical and temporal patterns of severe pneumonia causing critical illness during hajj influenza and the hajj: defining influenza-like illness clinically lack of nasal carriage of novel corona virus (hcov-emc) in french hajj pilgrims returning from the hajj 2012, despite a high rate of respiratory symptoms circulation of respiratory viruses among pilgrims during the 2012 hajj pilgrimage lack of mers coronavirus but prevalence of influenza virus in french pilgrims after respiratory viruses and bacteria among pilgrims during the 2013 hajj acquisition of streptococcus pneumoniae carriage in pilgrims during the 2012 hajj comparison of nasal swabs with throat swabs for the detection of respiratory viruses by real-time reverse transcriptase pcr in adult hajj pilgrims mass gathering and globalization of respiratory pathogens during the 2013 hajj social identification moderates the effect of crowd density on safety at the hajj pilot randomised controlled trial to test effectiveness of facemasks in preventing influenza-like illness transmission among australian hajj pilgrims in 2011 evaluation of ozone, nitrogen dioxide, and carbon monoxide at nine sites in saudi arabia during imported cases of middle east respiratory syndrome: an update umrah, and other mass gatherings: which pathogens do you expect? beware of the tree that hides the forest haut conseil de la sant ! e publique. health recommendations for travellers road map of an ear, nose, and throat clinic during the 2008 hajj in makkah, saudi arabia impact of ph1n1 influenza a infections on the otolaryngology, head and neck clinic during hajj acute respiratory viral infections among tamattu' hajj pilgrims in iran a case-control study of influenza vaccine effectiveness among malaysian pilgrims attending the haj in saudi arabia knowledge, attitude and practice (kap) survey concerning antimicrobial use among australian hajj pilgrims potential risk for drug resistance globalization at the hajj non-pharmaceutical interventions for the prevention of respiratory tract infections during hajj pilgrimage none. key: cord-284028-l0r7f9sr authors: lee, chi-wei; tsai, yen-shuo; wong, tai-wai; lau, chor-chiu title: a loophole in international quarantine procedures disclosed during the sars crisis date: 2004-12-30 journal: travel med infect dis doi: 10.1016/j.tmaid.2004.10.002 sha: doc_id: 284028 cord_uid: l0r7f9sr this study describes a loophole in the international quarantine system during the recent asian severe acute respiratory syndrome (sars) outbreak. specifically, that of travelers disguising symptoms of respiratory tract infection at international airports, in order to board aircraft to return to their home countries—notwithstanding the infection risks this involves to others. high medical fees for treatment to non-residents in epidemic areas were found to be the main cause for this behaviour. this phenomenon revealed a loophole in the control mechanisms of international quarantine procedures, letting travelers carrying a highly contagious virus slip by undetected and causing possible multi-country outbreaks of communicable diseases. clinical evidence collected from medical records at medical centers can highlight this oversight. from november 2002 onwards, the severe acute respiratory syndrome (sars) had spread rapidly via international air travel to at least 30 countries. as of december 31, 2003, reported cases had numbered 8096 with 774 deaths. reasons for its rapid global spread were the highly contagious nature of the virus with its air-borne route of infection, the busy links between affected countries, and probably inadequacies in international quarantine procedures. the increasing volume of international tourism and trade has raised the risks for translocation of exotic diseases. 1 in other words, the increased mobility, mixing and congregation of civilian populations from different nations increase the rate of transmissible diseases. 2, 3 countries need to cooperate more closely in the future, not only on finding the causes and the management of epidemic outbreaks, but also on preventing the further spread of them. for example, sars had affected people in many areas: in canada (toronto); in china (guangdong, hong kong, shanxi, beijing); in taiwan; in singapore; and in vietnam (hanoi). on march 12, 2003 , the world health organization (who) issued a global alert, 10.002 recommending that national authorities implement heightened surveillance for cases of sars. recommendations were aimed at limiting the spread of sars and protecting international air passengers. the screening measures for potential sars symptoms instituted by national health officials and port authorities, included interviews with passengers, as well as the taking of tympanic core body temperatures from boarding and disembarking passengers by way of electronic thermometers and infra-red cameras. national authorities also advised travelers with fever to postpone international travel from sars documented areas. international travelers were educated through the public media on the symptoms of sars and were advised to seek immediate medical attention should such symptoms occur. according to the who report, evidence had indicated that since the start of sars global surveillance at the end of february 2003, a number of suspected and probable cases of sars had departed from affected countries on flights to other countries (http://www.who.int/csr/sars/ archive/2003_04_11/en/). local transmission could conceivably have occurred inside the cabin of an aircraft to persons seated close to a sars infected person, by way of droplets discharged through coughs or sneezes. in total, 26 nations (27 administrative independent regions, including hong kong) were reported up to april 2003, to be infected by the sars epidemic, in part a consequence of international travel. in fact, the international traveler is an efficient vector for sars as well as new respiratory pathogens yet to emerge. 4 the aim of this study is to describe reasons for a loophole in international quarantine procedures. this study was divided into two parts: information was collected at the international airport of kaohsiung (taiwan), on the physical conditions of passengers who flew from hong kong and landed at kaohsiung from april 10 to 22, 2003. this information was compiled from questionnaires and brief interviews of arriving passengers. in addition, information was gathered from body temperature measurements performed on each arriving passenger who entered taiwan. records from at the emergency department of e-da hospital, in southern taiwan, of patients suffering from symptoms of respiratory tract infection who had departed recently from sars areas from march 19, 2003 onwards were analyzed. the investigation revealed that during this period a total of 46 passengers were symptomatic during transit on board aircraft, meaning that at least 2 and at most 9 passengers per day were found to be symptomatic during their flight. since the flying time from hong kong to kaohsiung is only 45 to 60 minutes, it is reasonable to suspect that symptomatic passengers were actually aware of their symptoms before boarding the aircraft. thus they fully understood that they were possibly infected with the sars virus when departing from an endemic area and before heading for taiwan, despite the aggressive screening procedures put in place by the hong kong customs and department of health at hong kong's international airport. in order to explain the circumstances for this observed phenomenon and the underlying reasons for such behavior, we proceeded to the second part of our study. here, six patients visiting the emergency department of e-da hospital, from march 19 to 22, 2003, were found to show symptoms from respiratory tract infections, after they had departed from a sars endemic area and had entered the territory of taiwan by air. as shown in tables 1 and 2, although none of the six patients were eventually diagnosed wild sars, this observed phenomenon disclosed a very important loophole in the control aspect of international quarantine procedures: the inability to prevent persons with a highly contagious virus from slipping past undetected and thus preventing the further spread of epidemics like sars on international travel routes. all of these patients admitted that extraordinarily high medical fees for non-residents in hong kong, was the major reason for them to hurry back to taiwan, where the cost medical care is significantly lower. in this study, we identified that there were loopholes in the international quarantine system for controlling the international spread of contagious disease like sars, especially when travelers lack a strong motivation to cooperate with national health authorities. this arises particularly when the high medical fees are imposed on non-local residents in endemic areas, were a significant financial burden. furthermore, the emergency room's medical records showed that patients were already aware of their symptoms such as cough or indications of high fever (though not necessarily sars) before they boarded their respective fights. nevertheless, they denied being sick before departure when questioned by health authorities, in full awareness of the infection risks, in order to reach taiwan. since taiwanese residents benefit from very low medical fees in their health care system, in contrast to hong kong's high hospital fees for non-residents. taiwan's medical fees are only v3.585 (nt$150) per attendance in the emergency room and just 10% of the total medical expense during the course of admission for in-patient care at a district hospital, with the remaining cost being subsidized by the national health care plan (see table 3 ). tables 4 and 5 show a strong correlation in different medical fees for residents and non-residents both in hong kong and singapore. for example, the admission fee for in-patient care (general acute beds) is v10.4 (hk$100) per day in hong kong for residents or hong kong identity card holders, while a non-hong kong resident has to pay v343.2 (hk$3,300) per day for the same treatment-33 times higher. in comparison, all taiwan nationals and residents are covered under the policy of the national health care insurance plan, and thus pay less than v11.95 (nt$500) per day for in-patient care. this cost differentiation for residents and non-residents in hong kong, is a phenomenon observed almost in every country in the world, with similar examples existing among different member countries in the patients admitted that they were symptomatic before their departure from epidemic areas of sars. european union. 5 this is only a natural human response for a symptomatic traveler to disguise his/ her illness at their point of departure, to flee back to his/her home country for medical care at a significantly lower cost. however, this apparent trivial aspect of human behavior turns out to be a very serious problem in terms of epidemics and quarantine control measurements, where communicable diseases could be introduced into a population by the arrival of outside foreign infectives. citing the example discussed here, the possibility exists that travelers may return home from a foreign trip with an infection acquired abroad. while an experimental model indicates that screening and quarantining of infectives can considerably reduce the infective equilibrium. 6 the egocentric human behavior of certain travelers who break quarantine rules, could be modified by better cooperation between governments. in today's highly mobile society, it is crucial to deter international travelers from spreading contagious diseases during an epidemic and lessons may be learned from the worldwide spread of sars so that precautions can be taken in the policy-making process for the future since a similar tragedy may repeat itself anytime, anywhere in the world. in response to the main issue identified in this report, governments need to set sensible medical fees for the temporary hospitalization of 'aliens' staying in their territories during periods of epidemic outbreaks. this cost could be shared by governments across the globe, with coordination by the who, so as to enforce quarantine measurements more efficiently. the existing cross-border care and international payment coverage policy within the european union can be seen as a good reference base for constructing such a cross-linking system to tackle this emergent problem of international quarantine. 7 this measure may stop people from becoming disease-vectors within their home countries and also to other passengers on the same plane who may carry infection to many different destinations all over the world. thus, it is of importance, that governments in endemic areas publicize such policies, targeting foreigners staying within their boundaries during an outbreak. it is estimated that the sum of inter-governmental medical expenses incurred by infective or potential infective patients hospitalized at sensible cost in the 'host countries', would be substantially lower than the total social costs caused by the spread of communicable diseases, if these infectives were allowed to return to their mother countries. thus, the aim of future research should be focused on the health and safety investment as well as risk control methods. 8 since global surveillance of sars began at the end of february 2003, some evidence has suggested that a number of suspect and probable cases of sars were caused by persons being infected during travel on board aircraft (http://www.wpro.who. int/sars/docs/interimguidelines/part6.asp). they were probably seated in close proximity to persons releasing droplets in the air on coughing or sneezing. such cases, gives impetus to more rigorous measures to prevent travel-related spread of sars or other communicable diseases. thus stricter travel enforcement must also be evaluated and added to existing quarantine measurements. this is in addition to the main focus of cross-border care and international payment coverage policies for aliens or temporary 'visitors' in afflicted areas. this sars outbreak may be regarded as a test of whether rigorous contact tracing and other stringent public health measures contained further spread, even though a large numbers of persons may have inadvertently been exposed to the virus. one intervention procedure to control the spread of infectious diseases is to isolate some infectives in order to reduce possible transmissions of the infection to susceptibles. total isolation may have been the first historical known infection control method, since biblical passages refer to the ostracism of lepers, then later in time plague victims were often isolated. the word 'quarantine' meant historically a period of 40 days, the length of time that arriving ships suspected of plague were required to lay in anchor off the harbour before being allowed to dock. this practice started in the 14th century at mediterranean ports during the outbreak of the bubonic plague. the word quarantine has evolved to signify a forced isolation or a stoppage of interactions with others. over the centuries, quarantine has been used to reduce the transmission of human communicable diseases such as leprosy, plague, cholera, typhus, yellow fever, smallpox, diphtheria, tuberculosis, measles, mumps, ebola and lassa fever. 9 the 'influenza pandemic preparedness plan' developed in the united states of america is an excellent model from which every other country in the world should learn and extrapolate its underlying spirit. this plan has as objectives: to limit the burden of communicable diseases, to minimize social disruption and to reduce economic loss in the future when similar outbreaks of pandemic does occur. 10 early in 2000, epidemiologists had warned the world that should the next pandemic be caused by a virus as deadly as that of 1918 influenza pandemic, the potential for disaster would be greater than ever. 11 as the world's population is now more than three times greater than it was in 1918, with nearly half that population residing in urban areas, including hundreds of millions crowded into slums and shanty towns in the developing world. faced with today's highly mobile transportation links, a virulent virus could easily spread around the world in a matter of days. another pandemic would challenge the world's public-health resources as never before. therefore, an effective response to future pandemics of viral infection proportions, such as the 1918 influenza pandemic, will demand the full support and complete cooperation of the public. 11 yet the global health community is not prepared for the next viral pandemic, according to klaus stöhr (who, geneva, switzerland), speaking at the international congress on infectious diseases (singapore, march 11-14, 2002) . 12 furthermore, mankind's history and this case study provides evidence that travelers have contributed significantly to the rapid spread of aids 13, 14 , influenza 13, 15 and sars, therefore strict international quarantine enforcement, must be considered for future epidemics. only then, would we be ready to confront similar or even tougher challenges of pandemic outbreaks. in fact, bilateral, as well as regional agreements among different governments on visitors' health care are becoming more common. for example, an extensive list of countries has reciprocal health care agreements with the united kingdom. 16 other non-economic reasons for return home of febrile passengers during the sars epidemic include fear for being infected in the epidemic region, reluctance to be isolated in a foreign country, unfamiliarity with foreign culture, planned travel schedule, etcetera. nevertheless, according to the record of the medical history taken in our emergency department, all six patients admitted that the big gap between medical costs in a foreign country and their mother country was the main reason for disguising their fever on departure. in contrast to sea-voyage, air travel journey is relatively short in duration. infected crew or passengers who travel on board ships would have their diseased status shown clearly during the long sea-voyage, and would have died or being quarantined when they arrived at their destined port. however, due to the relatively short duration of air-travel, the clinical condition of infected passengers on board airplane would not have sufficient time to progress to a serious stage which is obvious enough to detected by the custom at the destined airport. here lies the loophole of international quarantine which would be easily overlooked by airport custom, but not sea-port custom. thus, emergency departments or walk-inclinics are playing the important role in safeguarding the community from imported infectious diseases. emergency physicians should maintain a high level of awareness regarding potential outbreaks of infectious diseases of any kind and play a role in alerting public health authorities to any loopholes in quarantine procedures. the vulnerability of animal and human health to parasites under global change the philippines insurrection and the 1902-4 cholera epidemic: part i-epidemiological diffusion processes in war the philippines insurrection and the 1902-4 cholera epidemic: part ii-diffusion patterns in war and peace sars-lessons learned so far healthcare access and mobility between the uk and other european union states: an 'implementation surplus models for transmission of disease with immigration of infectives should i stay or should i go? waiting lists and cross-border care in the netherlands health a review of the application of health economics to health and safety in healthcare effects of quarantine in six endemic models for infectious diseases influenza pandemic planning: review of a collaborative state and national process epidemic and pandemic 'flu ready for the next influenza pandemic? hiv and pandemic influenza virus: two great infectious disease challenges travel and the spread of hiv-1 genetic variants further development of influenza surveillance in china and global impact on influenza control key: cord-302735-zal2gr28 authors: priyanka; choudhary, om prakash; singh, indraj; patra, gautam title: aerosol transmission of sars-cov-2: the unresolved paradox date: 2020-09-04 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101869 sha: doc_id: 302735 cord_uid: zal2gr28 nan the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), the aetiological agent 18 of coronavirus disease 2019 , has led to a global pandemic defying the 19 geographical borders and putting the lives of billions at risk. the commonly evident 20 symptoms include fever, altered sense of smell and/or taste, cough, sputum expectoration, 21 sore throat, dyspnoea, fatigue and myalgia; whereas the uncommon symptoms include 22 confusion, dizziness, headache, conjunctivitis, rhinorrhoea, nasal congestion, hemoptysis, 23 chest pain, bronchial breath sounds, tachypnoea, crackles/rales on auscultation, cutaneous the transmission of respiratory pathogens have been associated with three primary modes 30 known as "contact," "droplet," and "airborne" transmission. these modes are also being 31 speculated in the context of sars-cov-2, but the existing research-based literature and the 32 consequent guidance from the leading public health agencies are still paradoxical. the viable 117 sars-cov-2 in the air of a hospital room 1 with covid-19 patients. medrxiv aerosol transmission of sars-cov-2? evidence, 121 prevention and control munster 124 vj. aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 key: cord-307460-v6xgkg1p authors: hsu, yu-lung; lin, hsiao-chuan; wei, hsiu-mei; lai, huan-cheng; hwang, kao-pin title: temperature and the difference in impact of sars cov-2 infection (covid-19) between tropical and non-tropical regions in taiwan date: 2020-06-13 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101790 sha: doc_id: 307460 cord_uid: v6xgkg1p nan therefore, we believe that, all things being equal, the transmission of sars cov-2 differs 32 between tropical and non-tropical regions. however, we should not hastily conclude that 33 covid-19 incidence will decrease in the coming summer. this is because countries greatly 34 differ with respect to population density, disease burden, health care quality, infection control coronaviruses -drug discovery and 40 therapeutic options stability of sars coronavirus in human specimens and 42 environment and its sensitivity to heating and uv irradiation epidemiology and clinical 45 presentations of the four human coronaviruses 229e, hku1, nl63, and oc43 detected over 46 3 years using a novel multiplex real-time pcr method the pediatric burden of human coronaviruses 49 evaluated for twenty years coronaviruses in the pediatric population all coauthors contributed to study design hsu 57 and hsiao-chuan lin interpreted data we declare that all authors have no competing interests distribution of covid-19 patients around the world 64 distribution of local cases of covid-19 in taiwan key: cord-262454-bccrvapy authors: szente fonseca, silvia nunes; queiroz de sousa, anastasio; wolkoff, alexandre giandoni; moreira, marcelo sampaio; pinto, bruno castro; valente takeda, christianne fernandes; rebouças, eduardo; vasconcellos abdon, ana paula; nascimento, anderson l.a.; risch, harvey a. title: risk of hospitalization for covid-19 outpatients treated with various drug regimens in brazil: comparative analysis date: 2020-10-31 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101906 sha: doc_id: 262454 cord_uid: bccrvapy background: for the past few months, hmos have faced crowded emergency rooms and insufficient hospital and intensive-care-unit beds, all from the worst pandemic of this century, covid-19. methods: in a large hmo in brazil, our approach was to allow treating physicians to prescribe antiviral medications immediately at presentation, and prednisone starting on day-6 of symptoms to treat pulmonary inflammation. we implemented this covid-19 protocol for outpatients and studied 717 consecutive sars-cov-2-positive patients age 40 years or older presenting at our emergency rooms. results: use of hydroxychloroquine (hcq), prednisone or both significantly reduced hospitalization risk by 50-60%. ivermectin, azithromycin and oseltamivir did not substantially reduce risk further. hospitalization risk was doubled for people with type-2 diabetes or obesity, increased by two-thirds for people with heart disease, and by 75% for each decade of age over age 40. similar magnitudes of reduced risk with hcq and prednisone use were seen for mortality risk, though were not significant because of only 11 deaths among the 717 patients. no cardiac arrhythmias requiring medication termination were observed for any of the medications. conclusions: this work adds to the growing literature of studies that have found substantial benefit for use of hcq combined with other agents in the early outpatient treatment of covid-19, and adds the possibility of steroid use to enhance treatment efficacy. for the past few months, hmos have faced crowded emergency rooms and insufficient hospital and intensive-care-unit beds, all from the worst pandemic of this century, covid-19. in a large hmo in brazil, our approach was to allow treating physicians to prescribe antiviral medications immediately at presentation, and prednisone starting on day-6 of symptoms to treat pulmonary inflammation. we implemented this covid-19 protocol for outpatients and studied 717 consecutive sars-cov-2-positive patients age 40 years or older presenting at our emergency rooms. use of hydroxychloroquine (hcq), prednisone or both significantly reduced hospitalization risk by 50-60%. ivermectin, azithromycin and oseltamivir did not substantially reduce risk further. hospitalization risk was doubled for people with type-2 diabetes or obesity, increased by two-thirds for people with heart disease, and by 75% for each decade of age over age 40. similar magnitudes of reduced risk with hcq and prednisone use were seen for mortality risk, though were not significant because of only 11 deaths among the 717 patients. no cardiac arrhythmias requiring medication termination were observed for any of the medications. this work adds to the growing literature of studies that have found substantial benefit for use of hcq combined with other agents in the early outpatient treatment of covid-19, and adds the possibility of steroid use to enhance treatment efficacy. mankind has been facing one of the greatest challenges of the xxi century: a pandemic (1) caused by a new virus, sars-cov-2, thought to be transmitted by airborne particles and droplets and contact with contaminated surfaces or objects (2) . clinical manifestations of coronavirus disease 2019 (covid-19) patients range from asymptomatic to mild nonspecific signs and symptoms to severe pneumonia with organ function damage and eventual mortality (3, 4) . there is a clear need to try to stop disease progression as early in the disease process as possible. infected patients with comorbidities such as heart failure, type-2 diabetes, asthma or chronic obstructive pulmonary disease and obesity, and patients over sixty years of age are at substantially higher risk to develop severe disease and tend to have higher risks of death (5-7). many drugs have been tried in hospitalized patients, with largely discordant results (8) (9) (10) (11) . randomized double-blind controlled trials demonstrating benefit or lack of benefit of drugs in high-risk outpatients will not be available any time soon, as many clinical sites are still recruiting patients (12) . early outpatient illness is very different than hospitalized severe disease and treatment therefore will differ between these two distinct groups. relatively little is established about utility of medications in early outpatient treatment. currently (13, 14) it is understood that covid-19 is at least a four-phase illness: phase 1 is viral replication, followed by pulmonary inflammation in phase 2, "cytokine storm" and acute respiratory distress in phase 3, and disseminated multi-organ involvement in phase 4. for treatment at the beginning of the illness, there are indications that chloroquine and especially hydroxychloroquine (hcq) may be beneficial (15) (16) (17) (18) , but no specific antiviral medications have demonstrated proven efficacy as yet (19, 20) . recently, the brazil federal committee for medicine has approved the prescription of chloroquine and hcq for clinically suspected covid-19 patients at the physician's discretion with informed consent (21) and the health ministry has also endorsed the use of these medications (22) . brazil has the highest rate in south america in the ranking of covid-19 deaths, with more than 4.2 million people infected in the country (23) in circumstances of a large population still to be affected and with economic difficulties resulting in inadequate social distancing. data over march-may from the federal health ministry (24) show that more than 90% of hospitalized patients j o u r n a l p r e -p r o o f with severe respiratory distress who were tested were positive for sars-cov-2, with less than 5% detected with influenza. therefore, we assumed in clinical practice that most patients coming to the emergency room with influenza-like symptoms would have covid19 . with all that, we developed a protocol for early recognition and treatment of high-risk patients (in our population, age greater than 40 years because of generally poorer health standards, or with comorbidities) who would come to our outpatient network of emergency rooms with influenza-like symptoms: fever, cough, myalgia and headache, among others, and receive early treatment, provided to patients at the first doctor visit, using physician discretion from among hcq, azithromycin, ivermectin, oseltamivir, zinc sulfate, nitazoxanide and prednisone (the last starting on day-6 of symptoms). we evaluate here risks of subsequent hospitalization based upon outpatient use of these various medications. methods: patient data were analyzed from electronic charts of health maintenance organization (hmo) hapvida saúde, the largest brazilian hmo with 6 million members spread over five regions of the country. data were collected after informed consent and institutional ethics committee (4.087.824 cep-university fortaleza unifor) approval for this study. to-date, during the pandemic, more than 300,000 monthly emergency room (er) consults have occurred. patients were all seen at the ers of the widespread country hospital network and admitted if indicated. at the beginning of the pandemic in brazil, late march-april 2020, the north and northeast cities were more affected, with a great number of er consults and hospital and intensive-care-unit admissions. a protocol for early treatment of covid-19 was developed by a team of senior hmo medical staff and started in early may; it included clinical recognition of the commonly described main covid-19 signs and symptoms, and protocol criteria assessment for hospital admission vs outpatient care. patients coming with influenza-like symptoms such as fever, sore throat, myalgia, arthralgia or coryza would enter the covid-19 protocol. patients presenting with hypoxia, defined as the need of oxygen to maintain an oxygen saturation greater than 92%, respiratory rate of or greater than 24 respirations/minute, hypotension defined as systolic pressure less than 90 j o u r n a l p r e -p r o o f mm hg or diastolic pressure less than 60 mm hg, or with confusion or extreme lethargy were immediately admitted to the hospital. the remaining patients over age 40 or with comorbidities were defined as high-risk and treated as outpatients. the protocol specifics were chosen by the attending physician, and all of its steps were monitored for quality assurance. the protocol was largely automated through on-screen suggestions and physician choice boxes leading to successive screens, medication prescription choices, etc. after discharge from the er, patients received paper charts instructing them on isolation, symptoms to expect and medications to use, and qr codes for telemedicine, chat or phone consults. patients were instructed to return if symptoms of dyspnea, confusion or lethargy occurred. telemedicine was also always available to hmo patients on the hmo website. for discharged patients, the covid-19 protocol included (all as oral medications), as chosen by doctors and patients: hcq as first-line treatment, if used (400 mg bid day 1, 400 mg qd days 2-5), prednisone (1 mg/kg qd x 5 days, maximum 80 mg/day, no taper), azithromycin (500 mg qd x 5 days), ivermectin (12 mg qd x 2 days), plus symptom relievers. zinc sulfate, oseltamivir and nitazoxanide were also available to be prescribed but were used infrequently. as doctors quickly found that most of the prescribed hcq was not available at common drugstores, if prescribed it was decided to offer the drug free of charge to all patients who only had to sign informed consent to receive it. data were collected from the hmo database for consecutive patients registered from may 11 th to june 3 rd , 2020. we selected all patients 40 years and older who tested positive for sars-cov-2 using a realtime reverse-transcriptase-polymerase-chain-reaction (rt-pcr) assay of nasal and pharyngeal swab specimens (25) . to be clear, while all relevant patients with clinically likely covid-19 were offered treatment by the hmo, for the present report, we analyzed all those patients whose infections were subsequently confirmed by laboratory assay. the collected data included patient characteristics and comorbidities, age, gender, history of type-2 diabetes, hypertension, cardiac illness, pulmonary disease, other conditions, and facts of hospital admission and death. collected data were analyzed with multivariate unconditional logistic regression models to determine associations with medication use as well as other j o u r n a l p r e -p r o o f risk factors for hospital admission and death. age (in decades) and presentation delay (days) were treated as continuous covariates whereas all other variables were dichotomous. in addition to the medications, all of the presentation characteristics and comorbidities in table 1 were examined for statistical significance and for confounding adjustment. death outcomes were those considered to be due to complications associated with covid-19. a two-sided p-value less than .05 was considered statistically significant. results: from may to june, 24,927 patients were included in the covid-19 protocol, 56% from the northeast brazil states of ceará, bahia and pernambuco. seven hundred seventytwo patients (3.1%) were admitted to the hospital and 52 died (6.7% of those hospitalized, 0.2% of the whole cohort). within the cohort of 24,927 patients, because of scarcity of the tests and without selection by disease severity, 3,307 had testing for sars-cov-2 performed; 1,570 were age 40 years or over and 715 (45%) of these patients had positive rt-pcr assays for sars-cov-2. we also included 2 patients who had positive sars-cov-2 serology (table 1) . three hundred seventy-two patients were female (52%); the mean age was 50.6 years (range 40-93 years). the average delay from the start of symptoms to er visit was 4.6 days. common presenting symptoms included shortness of breath (198, 28%), cough (504, 70%), fever (452, 63%), myalgia (306, 43%) and sore throat (173, 24%); 221 (31%) patients had histories of cardiovascular disease, 123 (17%) had diabetes type 2, 73 (10%) were obese and 25 (3.5%) had chronic pulmonary disease. there were 114 hospital admissions (16%) and of these, 19 (17%) patients required mechanical ventilation and 11 (9.6%) patients died. the median time between start of symptoms and hospital admission was eight days; between hospital admission and death was seven days. one hundred twenty-two of the 717 patients received none of the medications, and 33 (27%) of them required hospitalization. associations with fact of eventual hospitalization are given in table 2 . the multivariate logistic regression model presented in the table shows that age, obesity (bmi > 30) and dyspnea were very substantial risk factors for hospital admission. each additional decade of j o u r n a l p r e -p r o o f age over age 40 multiplied the risk of admission by a factor of 1.75. use of prednisone and use of hcq were both associated with significantly reduced risk, and both drugs used together seemed to perform slightly better than either one alone. when the analysis was restricted to exclude patients hospitalized within five days, thus not eligible to receive prednisone, the results were essentially unchanged. history of pulmonary disease, presentation delay, or presentations with cough, myalgias, sore throat, headache or diarrhea were not associated with risk of hospitalization. presentation with fever, however, had or=1.93 (95%ci 1.18-3.14), p=.0085, but did not change the associations seen in table 2 , and with consideration for multiple comparisons of the various patient characteristics, may not be statistically significant. based on the model of table 2 , we also examined use of azithromycin, or=0.93 (95%ci 0.60-1.45) and use of ivermectin, or=1.17 (95%ci 0.72-1.90). zinc prescription was not given on its own and where prescribed was highly correlated with other medication use and had little independent information for estimation of its own association in the adjusted model. when the model of table 2 was performed including only individuals who had a history of at least one condition of obesity, diabetes or heart disease (73 hospitalized patients and 232 not hospitalized), the associations with the medications largely remained: for both hcq+prednisone, or=0.33 (95%ci 0.14-0.81), p=.015; for hcq alone, or=0.41 (95%ci 0.20-0.83), p=.013; and for prednisone alone, or=0.75 (95%ci 0.29-1.93), p=.55. we also examined the model of table 2 discussion sars-cov-2 will cause greater mortality than any recent contemporary pandemic; only when the pandemic ends it will be possible to assess the full health, social and economic impact of this global disaster (26) (27) (28) . preliminary data show that in developed countries, the impact will be huge. but in developing countries, where public health systems already face great challenges to provide basic health care to all in need, the impact will be several times greater (26) (27) (28) . these problems will not be solved anytime soon. in the midst of the sars-cov-2 pandemic, a feasible approach, with inexpensive drugs, relying on syndromic signs and symptoms rather than scarce laboratory tests may help many patients and will be even more important in developing countries. around the world there are already over 28 million confirmed covid-19 cases (29) . brazil has the third-largest number, with 4.2 million cases and 128,000 deaths as of september 9 th (29) . if this trend continues, in about six months, brazil will have the worldwide largest number of deaths of any country. in march 2020, the world health organization recommended the use of medications oseltamivir and antibiotics (30). on march 28, 2020, the fda issued an emergency use authorization for remdesivir and hcq for patients in both clinical trials and with severe hospitalized disease (31) . since then, pharmacological treatments have been controversial. on june 15 the fda retracted its earlier authorization and on july 1 posted warnings about its use, leaving hcq outpatient use not supported (32) . countries such as china and india have issued guidelines supporting the use of chloroquine or hcq in covid-19 (33, 34) . evidence of the real-world unimportance of arrhythmia and other cardiovascular adverseevent endpoints of hcq and hcq+az use is given in the large oxford-based record-linkage study (35) and in a study of 40% of the english population (36) . understanding the pathophysiology of covid-19 in the different clinical stages of the disease is important, as treatments will change according to progression of the disease (13) . our study showed that hcq alone, prednisone alone, and hcq plus prednisone did better than standard treatment for early stage covid-19. it may be that the corticosteroid benefit involves low levels of type j o u r n a l p r e -p r o o f i and iii interferons juxtaposed to elevated chemokines and high expressions of il-6. reduced initial innate antiviral defenses allow the virus to multiply, followed after a few days by relatively excess inflammatory cytokine production, allowing for steroids to reduce the latter in the early features of covid-19, before appreciable pneumonia has occurred (37) . hydroxychloroquine has a number of suggested beneficial actions for early covid-19, not least of which is its non-immunosuppressive immunomodulatory activity (38) . because all treatments have costs and benefits, treating all high-risk patients early would take a major effort from brazil's universal public system (sus) and its private hmos, but would be much less expensive than hospital-based inpatient treatment, which would probably be impossible on the scale needed. our study showed that about 10% of high-risk outpatients over age 40 treated with prednisone still required hospitalization, which is substantially better than the 24% among untreated patients, thus even this treatment plan could create a large hospital-bed demand. however, we found that even in hospital, these treated patients do better and their mortality is much lower. in an ideal world, large randomized double-blinded controlled clinical trials establish evidence, but take time to complete and many are not large enough for the randomization to be sufficiently effective in reducing biases. to-date, treatment protocols have proposed drugs with antiviral activity, and with anti-inflammatory responses, such as therapeutic regimens of ifn-α+lopinavir/ritonavir and ifn-α+lopinavir/ritonavir+ribavirin, among others. while cost-effectiveness of these regimens have been challenged, hcq is generic and has been prescribed for malaria for decades, as it has antiviral and anti-inflammatory properties. on march 27 th , 2020 the brazilian federal health authority issued a note saying that it would treat severely ill patients in the public system with hcq (39). on may 20 th, the same authority issued another note that hcq would be available for physicians to prescribe for outpatients and mild cases, according to symptoms and severity (22) . prednisone is also generic and inexpensive and has been used for many decades and does not interact adversely with hcq. our results demonstrate a positive benefit of hcq and prednisone in decreasing hospital admissions in a high-risk population over 40 years of age with rt-pcr-positive sars-cov-2 infection when started at first doctor visit. a high-risk outpatient benefit of hcq use has been summarized elsewhere (35) but to our knowledge this is the first time that efficacy of outpatient prednisone use has been reported. use of these medications also showed some evidence of reduced mortality in the study group, and larger studies of mortality will be needed to validate this finding. we observed that outpatient hospitalizations of the larger group of suspected covid-19 er patients, from the same hmo database before vs after the protocol started, march-april vs may, decreased significantly, 23% vs 9%, and mortality declined from 1.75% to 1.39%. for may, our hmo data also show that the mortality was less than covid-19 mortality for brazil as a whole. our study has several limitations. this is a retrospective, chart-based study, and even though our initial sample of patients was large, with almost 25,000 patients, few of these patients were tested due to the scarcity of rt-pcr tests. then, we chose to study only tested-positive sars-cov-2 patients to make sure we were dealing with confirmed cases of covid-19. limiting analyses to patients greater than 40 years of age further reduced our sample size. nevertheless, our experience of approaching and treating patients with influenza-like symptoms in this era of pandemic sars-cov-2 is useful and more generally applicable. in one state hospital network of the cohort this spring, more than 90% of patients admitted to the hospital with appreciable respiratory distress had positive rt-pcr for sars-cov-2 (40), so it seems reasonable to infer that it would be similar for patients with influenza-like illness presenting at the emergency room. also, our study involved a range of treatment medications assigned by hmo physicians using their clinical judgements, rather than mandated by study design. clinical treatment decisions allow for the possibility that sicker patients get more or more aggressive treatments, creating the potential of confounding by indication. the comorbidity distributions of the various treatments as shown in table 1 suggest that except for shortness of breath, patients not treated with hcq or j o u r n a l p r e -p r o o f prednisone may have been slightly less symptomatic than treated patients. however, this would if anything have tended to reduce the magnitude of risk lowering that we found for these medications toward the null. a pattern of chronic comorbidity differences is not apparent in the table; nevertheless, our results were adjusted for those comorbidities where associations with risk of hospitalization were observed ( table 2 ). in spite of the aforementioned, our study was large enough to have observed statistically significant results and was based on actual clinical conditions and data recorded in active clinical charts, to enable reasonable inference about lack of reporting biases in the analyzed data. our analyses thus show that it is possible to give hcq with companion medications in an early stage protocol that proves to be safe, and warnings about cardiac arrhythmia adverse events are unnecessary unless significant contraindications are known. treatment-failure mortality, while small, is still the major concern of patient management. our new protocol is continuing in clinical practice in our hmo, and we hope for it to be more generally applied across the rest of brazil as quickly as possible. we found early outpatient use of hcq and prednisone, both as individual prescriptions and used together, to lower the risk of hospitalization in symptomatic high-risk covid-19 patients presenting for primary care at the emergency rooms of our large hmo in brazil. other than the small numbers of treatment failure, no potentially life-threatening adverse events were recorded with medication treatment. these medications were found to be safe and beneficial for early high-risk outpatient treatment of covid-19. j o u r n a l p r e -p r o o f more than 50 manufacturers of the various medications analyzed herein. this past work was not related to any of these medications and was completed more than two years ago. he has no ongoing, planned or projected relationships with any of these companies, nor any other potential conflicts-of-interest to disclose. none of the 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(2019-ncov) in vitro in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) conselho federal de medicina. processo-consulta cfm n o 8/2020 -parecer cfm n o 4/2020. tratamento de pacientes portadores de covid-19 com cloroquina e hidroxicloroquina orientações do ministério da saúde para manuseio medicamentoso precoce de pacientes com diagnóstico da covid-19 infogripe-monitoramento de casos reportados de síndrome respiratória aguda grave (srag) hospitalizados variation in false negative rate of rt-pcr based sars-cov-2 tests by time since exposure the benefits and costs of social distancing in rich and poor countries united nations development programme. socio-economic impact of covid-19 the socioeconomic implications of the coronavirus pandemic (covid-19): a review johns hopkins coronavirus resource center. covid-19 map -johns hopkins coronavirus resource center. johns hopkins coronavirus resource world health organization. clinical management of severe acute respiratory infection j o u r n a l p r e -p r o o f ( sari) when covid-19 disease is suspected: interim guidance based on fda's continued review of the scientific evidence available for hydroxychloroquine sulfate (hcq) and chloroquine phosphate (cq) to treat covid-19, fda has determined that the statutory criteria for eua as outlined in section 564(c)(2) of the food, drug, and cosmetic act are no longer met fda news release. coronavirus (covid-19) update: daily roundup national china health office medical letter (2020) 184. notice on issuing the new coronavirus pneumonia diagnosis and treatment plan (trial version 7) government of india, ministry of health and family welfare, directorate general of health services (emr division) early outpatient treatment of symptomatic, high-risk covid-19 patients that should be ramped-up immediately as key to the pandemic crisis hydroxychloroquine for prevention of covid-19 mortality: a population-based cohort study can steroids reverse the severe covid-19 induced 'cytokine storm immunomodulators in sle: clinical evidence and immunologic actions perfil epidemiologico dos pacientes hospitalizados por sindrome respiratória aguda grave (srag) no estado do ceará. 05 de maio de 2020/pagina9/36 acknowledgements: dr. risch acknowledges past advisory consulting work with two of the declarations travel medicine and infectious disease requires that all authors sign a declaration of conflicting interests. if you have nothing to declare in any of these categories then this should be stated. a conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). it may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. signature (a scanned signature is acceptable, dr. risch acknowledges past advisory consulting work with two of the more than 50 manufacturers of the various medications analyzed herein. this past work was not related to any of these medications and was completed more than two years ago. he has no ongoing, planned or projected relationships with any of these companies, nor any other potential conflicts-of-interest to disclose. none of the other authors have any potential conflicts of interest to disclose.no funding involved. j o u r n a l p r e -p r o o f key: cord-295601-jdtmtjx5 authors: kabir, mahvish; afzal, muhammad sohail; khan, aisha; ahmed, haroon title: covid-19 pandemic and economic cost; impact on forcibly displaced people date: 2020-04-06 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101661 sha: doc_id: 295601 cord_uid: jdtmtjx5 nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid covid-19 pandemic and economic cost; impact on forcibly displaced people dear editor, we read with great interest the recent publication of illness among travelers returning from a mass gathering of religious purpose between august 2015 and april 2019 [1] . the current outbreak of covid-19 is estimated to cost $1 trillion to world's economy during year 2020. according to experts this impact is even worse than great financial crisis that world faced in 2007-2008 [2, 3] . countries are cutting interest rates and revising their expenditures and might have to cut donations to different programs run by united nations [2] . there are 70.8 million forcibly displaced people in the world, among these there are 40.3 million internally displaced people (idps), 25.9 million refugees and 3.5 million asylum seekers. factors contributing to the low standards of living for these people include lack of space, poor healthcare facilities, high population density, and low levels of education [4] . people in refugee camps are already fighting for basic necessities of life and are currently under high risk of acquiring covid-19. there are inadequate facilities for sanitation, washing and disinfection in these refugee camps [5] . furthermore, unviability of precautionary equipment like hand sanitizer, soaps, disinfectants, masks and high population density makes the scenario worse. these refugee camps are mainly monitored and run by unhcr. the funding system of unhcr is entirely dependent on voluntary donations from different rich governments across the globe [4]. america, european union, scandinavian countries along with some other strong economies are main donors of unhcr (fig. 1) . data analysis revealed that 15 top economies of the world are badly hit by this covid-19 outbreak. there is a sharp decrease in economic activities ranging from decline in restaurant and hotel bookings, air travels, fuel consumption, retail sector and even media industry [2, 3] . this economic crunch will have an effect on donation programs of these countries in coming months. till now, 196 countries are hit by this pandemic and countries have to spend a lot more money in their own health and public welfare sector [4] . there are chances that unhcr will face a drop in funds. this will further worsen the situation for these displaced people including 37 million children living in these camps [5, 6] . world has to act smartly in order to prevent another human crisis in coming months. periodic diarrhea, malaria and polio cases had been reported from these refugee settlements in the past [6] . it is high time for global community to act swiftly to save these lives. not applicable. the authors declare that they have no competing interests. international mass gatherings and travelassociated illness: a geosentinel cross-sectional, observational study real-time data show virus hit to global economy the arc of migration and the impact on children's health and well-being forward to the special issue-children on the move etiologies of diarrhea and drug susceptibility patterns of bacterial isolates among under-five year children in refugee camps in gambella region, ethiopia: a case control study addresses: mahvish.k82@gmail.com (m. kabir), sohail.ncvi@gmail.com (m.s. afzal) haroon ahmed * department of biosciences key: cord-316097-608qex0d authors: al-tawfiq, jaffar a. title: asymptomatic coronavirus infection: mers-cov and sars-cov-2 (covid-19) date: 2020-02-27 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101608 sha: doc_id: 316097 cord_uid: 608qex0d nan the occurrence of asymptomatic individuals with coronaviruses or other viruses may pose a significant public health issue. a recent review in this journal showed that an increase in the rate of asymptomatic individuals with the middle east respiratory syndrome coronavirus (mers-cov) increased from 0% to 28.6% [1] . actually, as the mers-cov progressed overtime there was more identification of asymptomatic individuals due to increased surviellance and contacts testing. this increase had proportionally but inversely affected the case fatality rate. it is expected that early on the course of any outbreak that severe cases are recognized first and then less severe (mildly or asymptomatic) cases are detected with increasing frequency. the extent of asymptomatic mers-cov cases is about 9.8% from different studies, table 1 [1]. a study of human rhinovirus showed that asymptomatic infection was four times as common as symptomatic infection [2] and another study showed that the rate of rhinovirus infection among a pair of asymptomatic parents of a rhinovirus symptomatic child was one of 36 (2.8%) with an overall positivity of 23.5% among symptomatic subjects and 3.6% of asymptomatic subjects [3] . asymptomatic carriage of influenza virus was estimated to be 5.2%-35.5% [4] based on serology, the positivity rate was 13% in asymptomatic sars 4% in those with mild symptoms, and 82% in those with severe disease [5] . since the emergence of sars-cov-2, (known initially as 2019-ncov), in wuhan, china, in december 2019, the number of global cases had increased significantly. the increase in the number of cases is alarming and brought the fear of having viral transmission from asymptomatic individuals. one report indicated that an asymptomatic person was able to transmit the virus to another patient in germany [6] . in addition, in a family cluster of cases who went to wuhan from shenzen, the parents and the grandparents who visited a family member in a hospital had symptoms and they tested positive for sars-cov-2 (2019-ncov). the family insisted in testing a 10-year-old asymptomatic boy and the tests were positive as tested by rt-pcr in nasopharyngeal and throat swab samples and the ct-scan showed mild infiltrate [7] . the contribution of asymptomatic persons with mers-cov or sars-cov-2 to the transmission is not well characterized. those asymptomatic cases may play a role in the transmission and thus pose a significant infection control challenge. however, the contribution of asymptomatic cases in the transmission of these viruses is not well known and deserve further studies to examine the extent of occurrence and the role in transmission. these studies should examine the clinical course of those individuals, viral dynamics, viral loads and contribution to the transmission. it is crucial to evaluate the burden of asymptomatic individuals. such studies will enhance the understanding of the pathogenesis of these emerging viruses and will inform policy makers to make scientifically sound recommendations. asymptomatic middle east respiratory syndrome coronavirus (mers-cov) infection: extent and implications for infection control: a systematic review comparison of asymptomatic and symptomatic rhinovirus infections in university students: incidence, species diversity, and viral load human rhinovirus infections in symptomatic and asymptomatic subjects heterogeneous and dynamic prevalence of asymptomatic influenza virus infections asymptomatic sars coronavirus infection among healthcare workers transmission of 2019-ncov infection from an asymptomatic contact in germany a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster key: cord-311979-l1iw6449 authors: cimolai, nevio title: more data are required for incubation period, infectivity, and quarantine duration for covid-19 date: 2020-04-27 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101713 sha: doc_id: 311979 cord_uid: l1iw6449 nan in some respiratory, urine, and stool samples for more than fourteen days [2] . for mers-cov, nasopharyngeal samples have yielded live virus in some past fourteen days [3] . early reports from the asian covid-19 experience continue to prompt a need to reconsider if not revise approaches to control. some have proposed possible transmission during the incubation period [4] . the suggestion that the incubation period can be extended beyond fourteen days is receiving support [5] . although it is more common for the incubation period to be less than one week, 97 to 99% confidence intervals for the tail-end of excretion are more than double the latter timing. if the majority of patients become ill in less than two weeks, the finding of outliers beyond the latter may not be common in a small affected population. to the contrary, a very large population being affected is very likely to have such outliers which could complicate the pattern of spread. some patients shed the virus in a relatively asymptomatic state [6] . the latter will again have the potential to complicate control measures. furthermore, the concept that patients only excrete virus when they become symptomatic is not in keeping with most known viral respiratory infections otherwise. the existing data therefore beckon reconsideration of several important parameters. for the definition of the infectious period, an initiation of timing prior to the actual onset of symptoms, if they occur, seems prudent. likewise, an extension to a safer end limit for excretion past fourteen days could also attract support. extension to the quarantine period for a patient with a laboratory-confirmed infection or for a definitive close contact should be considered. greater stringency for the follow-up of casual contacts could also be applicable. if covid-19 was largely a mild disease, further stringency in these regards would be unpalatable to many. in these uncertain times, given the crescendo to a global pandemic and given the observed morbidity, some further consideration should be given to these very important epidemiological topics. most will recognize that an extension to infectious periods or isolation/quarantine times has the potential to significantly complicate resources or unduly stretch capabilities, but error towards greater safety has its merits. in large part, we have relied on china to provide timely epidemiological data, but other countries are now in a position to re-analyze some of these critical issues as lagier and colleagues and others have rightfully begun. testing the repatriated for sars-cov2: should laboratory-based quarantine replace traditional quarantine environmental contamination and viral shedding in mers patients during mers-cov outbreak in south korea a familial cluster of infection associated with the novel 2019 novel coronavirus indicating possible person-to-person transmission during the incubation period the incubation period of coronavirus disease covid-19) from publicly reported confirmed cases: estimation and application unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (covid-19) implicate special control measures key: cord-314609-83t1je92 authors: daw, mohamed a. title: corona virus infection in syria, libya and yemen; an alarming devastating threat date: 2020-04-02 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101652 sha: doc_id: 314609 cord_uid: 83t1je92 nan since its emergence, the novel coronavirus (2019-ncov) infection has been quickly spreading through all over the world [1] . however, no study has yet determined the impact of this infection on countries with armed conflicts such as syria, libya and yemen. here in we would like to highlight the burdens of corona virus on these countries and how it could be contained. armed conflicts have resulted a high rates of mortality, injuries and population displacement. the highest rate of mortality was reported in the syrian conflict (7; 1000) followed by libya (5; 1000) and yamen (3; 1000). such conflicts were complicated by the destruction of health care system, lack of food and unstable daily life [2] . this was resulted in emergence of highly infectious diseases such as hemorrhagic fever, cholera and tuberculosis [3] . the emergence of the new covid-19 has resulted in a large number of deaths in european countries like italy, spain and france which considered to have heath care services with good quality an probably the best standards. regarding the infectious period, transmissibility, clinical severity, and extent of community spread, the european public health measures are not able to fully contain the outbreak of covid-19.thus they are facing this pandemic hardly and appealing for international help [4] . hence then the spread of this contagious infection in syria, libya and yemen will have a catastrophic impact not only on the citizens of these countries but all over the world. corona virus have been confirmed in all countries surrounding syria and full alert has been utilized in jordan, iraq and lebanon, similarly those countries surrounding libya, (egypt, algeria and tunisia)as well as those surrounding yemen (oman and saudi arabia and even the african horn countries and madagascar) [5] . therefore, concerns have been raised on the actual status of the spread of the corona virus infection in these countries and how they can be considered safe. these conflict countries are particularly prone to infectious disease such as corona virus and indeed difficult to trace and even hard to control. as many people were injured and thousands have been hold in prisons, refugees and immigrants camps without sanitation and food. despite that who and whole world was united to fight against this pandemic, these countries were left alone with corona virus and no help was offered. hence then global alert should be mounted to help these countries and specific plans have to be implemented. these may include but not limited to emergency supply to the basic needs such as gloves masks and disinfectants which lacking in these countries. building emergency hospitals for infected patients occupied with ventilation equipment and icu services. in addition to specific quarantine places for suspected cases. screening tests, particularly detection of corona via swabs or blood quick tests which to be obligatory implemented. the authorhas no conflict of interest to disclosure. no competing of interest. the continuing 2019-ncov epidemic threat of novel coronaviruses to global health-the latest 2019 novel coronavirus outbreak in wuhan, china trends and patterns of deaths, injuries and intentional disabilities within the libyan armed conflict libyan healthcare system during the armed conflict: challenges and restoration can we contain the covid-19 outbreak with the same measures as for sars? lancet infect dis preliminary epidemiological analysis of suspected cases of corona virus infection in libya. travel medicine and infectious disease key: cord-313546-rlq4v0ca authors: bielecki, michel; gerardo crameri, giovanni andrea; schlagenhauf, patricia; buehrer, thomas werner; deuel, jeremy werner title: body temperature screening to identify sars-cov-2 infected young adult travellers is ineffective date: 2020-08-05 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101832 sha: doc_id: 313546 cord_uid: rlq4v0ca nan we are writing this letter to the editor of "travel medicine and infectious diseases" to alert readers of the futility of body temperature screenings at airports and border entry points. body temperature screening (fever) is the primary test performed at the borders of some countries and concerns have been raised about its efficacy [1] . a recent study suggests low efficiency of such screening procedures among hospitalized patients [2] ; however, data are lacking for young adults who often present with mild or asymptomatic disease. crucially, this is the part of the population considered to be highly contagious [3] . this is also the population segment most likely to travel and encounter body temperature screening which has been implemented at airports around the world. data from previous outbreaks of other viruses (ebola, influenza h1n1) suggest that the number of cases detected by screening for body temperature is minimal or non-existent. sars-cov-1 screening procedures in canada, singapore, and australia seem to have detected zero cases overall. simulations performed modelling covid-19 suggest that, at best, 44% of cases could be detected during exit screenings using body temperature measurements [4, 5] . we evaluated the body temperature of 84 covid-19 patients twice daily for fourteen days after diagnosis by pcr. these patients were part of a cohort of young (median age 21), predominantly male recruits in military basic training of the swiss armed j o u r n a l p r e -p r o o f forces. the outbreak of covid-19 as well as the demographic characteristics of this cohort is described elsewhere [3] . the tympanic temperature of symptomatic patients with pcr confirmed covid-19 was significantly higher than the temperature of unaffected controls ( figure 1a ), but the distribution density curves of temperatures overlap considerably between both groups. sensitivity and specificity were calculated by comparing the two groups ( figure 1b the temperature data started was collected on the day recruits presented with symptoms, and not at random, thus, the sensitivity is probably overestimated, since body temperature is highest at the day of presentation: shortly after presentation, body temperature normalized ( figure 1c) , and after five days, no patient had fever anymore, while infectivity is reported to last up to 10 days post-infection. 83% of our patients never developed a fever and, with one exception, no one suffered from fever for longer j o u r n a l p r e -p r o o f than three days ( figure 1d ). in our evaluation of young army recruits, a temperature cut-off of 38°c only allows for the identification of the minority of cases, while an even higher cut-off value of 38.5°c misses 92% of all covid-19 patients at the time of presentation in this age category. screening for fever is not sensitive enough to detect the vast majority of covid-19 cases in the age group between 18-25 years. even a low-temperature cut-off value of 37.1°c will miss more than a third of symptomatic cases of covid-19 on the day of diagnosis and will cause a large number of false-positives. the cdc considers screening employees for temperature as a possible strategy to combat the further spread of covid-19 [6] . this raises the need to develop new clinical criteria to detect cases of covid-19 as temperature-based random screening proves to be virtually useless for young adults as shown here in our evaluation. we reinforce the who's recommendation that widespread testing for sars-cov-2 is currently the only available efficient way to monitor the trajectory of the infection and control the spread of covid-19. screening temperature at borders is a strategy that has been pursued in the past and has proved to be both expensive and ineffective. we advocate the evaluation of, novel non-invasive screening approaches, such as testing saliva samples for sars-cov-2 with rapid follow-up on positives. this may prove to be a fast and more sensitive alternative to body temperature screening at borders. coronavirus disease-2019: is fever an adequate screening for the returning travelers temperature screening has negligible value for control of covid 19 social distancing alters the clinical course of covid-19 in young adults: a comparative cohort study exit and entry screening practices for infectious diseases among travelers at points of entry: looking for evidence on public health impact cmmid ncov working group. effectiveness of airport screening at detecting travellers infected with novel coronavirus (2019-ncov) key: cord-323622-229kub7c authors: ou, xueting; zhou, liyang; huang, huanliang; lin, yuebao; pan, xingfei; chen, dexiong title: a severe case with co-infection of sars-cov-2 and common respiratory pathogens date: 2020-04-16 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101672 sha: doc_id: 323622 cord_uid: 229kub7c nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid to the editor since december, 2019, corona virus disease 2019 (covid-19) caused by sars-cov-2, has spread to the majority of countries worldwide [1, 2] . here, we reported the clinical characteristics of a severe case with co-infection of sars-cov-2 and common respiratory pathogens. the patient was a 65-year-old woman, who had severe clinical manifestations of covid-19, including symptoms, decreased lymphocyte counts, abnormal chest ct images. next-generations sequencing (ngs) was used to test whether she was co-infected with other pathogens besides sars-cov-2. the sputum samples were collected and found the presence of haemophilus parainfluenzae and moraxella catarrhalis by ngs. on jan 22, 2020, she travelled from wuhan to guangzhou, china by high speed rail. from feb 11, she developed fever lasted for 9 days, and developed cough as well as sore throat, without chills, headache, arthralgia, myalgia. on feb 20, she was transferred to the third affiliated hospital of guangzhou medical university with a body temperature of 38°c. the next day, she developed a bit shortness of breath, with a body temperature of 37.5°c. on feb 21, blood routine tests showed normal white blood cell counts, but decreased lymphocyte counts. the blood glucose was increased. chest ct scans showed bilateral diffuse ground-glass opacities and consolidation (fig. 1) . nasopharyngeal swab samples were collected twice and both were negative for sars-cov-2 tested by qrt-pcr. however, sputum samples collected on the same day were positive for sars-cov-2 by ngs. furthermore, haemophilus parainfluenzae and moraxella catarrhalis were also found in the sputum samples by ngs. in the afternoon of the same day, the oxygen saturation values of the patient decreased to 91.2%, and the partial pressure of oxygen in arterial blood decreased to 61.2 mmhg. therefore, she received high-flow nasal cannula oxygen therapy (40% concentration, flow rate 60 l/min). the patient was diagnosed as severe covid-19, and was transferred to the first affiliated hospital of guangzhou medical university for isolation and treatment where are designed to treat severe covid-19 cases by local health authorities. more and more covid-19 cases have been reported by the majority of countries worldwide [2] . health-care professionals do their best to treat patients with covid-19. unfortunately, 85,522 cases died of covid-19 globally by april 9, 2020 [2] . this implies that we need further to improve how to treat covid-19, especially for severe cases. in the present study, the cause that resulted in severe condition of the patient could be the co-infection of sars-cov-2, haemophilus parainfluenzae and moraxella catarrhalis. nowadays, more attentions are paid to sars-cov-2, so it is easy to neglect patients infected with other pathogens besides sars-cov-2 during the outbreak of covid-19. when we face severe covid-19 cases, we need to think about more, especially co-infection. older patients, having diabetes, hypertension are causes of severe covid-19 cases [3, 4] . furthermore, patients with diabetes are also easily infected with pathogens [5] . anyway, we should be aware of the co-infection of other respiratory pathogens in patients with sars-cov-2 infection. different kinds of detection methods should be used to find out pathogens in the pandemic of sars-cov-2. a novel coronavirus emerging in china -key questions for impact assessment world health organization clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china quantifying the risk of infectious diseases for people with diabetes the present study was funded by national natural science foundation of china (81401306) key: cord-320893-bgn04zh3 authors: mubarak, naeem; zin, che suraya title: religious tourism and mass religious gatherings — the potential link in the spread of covid-19. current perspective and future implications date: 2020-06-09 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101786 sha: doc_id: 320893 cord_uid: bgn04zh3 nan religious tourism -visit to sacred places in a given country -is a huge market that significantly contributes in the revenue of many countries. churches, mosques, temples, shrines, synagogues, gurdwaras and other sites of religious significance attract hundreds and thousands of tourists globally. [1] religious tourism takes full swing in certain months and results in mass religious gatherings (mrgs) which pose a significant public health risk in context of the potential spread of infections across the borders and within the communities. it has always been challenging for the governments to effectively implement preventive measures in mrgs. table 1 enlists some of the prominent planned mrgs in different parts of the world. in the past, mrgs, for instance kumb mela, and hajj 2013, have been identified as the locus of spread of antibiotic resistant bacteria and respiratory infections. [2] religious tourism and mrgs have been linked with the explosive spread of covid-19 across the globe. to begin with, 35% of the new malaysian covid-19 cases stemmed from an mrg of 19000 muslims which include 1500 foreigners from 30 countries. this was organized by tableeghi jammat, a muslim evangelists group involved in proselytization of masses. this transmission has now been termed as the largest known viral vector that spread the virus to other countries. [3] in iran, religious tourism -a substantial source of revenue congregations. [4] hajj -an obligatory pilgrimage for muslims to the "house of allah" in mecca, saudi arabia -is the most diverse mrg in the world (2.5 to 3 million pilgrims, from 180 countries in 2019). respiratory infections were common among the hajj pilgrims and many studies reported low adherence and implementation of preventive measures during the hajj in the previous pandemic of h1n1(2009) and mres outbreak (2013). [5, 6] covid-19 has prompted saudi government to consider cancelation of the hajj this year. however, it would not be an easy decision, and most likely saudi kingdom will open its boarder for hajj-2020 (28 th july-2 nd august) because of the associated religious emotions and potential economic loss of $8.5 billion revenue from the religious tourism pertaining to hajj. in this case, any country opening its boarder for religious tourism and mrgs must demonstrate capability to implement adequate preventive measures and diagnostic capabilities. furthermore, to avoid any potential ramifications, authors suggest restrictions on the entry of the hajj pilgrims who are/from: a. epicentres and hotspots, b. over 50 years old, c. chronic disease patients with diabetes and cardiovascular complications, d. countries with suboptimal diseases surveillance system, and e. countries with inadequate quarantine and diagnostic infrastructure for returning pilgrims saudi arabia needs to deploy a pre-emptive approach for all the necessary arrangements. the threat of the virus spread out of hajj could be a reality, hence, time for action is now or never. table 1 prominent mass religious gatherings in the world religious tourism -a review of the literature hamer dh; geosentinel network.international mass gatherings and travel-associated illness: a geosentinel cross-sectional, observational study a single mass gathering resulted in massive transmission of covid-19 infections in malaysia with further international spread the missing link for an effective social distancing in pakistan. time for some unpopular decisions mass gathering-related mask use during 2009 pandemic influenza a (h1n1) and middle east respiratory syndrome coronavirus covid-19: preparing for superspreader potential among umrah pilgrims to saudi arabia key: cord-311011-xzfnzbcf authors: chen, juan; feng, zhan-hui; ye, lan; cheng, yong-ran; zhou, meng-yun; li, yafei; du, chong; wang, liansheng; wang, ming-wei title: travel rush during chinese spring festival and the 2019-ncov date: 2020-04-22 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101686 sha: doc_id: 311011 cord_uid: xzfnzbcf nan travel medicine and infectious disease journal homepage: www.elsevier.com/locate/tmaid we read with interest the report on 2019-ncov [1] and would like to provide travel rush during chinese spring festival and the 2019-ncov in china.chinese spring festival travel rush refers to the massive use of public (and private) transportation around the spring festival. it is a huge-scale phenomenon of high pressure transportation that occurs around the lunar new year in china. the travel rush usually begins 15 days before lunar new year's day and lasts for 40 days. a report from the chinese ministry of transportation shows the total number of public transportation trips during this period in 2019 was 2.98 billion, a number equivalent to all europeans, oceanians, and africans collectively travelling once. therefore, the bbc referred to the chinese spring festival travel rush as "the world's largest population migration every year." the 2020 spring festival travelling started on january 10 and will end on february 18, a total of 40 days. due to the outbreak of 2019-ncov in wuhan, china, this year's travel rush is special. the 2019-ncov outbreak has attracted worldwide attention. several of the world's most influential magazines rushed to report about the epidemic [ [2] [3] [4] ]. at our institute, we study not only the epidemiological characteristics of the 2019-ncov epidemic, but also its effects on the actual situation in china. this includes the effects on population mobility during the chinese spring festival, and how this affects changes in the 2019-ncov-infected population. we used the baidu's big data to obtain five million trips and destinations of people travelling out of wuhan between january 10 and 22, 2020, ahead of the chinese spring festival. wuhan was sealed off on january 23, 2020. from that date, people were prohibited from leaving wuhan and all bus, subway, ferry, and long-distance passenger transportation were suspended. according to the new england journal of medicine, the average incubation period for the 2019-ncov is 5.2 days [5] . we performed correlation analysis based on the data released by the chinese national health commission, and show that incidence rate was higher in the regions receiving the largest number of travelers during this period, further confirming the epidemiological characteristics ( fig. 1a-c) . although the measures that wuhan government took had been implemented, it is clear that the effect is not satisfactory. those people who returned to their hometown or travelled for sightseeing had already left wuhan before its closure. as a result, 2019-ncov was brought to other provinces across china as well as to other countries around the world, causing worldwide concern. with the progress of the 2019-ncov epidemic, as of january 31, 2020, a total of 9692 cases were diagnosed and 213 people have died. it is not known what trend the 2019-ncov epidemic is going to take and when it will reach its peak. we think that the beginning of the chinese spring festival travel rush was an important factor in spreading the 2019-ncov. if the chinese government would have implemented the closure of wuhan before the start of the travel rush, it is possible that the impact of 2019-ncov would have been considerably lower. we should also pay attention to the fact that the chinese spring festival travel rush is about to enter its second climax towards february 18, 2020, and with it the problems will come again. people who are now closed in wuhan will start returning to their work places in other parts of china. this "second big migration," when the workers return to work, should be at the focus of our attention. this second migration process might escalate the epidemic as we are about to quell it. the attention of the government is required to minimize the impact of this second wave of migration. we envisage two solutions: first, after the spring festival holidays, to let those in wuhan return to their original places of residence or places of work where they should be isolated immediately and be monitored for two weeks. people outside wuhan should not be allowed to enter wuhan for the time being. second, closure of wuhan should continue until the 2019-ncov epidemic has subsided. only then people would be allowed to go in and out of wuhan. this approach would take longer. it has to be pointed out that no matter what approach the chinese government will take, the public should be vigilant and cooperative to ensure that no one is infected again. it is clear to all that the chinese government has taken strong measures to strengthen the country and control the progress of the 2019-ncov epidemic. we hope that our suggestion can help china, and contribute to bringing the battle against 2019-ncov to an early and successful end. the association between domestic train transportation and novel coronavirus outbreak in china, from 2019 to 2020: a data-driven correlational report clinical features of patients infected with 2019 novel coronavirus in wuhan, china china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia key: cord-310149-8idvf79g authors: antinori, spinello; torre, alessandro; antinori, carolina; bonazzetti, cecilia; sollima, salvatore; ridolfo, anna lisa; galli, massimo title: sars-cov-2 infection: across the border into the family date: 2020-06-09 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101784 sha: doc_id: 310149 cord_uid: 8idvf79g nan spinello antinori 1,2 , alessandro torre 1 , carolina antinori 3 dear editor, italy has been one of the countries most affected by the covid-19 pandemic since 21 february 2020 and, as of 18 april 2020, the lombardy region alone has recorded 64,135 confirmed cases and 11,851 deaths, respectively 36.5% and 51% of the national burden. during the first weeks of the epidemic, before lockdown measures had been put in place, the dramatic increase in the number of patients requiring hospitalisation and intensive care led to the complete saturation of the region's hospital beds despite the rapid effort of the regional health authority to satisfy the demand [1] . at the same time, the number of laboratories equipped to confirm covid-9 diagnoses by means of the real-time reverse transcriptase-polymerase chain reaction (rt-pcr) testing of nasopharyngeal swabs was very limited. in this dramatic context, the patients who turned to the regional emergency service for influenza-like illness (ili) were advised to stay at home and request assistance only in the case of dyspnea. however, as there was no surveillance programme with the possible as shown in figure 1 , the wife and children proved to be igg positive (three by both tests, and one by the orient gene test alone), and the index case was also positive for igm at the orient gene test. this family cluster of probable covid-19 cases merits a number of comments regarding the dynamics of the spread of covid-19 and the importance of adding new controls, particularly in the light of the future gradual relaxation of containment measures. firstly, although formally unproven, it is likely that our index case became infected outside italy, a fact that underlines the importance of the rapid sharing of surveillance measures in order to increase our ability to detect imported cases in this globalised world. secondly, although the index case voluntarily isolated himself from the rest of his family as soon as he developed symptoms, it is also likely that he transmitted the infection to the rest of his family during the pre-symptomatic phase of infection. initial studies carried out in china found that asymptomatic patients are associated with a 5% transmission rate [2] , but this figure was found to be as high as 42% in a recent northern italian study, which supports the view that asymptomatic (or pre-symptomatic) subjects have played a major role in fuelling the covid-19 outbreak in italy [3] . it should be highlighted that self-quarantine is not the same of isolation, a measure which separates subjects identified as infected from othesr who are not. nevertheless, proactive case finding with case management as adopted by the model of veneto region in italy [4] or by drive-through coronavirus testing centers such as those employed in china, south korea and israel have shown to be valid measures to contain the epidemic [5] however, although covid-19 transmission by asymptomatic subjects is a critical factor for ensuring an effective public health response to the epidemic, the best method of identifying asymptomatic infections is still unclear. the decision not to search for sars-cov-2 in people with mild symptoms and not to include them in surveillance programmes is at least questionable, particularly because the future relaxation of containment measures will require even more active surveillance in order to ensure the early detection of new cases or clusters. the clinical definition of covid-19 has so far mainly concentrated on patients with severe disease, and much less is known about the fraction of mildly symptomatic infections not requiring hospitalisation. it is interesting to note that all but one of the family members described in this report complained of altered smell and taste, and that an increasing number of reports suggest that these are so frequent in the early phase of covid-19 that they may be considered clinical markers of the disease [6] . 5 thirdly, we retrospectively identified this family cluster using two rapid serological tests. a number of such tests have become available but none have been approved by the regulatory authorities and their diagnostic accuracy is still being debated. however, the findings of recent studies suggest that they are sufficiently accurate to be used for public health purposes as well as being an invaluable epidemiological means of screening a large number of subjects. finally, it should be mentioned that people with suspected covid-9 (such as the members of our family) do not appear in the official statistics concerning the covid-19 epidemic. given that it is unlikely that ours an isolated event, it is possible that overlooking mildly symptomatic cases is leading to a serious underestimate of the real burden of covid-19. . serological testing of the five family members involved in a probable covid-19 cluster baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lumbardy region characteristics of covid-19 infection in beijng suppression of covid-19 outbreak in the municipalità of vò covid-19 in italy: lesson from the veneto region drawing on israel's experience organizing volunteers to operationalize drive-through coronavirus testing centers self-reported olfactory and taste disorders in sars-cov-2 patients: a cross-sectional study dr carlo parravicini for assistance in figure production written informed consent was obtained from all of the subjects, including the parents of the children none key: cord-321720-5sfwyn9g authors: hanscheid, thomas; valadas, emília; grobusch, martin p. title: coronavirus 2019-ncov: is the genie already out of the bottle? date: 2020-02-07 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101577 sha: doc_id: 321720 cord_uid: 5sfwyn9g nan once again, a virus has jumped the species barrier. coronavirus 2019-ncov emerged apparently in a wet market in china, and after a few weeks the number of cases already exceeds those of sars in 2002/ 03 ( fig. 1 ) [1] in terms of both morbidity and mortality. excellent publications have addressed many aspects of a possible novel endemic/ pandemic zoonosis, often with a focus on mers-cov (2-4), including prevention [2] , drug and vaccine-development for coronaviruses [3] , or the importance of "a 'one health' approach to control … …zoonotic pathogens with epidemic potential" [4] . the hugely increased appetite for meat-products worldwide, but also in china [5] , is likely to increase livestock production and sale, as well as scavenging of remaining wildlife resources, primarily the latter with consequent increases in the risk of exposure to novel infectious agents. the role which few available drugs, e.g. nucleoside analog remdesivir, lopinavir-ritonavir and ribavirin, which showed some limited activity in sars/mers-cov [3] , might play in the prevention or curbing disease episodes is not clear yet; neither the role of other compounds with some limited limited level of evidence of (not even necessarily 2019-ncov) inhibitory activity mainly from animal testing, such as some antimalarials [6] . the development of therapeutic monoclonal antibodies and vaccines has been hampered in the past by the unpredictability of the next, emerging coronavirus [3] . the sudden public interest in a coronavirus vaccine seems somewhat ironic, given that vaccine hesitancy was identified as one of the ten global threats to health, identified in 2019 by the world health organization (who). however, the story of the ebola vaccine [7] casts serious doubts on claims by some officials that a vaccine for the current 2019-cov strain could be made available in a few months, given the huge challenges in developing, clinical testing, mass-producing and distributing such a vaccine. of course, this makes prevention efforts the best, if not only practical option [2, 4] . news about travel restrictions, looming economic turmoil and the (perceived) risk for one's personal health ring alarm bells around the globe. the number of cases may be much higher than the daily, everincreasing numbers reported, as many infected individuals may be asymptomatic, or only be slightly symptomatic, yet still be infectious, as indicated by the viral load of 10 8 copies/ml sputum in the first german case [8] . the case-fatality-rate (cfr) in confirmed cases in china is rather stable at around 2% so far (figure) , although lower than for sars (~10%) or mers (~30%) [3] [4] [5] . pandemic influenza, often used as a fig. 1 . epidemiological curve of 2019-ncov and sars (data source who [1] ). all cases in china, with numbers of deaths and severe cases from the who situation reports (1-15) as of 5th of february. note, the case fatality rate is very stable at around 2%, as well as the rather high rate of severe cases of around 15% (red arrow). comparison at the moment, had an estimated cfr of 0.5% in confirmed cases and 0.05% in symptomatic cases during the 2009 season (h1n1) [9] . while it is expected that the 2019-ncov causes more severe disease in those with underlying medical conditions, the first published case series (n = 99) reports that only 50% had co-morbidities, while the first two fatal cases had none, other than being smokers [10] . this leaves an important number rather overlooked: the number of severe cases (arrow in fig. 1 ) which hovers around the 15% mark. it may be assumed that these patients require hospitalization, if not ventilation-based intensive care treatment. given the limited number of (ventilator-equipped) intensive care beds, let alone negative pressure isolation beds, it seems obvious that even the treatment capacities of the most affluent countries will be very quickly exhausted if the epidemic spreads further. this is reminiscent of the large west-african ebola virus disease outbreak 2013-2016, where possibly many people died of other ("usual") health problems because the regular healthcare services were overwhelmed, if not rendered entirely dysfunctional [11] . hopefully, china does manage to control this outbreak. if 2019-cov reaches other densely populated areas with fragile health systems (a case was already observed in india [1] ), we may be well underway towards a pandemic. no funding received. none of the authors has any conflict of interest to declare. who. novel coronavirus (2019-ncov) situation reports mers-cov as an emerging respiratory illness: a review of prevention methods broad-spectrum coronavirus antiviral drug discovery taking forward a 'one health' approach for turning the tide against the middle east respiratory syndrome coronavirus and other zoonotic pathogens with epidemic potential meat consumption the use of antimalarial drugs against viral infection make ebola a thing of the past': first vaccine against deadly virus approved transmission of 2019-ncov infection from an asymptomatic contact in germany case fatality ratio of pandemic influenza epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study effects of response to 2014-2015 ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa key: cord-286029-rafcdzhm authors: bogaards, johannes antonie; putter, hein; jan weverling, gerrit; ter meulen, jan; goudsmit, jaap title: the potential of targeted antibody prophylaxis in sars outbreak control: a mathematic analysis() date: 2006-05-05 journal: travel med infect dis doi: 10.1016/j.tmaid.2006.01.007 sha: doc_id: 286029 cord_uid: rafcdzhm background: severe acute respiratory syndrome (sars) coronavirus-like viruses continue to circulate in animal reservoirs. if new mutants of sars coronavirus do initiate another epidemic, administration of prophylactic antibodies to risk groups may supplement the stringent isolation procedures that contained the first sars outbreak. method: we developed a mathematical model to investigate the effects of hospital admission and targeted antibody prophylaxis on the reproduction number r, defined as the number of secondary cases generated by an index case, during different sars outbreak scenarios. results: assuming a basic reproduction number r(0)=3, admission of patients to hospital within 4.3 days of symptom onset is necessary to achieve outbreak control without the need to further reduce community-based transmission. control may be enhanced by providing pre-exposure prophylaxis to contacts of hospitalized patients, and through contact tracing and provision of post-exposure prophylaxis. antibody prophylaxis may also be employed to reduce r below one and thereby restrict outbreak size and duration. conclusions: patient isolation alone can be sufficient to control sars outbreaks provided that the time from onset to admission is short. antibody prophylaxis as supplemental measure generally allows for containment of higher r(0) values and restricts both the size and duration of an outbreak. severe acute respiratory syndrome (sars) was the first major outbreak of a newly emergent communicable disease in the 21st century, affecting over 8000 persons on multiple continents. 1 its appearance stirred an unprecedented coordinated effort to control transmission and morbidity, motivated by fears that local outbreaks might give rise to a major pandemic within months. from the onset, mathematical modeling has proven to be a very useful tool for evaluating the impact of the control measures instigated. [2] [3] [4] the sars outbreak originated in the guangdong province of china, from where it spread to hong kong and next to vietnam, singapore and canada. on 15 march 2003 , the world health organization (who) issued a second global alert together with a name for the new disease and a case definition. 1 the outbreak was fully contained by july 2003, the last case occurring in canada. sars coronavirus, the causative agent of the new disease, 5,6 most likely was transmitted to humans by the masked palm civet (paguma larvata). 7 adaptation to human transmission is possible through a single mutation in the spike glycoprotein of a civet sars-like virus. 8, 9 as sars-like viruses continue to circulate in animal reservoirs, 10,11 the risk of another major outbreak remains. the identification of measures that make sars controllable is key in planning a public health response to future outbreaks. 12 measures that successfully controlled the 2003 sars epidemic could probably be supplemented by specific antiviral strategies, such as protective ring vaccination or targeted antibody prophylaxis. although a protective vaccine against sars is still elusive, antibodies with neutralizing capacity have been characterized, specifically human monoclonal antibodies directed against the spike glycoprotein of sars coronavirus. 13 prophylactic administration of such an antibody in ferrets before intratracheal challenge with a high dose of human sars coronavirus completely prevented the development of lung pathology and abolished viral shedding in pharyngeal secretions. 14 these data suggest that antibody prophylaxis might offer clinical protection against sars and block air-borne transmission of sars coronavirus. to evaluate the potential of antibody administration as prophylaxis in sars outbreak control, we designed a mathematical model. in this model a distinction was made between sars transmission before and after an infected individual was hospitalized. we considered two qualitatively different strategies of antibody administration: first, pre-exposure prophylaxis targeted at susceptible persons coming into contact with hospitalized sars cases (e.g. health care workers or close friends and relatives); and second, post-exposure prophylaxis targeted at exposed persons having been identified through contact tracing of hospitalized sars cases. based on our model, we derived an expression for the effective reproduction number of sars to study conditions for containment and we explored how the size and duration of an outbreak depend on the efficacy of control. the model is a modification of the discrete-time seir model, 15 the modification being that we distinguish between infectious individuals in the community and those that are hospitalized and possibly put in quarantine (fig. 1) . we suppose that death or recovery only occur after a person has been admitted to hospital. in addition, we suppose that those infected or removed constitute only a small fraction of the total population, i.e. s is taken to be approximately constant. this simplifies the transmission dynamics to an essentially linear system. consequently, the model does not apply to the stage of an epidemic where saturation of incidence will occur due to high prevalence of infection and/or natural immunity. to allow for time-dependent transition and transmission probabilities, we divided every state into categories that denote either the time since infection or the time since onset of clinical symptoms. within each model state and category, independent identically distributed bernoulli trials are performed for every person to determine whether an asymptomatically infected person becomes symptomatic and thus infective (probability f); whether a symptomatic and infectious person is admitted to hospital (probability z); or whether a hospitalized patient recovers or dies from complications due to sars (probability g). the parameter f depends on the time since infection, whereas the parameters z and g depend on the time since onset of clinical symptoms. the infectivity of an individual also depends on the time since onset of clinical symptoms. the time from infection to onset of clinical symptoms and the duration of the symptomatic period reflect specific biological features of the virus-host interaction. we assume that their distributions are not affected by intervention measures. the assumption of invariant distributions seems reasonable because therapeutic treatment is currently not available for sars coronavirus infection. it follows that hospitalization does not alter the overall duration of the symptomatic period, although it may affect infectivity. conversely, the conditional probability that a hospitalized patient recovers or dies from complications due to sars depends on the cumulative probability that a person has article in press figure 1 schema of the flow of individuals between epidemiological compartments. members of the susceptible population (compartment s) may become infected after contact with an infectious person. infected persons first enter an asymptomatic phase. because there is no evidence of pre-symptomatic transmission of sars, we assume that infectivity begins with the onset of clinical symptoms. hence, the exposed population (compartment e) is composed of non-infectious, asymptomatically infected individuals whereas the infectious population (compartment i) is composed of symptomatically infected individuals, some of which have been diagnosed with sars and are admitted to hospital (superscript h). as death from sars takes place on a similar timescale as recovery, we consider a composite endpoint of persons who have either died or recovered from sars (compartment r). been admitted to hospital, as follows: here, f t denotes the cumulative probability that an infected person becomes symptomatic at or before day t of infection; g t denotes the cumulative probability that a symptomatic person recovers or dies at or before day t of disease; and h t denotes the probability that a symptomatic person is admitted to hospital at or before day t of disease. with b t we denote the expected number of secondary infections at day t since onset of clinical symptoms. it is the product of the infectivity of an infected individual and the daily number of close contacts with susceptible persons. for simulation purposes, we assume that the number of secondary infections follows a poisson distribution with expectation b t . hospitalization results in a transmission rate reduction, such that the number of secondary infections follows a poisson distribution with expectation cb t with co1. let h t denote the unconditional probability that a person is admitted to hospital at day t of disease. let u t;k be the probability that a person admitted to hospital at day t of disease is not discharged at or before day t þ k. we assume that discharge only occurs after a person has been admitted to hospital, hence g t ph t . the probability that a person is not discharged at or before day t þ k, conditional on being admitted to hospital at day t, is the reproduction number of an infectious disease is defined as the expected number of secondary cases generated by an index case. assuming that transmission before onset of clinical symptoms does not occur, the reproduction number can be formulated as we assume that f t and g t are both determined by the biological features of the virus and the human host. in contrast, h t and b t will change through adaptive behavior, although the extent to which these can be manipulated is limited by infrastructural and behavioral constraints. given functions for the distribution of onset-to-admission time and transmission rate before the implementation of public health measures, we define the basic reproduction number r 0 as the average number of secondary cases before intervention is in place. general control measures are those not specifically aimed at sars coronavirus infection per se. in this paper, we focus on transmission rate reduction following hospitalization (lowering c) and shortening the time from onset of disease to hospital admission (altering h t ). contact rate reduction in the general population, also known as social distancing, will affect the expected number of secondary infections for any day prior to hospitalization (altering b t ). administration of antibodies can be considered in two ways. pre-exposure prophylaxis is aimed at preventing infection, whereas post-exposure prophylaxis to persons already infected may prevent clinical symptoms and block further transmission. to this end, we define v t as the probability that a contact of a person who transmitted infection at day t of disease will be supplied with antibodies before development of symptomatic disease. let w t;k denote the conditional probability that a person who transmitted infection at day t of disease is hospitalized at day t þ k, then we can write here, p denotes the traceable fraction of an index case's contacts, where we adopted a fixed duration of r days for a contact to be traced. if transmission occurs within the hospital, w t;0 ¼ 1 and the expression reduces to else, w t;k should be evaluated conditional on the probability of not being admitted to hospital before day t. hence, if we assume that contact tracing with post-exposure prophylaxis will be performed once pre-exposure prophylaxis has brought hospital-based transmission to an end, then the expected number of secondary cases generated by an index case reduces to we define the critical immunization coverage as the minimal fraction p of contacts traced within r days to be immunized in order to reduce r below one given a particular r 0 . model parameters and their baseline values are listed in table 1 . f t has been fitted to a gamma distribution with mean 4.6 days and variance 15.9 days 2 . 16 g t was obtained by fitting a weibull distribution to the times from symptom onset to either death or recovery. using percentage survival minus discharge from hospital as reported for three age categories, 16 we obtained a mean duration of 24.3 days. taken together, the total time spent in compartments e and i thus averages 1 month. the expected number of secondary infections at day t since onset of clinical symptoms was assumed to obey the functional form: this form is suggested by the observation that viral load in pharyngeal secretions peaks in the second week after onset of clinical symptoms and declines thereafter. 17 additional follow-up studies of viral shedding showed that one in four sars patients still tested positive 1 month after symptom onset. 18 by fitting b t to the percentage testing positive over time we obtained an estimate of the parameter a 2 . the product of infectivity and contact rate was subsequently rescaled through a 1 to obtain a given basic reproduction number r 0 . the average number of secondary cases generated by an index case before the issuance of the first global sars alert was approximately 3, but varied substantially over time and between geographic locations. 19 scaling of b t presumes knowledge of h t and c. h t was assumed to follow a gamma distribution, with variance set equal to 1 2 mean 2 . 12 as we obtained most parameters from the literature pertaining to the 2003 sars outbreak in hong kong, we scaled infectiousness conditionally on a mean time from onset of disease to diagnosis of 7.4 days, which was the average interval for hospital admission during the weeks prior to the first global sars alert. 19 in line with initial estimates that hospitalized patients transmitted infection at about 20% of the rate of symptomatic patients in the community, 3 we took a baseline value c ¼ 0:20. an outbreak cannot be contained whenever the expected number of secondary infections generated by an index case exceeds one. the condition for outbreak control can be formulated as here, y is the proportion of secondary infections occurring prior to hospital admission. clearly, an outbreak can only be contained when the average index case has not transmitted infection prior to hospital admission. thus, yro1 is a necessary condition for outbreak control. if this condition is not met, community-based transmission is enough to sustain epidemic growth. the condition yro1 can be met through social distancing or through admission interval reduction. using baseline parameter values, we estimate yr 0 ¼ 2:09, i.e. with a mean admission interval of 7.4 days approximately two out of every three infections occur prior to hospital admission. if social distancing alone was to account for outbreak control, contact rate would have to decline by ðr 0 à 1þ=yr 0 ¼ 96%. shortening the time from onset of disease to hospital admission and thereby decreasing the opportunity for community-based transmission, is more efficient to control the spread of sars. an average admission interval of 4.3 days would bring yr just below one. however, at c ¼ 0:20 the number of secondary infections occurring within hospitals is in itself enough to sustain epidemic growth with an admission interval of 4.3 days (fig. 2a) . hospital transmission rate needs to be less than 15% of communitybased transmission in order to achieve ro1 without having to rely on contact rate reduction in the general population (fig. 2b) . the sars outbreaks in 2003 were characterized by a considerable degree of heterogeneity in the number of secondary cases generated by an index case. 19 epidemic curves were particularly shaped by the occurrence of clusters of exceptionally high transmission, termed ''super-spreading events'' (sses). 3, 18 the extent to which sses affect the reproduction number of infection depends on their relative frequency and magnitude, 3 and these in turn determine the opportunity for outbreak control. we therefore investigated the robustness of control through admission interval reduction and patient isolation procedures in the containment of sars transmission over a range of basic reproduction numbers. reduction of the admission interval is insufficient to contain sars outbreaks with r 0 ¼ 3 at c ¼ 0:20. if patients were already admitted to hospital before onset of clinical symptoms, corresponding to a zero admission interval, an hospital outbreak could be contained if r 0 o2.2 at c ¼ 0.20; if r 0 o4.5 at c ¼ 0.10; or if r 0 o9.0 at c ¼ 0.05 (fig. 2c) . reducing the relative rate of hospital transmission thus 19 y cumulative distribution function in days since infection. 16 z the mean and variance of the distribution are denoted by m and s 2 , respectively. y cumulative distribution function in days since onset of clinical symptoms. 16 z the shape and scale of the distribution are denoted by a and b, respectively. ãã before implementation of control measures. 3 yy the symbol t denotes the time (in days) since onset of clinical symptoms. zz fitted to the percentage sars patients with viral shedding in nasopharyngeal aspirate 17, 18 and subsequently scaled to r 0 . 19 yy applies to model with pre-and/or post-exposure antibody prophylaxis. facilitates control over an extended range of r 0 values, especially for short admission intervals. pre-exposure prophylaxis targeted at susceptible persons coming into contact with hospitalized sars patients could be very effective in reducing hospital transmission. even if prophylaxis would have limited efficacy, the range of reproduction numbers over which outbreak control can be achieved may increase significantly. if patients are already admitted to hospital before onset of clinical symptoms, the range of reproduction numbers that can be contained increases by a factor e 21 , where e denotes the fraction of the target population that remains susceptible in spite of immunization. as an example, if antibody prophylaxis would render three out of four persons non-susceptible to infection, i.e. e ¼ 1 4 , the range of reproduction numbers that can be contained would increase by a factor four (fig. 2c) . the range of reproduction numbers that can be contained with an admission interval greater than zero may also improve significantly through targeted pre-exposure anti-body prophylaxis. if hospital transmission could be blocked completely, the range of r 0 values that can be contained increases steeply with admission interval reduction (fig. 2c) . when general measures (such as patient isolation procedures) are able to reduce hospital transmission rate to c ¼ 0.05, outbreaks can be contained if r 0 o5.0 with a 2-day admission interval. pre-exposure antibody prophylaxis targeted at those coming into contact with hospitalized sars patients could improve the condition for outbreak control to r 0 o6.8 for e ¼ 1 2 and to r 0 o8.4 for e ¼ 1 4 . the critical coverage of an index case's contacts that must be supplied with post-exposure prophylaxis to achieve ro1 increases with r 0 and with the time from onset of disease to hospital admission. for large admission intervals, outbreak control via contact tracing and post-exposure prophylaxis is only possible with relatively low transmissibility. for instance, full coverage with a 5-day admission interval would just suffice to keep an outbreak at bay if r 0 o4.2, assuming no transmission occurs after hospitalization and 1 table 1 ). the dotted line in (a) refers to the condition for containment ro1. in (b), the dotted line refers to the baseline value of c ¼ 0.20. (c) shows how the condition for containment depends on the basic reproduction number, with the dotted line referring to the baseline value r 0 ¼ 3. day is needed for a contact to be traced, i.e. c ¼ 0 and r ¼ 1 (fig. 3a) . with a 2-day admission interval, full coverage could be sufficient to contain an outbreak characterized by r 0 o27. post-exposure prophylaxis generally extends the range of r 0 values that can be contained, but the extent to which control is facilitated depends on the admission interval. the extent to which post-exposure prophylaxis in the community can enhance control is also limited by the time that is required for contact tracing. the range of reproduction numbers that can be contained declines when more days are needed for a contact to be traced. for instance, with p ¼ 0.50 the range of reproduction numbers that can be contained with a 2-day admission interval reduces from r 0 o15.3 to r 0 o13.2 if contact tracing takes 3 days instead of one (fig. 3b) . ongoing hospital transmission effectively reduces the range over which control can be achieved, especially for less effective contact tracing (fig. 3c) . antibody prophylaxis may be employed to achieve ro1 if this has not been achieved already through admission interval reduction and patient isolation procedures. antibody prophylaxis might also be employed to reduce r below one. the size and duration of an outbreak become increasingly restricted as r approaches zero. as the number of secondary infections follows a poisson distribution, the probability of an index case not transmitting infection is exp{-r}. the distribution of the size of an outbreak x generated from n initial cases is of the form 20 : this distribution is appropriately defined for xxn and ro1. when r is reduced by a factor j then the probability that no transmission occurs from n initial cases increases by a factor expfð12jþnrg. on the other hand, the probability that an outbreak generated from n initial cases attains a final size x4n decreases by a factor j x2n expfð12jþxrg. from this it can be inferred that the expectation of the size of an outbreak diminishes as r approaches zero. the benefit of antibody prophylaxis in reducing r below one was verified by stochastic simulation. estimates of outbreak size and duration are based on a thousand model runs, each seeded with n ¼ 10 initial cases and r 0 ¼ 3. in simulations, the average time from onset of disease to hospitalization is assumed to decline from the baseline value of 7.4 to 3 days once the first couple of sars patients have been identified. hospital transmission rate is set at 5% of community-based transmission. these measures figure 3 critical vaccination coverage for containment of sars transmission as a function of the basic reproduction number r 0 and the time from onset of disease to hospital admission. in (a) and (b), it is assumed that hospital-based transmission is effectively blocked, i.e. c ¼ 0. the duration of contact tracing for post-exposure prophylaxis is set at r ¼ 1 day in (a) and at r ¼ 3 days in (b). in (c), the duration of contact tracing is set at r ¼ 1 day, but hospital-based transmission is assumed to continue at 5% of the rate of community-based transmission, i.e. c ¼ 0.05. yield r ¼ 0.87, hence they are in principle enough to contain an outbreak. to investigate the additional benefit of antibody prophylaxis, we compare this baseline model to a model with pre-exposure prophylaxis, given to all persons who come into contact with hospitalized sars patients, and to a model with both pre-and post-exposure prophylaxis, given to a fraction of persons contacted prior to hospital admission. in the latter model, it is assumed that 50% of contacts can be traced within 2 days of an index case's hospital admission. an outbreak may take considerable time to subside if public health measures result in r ¼ 0.87 (fig. 4a) . the total size of an outbreak expected from n ¼ 10 initial cases is 109 (sd 97), while it takes on average 176 (sd 90) days until the last patient is discharged from hospital. pre-exposure prophylaxis, given to all persons who come into contact with hospitalized sars patients, results in r ¼ 0.56 (fig. 4b) . the impact of this reduction in the reproduction number is readily apparent, with outbreak size and duration decreasing to 33 (sd 16) cases and 75 (sd 19) days, respectively. adding post-exposure prophylaxis with p ¼ 0.50 and r ¼ 2 days to the spectrum of control measures further reduces the reproduction number to r ¼ 0.44 (fig. 4c) . accordingly, the expected size of the outbreak is decreased to 26 (sd 11) cases and the time until the last patients is discharged from hospital is decreased to 68 (sd 15) days. the normal variation on a double logarithmic scale implies highly skewed distributions for both outbreak size and duration. indeed, large-scale outbreaks represent a significant proportion of outcomes with r ¼ 0.87. the 95th percentiles for outbreak size and duration are 295 cases and 346 days, respectively (fig 4a) . large outbreaks are still possible, yet they become less likely, at lower reproduction numbers. the 95th percentile of outbreak size is 66 cases with r ¼ 0.56 (fig. 4b ) and 47 cases with r ¼ 0.44 (fig. 4c) . further reductions may be achieved through faster and more effective contact tracing or through admission interval reduction. with a 2-day interval for hospital admission and 1 day for contact tracing, r ¼ 0.20 and the 95th percentiles of outbreak size and duration are 31 cases and 77 days, respectively (fig. 4d ). in this paper we present a generic model for the initial stage of a sars epidemic and evaluate the effect of different infection control measures on the reproduction number r, defined as the number of secondary cases generated by an index case. specifically, we studied how targeted administration of prophylactic antibodies might supplement stringent patient isolation procedures in a future sars outbreak. mathematic analysis and numeric simulation demonstrate that the addition of antibody prophylaxis to control measures generally allows for containment of higher r 0 values and restricts both the size and duration of an outbreak. our model differs from most published mathematical sars models, 3, 4, [21] [22] [23] in that we allow for non-constant infectivity over the course of infection. there is strong evidence that viral shedding slowly increases over the course of infection and reaches a peak in the second week after onset of clinical symptoms, 17, 18 suggesting that the assumption of a constant infectivity does not hold. analysis of a model using non-constant infectivity revealed that control of sars through patient isolation was mainly established due to the relatively late infectivity peak during infection. 12 hence, failure to capture this aspect in the transmission dynamics of sars could have led to misleading conclusions. our approach differs from other mathematical sars models where non-constant infectivity was used, 12, 24 in that we explicitly allow for an asymptomatic period of infection during which transmission does not occur. hence, our model cannot be classified an ''age of infection'' model because infectivity depends on the time since onset of clinical symptoms rather than the time since infection. an ''age of infection'' model would allow transmission to occur before onset of clinical symptoms, a supposition that is-in the case of sars-not supported by data. however, our conclusions would not alter if we allowed for the possibility of pre-symptomatic transmission given that infectivity in the early stages of infection would be typically low. 17, 18 finally, our model is parameterized through empirically defined waiting times. it has recently been demonstrated that ignoring the latent period of infection or making the common approximation of exponentially distributed waiting times gives rise to overtly optimistic predictions for the outcome of control strategies. 25 although we have made simplifications in other aspects, notably the assumption of a constant pool of susceptible individuals, we feel that the model accurately describes the initial stage of an epidemic. it has been pointed out before that patient isolation can in principle contain an outbreak of sars, provided that the time from onset to admission is short. 12 the contribution of other measures in the control of the 2003 sars epidemic, e.g. quarantine of exposed individuals and widespread use of facemasks, is debatable. a modeling study aimed at simulating the potential response to sars in japan concluded that quarantine of the exposed population would be one of the most effective policy procedures. 21 it has even been suggested that, despite the considerable costs involved, quarantine measures in canada have not only saved lives but also costs. 23 this impact of quarantine is remarkable given the lack of pre-symptomatic transmission of sars. within our modeling framework, the benefit of quarantining exposed individuals can only be interpreted in terms of admission interval reduction and contact rate reduction for any day prior to hospitalization. our results are in line with the finding that personal protection measures in the general population (such as the use of facemasks) offer little protection to the community. 26 we also demonstrate that patient isolation procedures alone will not prevent a sars epidemic if the transmission rates are only slightly increased compared to the outbreaks in 2003, unless additional measures-such as contact tracing -are put in place. these findings are reminiscent of modeling results obtained for smallpox control. 12, 26, 27 if new variants of sars coronavirus do initiate another epidemic, the question is to what extent they will resemble the etiologic agent of the first outbreak. the 2003 sars epidemic was characterized by a high degree of heterogeneity in the number of secondary cases generated by an index case. 3, 18 whether this heterogeneity represents variability in viral biology or host behavior is unclear, but the available data suggests that sars can be highly contagious. as the etiologic agent of sars continues to circulate in natural host species it may evolve into a more transmissible strain. 10, 11 to maximize the opportunity of containment of potentially more transmissible sars coronavirus variants, and to minimize the size and duration of an outbreak, existing control strategies should be supplemented with specific antiviral strategies. passive immunization would seem appropriate in a contingency situation, as it can provide a person with instant albeit short-lived protection against infection and could also be used as a post-exposure prophylaxis to prevent disease progression. in rabies, passive immunization is commonly used in combination with vaccination to prevent rabiesexposed individuals from becoming symptomatic. 28 community-wide containment of infectious disease outbreaks by means of antibody prophylaxis has only been described in a number of cases. in the late 1980s, an outbreak of hepatitis a in a religious community provided an opportunity to assess the impact of immune globulin on the course of the outbreak. 29 here, the incidence of hepatitis among immune globulin recipients stopped 2 weeks after a 5-day campaign of mass administration. 29 passive immunization using polyclonal sera has also been reported to prevent infection with respiratory viruses. 30 we have previously characterized monoclonal antibodies directed against the spike glycoprotein of sars coronavirus, 13 which were highly effective when tested in ferrets. 14 results from pre-clinical development demonstrate that a combination of two monoclonal antibodies against sars acts synergistically, 31 hinting at the prospect of an antibody cocktail as a feasible and efficient prophylaxis. the monoclonal antibody cocktail is targeted at two distinct epitopes on the receptor-binding domain of the spike glycoprotein, one of which recognizes the residue that was critical for adaptation to human transmission. 8, 13, 31 evolution towards human transmission of novel sars-like coronaviruses would likely require the same adaptation, thus preserving the neutralization potential of the antibody cocktail in case a new sars outbreak occurs. the extent to which antibody prophylaxis may enhance sars outbreak control measures hinges on the transmissibility of the disease and on the effectiveness with which general infection control measures are introduced. a comprehensive contingency plan for controlling future sars outbreaks should aim to maximize the range of r 0 values that can be contained, and to minimize the size and duration of an outbreak. our analysis demonstrates that antibody prophylaxis would be an effective addendum to the array of existing public health measures to control sars. world health organization. consensus document on the epidemiology of severe acute respiratory syndrome (sars) geneva: department of communicable disease surveillance and response, who epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions transmission dynamics and control of severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome koch's postulates fulfilled for sars virus adaptation of sars coronavirus to humans structure of sars coronavirus spike receptor-binding domain complexed with receptor cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human identification of a novel coronavirus in bats severe acute respiratory syndrome coronavirus-like virus in chinese horseshoe bats factors that make an infectious disease outbreak controllable molecular and biological characterization of human monoclonal antibodies binding to the spike and nucleocapsid proteins of severe acute respiratory syndrome coronavirus human monoclonal antibody as prophylaxis for sars coronavirus infection in ferrets infectious diseases of humans: dynamics and control the epidemiology of severe acute respiratory syndrome in the hong kong epidemic: an analysis of all 1755 patients clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study epidemiology, transmission dynamics and control of sars: the 2002-2003 epidemic different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures branching process models for surveillance of infectious diseases controlled by mass vaccination ming tang i. modelling potential responses to severe acute respiratory syndrome in japan: the role of initial attack size, precaution, and quarantine network theory and sars: predicting outbreak diversity the economic impact of quarantine: sars in toronto as a case study the kermack-mckendrick epidemic model revisited appropriate models for the management of infectious diseases modeling control strategies of respiratory pathogens ring vaccination and smallpox control clinical practice. prophylaxis against rabies a community-wide outbreak of hepatitis a in a religious community: impact of mass administration of immune globulin centers for disease control and prevention. prevention of varicella: recommendations of the advisory committee on immunization practices (acip). mmwr recomm human monoclonal antibody combination against sars coronavirus: synergy and coverage of escape mutants key: cord-266313-b518n9dx authors: cao, yu-chen; deng, qi-xin; dai, shi-xue title: remdesivir for severe acute respiratory syndrome coronavirus 2 causing covid-19: an evaluation of the evidence date: 2020-04-02 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101647 sha: doc_id: 266313 cord_uid: b518n9dx the novel coronavirus infection that initially found at the end of 2019 has attracted great attention. so far, the number of infectious cases has increased globally to more than 100 thousand and the outbreak has been defined as a pandemic situation, but there are still no “specific drug” available. relevant reports have pointed out the novel coronavirus has 80% homology with sars. in the difficulty where new synthesized drug cannot be applied immediately to patients, “conventional drug in new use” becomes a feasible solution. the first medication experience of the recovered patients in the us has led remdesivir to be the “specific drug”. china has also taken immediate action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics for corona virus disease 2019 (covid-19). we started from the structure, immunogenicity, and pathogenesis of coronavirus infections of the novel coronavirus. further, we analyzed the pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting experiments on covid-19. the novel coronavirus 2019 (2019-ncov), officially named severe acute respiratory syndrome coronavirus 2 (sars-cov-2), is a newlyemerged human infectious coronavirus. since december 2019, it has spread rapidly in china in a short period of time. as of march 17, 2020, there have been 81116 confirmed cases and 3231 deaths. it has also outbreak in other countries, such as korea, japan, italy, singapore, and iran, with a total of 85296 cases confirmed. due to it is a newlyemerged virus, researchers have taken quick actions to isolate the virus and perform gene sequencing, making identifying treatments possible. even so, it takes time to develop new drugs and vaccines, as well as to explore biotherapeutics, thus it is unlikely to be applied to patients with urgent need. therefore, "conventional drug in new use" becomes a viable solution. the sars-cov-2 is 80% homologous with the acute respiratory syndrome-associated coronavirus (sars-cov), which also broke out in china in 2002, and some enzymes are even more than 90% homologous [1] . consequently, we are expecting to find drugs for the treatment of covid-19 from the experience of sars-cov and middle east respiratory syndrome (mers-cov). some drugs, such as ribavirin, interferon, lopinavir, and corticosteroids, have been used in patients with sars or mers [2] , within the selection range of "conventional drug in new use". through clinical treatment of the covid19 , it has been found that neuraminidase inhibitors (oseltamivir, peramivir, zanamivir), ganciclovir, acyclovir, ribavirin are ineffectual and not recommended for clinical application [3] . when we set our sights on the broad-spectrum antiviral drugs, we found that a drug unlisted, remdesivir, has demonstrated strength in trials related to mers-cov and ebola virus infection. in the united states, the first patient with covid-19 has shown significant improvement in clinical symptoms within 24 h of treatment with remdesivir. this case has convinced the public that remdesivir could become a new "specific drug" for covid-19. this article starts from the structure, immunogenicity, and pathogenesis of infection of the sars-cov-2, and then analyzes the feasibility of conducting trials and putting into clinical use of covid-19 from the pharmacological characteristics and successful cases of remdesivir. different from sars-cov and mers-cov, and becomes the seventh member of the coronavirus family to infect humans [4] . sars-cov-2 shows the typical beta coronavirus organization: 5′ untranslated region (utr), replication enzyme coding region, s gene, e gene, m gene, n gene, 3' utr, and several unidentified nonstructural open reading frames ( fig. 1 ) [4] . the replication enzyme coding region mainly expresses and encodes two large genes: orf1a and orf1b, which encode 16 nonstructural proteins (nsp1~nsp16) that are highly conserved throughout the coronavirus. s gene, m gene, e gene, and n gene respectively encode four main structural proteins: spike (s), membrane (m), envelope (e), and nucleocapsid (n) proteins. the s protein is the receptor binding site, which is on the viral surface; the m protein shapes the virions, promotes membrane curvature, and is responsible for the transport of nutrients across cell membranes; the e protein plays a role in the assembly and release of virus, and is involved in viral pathogenesis; the n protein can bind virus rna genome and maintain its stability [5] . among them, s protein plays a key role in virus recognizing and binding to host cell surface receptors, and mediating the fusion of virus envelope and cell membrane [6] . through the analysis of the whole genome sequence of sars-cov-2, it shares 40% sequence similarity with mers-cov and 80% sequence similarity with sars-cov, indicating that sars-cov-2 is more compatible with sars-cov [7] . in addition, by performing systematic structural simulations and immunogenicity scans of the s proteins of all coronaviruses, as well as calculating the immunogenic distance between sars-cov-2 and other coronavirus subtypes, it can be concluded that the immunogenicity of the s protein of sars-cov-2 is closer to that of sars-cov [8] . it is known that sars-cov enters target cells by binding the s protein to the ace2 receptor on the cell surface, which is triggered by the cell serine protease tmprss2 [9] . in view of the 76% amino acid similarity between sars-cov-2 and sars-cov [10] , we can speculate that the novel coronavirus may have a similar function to sars-cov, which has been preliminary proved in bioinformatics prediction methods as well as in vitro tests [9] . previous studies have shown that 4 of the 5 key amino acids of the s protein on the surface of sars-cov-2 that binds to angiotensin-converting enzyme 2 (ace2) receptor on the target cells have changed. it was suspected it may affect the affinity of the s protein to ace2 receptor, and in turn affect the spread of the virus among the public [10] . however, through calculation methods of molecular structure simulation, the interaction between the s protein of sars-cov and the ace2 receptor has perfectly maintained in a holistic manner [11] . at present, it has been proved that the binding affinity between the extracellular domain of the s protein of sars-cov-2 and ace2 receptors is about 10-20 times higher than that of sars-cov, which may facilitate human-to-human transmission of sars-cov-2 [12] . covid-19 is a respiratory syndrome caused by sars-cov-2 infection. in general, covid-19 is an acute resolved disease, and the most common symptoms at onset are fever, dry cough, and fatigue, partly with nausea, diarrhea, or other gastrointestinal symptoms. compared with sars and mers, covid-19 has milder clinical symptoms and lower fatality [13, 14] , but it can also be fatal. severe patients may develop diffuse alveolar injury, progressive respiratory failure, and acute respiratory distress syndrome (ards) and so on. similar to sars-cov, the receptor binding domain (rbd) of s protein on the surface of sars-cov-2 binds to the ace2 receptor on the cell surface to facilitate the virus entering the host cell; then the virus exposes its rna, translates its rna replicase, and forms an rna replicase-transcriptase complex. through transcription and replication, the complex forms rna negative strands that will be translated for the structural proteins of the virus later. then the structural proteins and rna in the cytoplasm assemble into new viral particles, which are released from infected cells by exocytosis to infect other cells (fig. 2 ). each infected cell produces thousands of novel viral particles that spread to bronchi, eventually reach the alveoli, and extrapulmonary organs, causing pneumonia and targeted organic infections. however, the ace2 receptor is not only expressed in the respiratory organs. it has been reported that, by using the rna-seq method to express ace2 receptors in human tissues, the number of ace2 receptors expressed in the gastrointestinal tract (high in esophagus, small intestine, and colon, but low in stomach), kidneys, and testes is nearly 100 times higher than that in the lung [15] , suggesting that these tissues may also be the target organs for sars-cov-2 invasion. it may explain why some patients with covid-19 developed other system injuries clinically besides respiratory system injuries. furthermore, it have been found that sars-cov-2 nucleic acid detection is positive in the feces of some patients, indicating that there may be live virus in the feces, and the digestive system may be a potential route for covid-19 [16] . in covid-19, in addition to the direct damages caused by the virus, the indirect immune injuries caused by the injured tissues also attract great concern, which may be related to the severity and fatality of the disease. previous studies have shown that pulmonary inflammation and extensive lung injury in patients with sars are associated with an increase in proinflammatory cytokines (such as il-1β, il-6, il-12, ifn-γ, ip-10, and mcp-1) in serum [17] . and it has been reported that the mers-cov infection induced elevated proinflammatory cytokine concentrations (such as ifn-γ, tnf-α, il-15, and il-17) in serum [18] . we note that patients with covid-19 also have high levels of il-1β, ifn-γ, ip-10, and mcp-1 in their serum, leading to activation of the th1 cell responses. furthermore, the concentrations of gcsf, ip-10, mcp-1, mip-1a, and tnf-α in icu patients were higher than those in non-icu patients, indicating that cytokine storms were associated with disease severity. apart from this, sars-cov-2 infection also activates the secretion of cytokines (such as il-4 and il-10) in th2 cell responses that suppress inflammation, which is different from sars-cov infection [17] . further researches are needed to investigate the responses of th1 and th2 in sars-cov-2 infection to elucidate the pathogenesis of currently, the pathogenesis of covid-19 is unclear. the first pathologic autopsy of a patient with covid-19 demonstrated that the lungs of the patient reviews diffuse alveolar injury and pulmonary hyaline membrane formation, consistent with ards. the overall pathological manifestations of the lungs were similar to sars and mers. flow cytometry signified that the number of cd4 + and cd8 + t lymphocytes in peripheral blood was greatly reduced, but their state was overactivated. other than this, ccr4 + and ccr6 + th17 lymphocytes with highly proinflammatory effects increased in cd4 + t lymphocytes; cd8 + t lymphocytes had a high concentration of cytotoxic granules, of which 31.6% were perforin positive, 64.2% were particle lysin positive, and 30.5% were both particle lysin and perforin positive. it manifests that the severe immune injury in this patient may be closely linked to the overactivation of t lymphocytes characterized by the increase of th17 lymphocytes and the high cytotoxicity of cd8 + t lymphocytes [19] . we presume that the failure to develop a full adaptive immune response to covid-19 could be due to: the progression of pneumonia was too rapid to allow the available establishment of adaptive immune responses. likewise, the counts of peripheral cd4 + and cd8 + t lymphocytes were substantially reduced, leading to insufficient immune defenses. furthermore, peripheral t lymphocytes are in an over-activated state, manifested by increase of th17 and high cytotoxicity of cd8 + t lymphocytes, accounting for to a certain degree of immune injury in patients. this over activation not only failed to establish an immune response, but also caused tissue injuries, mostly manifested as severe injury in the lungs, and some patients died of multiple organ failure. this situation further accelerates the deterioration and shortens the course of the disease, hampering the establishment of fully adaptive immune response. the immunopathological injuries caused by the over activation also provides us with an idea for treating covid-19, for example, we can probably apply the il-17 inhibitor (secukinwmab) directed against th17 cell activation, but it still need more exploration. also, vaccines are also one of the solutions to make up for the lack of adaptive immune response. the latest study terms that the changes of viral nucleic acid in patients with covid-19 is similar to that in patients with influenza, but different from those with sars. viral load can be detected not only in symptomatic patients but also in asymptomatic patients, pointing out the potential for virus transmission in asymptomatic or mildly symptomatic patients. these findings are coherent with reports evidencing that the virus transmission may have occurred early in infectious processes, illustrating that case detection and isolation may require a different strategy from that required to control sars-cov [20] . remdesivir (gs-5734) is a nucleoside analogues drug (fig. 3b ) with extensive antiviral activity and effective treatment of lethal ebola and nipah virus infections in nonhuman primates [21] . as an rna-dependent rna polymerase (rdrp) inhibitor, it can inhibit the replication of multiple coronaviruses in respiratory epithelial cells. a recent study reported that remdesivir competes with natural counterpart atp. once remdesivir added into the growing chain (i position), it cannot cause an immediate stop. on the contrary, it will continue to extend three more nucleotides down to stop the strand at (i + 3) position (fig. 2) [22] . in the ces1c (−/−) mouse sars model, the preventive treatment trial of remdesivir achieved satisfactory results. administering 1 day after the onset of the disease, lung virus titers decreased significantly, fig. 2 . sars-cov-2 invasion process and how remdesivir works 1 sars-cov-2 enters target cells by binding the s protein to the ace2 receptor on the cell surface; 2 remdeivir, the nucleotide analogues, act as rdrp inhibitors, can provide a scheme for blocking rna replication; 3once remdesivir added into the growing chain (i position), is cannot cause an immediate stop. on the contrary, it will continue to extend three more nucleotides down to stop the strand at (i + 3) position; 4 remdesivir triphosphate cannot be removed by nsp14-exon. the original structure of the drug is derived from drugbank (https://www.drugbank.ca, accessed feb 25). with improvements on pulmonary function. administering 2 days after the onset, the pulmonary virus titer can be obviously reduced, but the survival rate of mice is still relatively low. this study implied that when the pulmonary injuries reach the maximum, simply reducing the virus titer can no longer suppress the strong immune responses in mice, also showing that administering before the peak of virus replication can significantly improve symptoms of the infected mice [23] . in a rhesus monkey model infected with mers-cov, treating with remdesivir 24 h before infection can completely prevent symptoms caused by mers-cov, strongly inhibit viral replications in the respiratory tract, and prevent the formation of pulmonary lesions. administering remdesivir 12 h after infection provides clear clinical benefits, reducing clinical symptoms, lung virus replication, and lung lesions [24] . pharmacokinetic experiments in cynomolgus monkeys showed the first-pass effect of oral remdesivir resulted in a low bioavailability of the drug. intramuscular injection of 3 mg/kg had a 50% survival rate compared with the control group. administering intravenously at a dose of 10 mg/kg, remdesivir rapidly decomposed into the original drug (nucleoside phosphate) in rhesus monkeys. within 2 h, remdesivir quickly distributed in peripheral blood mononuclear cells (pbmcs), and soon afterwards activated to nucleoside triphosphate to reach a peak, with a survival rate of 100% [25] . as for pharmacokinetic studies in vivo, after the intravenous infusion of the remdesivir solution formulation at a single dose of 3-225 mg for 2 h, it showed dose-linear pharmacokinetics. intravenous infusion of 150 mg of a remdesivir solution repeated 1 h per day showed a linear pharmacokinetics over a period of 14 days. after intravenously injecting 75 and 150 mg of remdesivir solution formulations over 2 h, the pharmacokinetic profile was similar to that of a lyophilized formulation. intravenous infusion of 75 mg of drug over 30 min provides similar levels of parent drug exposure to the same dose over 2 h (table 1) . after the intravenous infusion, remdesivir will enter the cellular metabolism to form active gs-443902 (fig. 3c) , but the frequencies of pbmcs exposure of gs-443902 is higher than those of intravenous infusion of remdesivir 150 mg within 2 h. studies in pbmcs show that the half-life of gs-443902 is more than 35 h [26] . in the case of daily administration, the active substance of the drug gs-443902 will accumulate in vivo. as a result, in large-scale clinical trials, after the first dose of 200 mg is administered, the subsequent dose is adjusted to 100 mg to ensure the proper blood concentration in vivo [27] . intravenous infusions in previously phase i clinical trials have good safety and pharmacokinetic properties. also, no cytotoxicity, hepatorenal toxicity, or no serious adverse reactions related to metering have been observed in climbing experiments. subjects were tolerant in studies that repeated 150 mg intravenously daily for 7-14 days. remdesivir did not show any renal injuries in a multi-dose study [26] . phase ii clinical trials were conducted in ebola virus-infected patients. in clinical trials of anti-ebola drugs, the fatality rate of patients in the experimental group using remdesivir was 53%, and the efficacy was significantly worse than that of the two monoclonal antibodies mab114 (fatality rate 35%) and regn-eb3 (fatality rate 33%) [27] . the 53% fatality rate was not significantly different from the average 50% fatality rate of ebola virus infection, and as a result, phase ii clinical trials were stopped. nevertheless, in consideration of ebola's high lethality and monoclonal antibodies with more obvious therapeutic effects, when there are merely 175 patients injected remdesivir, we cannot assume remdesivir of no avail. the small sample size is not enough to deny the effect of remdesivir. moreover, receptors of ebola virus are widely distributed in vivo, not only to the respiratory tract, but also to the digestive tract, urinary tract, and blood system, etc., causing mortally hemorrhagic fever; in addition, ebola virus persists in the eyes and central nervous system for long [28] . once remdesivir entering body, it will be quickly distributed to the testis, epididymis, eyes, and brain, but relatively less in eyes and brain [29] . all these indicate that the wide range of spread of ebola virus in the high lethality tissues make remdesivir control ebola ineffectively. the wuhan virus research institute conducted in vitro experiments on covid-19 of remdesivir and found that remdesivir was the fastest-acting and most powerful antiviral agent. in the primary culture of human airway epithelial cells in vitro, sars-cov's ic 50 = 0.069 μm, mers-cov's ic 50 = 0.074 μm, and the dose-dependent effect on virus inhibition [2] , which is speculatively related to the fact that remdesivir triphosphate cannot be removed by nsp14-exon [30] . it has been conjectured the loss of function of exonuclease may be involved with the three additional nucleotides added after the incorporation of remdesivir into the extended strand [22] . in vitro and animal models, remdesivir has demonstrated activity against both sars and mers that also belong to coronaviruses, and theoretically provides support its effectiveness in treating covid-19. presently, there have been successful cases of remdesivir in the treating covid-19. the new england journal of medicine reported the entire course of rehabilitation of the first patient with covid-19 in the united states. the patient once visited wuhan but was neither directly exposed to wuhan seafood market nor had direct contact with the diagnosed patients. he returned to washington on january 15, 2020. on 19 january, due to cough and fever for four days, he went to the hospital for emergency treatment, and was then diagnosed with covid-19. his condition was stable from the second to the fifth day of admission (the sixth to ninth day of onset). on the evening of the fifth day of admission, the blood oxygen saturation decreased to 90%. the condition continued to worsen, and chest radiographs on the sixth day of admission (tenth day of onset) showed typical characteristics of covid-19. in view of the continuous aggravation of the patient's clinical symptoms, the physicians gave a chartered medication (compassionate use) to remdesivir on the evening of the 6th day of admission, and began to give intravenous to the patient on the evening of the seventh day of admission (the eleventh day of onset), without adverse reactions. vancomycin was discontinued that night and cefepime was discontinued the following day. on the eighth day of admission (the twelfth day of onset), the patient's clinical symptoms were improved, and the oxygen saturation increased to 94%. although the patient was still hospitalized as of january 30, 2020, all symptoms had been resolved except for cough and occasional running nose [31] . it is worth noting that from the data in the article, it can be found the viral load of patients has decreased before remdesivir injection (table 2) , which is not described in detail in the original report. it's known that the viral infection is self-limiting, and the patient is a mild to moderate infectious case with a controlled fever in time, thus it is possible that his recovery is related to the role of self-defense mechanisms and supportive treatment as well. it cannot be inferred that table 1 drug concentrations in plasma and the concentration of pharmacologically active substances in pbmc in healthy people. the improvement of patients' condition after taking the drug is definitely connected to remdesivir. whether there is a link between the improvement of the symptoms and the drug is worth further consideration. clinical symptoms, especially respiratory symptoms, have been improved significantly within 24 h, bringing hope for the treatment of patients with severe covid-19. for covid-19 no specific medication is available, remdesivir is expected to be a "specific drug". however, for the acute infectious diseases, reducing the number of viral copies in the body is the key point. also, the efficacy of the drug should be focused on the pharmacokinetics and kinetics data of covid-19 in the ongoing phase iii clinical trials. the outbreak of sars-cov-2 in wuhan constituted an epidemic threat in china. the world health organization announced it a public health emergency of international concern on january 30, 2020. during the outbreak, the number of confirmed cases in china showed an exponential growth. the people and the government of the country tried their best to fight the epidemic with soaring combat mood. the nation's enthusiasm to fight the epidemic provides the trials on covid-19 a favorable environment. at the same time, article 23 of china's new drug administration law, which came into effect on december 1, 2019, has enabled the "compassionate use" to develop adaptively in china. two clinical trials on remdesivir have passed the most stringent ethical review of the 74 projects. on february 5, 2020 the trial has officially launched with experimental drugs provided by gilead sciences for free in china by professor chen wang, an academician of chinese academy of engineering, an internationally renowned respiratory expert who successfully suggested chinese government building "fang cang" hospitals to cure more than 10 thousand mild or prepatent covid-19 patients [32] . due to the large number of confirmed cases of covid-19 in china with no effective drugs, it is easy to collect clinical samples for trials theoretically. however, the rigor of the included samples hindered recruitment. as public attach more attention on prevention and treatment, fewer patients meet stringent inclusion criteria, resulting in a slow recruitment process. another reason is that there are plenty of drugs in the clinical trials, speeding up the patients' leaving hospital. nevertheless, it has been reported that more severe patients have been recruited, which provides favorable conditions for the trial of the severe group, and as a result, at least, it can be rapidly applied to the clinical treatment of severe patients in the near future. the need of treatment on covid-19 is urgent, so if the results of clinical trials prove it has the potential to benefit the treatment, according to china's "compassionate use", remdesivir will be more immediately used in patients with severe illness. meanwhile, the opening of green channels under special circumstances to speed up the review and approval process of the drug approval center will undoubtedly help save the lives of critical patients and promote the developing of "specific drugs". in the absence of clinical trial results, it is still difficult to put remdesivir into large scale clinical use [33] . with the political support, the rapid development of clinical trials on remdesivir is imperative. a drug, gs-441524 (compound a, fig. 3a ) for treating feline infectious peritonitis (fip) caused by coronavirus infection in cats has been tested in cats. its safety and effectiveness in treating fip have been proven [34] , with fda's approval. it can be seen from the structure that remdesivir is phosphorylated from gs-441524, with identical target rdrp (fig. 2) . it is noteworthy that though coronavirus reproduces more than 20 generations in gs-441524 yields resistance, the resistant virus is still sensitive to high concentrations of remdesivir and the fitness of the resistant virus has reduced to the same level as wild-type mers-cov [35] , which avoids resistant mutant coronaviruses from producing resistant supervirus. at the beginning of developing remdesivir, gilead science selected a large number of nucleosides or their prodrugs to conduct in vitro growth inhibition experiments on ebola-infected human microvascular endothelial cells in the laboratory and found compound a showed inhibitory activity (ec 50 = 0.78 μm), and the compound a was gs-441524. thereafter, on the basis of compound a, after examining the activity and toxicity of compounds surrounding compound a, modifying the prodrug, and optimizing amino acids and acyl groups, the cynomolgus monkey performs a pharmacokinetic test to select a structure such as gs-5734 (fig. 3b) [25] . although in phase ii it was not as effective as competitive drugs and clinical trials were terminated, remdesivir showed good safety and pharmacokinetics in both phases i and ii clinical trials. covid-19 has once again brought remdesivir to the stage of clinical trials. whether the results of phase iii clinical trial will make its comeback to the stage is worthy of expectation. phase ii clinical trials have demonstrated human tolerance to remdesivir. of the 175 patients in the phase ii clinical trial administering remdesivir, 9 were reported to have serious adverse reactions, 8 of whom were considered not related to drugs, and 1 with severe hypotension was thought to be drug-related, but still not confirmed [27] . the gs-441524, a drug used to treat fip, has shown a high degree of safety in feline trials as well. the focal injection site reactions only showed in immediate pain with vocalization, occasional growling, and postural changes lasting for 30-60s. these initial reactions were relieved after the owners became more adept at administering the injection. except for a cat with a slight increase in urea nitrogen and sdma of the third round of treatment, no other symptoms of systemic poisoning were observed [34] . relevant research signified that through a large number of synthesis and structure-activity analysis, the toxicity was greatly reduced after gs-411524 was synthesized into gs-5734 (remdesivir) [36] . the safety of remdesivir in human is further speculated. coronaviruses must replicate nucleic acids to generate new progeny virus after entering human cells. sars-cov-2 is known to be single stranded rna virus, so rdrp must be used to replicate nucleic acids. remdesivir, a nucleotide analogues, act as rdrp inhibitor, can provide a scheme for blocking rna replication. related studies have found that it plays a role in the final stage of entering the cell, which is consistent with its expected mode of action. wuhan virus research institute carried out a vitro inhibition test and found that remdesivir can block virus infection at very low micromolar concentration of vero e6 cells infected with virus, and the cell selectivity is high (ec 50 = 0.77 μm, cc 50 > 100 μm, si > 129.87) [2] . in an anti-ebola infection experiment on cynomolgus monkeys, intravenous injection of 10 mg/kg of remdesivir, the drug can exist in the blood for a long time and can inhibit to ebola virus with a percentage of 100 [25] . wuhan virus research institute's research that applied remdesivir to vero e6 cells with an ec 90 = 1.76 μμ, lower than that of the monkey model, draw to a speculation that it could also play a role in sars-cov-2 infected monkeys. based on the effectiveness in previous researches, although there are many unknowns and limits of remdesivir, the phase iii clinical trials on sars-cov-2 are not only a fight against this epidemic, but also of strategic importance to reserve more effective antiviral drugs for the future. strategic reservation for antiviral drugs will avoid the difficulty of medicine unavailable when an outbreak comes again. remdesivir's situational and political superiority, as well as its previous research results and application effects make it imperative to carry out the clinical trials focusing on the sars-cov-2. given that sars-cov-2 is an rna virus that is easy to mutate, the rapid starting of clinical trials is undoubtedly a right choice to prevent the resistance mutation due to blind medication. it has been covered in the world health organization (who) director-general's opening remarks at the media briefing on covid-19 on february 20, 2020 that the two clinical trials on remdesivir of therapeutics prioritized by the who r&d blueprint are y.-c. cao, et al. travel medicine and infectious disease xxx (xxxx) xxxx expected preliminary results in three weeks. on february 24, the who cast a vote of confidence for gilead sciences' experimental antiviral drug, remdesivir, indicating that remdesivir has great potential and may be the best candidate for the treatment of covid-19. whatever the progress of the clinical trials is, we are expecting that the clinical trials of remdesivir, a starring 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4-aza-7,9-dideazaadenosine c-nucleosides travel medicine and infectious disease xxx (xxxx) xxxx key: cord-275605-mbiojk39 authors: benkouiten, samir; al-tawfiq, jaffar a.; memish, ziad a.; albarrak, ali; gautret, philippe title: clinical respiratory infections and pneumonia during the hajj pilgrimage: a systematic review date: 2018-12-04 journal: travel med infect dis doi: 10.1016/j.tmaid.2018.12.002 sha: doc_id: 275605 cord_uid: mbiojk39 background: the islamic hajj pilgrimage to mecca is one of the world's largest annual mass gatherings. inevitable overcrowding during the pilgrims' stay greatly increases the risk of acquiring and spreading infectious diseases, especially respiratory diseases. method: the medline/pubmed and scopus databases were searched for all relevant papers published prior to february 2018 that evaluated the prevalence of clinical symptoms of respiratory infections, including pneumonia, among hajj pilgrims, as well as their influenza and pneumococcal vaccination status. results: a total of 61 papers were included in the review. both cohortand hospital-based studies provide complementary data, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during the hajj. respiratory symptoms have been common among hajj pilgrims over the last 15 years. in cohorts of pilgrims, cough ranged from 1.9% to 91.5%. however, the prevalence rates of the most common symptoms (cough, sore throat, and subjective fever) of influenza-like illness (ili) varied widely across the included studies. these studies have shown variable results, with overall rates of ili ranging from 8% to 78.2%. these differences might result from differences in study design, study period, and rates of vaccination against seasonal influenza that ranged from 1.1% to 100% among study participants. moreover, the definition of ili was inconsistent across studies. in hospitalized hajj pilgrims, the prevalence of pneumonia, that remains a major concern in critically ill patients, ranged from 0.2% to 54.8%. conclusions: large multinational follow-up studies are recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. matched cohorts ensure better comparability across studies. however, study design and data collection procedures should be standardized to facilitate reporting and to achieve comparability between studies. furthermore, the definition of ili, and of most common symptoms used to define respiratory infections (e.g., upper respiratory tract infection), need to be precisely defined and consistently used. future studies need to address potential effect of influenza and pneumococcal vaccine in the context of the hajj pilgrimage. ksa for several weeks throughout the month-long hajj season, presenting a major public health and infection control concern, and a challenge both for the saudi authorities, as well as for the national authorities of the countries of origin of the pilgrims. in addition to physical exhaustion, sleep deprivation [3] , and heat stress [4] , inevitable overcrowding, both in housing and ritual sites, especially in mina encampment (this is approximately a 3-kilometer square area where pilgrims are accommodated in air-conditioned semi-permanent tents, some with up to 50-100 people) and inside the sacred mosque in mecca (with up to six pilgrims per square meter) [5] , greatly increases the risk of acquiring and spreading infectious diseases [6] [7] [8] , especially respiratory diseases [9, 10] . to minimize the spread of infections during the pilgrimage or in the pilgrims' home countries upon their return, vaccination and non-pharmaceutical interventions are thus recommended by national and international public health agencies [11, 12] . we carried out a systematic review of cohort and hospital studies that reported the prevalence of clinical symptoms of respiratory infections and pneumonia among pilgrims during the hajj, and both their influenza and pneumococcal vaccination status, with the aim to provide data allowing the investigation of the impact of this large mass-gathering event on public health policies and services and to identify potential targets for preventive measures. this review was performed according to preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines (http://www.prismastatement.org). the medline/pubmed and scopus databases were searched for all relevant papers published prior to february 2018, using the terms: in addition, the saudi epidemiology bulletin (http://seb. drupalgardens.com/) was hand searched for additional papers for inclusion. finally, the reference lists of reviewed articles were searched for additional relevant papers. for inclusion, the article had to meet the following criteria: (1) original study involving hajj pilgrims; (2) detailed description of the study population, including influenza and pneumococcal vaccination status when available; (3) clinical or self-reported respiratory symptoms and diseases. only articles published in english were included for review. we excluded cohort studies with less than 50 participants and case reports. we also excluded studies conducted among selected groups of individuals suffering from respiratory tract infections, due to lacking denominator data. the two authors independently performed the searches, screened titles/abstracts for eligibility, selected papers that appeared to be relevant according to the review's inclusion criteria, and reviewed each of the selected manuscripts in full. the data were extracted from the included papers by one reviewer (sb) and collected in the summary table that was included in the review. the extracted data were checked by the two authors (sb and pg) for accuracy. minor discrepancies were resolved by the authors' discussion. the search strategy initially yielded 391 records, of which 143 were duplicates. twenty-nine additional papers were identified through manual searches. of the 277 papers identified 183 records were excluded after screening the title and abstract. of the 94 full text articles reviewed, 61 were deemed suitable for inclusion in this review influenza-like illness (ili) was defined according to the presence of the triad of cough, subjective fever and sore throat. c ili was defined as subjective (or proven) fever plus one respiratory symptom (e.g. dry or productive cough, runny nose, sore throat, shortness of breath). d ili was defined as subjective (or proven) fever and at least one respiratory symptom such as cough, sore throat and rhinorrhea. e ili was defined as symptoms and signs such as: sudden headache, dry cough, high grade fever, myalgia, coryza, malaise and loss of appetite with an abnormal general appearance. f upper respiratory tract infections (urti) was defined as any person who reported having developed at least one of the constitutional symptoms (fever, headache, myalgia) and one of the local symptoms (running nose, sneezing, throat pain, cough with/or without sputum) after reaching mecca for the hajj or within 2 weeks from return to riyadh. g acute febrile respiratory infection (afri) was defined as the presence of subjective fever plus at least one respiratory symptom (cough, sore throat, runny nose or breathlessness). h two travelers who reported ''bronchitis'' as a symptom were also included. i ili was defined as fever plus sore throat and/or coughing. j common cold was defined as sore throat with coryzal symptoms, and low grade fever. k ili was defined as fever > 38.5°c, myalgia, low back pain, coryzal symptoms and cough. l acute respiratory infection (ari) was defined as one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (running nose, sneezing, throat pain, cough with/without sputum, difficulty breathing). m ari was defined as any person suffering from at least one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (runny nose, sneezing, throat pain, cough with/without sputum, difficulty in breathing) developing after reaching makkah for the hajj. n ili was defined as cough and fever > 38°c with or without the coryzal symptoms and myalgia. o ari was defined as any person suffering from at least one of the constitutional symptoms (fever, headache, myalgia) along with one of the local symptoms (runny nose, sneezing, throat pain, cough with/without sputum, difficulty in breathing) developing after reaching mecca for the hajj. p ili was defined as sore throat with either temperature ≥38.8°c or cough. q cough or sore throat or rhinorrhea or muscle ache or headache. according to the inclusion/exclusion criteria. the results of the search strategy are shown in fig. 1 . a total of 45 publications were identified. these studies were conducted among cohorts of pilgrims from the 1999 through the 2015 hajj seasons. the results of these studies are presented in table 1 . various study designs were used, including cross-sectional studies, case-control studies, and prospective cohort studies with follow-up of pilgrims, before, during and after the hajj. participants were from different countries and continents (africa, north america, asia, europe, as well as from australia), with the majority from iran, and they were recruited from different settings, including travel medicine clinics, vaccination centers, hajj travel agencies, international airports and transit zones, mecca's city and mina encampments. their numbers varied widely in these studies, ranging from 106 to 107,074. respiratory symptoms were common during the hajj. overall, the prevalence of cough ranged from 1.9% in domestic and international pilgrims in 1999 [13] to 91.5% in malaysian pilgrims in 2007 [14, 15] ( table 3) . more recent studies, conducted in different populations of pilgrims during the 2011-2014 hajj seasons, reported prevalence of cough ranging from 46.3% to 86.8% [16] [17] [18] [19] [20] [21] [22] [23] [24] . these studies also reported a comparable prevalence of sore throat ranging from 34.7% to 91% among pilgrims [16] [17] [18] [19] [20] [21] [22] [23] . in addition, many of these studies have investigated the epidemiology of respiratory tract infections among pilgrims by estimating the common prevalence of upper respiratory tract infection (urti), acute respiratory infection (ari) or influenza-like illness (ili), which were inconsistently defined across studies by a combination of general symptoms (e.g. cough, sore throat and fever). overall prevalence of ili varied in these studies from 8% to 78.2% [14] [15] [16] [18] [19] [20] [21] [22] [23] ( [47, 48] . however, the ili syndromic case definition used in the 2003-2004 study (ili was defined as cough and fever of more than 38°c with or without the coryzal symptoms and myalgia) [41, 42] was different with that used in the 2004-2008 study (ili was defined as symptoms and signs such as sudden headache, dry cough, high grade fever, myalgia, coryza, malaise and loss of appetite with an abnormal general appearance) [47, 48] . also, it is unclear from the 2005 study [46] if the definition used was consistent with those used in the two previous studies [41, 42, 47, 48] . in a recent large study, conducted among 3364 egyptian pilgrims between 2012 and 2015, the prevalence of ili was 30.4% (ili was defined according to the world health organization definition as the presence of measured fever of ≥38 c°, and cough; with onset within the last 10 days) [45] . other studies of different sizes (from 129 to 468) and design were conducted from 2007 through 2014 among different populations of pilgrims using a common ili definition (the association of cough, sore throat, and subjective fever). these studies have shown variable results, with overall rates of ili ranging from 8% to 78.2% [14] [15] [16] 18, 19, [21] [22] [23] 25, 26, 31, 35, 37] . thus, during the 2013 hajj season, while the highest prevalence of ili was observed among malaysian pilgrims, with a prevalence estimated at 78.2% [25] , a lower prevalence was observed among french pilgrims (47.3%) [18, 21] . coverage of seasonal influenza vaccination among pilgrims was evaluated in many studies, which have yielded varying results, with reported rates of influenza vaccination ranged from 1.1% to 100% [14, 15, 18, [21] [22] [23] 25, 26, 28, 29, [31] [32] [33] [34] 36, 37, [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [53] [54] [55] [56] . a variation over time in influenza vaccination coverage was observed, as exemplified by a rate of 10.5% observed in a survey of pilgrims from riyadh in 2003 [43] , but 94.4% in a similar survey in 2010 [32, 33, 36] . during the 2013 hajj season, influenza vaccination rates also varied according to pilgrims' country of origin [29] , with 20% observed among saudi pilgrims, 80% among qatari pilgrims, and 87% among australian pilgrims, while a study involving french pilgrims interestingly reported that none of them had received the 2013 influenza vaccine before departing for the hajj because the vaccine was not available at this time [18, 21] . the majority of the studies reported influenza vaccination coverage among pilgrims, but only 13 [18, 19, [21] [22] [23] 25, 27, 28, 31, [46] [47] [48] 55] reported their pneumococcal vaccination status, with rates ranging from 1.2% among a multinational cohort of 1676 pilgrims from 13 countries (from africa, asia, usa and europe) in 2013 [28] to 51.2% among a small study of 129 french pilgrims in 2013 [18, 21] . of the 61 publications that were included in this review, 16 specifically addressed ill hajj pilgrims at health care facilities from 1993 through 2014 hajj seasons. medical facilities included primary health care centers (phccs) and different specialized wards in tertiary care hospitals, including ear, nose and throat (ent) departments, intensive care units, emergency units, infectious disease units and unspecified medical units. pilgrim participants were included either as inpatients or outpatients. the results of these studies are summarized in table 2 . overall, the prevalence of upper respiratory tract infections (urti) ranged from 1.4% to 42.1% (table 3 ). this prevalence was 1.4% among 141 pakistani pilgrims who attended the king abdul aziz hospital in medina during the 1992 hajj [57] and 42.1% among 3087 saudi and non-saudi patients (47.5% of them were pilgrims) who attended the ent clinic at al-noor specialist hospital in mecca during the 2009 hajj [58] . pharyngitis was also frequently reported among ill pilgrims. thus, in this study of 3087 pilgrims during the 2009 hajj, the overall prevalence of pharyngitis was 45.7% [58] . more recently, in 2008, the prevalence of pharyngitis in a large cohort of 4136 outpatients patients from 82 nationalities who attended 13 randomly selected mina phccs (94.9% of whom were pilgrims) was found to be 23.7% [59, 60] , and 61% in a study of 1047 saudi and non-saudi patients (2.3% of them were inpatients) [61] . however, in this second study of 1047 patients, only 34.5% were pilgrims. on the contrary, lower prevalence rates of bronchitis were reported during the hajj (1.4%-9.6%) [59] [60] [61] [62] [63] . a recent retrospective cross-sectional multicenter study of 185 turkish inpatients (87.5% were pilgrims) who returned to turkey from the arabian peninsula countries between 2012 and 2014 reported a slightly higher prevalence of acute tracheobronchitis (13.6%) [64] . in addition, in this study, pneumonia was among the most common clinical diagnosis among the hospitalized hajj patients and represented about half of diagnoses [64] . as pneumonia remains a major concern in critically ill patients, most of them reported the prevalence of pneumonia among pilgrims [57, 59, 60, [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] , with reported rates ranging from 0.2% in 2008 in 13 randomly selected mina primary health care centers [59, 60] to 54.8% in 2004 in two icu in mecca [68] (table 3 ). the prevalence of pneumonia was not reported in 3 papers [58, 61, 72] . pneumonia was the second most common admitting diagnosis (22%) in a study of 140 patients admitted to the icus in four hospitals in mina during the 2004 hajj [68] . this result is further confirmed by a recent study of 452 critically ill hajj patients, of over 40 nationalities, admitted to 15 hospitals in 2009 and 2010. in this study, pneumonia was defined as the primary cause of critical illness (27.2%) of all icus admissions during the hajj [65] . also, in another prospective study of pilgrims admitted in two major icus in mecca for the 2004 hajj season, community acquired pneumonia (cap) was the commonest source of sepsis, 54.8% [66] . [57] acute bronchitis: 1.4% a upper respiratory tract infection (urti) was defined as an acute infection that includes tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. b acute tracheobronchitis was defined as a patient with dry cough and/or low-grade of fever (< 38°c), sub-sternal pain, and fatigue in the absence of opacities on chest x-ray. c acute exacerbation of chronic obstructive pulmonary disease (copd) was defined as an association with increased frequency and severity of coughing and/or shortness of breath and wheezing, increased amount of sputum production, and/or a change in appearance of sputum in a patient with copd. d was not defined. the purpose of this review was to provide syndromic surveillance data that may be useful, in conjunction with microbiological data that will be presented in further papers, for the surveillance of respiratory infections and pneumonia during the hajj. despite the fact that some of the included studies in our review were performed among small numbers of pilgrims and cannot be extrapolated, it is clear from this work that respiratory symptoms have been common among hajj pilgrims over the last 15 years, as evidenced by the high prevalence of cough (over 90%) among malaysian pilgrims during the 2007 hajj [73] . cough is a common symptom among pilgrims [16, 74] and likely results from crowded conditions during the hajj. this close contact among such individuals may increase the risk of the transmission of respiratory pathogens, and therefore may contribute to respiratory disease outbreaks. climatic conditions and air pollution in mecca and surrounding holy sites during the hajj [75] may also play a role. recent follow-up studies thus evidenced a significant acquisition of respiratory viruses, particularly rhinovirus, influenza virus, and coronaviruses other than middle east respiratory syndrome coronavirus (mers-cov), and of bacteria, including streptococcus pneumonia, hemophilus influenza, staphylococcus aureus and klesiella pneumonia by hajj pilgrims upon their return from the hajj [76, 77] . respiratory diseases are the most common diseases observed among pilgrims attending mina primary health care centers [59] and a major cause of hospital admission during the hajj [70] , with pneumonia a leading cause of admission to intensive care units [62, 68] , where they are responsible for about half of the cases of sepsis [66] . unfortunately, while numerous articles on hajj pilgrims were retrieved from our literature search, relatively few recent articles specifically addressed ill pilgrims in the context of hospital settings. the use of cohort studies allows investigators to evaluate the actual incidence of clinical events in hajj pilgrims since it provides a denominator, but may not identify and capture the prevalence of some underlying conditions and of severe forms of respiratory tract infections, which are more likely to be evidenced in hospital patient populations. conversely, hospital studies use data that may be biased, frequently lacking denominator values, and so probably overestimating the occurrence of severe illness. moreover, a hospital-based study will, by definition, not capture some minor illness cases that do not require hospitalization. the prevalence rates of cough, sore throat and subjective fever varied widely across the included studies. these differences may result from differences in study design that may lead to potential biases (for example bias related to the method of data collection, using either selfreport questionnaires or telephone interview), study period (with regards to the seasonality of respiratory viral infections), and rates of vaccination against seasonal influenza among study participants which may widely vary from one study to another, as described in this review. thus, all data regarding the pilgrims, including demographic data, medical history, clinical data and information on vaccination status and compliance with non-pharmaceutical preventive measures, should be carefully collected by using standardized questionnaires. in addition, in the context of syndromic surveillance for respiratory pathogens, data regarding the pilgrim's symptoms should be collected prospectively during face-to-face interviews by trained medical investigators who travel with the pilgrims. one important result of this review is the finding of a lack of consistency ili syndromic case definitions across included studies. thus, in a 2003 study (that did not fulfill the inclusion criteria for this review) [78] , of 1310 malaysian pilgrims who had a clinic visit for upper respiratory tract symptoms at five clinics during the 2000 hajj, with the aim of determining influenza vaccine effectiveness against clinically defined ili, 63% had ili (defined as sore throat in combination with either temperature ≥38°c or cough) and 14% had influenza by the cdc definition (defined as measured fever [≥100°f (37.8°c)] and a cough and/or a sore throat). only one of the studies reported here used the cdc definition of ili or the who definition (an acute respiratory infection with measured fever of ≥38 c°a nd cough, with onset within the last 10 days) [45] . in his paper, rashid et al. demonstrated the low sensitivity of the cdc criteria and proposed therefore the use of the triad of 'cough, sore throat and subjective fever' to clinically define ili at the hajj or other mass gatherings, since this new simple clinical case definition is more specific and sensitive than the cdc definition [79] . this definition was used over the last years by french [16, 18, 19, [21] [22] [23] 31, 37] , malaysian [14, 15, 25] , indian [26] and afghan [35] investigators leading cohort studies among hajj pilgrims, thus allowing more reliable comparisons of findings between studies (table 1) . respiratory diseases are a major concern during the hajj. nonpharmaceutical interventions (e.g., hand hygiene, wearing face masks, social distancing) are known to reduce the spread of respiratory viruses from person to person and are therefore recommended to pilgrims by public health agencies. although hand hygiene compliance is high among pilgrims, face mask use and social distancing remain difficult challenges. data about the effectiveness of these measures for preventing acute respiratory infections at the hajj are limited, and results are contradictory, highlighting the need for future large-scale studies [80] . in addition to non-pharmaceutical interventions, vaccination against influenza is recommended for all hajj pilgrims by the ministry of health of saudi arabia [11, 12] . differences in study design and heterogeneity in the ili definition across studies make it difficult to compare findings from different studies and inhibits the drawing of conclusions regarding the potential effects of this vaccination on related clinical symptoms of influenza disease. however, recent papers by alqahtani et al. and alfelali et al. found the influenza vaccine to be effective, respectively, against both laboratory-confirmed influenza [81] and clinical influenza [82] . as influenza vaccination is generally considered effective in reducing influenza-related infections, the scientific committee for influenza and pneumococcal vaccination guidelines (scipv) thus recommends, in its recent guidelines, an influenza vaccination for all people, especially those at high risk, at least 2 weeks before the hajj [83] . it also recommends, for the next hajj seasons that will take place from june to september, the administration (prior to the hajj) of the southern hemisphere influenza vaccine for pilgrims from the southern hemisphere (where influenza positivity rates are higher during this period). furthermore, as the influenza vaccine is not expected to be available for pilgrims from the northern hemisphere before these next hajj seasons, the scipv also recommends the administration of the southern hemisphere influenza vaccine for those pilgrims from the opposite hemisphere before the hajj [83] . because of the mismatching between circulating and vaccine strains that has frequently occurred since 2003 [84] , alfelali et al. recommends, when the composition of influenza vaccines differs and whenever logistically feasible, taking into consideration the dual vaccination of hajj pilgrims with both the southern and northern hemispheres' vaccines. however, such strategy is impaired by the frequent unavailability of the southern hemisphere influenza vaccine in the northern hemisphere. the issue of influenza vaccine availability to match southern and northern hemispheres was discussed by the saudi ministry of health in consultation with the who and it was recommended to use the available hemisphere strain as long as there is a match in circulating strains [85] . despite the risk of acquisition of s. pneumoniae during the hajj, there is currently no consistent guideline on the use of pneumococcal vaccine for hajj pilgrims across pilgrim countries of origin [86, 87] . thus, and because many of the hajj pilgrims are elderly and have chronic illnesses and underlying risk conditions for which pneumococcal vaccination is recommended [86] , the scipv also recommended, in its 2016 pneumococcal vaccination guidelines, pneumococcal vaccination of the atrisk population at the appropriate time before the hajj, using the 2 types of pneumococcal vaccines that are currently available: the 23valent polysaccharide pneumococcal vaccine (ppsv23) and the 13-valent conjugate vaccine (pcv13) [88] . however, it did not recommend providing a pneumococcal vaccine routinely to healthy persons aged less than 50 years, because of lack of evidence. in addition, it has been well demonstrated that the conjugate vaccine against s. pneumoniae targets the most virulent serotypes associated with invasive pneumococcal diseases (ipd) that are also associated with antibiotic resistance [89] . these arguments reinforce the need for compliance with current recommendations for vaccinating at-risk hajj pilgrims against ipd and influenza [89] . respiratory tract infections, including influenza, continue to be a major concern during the hajj. both cohort-and hospital-based studies provide complementary data and potentially useful information, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during this mass gathering. large multinational follow-up studies are thus recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. matched cohorts ensure better comparability across studies, particularly in terms of origin of pilgrims and possible travelling conditions. however, the study design and data collection procedures should be standardized, to facilitate reporting and to achieve comparability between studies. furthermore, the definition of ili, and of most common symptoms used to define respiratory infections (e.g., urti), needs to be precisely defined and consistently used. future studies need to address the potential effects of influenza and pneumococcal vaccine in the context of the hajj pilgrimage. moreover, because of the mismatching between circulating and vaccine strains that has frequently occurred since 2003 [84] , alfelali et al. recommends, when the composition of influenza vaccines differs and whenever logistically feasible, taking into consideration the dual vaccination of hajj pilgrims with both the southern and northern hemispheres' vaccines. however, such strategy is impaired by the frequent unavailability of the southern hemisphere influenza vaccine in the northern hemisphere. despite the risk of acquisition of s. pneumoniae during the hajj, there is currently no consistent guideline on the use of pneumococcal vaccine for hajj pilgrims across pilgrim countries of origin [86, 87] . thus, and because many of the hajj pilgrims are elderly and have chronic illnesses and underlying risk conditions for which pneumococcal vaccination is recommended [86] , the scipv also recommended, in its 2016 pneumococcal vaccination guidelines, pneumococcal vaccination of the at-risk population at the appropriate time before the hajj, using the 2 types of pneumococcal vaccines that are currently available: the 23-valent polysaccharide pneumococcal vaccine (ppsv23) and the 13-valent conjugate vaccine (pcv13) [88] . also, it did not recommend providing a pneumococcal vaccine routinely to healthy persons aged less than 50 years, because of lack of evidence. respiratory tract infections, including influenza, continue to be a major concern during the hajj. both cohort-and hospital-based studies provide complementary data and potentially useful information, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during this mass gathering. large multinational follow-up studies are thus recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. matched cohorts ensure better comparability across studies, particularly in terms of origin of pilgrims and possible travelling conditions. however, the study design and data collection procedures should be standardized, to facilitate reporting and to achieve comparability between studies. furthermore, the definition of ili, and of most common symptoms used to define respiratory infections (e.g., urti), needs to be precisely defined and consistently used. future studies need to address the potential effects of influenza and pneumococcal vaccine in the context of the hajj pilgrimage. none. the authors have no conflicts of interest to declare. the general authority for statistics in the kingdom of saudi arabia from hajj services to mass gathering medicine: saudi arabia formalizes a novel discipline hajj: journey of a lifetime social identification moderates the effect of crowd density on safety at the hajj hajj: infectious 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and review of the literature trend of diseases among s iranian pilgrims during five consecutive years based on a syndromic surveillance system in hajj incidence of hajj-associated febrile cough episodes among french pilgrims: a prospective cohort study on the influence of statin use and risk factors mers-cov but positive influenza viruses in returning hajj pilgrims effect of influenza vaccination on acute respiratory symptoms in malaysian hajj pilgrims time to revisit presumptions on the essentiality of influenza vaccination for hajj pilgrims: a prospective cohort study international pandemic 2009 influenza a (h1n1) infection among 2009 hajj pilgrims from southern iran: a real-time rt-pcr-based study health related experiences among international pilgrims departing through king abdul aziz international airport effects of flu vaccine, solely or accompanied by pneumovax-23 vaccine on clinical consequences of the respiratory diseases among iranian pilgrims in hajj influenza among u.k. pilgrims to hajj medical problems of pakistani pilgrims in saudi arabia impact of ph1n1 influenza a infections on the otolaryngology, head and neck clinic during hajj pattern of diseases among visitors to mina health centers during the hajj season, 1429 h (2008 g) pattern of diseases among visitors to mina health centers during the hajj season road map of an ear, nose, and throat clinic during the 2008 hajj in makkah, saudi arabia causes of hospitalization of pilgrims in the hajj season of the islamic year pattern of surgical and medical diseases among pilgrims attending alnoor hospital makkah infections in travellers returning to turkey from the arabian peninsula: a retrospective cross-sectional multicenter study clinical and temporal patterns of severe pneumonia causing critical illness during hajj severe sepsis and septic shock at the hajj: etiologies and outcomes pattern of diseases among visitors of health care facilities in madinah during hajj season, 1428 h (2007 g) causes of 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can be found online at https:// doi.org/10.1016/j.tmaid.2018.12.002. key: cord-328056-y5x80tuw authors: popescu, corneliu p.; fischer, philip r. title: hydroxychloroquine-azithromycin for covid-19 – warranted or dangerous? date: 2020-05-30 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101764 sha: doc_id: 328056 cord_uid: y5x80tuw nan separate from the treatment outcomes data reported by million, the very existence of this paper provides encouragement in two ways. first, the paper demonstrates teamwork. thirty-seven coauthors combined their efforts to document care and outcomes of 1,061 patients. a nigerian igbo proverb states that "it takes a village to raise a child." similarly, a large team is required to mount such a huge clinical and research response to try to save patients from covid-19. in addition, the tmaid publishing team worked rapidly. this paper includes data from april 2020, was reviewed by six different peer-reviewers, was extensively revised, and was accepted and published in may 2020. the speed and effectiveness of a rigorous review and publication process attest to the value of teamwork. second, this paper exemplifies the value of the scientific process. fully separate from any celebrity opinions or political viewpoints, the authors proposed and studied a hypothesis in a rigorous observational study, presented their data carefully, responded effectively to the peer-review process and now make their data are available for public review and interpretation. with hydroxychloroquine-azithromycin treatment, mortality was effectively limited to "only" 0.9% among sars-cov-2-infected adults. even though this was a hospital-based study (though not limited to hospitalized patients), the mortality wasn't much higher than the 0.6% death rate of all those infected worldwide, and it is much lower than the 26.3% inpatient case fatality rate in a large british study. (4) the seeming safety and effectiveness of hydroxychloroquine-azithromycin is in contradiction to data in a study published just a week earlier that showed dangerously increased death rates in hydroxychloroquine, chloroquine, and macrolide-treated patients.(5) that multi-nation registry of 96,032 hospitalized sars-cov-2 patients in 671 centers on six continents included 14,888 who were treated with chloroquine or hydroxychloroquine, with or without a macrolide.(5) confounding factors were considered, and patients receiving remdesivir were excluded from the study. mortality rates were 9.3% in the control (non-hydroxychloroquine/chloroquine) group, 18% in those who received hydroxychloroquine, 23.8% in those who received hydroxychloroquine and a macrolide, 16.4% in those who received chloroquine, and 22.2% in those who received chloroquine with a macrolide. (5) specific features of million's study impact interpretation of the findings. first, study subjects were included based on positive viral testing, regardless of the presence or absence of symptoms. thus, some of these patients would probably not have become seriously ill whether or not they ever were diagnosed or treated. by contrast, the british study with a 23% case fatality rate(4) and the aforementioned,multinational registry study (5) only included those who were sick enough to be hospitalized. second, a total of 350 potential study subjects were excluded from million's study, some because of cardiac findings on screening and some because of use of other medications that might add increased cardiac risk. this was appropriate for the research methods and for patient safety, but this might have removed patients from consideration who would have had unfavorable outcomes (and, thus, increased the mortality rates toward levels comparable to other studies). third, there was no control group in million's study in france. it is possible that other helpful yet undocumented features of care in france, unrelated to medications, contributed to the seemingly favorable outcomes. widespread use of incompletely tested medications could potentially have dangerous side effects, and million's group wisely did not include patients with identified risk for arrhythmia in their study. they screened patients carefully and all had a preliminary ecg. among included patients, though, they found no obvious sign of medication toxicity. this too, is an important finding. in contrast, the multi-national study from mehra et al reported that new ventricular arrhythmias were approximately four times as common in those treated with hydroxychloroquine or chloroquine than in controls. (5) in that study, approximately 3.5% of control and treated patients had pre-existing arrhythmia on entry into the study (5) . this discrepancy in screening, may to some extent, explain the different outcomes. thus, the larger, multi-national observational study (5) found that hydroxychloroquine was associated with increased risk of death and increased risk of ventricular arrhythmias. but, the question arises whether this increase in mortality and of new ventricular arrhythmias in that study is not caused by an inappropriate prescription of the medication without considering the known side effects of hydroxychloroquine. hydroxycloroquine use in the usa was approved by fda in 1955. (6) hydroxychloroquine and chloroquine are both included in the world health organization (who) model list of essential medicines. (7) the arrhythmogenic side effects of hydroxychloroquine are well known, and million's team limited its use in accordance with this knowledge. while some readers will be encouraged enough by the results of million's study to "just do something" in giving hydroxychloroquine-azithromycin combined treatment to covid-19 patients, others will opt to await more "proof" of safety and efficacy from randomized blinded controlled clinical trials. indeed, such a trial was started. the world health organization solidarity trial (8) is assessing the antiviral remdesivir, the hiv drug combination lopinavir/ritonavir, the multiple sclerosis treatment interferon beta-1a, and the antimalarial drugs chloroquine and hydroxychloroquine. the study has already enrolled approximately 3,500 patients in 17 countries, and recruitment continues in over 400 hospitals in a total of 35 countries.(8) however, who has temporarily "paused" enrolment in the hydroxychloroquine arm of the study, not because of dangerous preliminary findings but, rather, because of data from the new multinational study. (5) perhaps relevant data will still emerge from the already-completed parts of the nowpaused hydroxychloroquine treatment arm in the solidarity trial. with an observational study, million and colleagues validate the legitimacy of considering hydroxychloroquine-azithromycin in treating hospitalized patients with covid-19. however, data from other studies raise a cry for caution, especially if considering giving this treatment to individuals who might have an underlying arrhythmia. with time, we should soon know whether hydroxychloroquineazithromycin use for covid-19 is warranted or dangerous. chloroquine is a potent inhibitor of sars coronavirus infection and spread repurposing of clinically developed drugs for treatment of middle east respiratory syndrome coronavirus infection early treatment of covid-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in marseille, france features of 20 133 uk patients in hospital with covid-19 using the isaric who clinical characterisation protocol: prospective observational cohort study hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis hydroxychloroquine sulfate monograph for professionals world health organization model list of essential medicines: 21st list 2019 key: cord-297954-87w2itin authors: memish, ziad a.; al-tawfiq, jaffar a.; alhakeem, rafat f.; assiri, abdullah; alharby, khalid d.; almahallawi, maher s.; alkhallawi, mohammed title: middle east respiratory syndrome coronavirus (mers-cov): a cluster analysis with implications for global management of suspected cases date: 2015-07-15 journal: travel med infect dis doi: 10.1016/j.tmaid.2015.06.012 sha: doc_id: 297954 cord_uid: 87w2itin since the initial description of the middle east respiratory syndrome (mers) in september 2012, a total of 1038 cases of mers-cov including 460 deaths have been reported from saudi arabia. from august 24, 2013 to september 3, 2013, a total of 397 patients and contacts were tested for mers-cov. of those tested, there were 18 (4.5%) mers-cov cases reported in al-madinah al-munawwarah with one large cluster. in this report, we describe the outcome, epidemiology and clinical characteristics of this cluster of which 4 cases involved healthcare workers. fourteen cases appeared to be linked to one cluster involving healthcare workers (hcws), family and patient contacts. of the 18 cases, five (including 2 hcws) were community acquired, two were household contacts, and 11 were healthcare associated (including 4 hcws). all except 4 cases were symptomatic and the case fatality rate was 39% (7 of 18). the outbreak resulted in human to human transmission of an estimated 6 cases. contact screening showed positive test in 1 of 56 (1.8%) household contacts, and 3 of 250 (1.2%) hcws. summary since the initial description of the middle east respiratory syndrome (mers) in september 2012, a total of 1038 cases of mers-cov including 460 deaths have been reported from saudi arabia. from august 24, 2013 to september 3, 2013, a total of 397 patients and contacts were tested for mers-cov. of those tested, there were 18 (4.5%) mers-cov cases reported in al-madinah al-munawwarah with one large cluster. in this report, we describe the outcome, epidemiology and clinical characteristics of this cluster of which 4 cases involved healthcare workers. fourteen cases appeared to be linked to one cluster involving healthcare workers (hcws), family and patient contacts. of the 18 cases, five (including 2 hcws) were community acquired, two were household contacts, and 11 were healthcare associated (including 4 hcws). all except 4 cases were symptomatic and the case fatality rate was 39% (7 of 18). the outbreak resulted in human to human transmission of an estimated 6 cases. contact screening showed positive test in 1 of 56 (1.8%) household contacts, and 3 of 250 (1.2%) hcws. ª 2015 elsevier ltd. all rights reserved. since middle east respiratory syndrome (mers) was described in september 2012, a total of 1038 cases of mers-cov including 460 deaths have been reported from saudi arabia [1] . the current case fatality rate is lower than the initial rate of 65% [2] . mers-cov is known to cause three patterns of transmissions [2e8]: sporadic cases, community-transmission [9] and healthcare associated transmissions such as the case in the zarqa, jordan [10, 11] , al-hasa, saudi arabia [12] and jeddah, saudi arabia [13, 14] . the exact source of the infection for most patients remains unknown. in this report, we describe the outcome, epidemiology and clinical characteristics of this cluster of mers-cov in al-madinah al-munawwarah of which 4 cases involved healthcare workers. all samples were tested in jeddah regional lab. we included all mers-cov cases reported from al-madinah al-munawwarah between august 24, 2013 and september 3, 2013. a confirmed case of mers cov is defined as an isolation of mers cov from a nasopharyngeal or a respiratory sample by real time reverse transcriptase pcr, as described previously [12, 15] . clinical information included demographic data, clinical symptoms and signs, co-morbidities, and contact with animals. during the study period, a total of 397 patients and contacts were tested for mers-cov. there were 18 (4.5%) mers-cov positive cases reported in al-madinah al-munawwarah with one large cluster. of those cases, 15 (83%) were male and 3 (17%) were females. twelve of the cases were saudis (67%) and 6 were non-saudis 33%. there were two possible clusters and two cases were sporadic in nature. the largest cluster included 15 cases and was thought to be initiated by a 55 year-old male resident. he was in the same hospital ward of a 74 year-old saudi male who was thought to acquire the infection in the healthcare setting. transmission then occurred in an additional 12 cases as illustrated in fig. 1 . another case was from qatar, the son of a patient sharing a room with the second case although the father tested negative for mers-cov. the second cluster was from the city of hanakia located 100 km from madina, and involved a 56 year-old male healthcare worker (hcw), who then infected another 39 year-old hcw. there was one sporadic case, a 50 year-old hcw, who had no contacts with other cases. the majority of the cases (61.1%) were healthcare associated infections and primary cases constituted 27.8% and intra-familial transmission was only 11.1%. the case fatality rate was 39% (7 of 18 cases). of the 14 symptomatic cases, 11 (78.5%) had at least two of the following chronic diseases: diabetes mellitus, hypertension, end stage renal disease, cardiac disease, sickle cell anemia, obesity, or smoking. only one patient had contact with animals, he was a healthcare worker and was asymptomatic. all of the 14 symptomatic cases had fever (100%), 64% had shortness of breath, 50% had cough, 35% had nausea, 35% headache, and 21% had sore throat. a total of 250 hcws were screened and 4 (1.6%) were positive. in addition, 56 family contacts were screened and 1 (1.8%) was positive. the current report illustrates the pattern of transmission of mers-cov. our data harmonizes with the previously described pattern of transmission of mers-cov [2e8]. the majority of the patients (61.1%) were healthcare associated infections and primary cases constituted 27.8% and intrafamilial transmission was only 11.1%. the recent jeddah outbreak in 2014 was documented to be secondary to intrahospital and inter-hospital transmissions [13, 14] . fig. 2 shows major mers-cov outbreaks in kingdom of saudi arabia. the rate of community infections seem to be low with expansion of the infection in the healthcare setting [5] . animal contact, especially with camels is uncommon among primary cases, and in our series only one patient had camel contact [3, 7] . the case fatality of these cases was 39%, compared to the overall case fatality in ksa of 44% [1] of the 14 symptomatic cases, 78.5% had at least two of underlying chronic diseases. the presence of comorbidities predisposes to increased risk of mers-cov and was shown to also correlate with case fatality rates [16] . screening of contacts yielded less than 2% positivity among hcws and family contacts. in a large screening of contacts, mers-cov was detected in 1.12% of hcws contacts and in 3.6% of family contacts [15] . however, the majority of the cases were acquired within healthcare facilities similar to the al-hasa and jeddah outbreak [12e14]. an interesting observation in this report is the link of one of the mers cases from qatar to this healthcare associated cluster. travel associated mers cases were reported from: turkey, austria, united kingdom, germany, france, greece, the netherlands, tunisia, algeria, malaysia, philippines, china, and the united states of america [17] . the recent occurrence of an outbreak in the republic of korea was started with a returning traveler [17e19]. the patient traveled to bahrain (18e29 april), the united arab emirates (29e30 april), bahrain (30 aprile1 may), saudi arabia (1e2 may), bahrain (2 may) and qatar (2e3 may) [17, 19] . the outbreak spanned 72 healthcare facilities which have treated patients and six healthcare facilities have documented nosocomial transmission [19] . as of june 24, 2015, this outbreak had caused 179 cases including 27 deaths [19] . the outbreak highlights the importance of infection control and early recognition and isolation of suspected cases [5] . the kingdom of saudi arabia also hosts one of the largest mass gathering in the world hosting millions of pilgrims during the annual hajj where pilgrims visit the holly cities of makkah and al-madinah [7] . the occurrence of mers-cov transmission during the annual hajj and subsequent development of a global epidemic is of a great concern. respiratory samples were obtained from all mers suspected cases during 2013 hajj season and all samples tested negative for mers-cov [20] . a cohort of 129 french hajj pilgrims were systematically sampled in 2013 with screened for mers-cov using nasal swabs prior to returning to france [21] . although, the majority (90.7) had respiratory symptoms, none was tested positive for mers-cov [21] . in 2012 and 2013 hajj season, a total of 5 million pilgrims from 184 countries visited makkah and al-madinah and no cases of mers-cov were detected during or after the hajj [22] . screening of 5235 adult pilgrims from 22 countries in 2013 showed no positive mers cases using nasopharyngeal swabs [23] . although only rare cases have been associated with the umrah pilgrimage so far, there is a need for continuing surveillance among travelers, pilgrims and hcw attending pilgrims [24] . middle east respiratory syndrome coronavirus: epidemiology and disease control measures coronaviruses: severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus in travelers an update on middle east respiratory syndrome: 2 years later middle east respiratory syndrome coronavirus infection control: the missing piece? middle east respiratory syndrome coronavirus: transmission and phylogenetic evolution travel implications of emerging coronaviruses: sars and mers-cov middle east respiratory syndrome coronavirus (mers-cov) in healthcare setting family cluster of middle east respiratory syndrome coronavirus infections epidemiological findings from a retrospective investigation hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description hospital outbreak of middle east respiratory syndrome coronavirus an observational, laboratory-based study of outbreaks of middle east respiratory syndrome coronavirus in jeddah and riyadh, kingdom of saudi arabia mers-cov outbreak in jeddahea link to health care facilities screening for middle east respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study middle east respiratory syndrome coronavirus (mers-cov)-17th update middle east respiratory syndrome coronavirus (mers-cov): summary and risk assessment of current situation in the republic of korea and china etiology of severe community-acquired pneumonia during hajjdpart of the mers-cov surveillance program lack of nasal carriage of novel corona virus (hcov-emc) in french hajj pilgrims returning from the hajj 2012, despite a high rate of respiratory symptoms the hajj pilgrimage and surveillance for middle east respiratory syndrome coronavirus in pilgrims from african countries prevalence of mers-cov nasal carriage and compliance with the saudi health recommendations among pilgrims attending the 2013 hajj imported cases of middle east respiratory syndrome: an update we are grateful to the staff of the ministry of health in al-madinah area and the staff of the regional laboratory, kingdom of saudi arabia. middle east respiratory syndrome coronavirus none. key: cord-340094-u3x4g8ul authors: d’alò, gian loreto; modica, domenico cicciarella; maurici, massimo; mozzetti, cinzia; messina, alessandra; distefano, alessandra; pica, francesca; de filippis, patrizia title: microbial contamination of the surface of mobile phones and implications for the containment of the covid-19 pandemic date: 2020-09-02 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101870 sha: doc_id: 340094 cord_uid: u3x4g8ul nan we read with interest the review by olsen & colleagues (2020) [1] underlining the possible role of mobile phones (mps) as possible source of microbial infection. at the same time, the paper pointed out that, among the 56 identified investigations regarding the microbiological contamination of the surface of the mps, only one study focused on the presence of viruses (specifically, the authors searched for viral rna [1] ). the emergence of novel coronavirus sars-cov-2 in december 2019 and its high transmissibility, resulting in a rapid coronavirus disease (covid-19) outbreak globally, has led the scientific community to look for undetected infection pathways [1] . the sars-cov-2 has been shown to spread not only from person to person but also through environmental and inanimate surfaces [2] . mps have been proposed to act as be "trojan horses" in propagating pathogens, including viruses, during epidemics and pandemics [1] . the growing number of reports regarding bacterial contamination of mps is contradicted by a paucity of advice provided to both healthcare workers and patients on the use and disinfection of mps, particularly in hospitals. the development of research investigating mps as vehicles of pathogens and their correlation with user habits could be useful to the world health organization (who) and to government agencies to increase public awareness and to formulate education material on mps hygiene [3] . in our recent work [4] we observed that, in a sample of 108 students in health care professions (hps), almost all of them (93%) used the telephone in the ward, and only 11% of those who used mps wearing gloves stated that they changed them after use during common health care. in the same sample, only 3% said they cleaned the surface of their phones daily. we collected very similar data in a subsequent study on a new sample of students in hps (n=83; use of mps in the ward: 89%; use without changing gloves: 47%; daily cleaning: 2%) (unpublished data) (figure 1) . these habits could potentially reduce or nullify the effect of hand hygiene procedures, since previously decontaminated hands may become contaminated again by microorganisms present on the device [3] . the covid-19 pandemic has strongly underlined the critical importance of hygiene practices to counteract the spread of pathogens: it has highlighted once again that a public health concern is not merely a medical problem, as it affects society as a whole [5] . the actual increased societal awareness has led major mps companies such as apple, samsung, and google to release guidances for proper mps disinfection [3] while cdcs recently published advices for cleaning and disinfecting high touch surfaces such as mps at home; according to cdcs, when no producer's guidance is available, alcohol-based wipes or sprays containing at least 70% alcohol should be used to sanitize electronic devices (https://www.cdc.gov/coronavirus/2019-ncov/prevent-gettingsick/disinfecting-your-home.html; updated may 27, 2020). in light of covid-19 pandemic, such procedures could be implemented also in the community, as a preventive measure to reduce the spread of the virus as well as other pathogens. taking into account the shortcomings in the current scientific landscape, further research is warranted, focusing both on the identification of viral material on the surface of mps and on the isolation of viruses that may be present, in order to understand whether and to what extent they remain viable and virulent after lying on the devices. not applicable. mobile phones represent a pathway for microbial transmission: a scoping review covid-19 diagnosis and management: a comprehensive review covid-19 and mobile phone hygiene in healthcare settings taking screenshots of the invisible: a study on bacterial contamination of mobile phones from university students of healthcare professions in the urgent need for integrated science to fight covid-19 pandemic and beyond key: cord-339444-f8lfob47 authors: bigna, jean joel; kamtchum-tatuene, joseph; noubiap, jean jacques title: claims about the safety and efficacy of early treatment of covid-19 with hydroxychloroquine and azithromycin must be supported by real evidence date: 2020-09-25 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101886 sha: doc_id: 339444 cord_uid: f8lfob47 nan based on data from 1061 covid-19 patients (94.7% symptomatic, 85.7% outpatients), the authors concluded that early treatment of covid-19 (before complications occur) with the combination of hydroxychloroquine and azithromycin (hcq+az) "is safe and associated with very low fatality rate" [1] . this claim is not supported by the data presented in their article and is, therefore, misleading. indeed, in the absence of a control group of patients who did not receive hcq+az, it is inappropriate to conclude that this therapeutic combination was associated with low fatality rate. this is a major concern, especially because spontaneous clearance of sars-cov-2 infection is more common in younger individuals who seem to represent the majority of the study cohort [2] . the authors do not provide a rationale for the decision not to consider a control group. this is a fundamental methodological point that would help to support the argument for a causal link between early hcq+az therapy and good clinical outcomes. furthermore, their safety data are also not generalizable because they are more likely to be driven by the specific demographic and clinical characteristics of the population. indeed, with a mean age of only 43.6 years, the study population likely represents a selected group of individuals with low prevalence of comorbidities known to favor the occurrence of hydroxychloroquine-related cardiac adverse events. moreover, the multivariable model used to explore factors associated with poor outcomes in this study presents some weaknesses. although age, some co-medications, viral load at inclusion, and national early warning score for clinical severity were included in the multivariable model, it is surprising that important factors such as sex and chronic conditions were omitted. there is evidence supporting the association of male sex and several chronic conditions, including those reported in this study, with poor clinical outcomes [3] . this is more concerning in view of the significantly higher prevalence of chronic conditions in patients with poor clinical outcome in this study. a more effective handling of potential confounders could have been achieved through a multivariable model including all known clinically relevant prognostic factors or the use of propensity score matching. finally, due to the retrospective nature of the study, it was not possible to consider blinding for outcome assessment. except for death, clinical outcomes such as transfer to intensive care unit (icu) or hospitalization for ten days may vary across physicians. for example, j o u r n a l p r e -p r o o f physicians may have a higher tendency to keep patients with chronic co-morbidities longer in hospital or to transfer them to icu. it is worth noting that the discussion of the study limitations is focused on the explanation of missing data without highlighting the methodological concerns. in conclusion, given the many limitations raised above, it is advisable to be more careful about claims of association between hcq+az and low fatality rates, especially when considering the latest evidence from a randomized controlled trial of hcq as postexposure prophylaxis where hcq did not prevent illness compatible with covid-19 or confirmed infection [4] . in addition, recommendations for a universal test-and-treat strategy made by the authors should be tempered since this was not studied. early treatment of covid-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in marseille, france. travel medicine and infectious disease factors associated with hospital admission and critical illness among 5279 people with coronavirus disease risk factors of critical & mortal covid-19 cases: a systematic literature review and meta-analysis a randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. the new england journal of medicine all authors contributed to writing this article and approved its final version. there is no funding source used for this paper. there is no competing interest. key: cord-337713-uuo1oeyc authors: ollarves-carrero, maria fernanda; rodriguez-morales, andrea g.; bonilla-aldana, d. katterine; rodriguez-morales, alfonso j. title: anosmia in a healthcare worker with covid-19 in madrid, spain date: 2020-04-13 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101666 sha: doc_id: 337713 cord_uid: uuo1oeyc nan during the course of the coronavirus disease 2019 (covid-19) pandemic, and its international spreading [1] , multiple countries have also raised the concerns of this emerging condition as an occupational disease. as cases increased and required healthcare, healthcare workers (hcws) have been recognized as a high-risk group to acquire the infection due to the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [2] , that may lead to a broad and changing spectrum of clinical disease, recently including olfactory and taste disorders. despite this, there are few reports in healthcare workers [3, 4] , also about the occurrence of anosmia and dysgeusia [5] . the patient, a 40-year-old venezuelan woman, works as a radiologist, attending patients in different areas of one service of nuclear medicine in a 900-bed hospital of madrid, spain. between march 1 and march 14, 2020, she provided care in the hospital, at the x-ray room, to multiple symptomatic patients, who tested positive by rrt-pcr to the sars-cov-2 and who had suggestive covid-19 imaging alterations (fig. 1 ). those days, healthcare workers were not yet using personal protective equipment (ppe), a measure implemented in her hospital a week later. on march 14, 2020, the physician presented with myalgias, headache, chills, abdominal pain, and diarrhea, persisting for five days, but with no fever, she took her temperature three times per day (fig. 1 ). she self-medicated with paracetamol. on march 16, she additionally presented with cough and anosmia. that day, she reported her clinical condition to the hospital but remained working until march 20, when a nasopharyngeal swab was collected, and she was on leave, at home ( fig. 1 ). from march 16 to march 18, her initial symptoms improved and resolved. however, the dry cough persisted and lasted 21 days, improving gradually, although interminttently, and her anosmia gradually improved and resolved after 14 days (fig. 1) . on march 24, her rrt-pcr test confirmed the viral rna of sars-cov-2. she remained at home till march 31, when her rrt-pcr was repeated and reported negative on april 1, and she returned to work at the hospital (fig. 1) . she lives with her husband, non-hcw, a 38-year-old man, and her son, 11 months old. the husband presented slight myalgia and asthenia during three days. her son did not have symptoms. both always had a normal temperature, and remained asymptomatic at home. neither were tested for sars-cov-2. for april 13, 2020 she continues well, as also her husband and son. for march 1, 2020, only 85 cases of covid-19 were reported in spain, but as of march 14, when her symptoms began, the country reported more than 6391 cumulated cases. all the hcw then needed to use the contact and respiratory precautions when attending patients with respiratory symptoms or/and flu-like illnesses in all areas with presumed ongoing community transmission of covid-19 in most countries [4] . in a case series of 138 patients treated in a wuhan hospital, 40 patients (29% of cases) were hcws [3] . among the affected hcws, 31 (77.5%) worked on general wards, 7 (17.5%) in the emergency department, and 2 (5%) in the intensive care unit (icu), then in any area hcws would be exposed and infected. our case also presented with, a still considered novel, the clinical manifestation of covid-19, the anosmia persisting for more than two weeks, and more prominent than other common clinical findings reported in this infection (e.g., fever, cough) [5] . olfactory and taste disorders are well known to be related to a wide range of viral infections, although not a high proportion of patients. multiple viruses can use the olfactory nerve as a shortcut into the central nervous systems, including the influenza virus, and cause even long-term olfactory disorders in some cases [6] . hypogeusia, dysgeusia, hyposmia, and dysosmia associated with covid-19 require more detailed studies in order to understand their pathophysiology, but especially their clinical course and implications. as the pandemic increases, early detection and suspicion of cases, based on broader clinical findings, would be useful, to aid diagnosis, in addition to the confirmation by the rrt-pcr. anosmia is not frequent in the context of common cold and flu, then, an increase in this finding, in the covid-19 context, make this case relevant. none. we declare that we have no competing interests. mfoc is the physician case reported in this article. temperature, mean value per day, she measured it three times per day. *generalized, with moderate to severe intensity, predominantly at the shoulder girdle. **holocranial, oppressive, with moderate intensity. ***predominantly at mesogastrium and hypogastrium, of slight intensity. ****watery stools, with no blood or mucus, reaching the first days, from four to five per day episodes. *****mostly dry, with a white appearance. s1, sample 1°; s2, sample 2°. +, positive. -, negative. < 14 pd, 14 previous days. the number at the end of each horizontal color bar represents the total number of days with the clinical finding. (for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) going global -travel and the 2019 novel coronavirus complete genome sequence of a 2019 novel coronavirus (sars-cov-2) strain isolated in nepal clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan the first locally acquired novel case of 2019-ncov infection in a healthcare worker in the paris area self-reported olfactory and taste disorders in sars-cov-2 patients: a cross-sectional study the olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system rodriguez-morales unidad procedimientos, policlínico neurología, centro de referencia de salud dr katterine bonilla-aldana latin american network of coronavirus disease lancovid-19), pereira, risaralda, colombia public health and infection research group, faculty of health sciences key: cord-324345-j43rpvwk authors: leong, hoe nam; lim, hong huay title: sars – my personal battle date: 2010-11-19 journal: travel med infect dis doi: 10.1016/j.tmaid.2010.10.007 sha: doc_id: 324345 cord_uid: j43rpvwk it isn’t every day that a doctor becomes a patient. it is more peculiar when it occurs with an unknown mysterious epidemic respiratory illness that kills. severe acute respiratory syndrome (sars) gripped the world in 2003, spreading via air-links and throwing the global economy into disarray. as a practicing physician in singapore, one of the first countries affected, i describe my first-hand account of my battle with this illness, how i acquired this illness in singapore, and eventually quarantine in frankfurt am main, germany. summary it isn't every day that a doctor becomes a patient. it is more peculiar when it occurs with an unknown mysterious epidemic respiratory illness that kills. severe acute respiratory syndrome (sars) gripped the world in 2003, spreading via air-links and throwing the global economy into disarray. as a practicing physician in singapore, one of the first countries affected, i describe my first-hand account of my battle with this illness, how i acquired this illness in singapore, and eventually quarantine in frankfurt am main, germany. ª 2011 elsevier ltd. all rights reserved. i vividly remember the time when i first saw the index patient with severe acute respiratory syndrome (sars) in singapore. she had just returned from a shopping trip from hong kong. she was unwell on the last day of the trip while her travelling companion had been unwell earlier. upon return, both eventually sought help at two different major hospitals in singapore. the index patient was admitted to tan tock seng hospital (ttsh) on saturday, (1st march 2003), and an infectious disease consult was sought on the following monday. i was the infectious disease registrar-oncall that day for ttsh. her presentation intrigued me, and with little hesitancy after discussing with my consultant, we assumed the medical management of the patient. the working diagnosis was atypical pneumonia of uncertain etiology. on that day, 3rd march 2003, the entity of sars-coronavirus was not even coined. at a much later time, i learnt that there were rumours of an 'infectious agent' in guangdong province, and various diagnosis were offered included chlamydia infection to avian influenza. she was nonetheless investigated, and managed as for atypical pneumonia. as a young enthusiastic registrar, i was determined to find the etiology to her infection. not wanting to miss any unusual signs, i examined the patient thoroughly twice daily. we explored and liaised with the various clinical laboratories to investigate the cause of her pneumonia. routine tests from sputum bacterial culture to respiratory viruses immunofluorescence to serology were unyielding. all investigations were fruitless. on the sixth day of her admission, i was referred another patient with atypical pneumonia. and again, i was presented with the same history of a young singaporean woman with atypical pneumonia in a returning traveler from hong kong after shopping. the incredulous similarity unsettled me as i asked the referring consultant if we were talking about the same patient. with this new referral, both patients were immediately isolated and an alert was issued to the ministry of health, singapore. this was to the credit of my consultant. it was an exceedingly busy day for me as i had to attend to new referrals, run an outpatient clinic, and subsequently draft a clinical summary of these two patients by the early evening. needless to say, i didn't go home till it was very late that night. it was subsequently elucidated that these two individuals acquired the disease while staying in the same hotel in hong kong from an ill visitor from guangdong province. 1 the next day was the weekly scheduled infectious disease round in my practicing hospital, ttsh, where infectious disease physicians from the various public hospitals in singapore would gather. each public hospital (singapore general hospital, national university hospital, and ttsh) would take turns to host the event that is held on all most fridays of the month. at this opportunity, we presented our cases, and discussed our findings. as a group of infectious diseases physicians, we had no inkling to the etiological cause. nonetheless, the patients remained isolated. eventually, the patient's fever defervesced on day 14 of illness. i wasn't scheduled to perform the ward round that day, but i returned to visit the patient that sunday morning. my curiosity had the better of me. on hindsight, i should not have, as i developed fever with chills and severe myalgia that very morning while going to work. that spelled the beginning of my own illness. for once, i appreciated what having chills meant. despite driving in hot-weather singapore, with the vehicular heater at its maximum setting, i failed to get any relief. coupled with the severe backbreaking myalgia and the absence of respiratory symptoms, i believed i had dengue fever. i drank plenty of fluids and took plenty of rest. the fever broke eventually on the tuesday morning. this was day three of illness. with this reassurance, i decided to continue on my scheduled trip to new york for a conference. my pregnant wife and my mother-in-law accompanied on this trip. the plans were that we would have a short holiday visiting relatives after the conference. the flight was pleasant but interrupted by the airline staff seeking assistance for a passenger who developed epigastric pain. my paediatrician wife and i rendered assistance. this turned out to be a blessing in disguise later. the next day i remained well and we toured the new york city prior to the start of the meeting that evening. when the lecture began, i felt extremely unwell, and developed severe chills and myalgia again. on returning to my room, i realised that i had broken out with a faint viral looking-like rash. i had a huge sigh of relief with the firm belief that my diagnosis of dengue fever was further reaffirmed. at that point in time, i had yet to develop any respiratory symptoms. my wife and i telephoned a colleague in singapore and we concurred to have a full blood count test done at the clinic the next day. the american physician we referred to by the hotel in new york was a board-certified travel physician. his associate examined me initially, and astutely identified crepitations on my right lung. a chest x ray demonstrated radiographic features of consolidation and a full blood count showed normal white cell count and platelets. the physician immediately made a diagnosis of atypical pneumonia and i was prescribed levofloxacin. he showed professional courtesy and offered me free samples. on my part, i made a decision to return home on the first flight out that evening. the physician tried to dissuade me as he felt i would recover in a few days. just prior to leaving the clinic, i decided to call home to singapore to update my family and a trusted colleague in singapore on this new development. it was easily 12 midnight in singapore time when i woke up my colleague! it turned out that this call was highlighted to the director of medical services, ministry of health, singapore, and a frantic search began for this sick doctor. i was halfway across the atlantic ocean when the ministry eventually found me. the crew servicing the passengers happened to be the same crew that serviced us on the flight out to frankfurt from singapore. naturally, we were identified out easily, like a sore thumb! we were cordoned off to the rear of the plane with three empty rows ahead of us. it was extremely professional of the aircrew to have treated us with dignity and respect. perhaps it was ignorance, but i was not treated as if i had a highly infectious agent. my respiratory symptoms of cough began with this flight, and in retrospect, i wish i had stayed in new york. when we arrived in frankfurt am main germany, the passengers and then the crew were taken off the plane, leaving my pregnant wife, my mother-in-law and myself as the last passengers. eventually, three germans boarded the plane in 'spacesuits'. i was full of admiration for my mother-in-law who took all these sudden news and men in full personal protective equipment (ppe, complete with powered air-purifying respirator) in unbelievable calmness. in a matter-of-fact tone, she told me composedly that she had watched television and knew what to expect e exactly! she had developed a cough by now, which she did not blame me for. the germans were clearly well-prepared for the scenario, having rehearsed this recently for a mock patient at the airport with a viral haemorrhagic fever. the hospital, klinikum der johann wolfgang goethe-universität, and its staff, led by professor hans-reinhard brodt, was exceptional in delivering the best care possible to me. as both my mother-in-law and myself were ill, we were moved to the intensive care unit in this isolation ward. my wife was cordoned off in a separate room. however, the nightmare with my illness has just begun. i became increasing short of breath with an unabating persistent fever. my respiratory symptoms that were nonexistent initially returned with a vengeance, as i had to cope with haggling bouts of cough that resulted in me desaturating on the oxygen monitor. every single attempt to change my posture would result in a severe bout of cough that frightened my mother-in-law. it appeared as if my lungs would be spit out at the next cough. at the end of each bout of coughing, there would be haemoptysis. this was a terrifying sight for a mother whose daughter was pregnant with my child. the thought of a fatherless child, no doubt, crossed her mind. my experience as a patient humbled me. i had no toilet privileges, as i was too unwell to get out of bed. for the love of my life, i was cursed that i couldn't bring myself to empty my bladder supine, but had to stand. it didn't help when it was frequently interspersed with bouts of coughing and haemoptysis every time i tried to position myself! science thus taught me, in cruel fashion, that i could hold 1 l of urine in my bladder. my wife eventually joined me when she developed fever at the end of the second day of arrival. the sense of guilt overcame me as i thought of the illness i had exposed my wife to. in this moment of desperation, i cried to god's help, and i offered my life for the safety of my wife and my unborn daughter. my hopes fell to despair when i became extremely breathless one evening despite being on a full-face oxygen mask of 100%. the sensation of breathlessness was extremely terrifying as i tried to take in deeper and deeper breaths to satisfy my air hunger, but to no avail. i felt suffocated as if the air had no oxygen. incredulously, i retained some sense of logic. i knew i had to avoid mechanical ventilation if i wanted to keep the odds in my favour. i struggled and prayed, and in the silence, i found peace. the night turned to day, and amazingly my recovery started. my mother-in-law never developed fever. her respiratory symptoms resolved by the evening of admission, and she was up and about, back to her usual spritely self. in jest, we attributed her health to her younger days when she worked in a farm. my wife miraculously had much milder symptoms. there was a fetal ultrasound assessment, which turned out well. the doctor avoided all chest radiographs of my wife to protect my unborn child. intravenous erythromycin, a category b drug, was the only drug prescribed for my wife. the managing physician allowed me to participate in the medical care and we actively discussed the choice of antibiotics. on the first day of admission, there was still no news of sars or any infectious agent. but the news of a new infectious agent (sars) broke out on the second day of admission, and i was given a promed email on this. this was 15th march 2007. with that news, my days as a patient in isolation continued. regularly thereafter, we were fed information from the promed by the attending healthcare workers. in the study of science, my mother-in-law, wife and myself were subjected to various samplings for viral cultures. it almost became a daily routine that we had daily nasopharyngeal and eye swabs. arterial blood gases (requiring a puncture on the radial artery) were performed regularly. the attending physicians had to do this while in their full ppe in thick industrial grade gloves. to their credit, they managed to perform these tests in those unwieldy suits and gloves. when i was better, i performed the blood sampling for my wife and mother-inlaw instead. for the benefit of science, i agreed to a bronchoscopic examination. they obtained an old scope and a respiratory physician was flown in for the procedure. the bronchoscopist was accomplished, but the experience was far from pleasant, but it gave me the moral authority to advise my subsequent patients when i submitted them for endoscopic examinations. a computer scan of the chest was performed when i was much better. the record of my stay and the findings was eventually published. 2 we all eventually recovered, and during the obligatory isolation, we had the chance to sample hospital german cuisine, and ordered in chinese takeaways and pizzas. indeed, frankfurt should be the place to eat frankfurters! the only recreation was the ice figure skating championship that was broadcasted during that period. the doctors were fantastic, and the nurses were unbelievably warm and understanding. we couldn't have received better care from anyone else. the solitude in isolation was deafening as the days wore on. my initial reading was with the only english book my wife asked from our german caregivers, the bible. it was through this episode that i first read the whole gospel according to luke. our friends and family took turns to call us to keep us entertained. we were regularly updated by colleagues fighting the battle in ttsh. without these friends, we would have clearly lost our sanity. the best gift came when dr asok kurup, my colleague in the singapore general hospital (sgh) came to visit me. he brought well wishes from my department; get well cards and an english novel. i felt 'loved' by my friends. i was a staff of sgh, and was rotated to ttsh as part of the infectious diseases training programme. despite the fact that i acquired the disease from another hospital, the ceo of singhealth, the administrative group for sgh, professor ser kiat tan, announced publicly that he would pay the entire hospital bill. this settled my worries. some time after my discharge, my employer was billed for my entire stay, including the quarantine charges. it was a large bill that i would never have been able to pay in a lifetime. professor tan made calls to me either personally or through his secretary. that offered a lot of hope for this patient. even singapore airlines offered my wife a bouquet of flowers, despite the trouble we created for them. they truly exemplified their motto e "a great way to fly". i am still grateful to their staff till this day. a lady approached our isolation unit one day, with magazines in english. she introduced herself in spattering bits of english and gesticulations as the matron of the hospital. she represented the hospital and felt for sorry our solitude. we were very grateful for this unusual warmth in the cold early spring in frankfurt am main. in return, we gesticulated wildly back at her, acknowledging her kindness. eventually we were discharged when our period of isolation was over. we were whisked off in a private car and quietly into the airport. we never went through immigration when we first arrived, and hence, technically, illegal immigrants! the flight back was uneventful. the crew knew of our special status but remained professional. on arrival in singapore, we were whisked into a waiting taxi and sent home. the journalists never got to me. we returned home to welcoming family, colleagues and friends, intermixed with hugs, kisses and warm handshakes. they were clearly relieved that we have survived this episode. this came amidst further news of infection and death caused by the virus. for me, it was great to be home. i visited sgh on the monday after, and greeted my colleagues. this was just when sars was identified in sgh. i was roped in to help with the transfer of patients from sgh to ttsh. thereafter, i started working in ttsh, working hand-in-hand with my colleagues in battling sars. my wife joined me subsequently on secondment from kk women's and children's hospital. together with other sars survivors, we formed a team, collecting respiratory samples from individuals suspected to have sars. my wife and i worked with various doctors. the camaraderie was amazing to say the least, and we made long lasting friendships with many people. sars was eventually controlled, and we returned to our previous positions. my daughter, was born in early september, full term with no apparent birth defect. we have survived an epidemic, and in 2009, the world was thrown into another epidemic of swine-origin h1n1 influenza. 3 as a physician, this experience has allowed me to better appreciate what a patient experiences. that solitude and isolation, is a horrific tragedy for both the physician and patient. and yet, as an infectious diseases physician, i have sadly implemented this order on many individuals. sometimes, these individuals die, alone, in desolation. the fear of an unknown mysterious illness is overbearing. coupled with isolation, this becomes defeatist. the impetus is thus with us physicians as we remember the aphorism by dr edward trudeau, "to cure sometimes, to relieve often, to comfort always". 4 we all can always comfort patients, even in isolation. since 2003, we have been blessed with two other children, vivianne and lucas. marianne, who is now six years old, is starting first grade this year. though tumultuous, the sars experience has taught us valuable lessons as doctors not otherwise taught in medical school. outbreak of severe acute respiratory syndrome e worldwide identification of a novel coronavirus in patients with severe acute respiratory syndrome no conflict of interest. key: cord-261303-xjbz9fw9 authors: ahmed, qanta a.; memish, ziad a. title: from the “madding crowd” to mass gatherings-religion, sport, culture and public health date: 2018-06-04 journal: travel med infect dis doi: 10.1016/j.tmaid.2018.06.001 sha: doc_id: 261303 cord_uid: xjbz9fw9 human behavior has long engaged in collective behavior assembling in crowds. the christian pilgrimage to the holy land has been recorded since the 4th century, while the hajj, islam's great pilgrimage, has existed for fourteen centuries, of which a body of literature devoted to the travelogues of the hajj has been recorded for over ten centuries. football is a sport played worldwide by more than 1.5 million teams and in 300,000 clubs. most however play outside of the officially organized sphere: more than 4 percent of the global population plays football, including 270 million amateur players. assembling for specific events is a uniquely human behavior, though the formal study of crowds did not begin until the mid-twentieth century. today mass gathering medicine focuses on the public health challenges to hosting events attended by a large enough number of people, at a specific site, for a defined period of time, likely to strain both the planning and response to the mass gathering of a community, state, or nation. all of us can recall attending a mass gathering, whether it be watching one's favorite rock group in performance or assembling for religious pilgrimage. certainly, the event itself is transporting and transforming and the unison of behaviors and activities can be enormously enriching, uplifting and overwhelming, just as much as they may be at times dangerous and high risk. this review seeks to draw contrasts and comparisons between sporting gatherings and religious gatherings with a chief focus on hajj, among the largest of all mass gatherings today. we will find there are some powerful similarities as well as stark differences. each bequeaths a legacy which can inform the other and, as we make our observations, we join with you and the legions of other investigators who continue to remain fascinated and enthralled by mass gatherings which are among the most beloved and beholden events of modern humanity. human behavior has long engaged in collective behavior assembling in crowds. built 2500 years bce, stonehenge in the british isles is thought to be the first monument and evidence of mass gatherings in the pre-historic era [1] . numerous burial sites have been found at the now designated unesco world heritage site adding to the belief that it was a focus of spiritual energy and ritual. christian pilgrimage to the holy land has been recorded since the 4th century. the hajj, islam's great pilgrimage, has existed for fourteen centuries of which a body of literature devoted to the travelogues of the hajj has existed for over ten centuries [2] . in 1750, thomas gray's 'elegy written in a country churchyard' referred to the 'madding crowd's ignoble strife' at once holding forth the sobriety on common ordinary country folk in contrast to the madding crowd which drove men to disgraceful uncontrolled and even violent behavior captured in the timeless phrase [3] . in 1852 charles mckay published his treatise on "extraordinary popular delusions and the madness of crowds" writing that 'men, it has well been said, think in herds; it will be seen that they go mad in herds, while they only recover their senses slowly, and one by one,". in 1874, the great writer thomas hardy wrote a novel which still remains recognized as a masterpiece of english literature, "far from the madding crowd,' focusing on the lives of rural dwellers who were left behind by the madding crowd of industrialization. even today the 'madness of crowds' continues to fascinate and enthrall. assembling for specific events is a uniquely human behavior, though the formal study of crowds would not begin until the mid-twentieth century. the civil rights movements sweeping across the united states in the1960s and the crowds that cycles of violent lynchings had drawn prior, first captured the attention of behavioral scientists interested in public gatherings. psychologists referred to the 'collective mind' (first observed by 1895 thinker gustav le bon) that developed when large numbers of people gathered to be together, and the 'de-individuation' that followed as a result whereby not individuals, but the larger group determines actions accounting for violence destruction and even murder that could result [4] . two schools of investigation developed, those focusing on disaster reliefthe public health needs of large number of people escaping or evacuating from a threat-and those who studied protest events. while many theories of behavior were proposed, researches remained mostly removed from the gatherings themselves and very little research was performed by direct observation of public gatherings themselves. at the time, modern travel had not yet permitted some of the massive scale of gatherings which have become commonplace since the late twentieth century. today mass gathering medicine focuses on the public health challenges to hosting events attended by a large enough number of people at a specific site for a defined period of time to strain the planning and response of a community, state, or nation. the definition is purposefully not linked to the size of the gathering or the number of people because each community has a varying capacity to manage crowds of people. all of us can recall attending a mass gathering, whether it be watching one's favorite rock group in performance or assembling for religious pilgrimage. certainly, the event itself is transporting and transforming and the unison of behaviors and activities can be enormously enriching uplifting and overwhelming, just as they may be at times dangerous and high risk. this review seeks to draw contrasts and comparisons between sporting gatherings and religious gatherings with a chief focus on hajj, among the largest of all mass gatherings today. we will find there are some powerful similarities as there as stark differences. each bequeaths a legacy which can inform the other and as we make our observations we join with you and the legions of other investigators who continue to remain fascinated and enthralled by the mass gatherings which are among the most beloved and beholden events of modern humanity [5] . as this article goes to press, one of the most awaited mass gatherings in modern historythe fifa world cup 2018 is underway [6] . the size of football is difficult to comprehend, nothing else compares in scale: football dwarfs the united nations, and even coca-cola, in international reach. across the globe, almost most five million referees, assistant referees and officials are directly involved in football, a sport played worldwide by more than 1.5 million teams and in 300,000 clubs. most people however play outside of the officially organized sphere. more than 4 percent of the global population plays football, including 270 million amateur players. 3. monotheisms, long congregating in mass gatherings, are on the rise most people are religiously affiliated. according to the pew research center report examining the global religious landscape published in december 2012, over 5.8 billion people-adults and children-are religiously affiliated [7] . at the time of this survey conducted examining more than 230 sovereign nations and territories, this amounted to 84% of the world population. while religions diversity is panoramic, three theisms predominate: christianity, islam and hinduism. the pew study examined 2500 censuses surveys and other registers of population finding 2.2 billion christians (32% of the world's population), 1.6 billion muslims (23% of global population) and 1.0 billion hindus (15% of global population). a half billion identify as buddhist and 14 million as jews-followers of judaism [7] . some 400 billion follow folk or traditional religions (including african traditional religions or chinese folk religions or native american religions). and, while well known, a tiny proportion-less than 1% of the earth's population-follow other religions including the yazidism, the bahai faith, sikhism, zoroastrianism and others. worth noting is that the religiously unaffiliated are themselves a group of over 1 billion-16% of the global population as populous as some leading theisms. the unaffiliated include atheists, agnostics and those declining to identify with any religion on surveys [7] . yet the fastest growing population in the world is the muslim population-it is expected to increase by 35% in the next twenty years [7] . by 2030 the global muslim population is expected to reach 2.2 billionrising more than twice the rate of the non-muslim population at a 1.5% growth rate compared to 0.7% annual growth rate for non-muslim populations. while slower than the 2.2% annual growth rate of muslims in the past thirty years, by these calculations, muslims will account for 26.4% of the 8.3 billion global population estimated by 2030. while the muslim world is long familiar with hosting one of the world's largest mass gatherings-the hajj, islam's pinnacle of worship which centers on mecca in saudi arabia, and to where millions of muslims travel from within the muslim world to the saudi kingdom -a sporting event of the scale of the world cup, itself one of the world's larger mass gatherings is an unprecedented mass gathering event. among religious gatherings, it is also the best studied informing the public health risks of mass gatherings across the world. in some ways football, the beautiful game reaches the dimensions of a religion given its vast appeal and global reach and devoted followers. but it is useful to consider the world cup as a sporting event on a par with the summer olympics and the more recently developed para-olympics while the hajj as a mass gathering centering on islamic belief is better understood within the context of other mass gatherings centered on other theist belief systems including the hindu kumbh mehla, world youth day and other pilgrimages [8] [9] [10] . christian mass gatherings include the world youth day, held every two or three years by the catholic church when almost a quarter of a million young catholics attend a mass gathering centered in varying cities for a live event anchored by the pope, first initiated by the late pope john paul ii in 1985 [10] . world youth day will be next held in more well-known and rooted in centuries of observance may be the christian pilgrimage to lourdes in france, a year-round event drawing more than 5 million in worship. lourdes, a small town in the southern pyrenees, itself has a population only of 15,000 yet because of the pilgrimage which has existed since 1858, it is now the second most visited city in france, second only to paris. in the catholic world, it is the third most important site of pilgrimage after the holy land and rome [12] . in asia, on one day, almost 8 million catholics gather in christian procession for the feast of the black nazarene. the black nazarene is life-sized wooden statue of jesus christ crowned with thorns believed to have been brought from mexico to manila on a galleon in 1606 by spanish missionaries. the galleon that carried it to the philippines caught fire, but the charred statue survived and was named the black nazarene. devotees gather for the 20-h procession around the holy icon which followers believe delivers miracles. the world's largest mass gathering however occurs in india. the kumbh mela is held periodically over twelve-year cycles, rotating in four different indian cities-allahabad, nasik, ujjain and hardwar. over 120 million hindus gather in each location at the banks of major rivers, including the ganges and the yumna in which pilgrims bathe as an act of worship on up to six important bathing days [9, [13] [14] [15] . worshippers assemble at each location over a three-month period during which time the festival is held, alternating at the different locations four times in every twelve-year cycle. festivals go on for 55 days in total. the bbc has reported that on a single day up to 30 million worshipers have gathered simultaneously [13] . these mass gatherings dwarf hajj, islam's pinnacle of worship centered on mecca, though both share the risk of human stampede [16] . islam's hajj however is the best studied of all mass gatherings and has driven much of the scientific enquiry into the modern mass gathering. as many as three and a half million muslims from 187 countries around the world gather for what is considered the final pillar in islam returning them to islam's birthplace in order to perform hajj. hajj is a series of week-long religious rites retracing the prophet mohammed's final visit to mecca during which he drew the lines of islamic pilgrimage which still stand today and delivered his final sermon revealing the final verses of the quran and sealing the foundations of islamic belief. even today, true to the prophet mohammed's final hajj, the modern hajj incorporates the prophet abraham's footsteps centuries before islam's inception and the legends of hagar, ishmael, adam and eve. with the rise in muslim population the hajj can be expected to grow in attendance and saudi arabia is preparing for these increased capacities investing in massive construction and infrastructure developments accordingly saudi arabia has committed $100 billion in both land and infrastructure expansion with much of this work ongoing [16] . the king abdul aziz international airport and the expansion of the haram sharif-the grand mosque surrounding the ka'aba-is to be completed 2018/2019. 'haramain' a high speed above ground railway linking mina to medina, the second holiest city in islam (often included in hajj rites) will be completed this year but opened to the public after extensive testing in 2018. the mecca-metro project connecting a four kilometer long station and two metro stations to the tune of $16.5 billion will be completed by the decade's end, greatly relieving congestion at the focal site of hajj. possibly the most beloved sporting events of all time are the olympics inspired by the athletic games held in ancient greece as far back as the 4th century bce. the modern olympics were conceived in 1894 with the formation of the international olympic committee which has governed every olympics since the games were first revived in 1896 [17] . olympic games draw mass gatherings. the london olympics in 2012 drew 8 million in attendance paying high prices for tickets. the more controversial and beleaguered rio olympics for 2016 sold only 82% of the 5 million tickets available even though the tickets were significantly cheaper [18] . regardless, the olympics, whether summer or winter and its counterpart, the special olympics, draw millions in attendance to watch the pinnacle of elite amateur sports. nation states win an intensely competitive bidding process to secure the event, which (like the fifa world cup) can define a nation and celebrate its culture. hosting the olympics is considered a rare privilege and nations, once winning the bid, work intensely during the seven-year lead time to the event to prepare both an appropriate legacy and also the necessary infrastructure for the events: olympic villages for the athletes, and the necessary response systems needed for health, security and disaster response. these are enormously costly events. perhaps it is the modern olympic games which have most inspired the foundations of studying medicine during sporting events physicians as david s jones noted physicians 'only slowly became interested' 'mostly in marathons' when the winner of the 1904 st. louis olympic marathon required four physicians in attendance after the race, due both to heat exposure and the pre-competition strychnine he had taken for performance enhancement [17] . by 1920, medical examinations for athletes had become mandated and in 1924. the united states sent its first physician with its olympic team to paris. slowly medicine began to interface with sports, igniting the field of sports medicine for the elite athlete. almost a hundred years later, today all attendees-spectators and athletes alike-are known to be exposed to risks which could endanger health during these spectacular events and the science of mass gathering medicine has come into view informed by the experience of managing the public health at these huge events. equally prestigious and just as hotly contested is the fifa world cup held every four years. this year's fifa world cup in 2018 is being held in russia, and the subsequent has been awarded to qatar, in 2022. interrupted only by world war two, the world cup has continued since its founding in 1930 held in uruguay, which, even then, drew more than half a million attendees. the brazil world cup in 2014 drew 3.4 million attendees. in all more than 35 million people around the world have attended a world cup event yet today in the televised era it commands audiences of billions [19] . the revenue generated by the fifa world cup is extraordinary -$5.7 billion during brazil 2014 -because of the cumulative television audiences watching all the matches and lucrative sponsorship dealsmore than 26.29 billion watched the 2006 world cup [20] . audiences can only be expected to be bigger in the era of live-streaming, enabling anyone with an internet connection to tune in, sometimes to watch games more than once. because of its scale, the fifa world cup is the most viewed sporting event today. given its unique experience and unparalleled popularity, fifa has contributed important understandings to the management of mass gatherings in both public health and public security aspects. legacy building has been very critical to fifa and is a deal-breaking aspect of each competitive bid, and often a focus of criticism after events. the crowds at mass gatherings are a captive audience and vulnerable to environmental, physical, infectious and non-infectious hazards. they are also increasingly prime targets for terrorism including bioterrorism. whether a sporting or religious gathering these risks are shared though their nature may vary [21] [22] [23] . both religious and sporting events can be at risk of stampedes which can evolve whenever crowds gather. while human stampede is lethal and devastating (forces of up to 4500 n/m can be generated by several people pushing in panic) with death resulting from acute venous hypertension, traumatic asphyxia, crush injuries to the torso and other catastrophic trauma, investigators in the field of human stampede note even in this modern era that there is a serious lack of high-level epidemiological data examining human stampedes. as a result, both experts and casual observers are mistakenly influenced by unbalanced media focus which trains its scrutiny on hajj each year and may be mislead in believing it is the only mass gathering at risk of stampede, and the single most frequent site of human stampedes. neither of these assumptions are true. hsu et al. searched both research and unconventional sources including media reports for evidence of human stampede incidents [24] . [25] . certainly, of the top ten most lethal human stampedes, seven occurred at religious gatherings, not exclusively the hajj but also other religious events. in india, 79% of all human stampedes occurred at religious festivals according to a recent exhaustive review [26, 27] . non-religious mass gatherings were also the site of human stampedes including political gatherings, sports events, entertainment venues and spontaneous gatherings. in phnom penh in 2010 a shopping stampede on black friday (usually implying major sales) resulted in 347 deaths [24] . but most human stampedes occurred not in the arabian peninsula -home of the hajj-but in developing nations in africa and southern asia. together south asia and africa suffer over half of the world's human stampede. yet each year, media coverage focuses intensely on saudi arabian hajj sites (mecca, medina, muzdalifah and arafat) devoid of this context. when stampedes occur in the developing world, mortality is more than eight-fold greater than when the stampede occurs in advanced societies like saudi arabia. this increased fatality is a result of lack of planning, inexperience with crowd management and crowd control, scant emergency services, limited trauma care and infield emergency services and limited onsite and first responder communication capabilities. saudi arabia each year goes to intense effort to prevent stampede, one of many physical hazards associated with hajj and as a result stampedes have been few and rare. despite a spiritual reluctance to bar any eligible muslim from hajj, saudi arabia does limit hajj attendees through global visa quotas. also, once a local muslim in ksa has been to hajj, hajj visas cannot be issued for the next five years limiting frequent performers of hajj. yet the major improvements in hajj crowd management have been through engineering: the multilevel bridge at jamarat, site of the stoning ritual which has been a previous site of stampedes at hajj; the re-engineering of the pillars at mina into elliptical columns in place of cylindrical columns to dissipate crowd densities and reduce crowd turbulence from developing, and the development of massive pedestrian causeways which are color coded, one way, and temporally controlled to ensure steady throughput of pilgrims by controlling pilgrim ingress into these causeways through optimized schedules. movement of the hajj crowds in these areas of high density and high emotion -both risk factors for stampede-is monitored in realtime through video graphic analysis. intervention can be implemented real-time, which can be both life-and limb-saving. detailed video recordings achieved at hajj examining crowd dynamics are primarily the means of assessing the flow of hajj crowds. in the future, more sophisticated assessment is likely to be achieved in a number of additional ways-through fixed-laser scanning devices, closed circuit television and fixed gps monitors [25, 27] . while a much smaller scale, human stampede at a british football match has been more exhaustively examined than any other stampede in history. the hillsborough stadium stampede was among the most disastrous events in football and examining its causes has been instructive if extremely painful for the football community and britain in particular [28, 29] . the 1989 fa cup semi-final was held in the hillsborough stadium in sheffield on april 15th, 1989 drawing two intense rivals-liverpool and nottingham forest -for a contest place in the final for the fa cupthe biggest sporting event in british football [30]. 24,000 liverpool fans traveled to sheffield for the event. authorities knew of the rivalries between both teams and because of the propensity for vandalism and hooliganism among fans on both teams, their entry to the stadium was deliberately segregated, as were the 'pens' designated for fans of each team. because of the bottleneck at the entrance and the large numbers of attendees, fans initially poured into two central 'standing only' pens-sections of the stadium demarcated by wire barriers, unaware that to either side of them thousands of empty seats were available. no one directed the congregating crowds to these more lateral areas on the right and left. as the time for kick-off was only minutes away, the chief superintendent (the police commander in charge of the event) allowed an additional gate to open as lines of liverpool supporters outside the stadium had built up. unaware that in the central standing pens crowd density was already high, the surge of 2000 additional people resulted in 96 deaths-men women and children and more than 766 injuries. all except one were liverpool fans. hillsborough remains the worst disaster in british sporting history. in 2016, british jurors, delebrating for 259 days (the longest inquest in british history)-emerged to convict the chief superintendent "responsible for manslaughter by gross negligence" due to a breach of his duty of care. the tragedy was compounded by the fact that the hillsborough match had been the first mass gathering under his command. this spiritual commitment which is of the utmost priority for them to complete hajj to the best of their abilities adding to a religious intensity and focused commitment despite harsh and difficult physical conditions imposed on the pilgrim whether by climate or congestion often in the face of sleep deprivation and other forms of self-denial required in the spiritual state of the hajjee. pilgrims are therefore vulnerable not only to their surroundings but to a fear of not completing hajj. stampedes are known to be triggered by fear, panic and as many investigators have noted, even by rumor. live surveillance of hajj crowds is vital to help pilgrims achieve their rites safely. hajj authorities can assess mounting crowd densities, blockage of foot traffic, bottlenecks and dangerous nascent crowd turbulence which can precipitate human stampede. supervision of the crowds at hajj is unlike any other mass gathering in the world [25, 27] . interagency communication between various authorities overseeing the hajj (security forces, civil defense and special forces experienced in crowd control) and is continuous and announcements through public communication can be made if needed. sms capable networks (instant messaging via cellphones) are also available and have been used for urgent health messaging to communicate to the vast numbers of attendees simultaneously. because the hajj is so trying and muslims, enjoined by the maker, remain so committed to completing it peacefully and without infringement or desecration of anyone else's efforts in pilgrimmage, the hajj crowd works informally together, shifting to accommodate the weak, the vulnerable, the disabled who are in the teeming crowds next to them. in this way hajj, like other religious mass gatherings, is infused with a collective spirituality that can be of enormous public health benefit. further, this spirit of protecting the entire muslim community is clearly deleinated in the teachings of islam to be a metaphor for life beyond hajj for all the world's muslim community-a reminder that we must live together in harmony to peacefully collaborate and support one another through hardship and vulnerability. additionally, these values greatly enhance the pilgrim populations' receptivity to public health planners and on site security in ensuring disaster management and crisis aversion can be achieved with as much cooperation as possible. unlike religious gatherings, mass gatherings connected to sport or music events can be complicated by the availability of alcohol, recreational and illicit drugs, all of which impede the ablity of an individual to remain safe within the mass gathering and impede the ability of the crowds to behave protectively towards the vulnerable [31] . these events are usually open air, often held in undesignated locations (particularly when considering electronic dance raves and may not benefit from experienced professional organizers). sometimes events are held in underground locations which were never designed to accommodate such capacities. participants are generally younger in age than those attending religious gatherings or the diverse ages seen in attendance of sports gatherings. music festivals, particularly the electronic dance movement event, are increasingly associated with intoxication and injuries [32] . targeting young people aged 15 to 25 they draw large crowds, sometimes in unregulated venues, but increasingly today in purpose-built locations. alchohol overuse and recreational drug use are commonly associated with these events. both mdma (3,4 methylenedioxy-n-methylamphetamine) and the notoriously named date rape drug (gamma hydroxybutyric acid) are liberally used at these events. lund et al. report that in a fifteen year period 68 deaths were recorded of drug related overdose at electronic music dance events. violence at such events has also been recorded with participants reporting stabbingssome severe enough to result in tube thoracostomy. matters are worsened by the fact that many participants self report ' preloading'drinking alcohol prior to entry to the event, a common practice at american events which can occur during 'tailgating'when americans often picnic around the trunk of their cars in the parking lots of the venues. while for most american families this means an innocent meal of hamburgers and hot dogs, for youngsters attending rave events this could mean 'preloading' particularly if attendees to the raves are under legal drinking age, adding to their vulnerability. excessive alcohol consumption with or without recreational drug use increases the risk of injury, sexually transmitted disease and extreme behaviors like the recently fire jumping and more traditional risks of sexual assasult. while the focus of this paper has been primarily planned mass gatherings, mass gatherings can erupt spontaneously. one such phenomenon is the celebratory riot which can develop for instance when a sporting team wins a match or tournament. hawkins et al. describe the spontaneous mass gathering of 52,000 fans which assembled when the university of north carolina men's basketball team played in the national collegiate athletic association, final four semifinal and national championship games in st. louis, missouri in the united states [32] . as a result of the matches, back in the team's home state of north carolina, two mass gatherings assembled on two consecutive nights drawing a total of 52,000 fans. celebrating their team, they lit bonfires in the downtown area of chapel hill where they were congregating and began fire jumpingjumping and dancing through the flames by way of a victory dance. a total of 58 revelers needed medical care including 27 from the on-the-ground ems responders and a total of 49 who needed emergency room admission. the average age of the injured was 23.8 years and they were predominantly male. most -65%had medical complaints relating to alcohol and didn't need hospital admission. of those who were admitted to hospital, one third had burns from firejumping. these injuries are a function of the sponetnaeity and unplanned nature of these mass gatherings which unlike planned mass gatherings lack well defined boundaries. revelers have no idea of how ems will reach them should the need arise, nor of the disruption to access, and public health demands by their incohrenent mass activities. further, such spontaneous gatherings are componded by the use of excessive alcohol and illicit drugs. the crowds unlike a catholic crowd at world youth day or a muslim crowd at hajj is widely diverse in their compositionwhile some revelers maybe hardcore hooligans or hoodlums others have never attended a mass gathering. the propensity for deliberate violence and even sexual assault can be created especially when vulnerable inexperrinced attendees find themselves caught in the melee. even the mood of the crowd-the collective mind-as earlier researchers referred to it-can vary from benign to malignant, from celebratory to activitely destructive. sexual assault can manifest in such circumstances. perhaps one of the most extraordinary sponetaneous mass gatherings of the last decade is now dubbed "tahrir square" first at the time of the arab spring reaching egypt in feburary 2011 and later, in response to newly elected mohammed morsi being deposed by a military coup in july 2013. while no academic papers exist in the literature at the time of writing concerning sexual assault at tahrir square, the mainstream media reported extensively on sexual assaults impacting women protestors at tahrir sqaure, shocking many in the region, particularly in the muslim majority world. sampsel et al. published the first reports of mass gathering associated sexual assault [33] . important data reported by sampsel et al. reveals that sexual assault occurs at mass gatherings peaking on specific holiday events-new years eve, canada day, halloween and university freshmans' week. women were more often assaulted if they were of younger age, had consumed alcohol or drugs and unlike most sexual violence which befalls women aged 18 to 30, the assailant at mass gatherings was not previously known to the victim. more often than not, victims declined to release the findings of their 'rape kit' as evidence to the police in the hope of seeking prosecution. the sexual assaults at these mass gatherings occurred both within a friend's home and also outdoors, as in tahrir square. unlike sexual assaults occurring independent of mass gatherings, the majority of women did not know their assailants suggesting perpetrators may seek out mass gatherings as cover for predicating sexual assault on vulnerable victims. sampsel noted the increase in sexual assault events in conjunction with mass gatherings which fell on canadian holidays and surmised that in this occassions the consumption of excess alcohol was more likely. sexual assault transpires much more often when the victim has consumed excess alcohol often spiked with covert drugs in an effort to render the victim unconscious and unable to resist assault. these patterns support the view that the nature of the revelry, and the young female revelers assembling in this gatherings are additionally vulnerable because of social behaviors at such mass gatherings leading to drug faciliated sexual assault. sixteen years post 9/11, it is impossible to consider mass gatherings independent of terrorism irrespective of their location. because of both the magnitude of citizens gathering at mass gathering events whether for celebratory or spiritual purposes, the prize of disrupting a civilian event often garnering extraordinary mass media attention proves very tempting for nefarious actors [34] . terrorists seek two goals: one to physically disrupt, kill and maim as many innocents simultaneously, and do so with maximum digitally transmitted reverberations to enhance the impact of their attacks. but they also act to instill fear and immobilization in the target population both at the event targeted, but more importantly in the desire to return to normal life. mass gatherings present perfect targets for both these goals. vulnerable events include political, sporting, entertainment events-political party conventions, sporting tournaments like the superbowl, the olympics or the fifa world cup. us experts in homeland security remark that when events tie mass gatherings of the american public with specific national events of celebration -independence day celebrations for example, or events honoring the military or the nation's patriotism threats are not only perceived to be tangible but escalating in risk. hazards that must be considered are diverse. biological agents, ever since the anthrax attacks immediately after 9/11 targeting government officials, remain a major concern. many events-consider a presidential inaugrationare open air. access is very difficult to limit and the dissemination of a biological agent over such massive crowds (exceeding a million people at president obama's first inauguration) pose terrifying consequences, particularly if military grade biological weapons were released. one agent could kill hundreds or hundreds of thousands of people depending on its virulence and the dose released. it is not inconceivable that sophisticated terrorists release a biological pathogen in a mass gathering of a population with no immunity to this agent. in 2003, homeland security notes that participants in an outdoor concert contracted hepatitis a, causing morbidity among a population never vaccinated for this virus [34, 35] . american cities hosting mass gathering events take this public health security threat very seriously. as far back as 2007, when miami hosted the superbowl xli bio-surveillance activities were expanded by three county health departments and the florida state department of health. they were prepared to identify a bioterrorism attack which might have been invisible during the mass event but become apparent within a two-week window of the superbowl xli. because of the enhanced bio surveillance, public health officials identified more illnesses, injuries, accidents and absenteeism than usual. most importantly, three different public health departments were able to successful data share and coordinate their responses to real-time findings. the federal bureau of investigation (fbi) is charged with identifying and generating intelligence about potential and actual terrorist attacks throughout the united states including attacks that can endanger mass gathering events. critical to the success of advance warning for these events is a clear line of communication and excellent education of the fbi concerning mass gatherings. a key recommendation the us committee on homeland security made was for the development of a national medical intelligence program which would enable combined knowledge of public health concerning bioterrorism to be located within a knowledge base of domestic intelligence concerning potential actors. critical to all these events is the collaborative approach. sharing resources across sectors and agencies whether public or private entities is critical to mass gatherings being safe-guarded. without such collaboration, agencies may compete with one another and hoard information, jeopardizing not only the mass gathering event but also the host city which may well swell in population to become transiently some of the largest cities in the country for the duration of the mass gathering event. global health security is a relatively novel concept: galvanizing public health responses to threats which could imperil the global community. most recently three pathogens have captured the imagination driving the movement to formalize a global health security agenda-literally a world prioritization of threats to public health security [17] . the ebola virus epidemic, the influenza pandemic and the mers-corona virus outbreaks in the arabian peninsula and south east asia all demonstrated the need for urgent coordinated international responses to avert devastating international impact. periodically health ministers from around the world meet to set the global health security agenda and streamline a multidisciplinary and coherent response to contain these threats. while a global health security agenda for mass gatherings has not been proposed, saudi arabia, in its experience of managing the hajj recognized at the inaugural meeting on mass gathering medicine in jeddah 2010 formalized the discipline of mass gathering medicine. six years on, it is time the mass gathering community call for proposals to set a global health security agenda for planned mass gatherings around the world. certainly, yellow fever while not yet a global threat, is a serious consideration for all mass gatherings receiving international visitors. certainly, each country hosting a mass gathering, whether religious or sporting, must enact surveillance and disease reporting mechanisms during the mass gathering events themselves to be able to identify case clusters or even infectious disease outbreaks. control measures and means to prevent these infections being exported back by the attendees to the attendees' countries of origin must be in place. countries receiving participants in events whether a religious pilgrimage or a mass sporting event must be ready with a public health surge capacity to respond to returning travelers especially at a time of heightened awareness of outbreak potential. surge capacity is especially important if host country's health systems are not to be depleted or placed under undue strain during mass gathering events. both authors declare no conflict of interest. one thousand roads to mecca: ten centuries of travelers writing about the muslim pilgrimage paperback the myth of the madding crowd (social institutions and social change) by clark mcphail (author) the psychology of health and wellbeing in mass gatherings: a review and a research agenda qatar steps up to global health security: a reflection on the joint external evaluation religious mass gatherings: connecting people and infectious agents a comprehensive review of the kumbh mela: identifying risks for spread of infectious diseases an influenza outbreak among pilgrims sleeping at a school without purpose built overnight accommodation facilities the practice of pilgrimage in palliative care: a case study of lourdes world's largest mass bathing event influences the bacterial communities of godavari, a holy river of india using mobile technology to optimize disease surveillance and healthcare delivery at mass gatherings: a case study from india's kumbh mela safeguarding the faithful -saudi arabia takes the long view olympic medicine twenty years of the fifa medical assessment and research centre: from 'medicine for football' to 'football for health the quest for public health security at hajj: q.a. ahmed the who guidelines on communicable disease alert and response during mass gatherings advancing the global health security agenda in light of the 2015 annual hajj pilgrimage and other mass gatherings cambodian bon om touk stampede highlights preventable tragedy the impact of crowd control measures on the occurrence of stampedes during mass gatherings: the hajj experience human stampedes during religious festivals: a comparative review of mass gathering emergencies in india crowd and environmental management during mass gatherings the hillsborough tragedy mass-gathering medicine: risks and patient presentations at a 2-day electronic dance music event fire jumpers: description of burns and traumatic injuries from a spontaneous mass gathering and celebratory riot characteristics associated with sexual assaults at mass gatherings committee on homeland security. majority staff report examining; public health, safety, and security for mass gatherings key: cord-312691-ynh84b98 authors: mohd, hamzah a.; memish, ziad a.; alfaraj, sarah h.; mcclish, donna; altuwaijri, talal; alanazi, marzouqah s.; aloqiel, saleh a.; alenzi, ahmed m.; bafaqeeh, fahad; mohamed, amal m.; aldosari, kamel; ghazal, sameeh title: predictors of mers-cov infection: a large case control study of patients presenting with ili at a mers-cov referral hospital in saudi arabia date: 2016-09-24 journal: travel med infect dis doi: 10.1016/j.tmaid.2016.09.008 sha: doc_id: 312691 cord_uid: ynh84b98 background: a case control study to better characterize the clinical features, laboratory, and radiological abnormalities associated with mers-cov infection in order to help with early identification of this syndrome from other respiratory infections. methods: eighty patients admitted to a hospital in riyadh, diagnosed with mers-cov infection based on rt-pcr were matched on age, sex, and the presence of a co-morbid condition on a basis of 1:2 to other patients admitted with respiratory symptoms and tested negative for mers-cov on rt-pcr. results: none of the reported mers-cov presenting symptoms was significantly associated with being infected with mers-cov. on the other hand, wbc count was significantly lower in patients with confirmed mers-cov infection (median 5.7 vs 9.3, p: 0.0004). neutrophil count was as well significantly lower in mers-cov patients (median 3.7 vs 6.7, p: 0.0001). both ast, and alt values were significantly higher in mers-cov infected group (ast median 42 vs 36, p: 0.03, and alt median 33 vs 28, p: 0.003). overall our mers-cov mortality rate was (10%) below the national figure of (40%). conclusions: none of the presenting symptoms are specific for mers-cov infection. and out of all the investigations wbc, neutrophil counts, ast and alt values have some predictive utility. mers-cov is a novel betacoronavirus that was discovered in 2012 after it was isolated from the respiratory secretions of a patient in saudi arabia who died with acute respiratory syndrome [1] . so far, all reported cases were diagnosed in the arabian peninsula (mainly saudi arabia) or epidemiologically linked to it [2e7] . up to april 2016 more than 1360 cases have been reported in saudi arabia alone with a mortality rate that exceeded 40% [8] . though the disease is believed to be zoonotic with strong evidence towards a camel reservoir [9e14], major outbreaks are believed to be nosocomial involving transmission within health care facilities [2,15e18] . early after its discovery, mers-cov infection screening was limited to those critically ill with severe acute respiratory illness [17,19e21] . later on the saudi arabian ministry of health issued guidelines for mers-cov screening in which they limited suspect cases to patients with clinical or radiological evidence of pneumonia, patients with respiratory illness along with a history of possible exposures to a mers-cov patient, and patients with unexplained acute febrile illness with hematological laboratory abnormalities (leukopenia or thrombocytopenia) and gastrointestinal or respiratory symptoms [22] . many studies were conducted in saudi arabia to characterize the illness associated with mers-cov [17,19e21] , but they were limited by the small sample size. studies done elsewhere were limited as well by the extremely small sample size [3e7], except in south korea where a large outbreak occurred between may and july of 2015 due to an imported case from the arabian peninsula [2] . travel associated cases have been observed in europe, notably in uk, france, germany, austria and italy with secondary cases in close contacts of index cases without a travel history suggesting person-to-person transmission [22e25] . in this study we tried to overcome the previous limitation by studying a larger cohort of mers-cov patients at our facility and comparing it to a control group in an attempt to look for predictors of mers-cov infection. in this study we followed a cohort of patients tested for mers-cov infection at prince mohammed bin abdulaziz hospital (pmah) emergency department, a governmental hospital in riyadh, saudi arabia, between april 1st 2014 and september 30th 2015. patients who were felt to have influenza like illness (ili) were screened for mers-cov and all patients who required admission and had any respiratory symptom (cough, shortness of breath, sore throat) were screened for mers-cov infection and followed up until discharged. we also included patients who were called for admission after a positive mers-cov test that was done at an earlier visit to our emergency department and individuals who were hospital quarantined due to a significant exposure history to a mers-cov patient. as pmah is the mers-cov referral center for governmental (public) and private hospitals in riyadh, saudi arabia, we excluded patients who were already diagnosed with mers-cov at other facilities and referred to our hospital for isolation and further management. due to the great heterogeneity of this cohort, and in an attempt to look for predictors of mers-cov infection, we matched the patients who tested positive for mers-cov (cases) to a control group from the rest of the study population who were admitted and repeatedly tested negative for mers-cov. we extracted a matched control for the positive cases based on age (within 5 years of age), gender, and presence of any comorbidity. the attempted matching was 1 case to 2 controls. respiratory samples (nasopharyngeal swapping or tracheal aspirates) were obtained from all patients and tested for mers-cov infection using real-time reverse-transcription polymerase chain reaction (rt-pcr). the specimens were submitted to and testing was carried out at the saudi ministry of health mers-cov regional laboratory. the test amplified both the upstream e protein (upe gene) and orf1a for mers-cov. a positive case was determined if both assays were positive. each patient was tested at least twice, each on a different day. reporting suspected and confirmed cases was the original purpose of data collection which was initially limited to date of admission, sex, age, nationality, designated hospital ward, results/dates of mers-cov testing, and patients' outcomes. data concerning presenting symptoms: fever, sore throat, cough, shortness of breath, and gastrointestinal symptoms (nausea, vomiting or diarrhea), as well as the initial laboratory work up: white blood cell count (wbc) 10 9 per liter, hemoglobin (hgb) grams per deciliter, platelets 10 9 per liter, creatinine micromoles per liter, albumin gram per liter, aspartate aminotransferase (ast) units per liter, alanine aminotransferase (alt) units per liter, and initial chest-x-ray (cxr) results were later extracted from the electronic medical records. we summarized the data by descriptive statistics. frequencies and percentages were calculated for categorical variables. continuous variables (mainly laboratory values) tended to have skewed distributions; thus we used medians rather than means. a conditional logistic regression analysis was conducted to identify the variables that are independently associated with mers-cov infection. the magnitude of association, presented as the odds ratio and 95% ci was also determined this way. all reported p values in this article are also based on the logistic regression. the laboratory measures were found to not be linearly related to the logit of mers-cov infection, so the values were broken into 4 approximately equally sized groups (via quartiles, referred to as quarters) and odds ratios estimated for each as compared to the first quartile as reference. note that for analysis of laboratory measures, a few people had to be excluded due to missing values. we used sas version 9.4 (sas institute, cary nc) to perform all of the analysis. the significance level for all of the statistical tests was set at 0.05. from 24,606 patients who presented to our emergency department between april 1st 2014 and september 30th 2015 with respiratory complaints, 3148 were tested for mers-cov. from those who were screened, only 757 patients were admitted. eighty one patients tested positive for mers-cov and the rest, 676 patients, repeatedly tested negative and were used to find matches to mers-cov cases. see fig. 1 . we were able to match all but two of the confirmed mers patients. for one of them we were only able to find one control, and for the other no match was found. this resulted in a total of 239 patients for analysis. table 1 shows the characteristics of both the mers-cov infected group and the control group. the median age for mers-cov patients was 40 years; 60% were males, 66.2% were saudi, and 16.2% were health care workers. 46% had at least one co morbidity; hypertension and diabetes were the most common. 80% of mers-cov patients were symptomatic; fever was the most common symptom among mers-cov infected group 58.7% (73% of the symptomatic patients), followed by cough 52.5% (73% of symptomatic patients). shortness of breath was the third common symptom that was reported by 37.5% of mers-cov infected patients (47% of the symptomatic patients). around 17.5% of mers-cov infected patients reported gi symptoms (22% of the symptomatic patients). sore throat was reported in 13.7% (17% of the symptomatic patients). in mers-cov infected group the median value for wbcs was 5.7 (iqr: 4.1e8.6), neutrophils 3.6 (iqr: 2.2e5.3), hgb 145 (iqr: 128e157), platelets 205 (iqr: 148e270), albumin 37 (iqr: 34e42), ast 42 (iqr: 26e105), alt 33 (iqr: 21e93), and creatinine 68.1 (iqr: 60.8e81.9). all of the above mentioned medians were within the normal ranges. almost 51% of mers-cov patients had chest x-ray findings upon admission. around 19% were sick enough to be admitted directly to the icu, and around 10% of mers-cov infected patients expired. as discussed above, matching was based on age (within 5 years of age), gender, and presence of any comorbidity. 64.8% of the control group were saudi and11.3% were health care workers. hypertension and diabetes were the most common comorbidities. 95% of the control group patients were symptomatic; fever 64.1% and cough 59.1% were the most commonly reported symptoms in the control group. around 35% complained of shortness of breath, and 14.5% had a sore throat. 13.8% of the control group reported gi symptoms. laboratory analysis showed a median wbcs value of 9.3 (iqr: 6.0e14.2), neutrophils 6.7 (iqr: 3.7e11.1), hgb 138 (iqr: 114e153), platelets 238 (iqr 170e338), albumin 36 (iqr: 32e41), ast 36 (iqr: 23e62), alt 28 (iqr: 14.5e48.5), and creatinine 70.1 (iqr: 61.4e86.9). almost 58% of the control group patients had chest x-ray findings upon admission. around 16.3% of the control group patients were sick enough to be admitted directly to the icu on presentation, and 4.4% of the control group patients expired during their hospital stay. there was no statistical difference in the proportion of saudi nationals (66.2% vs 64.8% or, 1.07; p z 0.82) as well as health care workers (16.2% vs11.3% or, 2.20; p z 0.16) between the confirmed and matched groups. though confirmed mers-cov patients were statistically less likely to be symptomatic (80% vs 95% or: 0.21; p: 0.001), no statistically significant differences between the two groups were found in regards to frequency of a specific symptom (fever, cough, shortness of breath, gastrointestinal symptoms or sore throat with p values of 0.43, 0.35, 0.74, 0.42, and 0.89 respectively). this was as well the case in regards to the presence of chest-x-ray findings upon admission (50.7% vs 57.8%, or: 0.72; p: 0.27). no significant statistical difference was observed between the mers-cov confirmed group and the control group in regards to intensive care unit need upon admission (18.7% vs 16.3%, or: 2.29; p: 0.67). though mortality rate seemed to be higher among mers-cov infected group, this was not statistically significant (10% vs 4.4%, or: 2.29; p: 0.11). the median wbcs counts (5.7 vs 9.3), as well as the median neutrophil counts (3.6 vs 6.7) were both lower in the infected group, and that was statistically significant (p values 0.0004 and 0.0001 respectively). the median alanine aminotransferase (alt) value was higher among mers-cov infected group compared to the control group (33 vs 28, p: 0.003). that was as well the case with aspartate aminotransferase (ast) (42 vs 36, p: 0.031). there was no statistical difference in the median values for hgb, platelets, albumin, and creatinine between the two groups, although the relationship for hgb was marginally significant (p values of 0.07, 0.22, 0.84, and 0.58 respectively). table 2 displays comparative analysis of significant laboratory values between confirmed and suspected cases. the odds of being a confirmed case was significantly lower for those with wbc in the 3rd and 4th quarters (wbcs 8.2) as compared to the reference category of patients with wbc less than the 25th percentile (wbcs < 4.8). the odds of being a confirmed case was significantly lower for those with neutrophil values in the 3rd and 4th quarters as compared to the reference category of patients with neutrophil less than the 25th percentile, with odds ratios 0.22 and 0.18 respectively (quartiles 2.93, 5.06, 9,38) for neutrophil. the median alt values were higher for those with confirmed mers-cov infection as compared to those without (median 33 vs 28 respectively). the odds ratios were significantly increased for patients with confirmed mers when alt values were in the 2nd and 4th quarters (alt 17e29, and alt > 60) as compared to patients with alt values in the lowest quarter (alt < 17); or z 3.72 and 5.94 respectively. patients with values between 29 and 60 did not have statistically significantly increased odds of confirmed mers. patients with confirmed mers had higher median values of ast (42 vs 36). patients with ast greater than 76.5 had statistically significant higher odds of having confirmed mers than those in the lowest quarter (values less than 24) with an odds ratio of 3.31, 95% ci: 1.24, 8.86. as observed in previous studies [17,19e21] , we found that having wbcs and neutrophil counts within the normal range is more likely to be associated with mers-cov. by comparing our cohort of mers-cov patients to another cohort of 47 patients diagnosed with mers-cov between september 2012 and june of 2013 described by assiri et al. [21] we can notice that both cohorts were predominated by male sex (60% vs 77%), though ours had a lower male proportion. male predominance, which was observed in almost every surveillance study [17,19e21] could be related to the culture in saudi arabia, where women wear veils that cover both the nose and mouth and may help protect from exposure, along with decreased outdoor activities compared to men. our patients' median age was 40 years compared to a median age in the range of 50e59 in the previous cohort. fever (59% vs 98%), cough (53% vs 83%), and shortness of breath (38% vs 72%) were the main symptoms, though our patients were less likely to be symptomatic. we also noticed that our patients were less likely to have co morbid conditions (46% vs 96%), less likely to have chest-x-ray abnormalities (51% vs. 100%) and had a significantly lower mortality (10% vs 60%). all this implies that, earlier in the outbreak, screening and diagnoses were limited to the very sick population who subsequently had a high mortality. in our patient population we were liberal in screening any potential admission who complained of respiratory symptoms and due to very strict infection control program we included individuals who were quarantined due to a significant exposure history to a mers-cov patient. by doing so we were aiming at preventing a possible mers-cov outbreak related to inadequate infection control measures. this helped uncover many asymptomatic or mildly symptomatic cases. this might also imply that the true burden of the disease in the kingdom is still uncovered and that we might be just seeing the tip of the iceberg. this theory was first brought up after a nationwide, crosssectional, serological study done between december 1st 2012 and december 1st 2013 in which serum samples from just over ten thousand individuals, whom age and sex distribution largely matched the general population [26] . this report has far reaching implications. in this study we found that none of the presenting symptoms helped distinguish those with mers-cov infection from the matched control group presenting with ili symptoms. almost half of mers-cov patients had no cxr abnormalities on presentation. in addition to raising significant questions on the validity of the current moh suspect case definition, this will challenge the practicing physicians in the emergency room in endemic and non-endemic countries on how to deal with patients presenting with ili symptoms [27, 28] . even with access to full viral panel on all ili patients and with evidence of influenza virus as the etiology, mers-cov can't be ruled out. this is based on data from iran where 3/5 mers cases had concomitant influenza infection [29, 30] . our study has a few limitations, the main being the lack of comprehensive testing for viral respiratory panels for patients admitted with ili symptoms (cases and matched controls). recently this has been added to the testing of all patients admitted with ili. a larger, prospective, multicenter study in the endemic areas is needed to better characterize the illness associated with mers-cov infection and specify its predictors. none. isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus outbreak in the republic of korea middle east respiratory syndrome coronavirus (mers-cov) the investigation team. first cases of middle east respiratory syndrome coronavirus (mers-cov) infections in france, investigations and implications for the prevention of human-to-human transmission on behalf of the mers-cov outbreak investigation team of the netherlands. middle east respiratory syndrome coronavirus (mers-cov) infections in two returning travellers in the netherlands laboratory-confirmed case of middle east respiratory syndrome coronavirus (mers-cov) infection in malaysia: preparedness and response first confirmed cases of middle east respiratory syndrome coronavirus (mers-cov) infection in the 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epidemiologic, and clinical description hospital outbreak of middle east respiratory syndrome coronavirus synthesizing data and models for the spread of mers-cov, 2013: key role of index cases and hospital transmission middle east respiratory syndrome coronavirus: a case-control study of hospitalized patients clinical aspects and outcomes of 70 patients with middle east respiratory syndrome coronavirus infection: a singlecenter experience in saudi arabia epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study infection prevention and control guidelines for middle east respiratory syndrome coronavirus (mers-cov) infection imported cases of middle east respiratory syndrome: an update travel implications of emerging coronaviruses: sars and mers-cov middle east respiratory syndrome coronavirus: current situation and travelassociated concerns presence of middle east respiratory syndrome coronavirus antibodies in saudi arabia: a nationwide, crosssectional, serological study an adult returned traveler from dubai hospitalized with an influenzalike illness (ili): middle east respiratory syndrome (mers) or influenza? infection control implications from a near mers case middle east respiratory syndrome (mers): a zoonotic viral pneumonia serial intervals of respiratory infectious diseases: a systematic review and analysis cluster of middle east respiratory syndrome coronavirus infections in iran none of the authors declared coi. key: cord-314421-j5psma9i authors: ahmed, qanta a.; memish, ziad a. title: the cancellation of mass gatherings (mgs)? decision making in the time of covid-19 date: 2020-03-14 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101631 sha: doc_id: 314421 cord_uid: j5psma9i our recommendation, as experts who have monitored health hazards at the hajj for over 15 years, especially if the situation with covid-19 continues to escalate globally is that hajj 2020 will be at risk of being suspended and a means for muslims to fulfill their rights in the future either personally or even by proxy need to be announced. the same holds true for the summer 2020 olympics in japan and for many other mgs and large gatherings. decisions in the time of covid-19 will be closely followed and will be a blueprint for other mass gatherings. the world has been put "on hold" by the emerging coronavirus outbreak which has now surpassed the combined toll of the 2003 severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) outbreaks in terms of deaths. the public health burden of the novel coronavirus disease 2019 (covid-19) is set to increase and it is a time for urgent decisions [1, 2] . two major mass gatherings (mg) -events attracting more than 25000 people in one location, -are on the horizon, with little sign of containment of the current outbreak [3] . in july, the south east asian nation japan hosts the summer olympics, shortly after the world's largest mg, the hajj, receives pilgrims to mecca, kingdom of saudi arabia (ksa) from all over the world [3, 4] . drawing muslims from over 180 nations, hajj is the single most international mg in the world. ksa, acutely aware of its international pilgrim-travelers has been vigilant of the coronavirus outbreak from its inception. while the summer olympics is at least seven years in planning, the hajj is an annual event based on the lunar calendar, for which the ksa prepares annually with a much more compressed schedule-no more than a 9-month lead time, with the dates moving 10 days in advance of the gregorian calendar annually. in 2020, hajj is scheduled to fall close to august 9th and to last up to 9 days. while the olympics will gather hundreds of thousands of attendees both in terms of competing athletes and domestic and international visitors, the hajj is islam's defining pilgrimage, a pivotal act of worship in a muslim's lifetime and one they often wait decades to fulfill. each hajj draws over 2.5 million attendees and, in some years, almost 3 million 'guests of god" as the ksa regards them. safeguarding the lives of millions of pilgrims is the cardinal duty and honor of the custodian of the two holy cities in islam. keeping hajj safe and sacrosanct are the overriding national priorities of the ksa and the ruling monarch. protecting the lives of pilgrims during hajj however is not only a matter of governing national policy for the ksa and its monarch, but a divinely ordained duty. the stakes for protecting hajj are therefore extremely high, not only in scale but also in terms of the religious mandate. while the ksa annually hosts 7.5 million religious' visitors-muslims can perform an abbreviated pilgrimage known as umrah any time of the year for which the ksa issues visas year-round. in the months leading up to ramadan-beginning this year on april 23rd and later the hajj -anticipated in august this year, the ksa attracts longer term religious pilgrims often in ksa for some weeks to months before the pinnacle act of hajj, one of the five pillars of islamic belief. with such huge number of pilgrims from almost every nation on earth, hajj planners and the ksa government have been focused on ways to contain the coronavirus through the lens of an international perspective. because the potential for both mgs-the olympics and the hajj-to be jeopardized by the outbreak is significant, huge efforts in the ksa are underway to assess and mitigate the risks to travelers, the vast majority of whom are religious pilgrims. we predict hajj 2020 may be suspended in the interests of global safety as well as a precaution for domestic containment in the ksa [5] . while almost unprecedented-the last time https://doi.org/10.1016/j.tmaid.2020.101631 received 11 march 2020; accepted 13 march 2020 hajj was canceled predates the formation of the modern ksa, islam mandates that the sanctity of human life be placed above all other rights including the right of god to demand worship by mankind. with this in mind, the ksa in canceling hajj 2020 well in advance of the events would be very much in line with islamic ideals and would contribute greatly to the safety of humanity in doing so [6] . we also predict that hajj planners and the saudi authorities will very much set the tone for the international community in addressing many forthcoming mass gatherings including the forthcoming olympics in japan (see fig. 1 ). if public health planners fail to anticipate coronavirus outbreaks during these remarkably international mg events, the ramifications will be global [7] . this is because mgs are effectively massive 'hubs' with the potential to disseminate infection. the mg participants, religious pilgrims and olympics spectators and participants can act as 'spokes' enabling spread of disease. mg facilitated spread of covid-19 could overshadow even the epicenter of the outbreak in wuhan, china. fortunately, public health experts and the field of mg medicine are seasoned at managing outbreaks and preparations are already underway and hajj planners have a uniquely intense and informed travel medicine and infectious disease xxx (xxxx) xxxx experience which is of enormous international value at this time. the hajj has handled the sars-cov outbreak, the ebola virus disease (evd) outbreaks, the rift valley fever (rvf) outbreak, zika virus, pandemic influenza h1n1 and the mers-cov outbreak all in the last decade [8] [9] [10] [11] [12] . management of these outbreaks involved close collaboration with multiple agencies both domestically across ksa and international intergovernmental collaboration [13] . immigration restrictions even for religious reasons were put in place and affected areas were categorically embargoed from sending pilgrims to mecca [9] . very early on thermal screening was incorporated across all ports of entry into the ksa. strongly worded guidelines were provided to travel and other physicians advising pilgrims in their countries of origin with the firm message that the elderly, the very young, and those with serious comorbidities-including diabetes and renal disease -were strongly discouraged from attending the hajj mass gathering in acknowledgement of the increased risk of respiratory infection [14] . basic precautions remain paramount and must be emphasized including cough etiquette, rigorous and frequent hand hygiene and the use of facemask when in contact with patients with upper respiratory tract symptoms. while health care workers (hcws) will be familiar with these measures, and hajj pilgrims are always escorted by hajj tour agencies who also provide basic education in infection control, the umrah pilgrim (the traveler making the mini-pilgrimage to mecca sometimes on the spur of the moment and at any time of the year) and the general public will not have experience in hand hygiene education. the public must be informed to wash hands with soap and water frequently, as well as before and after visits to the lavatory and before and after eating. the public must learn to wash their hands for at least -20 s -and when hands are not overtly soiled, to use an alcohol hand rub. while alcohol is forbidden for ingestion to the observing muslim, it is permitted for all medical purposes including as both a vehicle for medications and in topical form as alcohol hand hygiene agents. the ksa has been very far sighted in issuing religious fatwahs for such medical practices for over two decades with ksa's scholars issuing fatwas to reassure muslim patients and the wider public of the acceptability of the use of alcohol hand rub for the muslim without violating any principles of islam [15] . in this time of covid-19 outbreaks, religious authorities would do well to remind the muslim public of the legitimacy of alcohol hand rubs as safe and indeed preferred mode of hand hygiene and coronavirus containment. less well known is the enormous semi-permanent and highly mobile healthcare system that is activated in the hajj season, the months leading from ramadan to after the hajj ends. this provides on-site acute medical care including acute care for critical illness at all the hajj sites. the enormous effort of this temporary but massive and sophisticated healthcare system that ksa engages and operates for the purposes of the religious pilgrim visiting in hajj season means that many thousands of hcws must travel to the hajj sites as well. sometimes they are hired from outside the country, many international volunteer doctors and other personnel seek to serve the 'guests of god'. these workers are also at risk should hajj be allowed to continue in the face of an accelerating covid-19 outbreak. the impact would be two-fold. not only of more health care personnel exposed to active disease with the threat of severe infection in localized pockets and then transmission to others seeking medical care, but also a twofold burden on the hcws-caring for patients afflicted by the outbreak or compromised by it somehow and managing fellow colleagues sickened by the intensification of exposure. the semi-permanent health services at hajj are already siphoning off critical healthcare staff from their usual responsibilities throughout the ksa managing a population of close to 32 million including 10 million expatriates. in a scenario with colleagues falling ill and on some occasions dying, the wider saudi healthcare system could be singularly more impacted by the covid-19 crisis during hajj than any other healthcare workforce yet to date. the long-term impact of such an outcome is as yet unknown and difficult to predict. facemasks could mitigate aerosolized transmission especially in areas of high-density during mgs-where crowd densities in hajj can reach 9 persons per square meter. as the public starts to purchase supplies, mass purchasing can cause shortages for masks which would be best used by hcws in the healthcare setting. many hospitals have removed all n95 masks from open access on medical floors and units to be reserved for an acute outbreak when these masks will be needed to provide protection for hcws in close contact to exposed persons. in line with containment, the saudi cdc has recommended the avoidance of travel to outbreak nations, and for persons returning from these regions, 14-day quarantine periods at home-excluding the hcw or hospital employee from the workplace-are now in force. globally, purveyors have been legally prohibited from price hiking facemasks and gloves which have sold in an unprecedented fashion both in high volume and-until the restriction -exorbitant pricing [16] . we are already learning that what is much more challenging in terms of sars-cov-2 is the asymptomatic status. this allows infected persons without symptoms to move freely in society infecting others and therefore the opportunity for detection is very low [17] [18] [19] [20] [21] . there is evidence that the impact of large gatherings on disease transmission is also reaching the awareness of other governments. switzerland has announced a ban on events expected to draw gatherings of over 1000 people. france has issued a temporary ban of all public gatherings of over 5000 people. it is increasingly likely that massive international events will be postponed or canceled entirely until we begin to see regression and ultimately resolution of this outbreak. a secondary and perhaps more palpable impact of the outbreak has been panic. panic has impacted the global market. china rightly prolonged the closure of the chinese stock market, the largest market in the world, trading over 16% of the global market-as the outbreak became apparent. this was a wise move to avoid volatile reverberations across global markets as panic concerning the outbreak set in [22] . the economic impact of the coronavirus on china has been much greater already than the impact of the swine flu. this is because china's economy is now seven-fold bigger than it was then in 2003 and china is much more integrated in global supply chains now than it was then. thus, a greater impact on china translates as more significant reverberations in the global markets. sars reduced china's gdp by 1% in 2003-then 100 billion renmibi at a time when china represented only 4% of the global gdp. today the losses are already far greater. last week witnessed the biggest market correction in the us stockmarket since 2008 and the fastest correction in history. this correction comes at a time of one of the most fundamentally strong periods of economic growth in us history. with the outbreak likely to reach the united states in more substantial scale than the initial handful of cases that are now being reported there is real risk of a market correction developing into an economic recession and with a general election imminent the domestic political ramifications here in the us are enormous. because of all the aforementioned reasons, curtailing mgs at this time is crucial. tragically china's experience has been telling in this regard too and we must learn from the events there. wuhan officials allowed over 5 million people to leave wuhan where they were exposed to and some of them incubating the coronavirus weeks before the city was quarantined on january 22nd. the virus was thus rapidly propagated across china and then globally. today all 33 provinces of china have reported outbreaks in large cities. both outbreak management and mg management require clear communication and responsive political approaches. much has been learned from the experience with sars and the chinese authorities have been much more transparent than in the past. the stakes are extremely high. china is also sharing its data widely and engaging international experts with valuable and timely insights. china must be commended for many aspects of disease management at this time of crisis. similarly when ksa has faced the extremely delicate balance of welcoming religious pilgrims for both hajj and umrah this year many of whom have waited a life time to enact their religious rites, and weighing the impact of propagating outbreaks, difficult and unpopular decisions have to be made to safeguard not only the mass gathering but also the wider global community. one clearly impact the other. ksa has made an unprecedented and courageous decision by temporarily banning the umrah by curtailing religious tourism from all international destinations in addition to local umra and suspending the recently introduced tourism e-visa (recently launched for 49 nations) for all nations now at-risk countries. this is in addition to banning travel of saudi's to affected countries and closing land borders with uae, bahrain, kuwait and jordan. these bans while impeding the rights of millions of muslims to fulfil religious islamic rites have been widely supported by the organization of the islamic cooperation, world health organization and also by other individual muslim governments including egypt which indicated the ban was indeed in line with sharia principles of holding sacrosanct the right to human life above all else, a right that muslims must preserve for all humanity irrespective of creed or belief. while some optimistic reports suggest the outbreak is slowing, and china is now reporting fewer cases daily while cases outside of china are rising, public health officials everywhere will be vigilant of the forthcoming mass gatherings in the arabian peninsula and se asia. hajj planners, public health experts and mass gathering medicine experts must collaborate intensely in advance of these events for the best possible outcomes. while smaller events such as the formula one race to be held in china in april have already been postponed, a final decision for postponing the olympics and the hajj has not been made awaiting more data on how this infection evolves over time. our recommendation as experts who have monitored health hazards at the hajj for over 15 years, especially if the situation with covid-19 continues to escalate globally is that hajj 2020 will be at risk of being suspended and a means for muslims to fulfill their rights in the future either personally or even by proxy must be rapidly announced. while that decision will be heartbreaking for individual muslims and both spiritually and economically damaging for the kingdom, solace will be obtained in knowing the muslim majority world can contribute to the wellbeing of humanity. further, the kingdom has the opportunity to lead the world in acknowledging that even the most beloved and long-awaited mass gathering events including the olympics must sometimes be suspended, postponed or canceled. hajj planners frequently consult on the management of mass gatherings including the us inauguration, the olympics and the world cup. their preemptive management of the coronavirus crisis in the setting of the world's largest and most diverse mass gathering is being closely followed and will be a blueprint for other mass gatherings soon following. while the approaches are myriad, the time for international geopolitical and public health collaboration and solidarity is now, we must save no resources to protect both regional and international populations. coronavirus disease 2019 (covid-19) situation report -51 emergence of a novel human coronavirus threatening human health mass gatherings medicine: public health issues arising from mass gathering religious and sporting events health risks and precautions for visitors to the tokyo 2020 olympic and paralympic games van thuan hoang covid 19: will the 2020 hajj pilgrimage and tokyo olympic games be cancelled covid-19 -the role of mass gatherings covid-19: preparing for superspreader potential among umrah pilgrims to saudi arabia travel implications of emerging coronaviruses: sars and mers-cov the hajj in the time of an ebola outbreak in west africa hajj 2016: under the shadow of 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family cluster with sars-cov-2 infection. pii: s1473-3099 lancet infect coronavirus set to weaken china's ailing economy: business. downturn deadly outbreak forces banks, shops and factories to shut as growth rate hits 30-year low [usa region] weinland. london (uk) [london (uk): don. financial times key: cord-353507-n01ce0x3 authors: dao, thi loi; nguyen, the diep; hoang, van thuan title: controlling the covid-19 pandemic: useful lessons from vietnam date: 2020-07-10 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101822 sha: doc_id: 353507 cord_uid: n01ce0x3 nan in december 2019, an outbreak of respiratory infectious disease (covid-19) due to a novel coronavirus (sars-cov-2) emerged in wuhan city, a chinese province of hubei. on 12 march 2020, the outbreak was declared as a pandemic. up to 08 july 2020, this pandemic has affected 213 countries and territories around the world and international conveyances with 11,980,595 cases and 547,321 deaths [1]. vietnam faces a high risk of a severe covid-19 outbreak, as the country has a nearly 1,500 km border with china and a large population of nearly 100 million people. despite limited resources of middle-income country, vietnam has managed to take the control of the outbreak since the first cases were confirmed more than five months ago. vietnam can be considered as successful in controlling the covid-19 pandemic. until now, 369 cases were confirmed (342 recovered), no deaths, and no new cases circulated in community from april 16, 2020 were reported [2] . vietnam reported the first two cases in the country on 23 january 2020 [3] . on the next day, the government ordered the activation of the emergency prevention system against sars-cov-2 [2] . on january 31, 2020, vietnam ceased all flights to china and hong kong. the border with china was also shut few days later. after new infections in march, all international flights were grounded, and a nationwide lockdown commenced on april 1, 2020 for two weeks. all schools have closed for more than 3 months. use of face masks was mandatory in public places. gatherings of more than 30 individuals or festivals, religious ceremonies and sporting events were also banned. vietnam has 63 provincial health departments, an approximately 600 district health centers and more than 11,000 primary health stations [4] . while hospitals provide medical care for covid-19 patients, the primary health stations are responsible for prevention activities and total support for hospitals. in fact, an approximately 97,000 health officers at community level in these sections [4] serve as the frontline workers to provide information, advice, guidance, and isolation facilities if needed. the national institute of hygiene and epidemiology succeeded in culturing the sars-cov-2 on february 07, 2020. that has allowed local institutions to produce test kits. overall, 110 laboratories can perform real-time pcr test for sars-cov-2 identification, with a capacity of more than 25,000 tests per day [2] . as of july 08, 2020, 275,000 tests were realized, the nation had the highest test per confirmed case ratio in the world [1]. vietnam is one of the best countries conducting intensive surveillance and lockdown operation for all newly covid-19-confirmed cases. when a test revealed positive, the patients (named f0) were immediately isolated in health facilities. they must also complete a questionnaire giving the name of all the people they had recently contacted. people in the close contact with the confirmed case, named f1, must undertake testing and government-run quarantine. those had close contact with f1 (f2) must be isolated in dedicated accommodation facilities. f3 were individuals in close contact with f2 must self-isolate at home [5] . in vietnam, the police will not hesitate to wake the citizen up at midnight to warn that one of their relatives is infected. this is an intrusive system, but the majority of people fully conform to it. charges for sars-cov-2 test, accommodation and food during quarantine and treatment are totally free, regardless of nationalities of cases. this epidemiological investigation has succeeded to identify the infection sources thereby controlling the outbreak. multiples effective measures have been key to fight the covid-19 pandemic in vietnam to date. nevertheless, as the pandemic is happening at the fast speed and with the complicated level, combating the outbreak becomes more challenging mission for vietnam and the world. no funding general information for quick response of national steering committee for epidemic covid-19 prevention importation and human-to-human transmission of a novel coronavirus in vietnam an adaptive model of health system organization and responses helped vietnam to successfully halt the covid-19 pandemic: what lessons can be learned from a resource-constrained country ministry of health. classification and isolation of infected and suspected people with covid-19 infection according to recommendation of ministry of health the authors declare that they have no conflict of interest key: cord-335007-27a3h2lo authors: dreyer, nancy a.; reynolds, matthew; defilippo mack, christina; brinkley, emma; petruski-ivleva, natalia; hawaldar, kalyani; toovey, stephen; morris, jonathan title: self-reported symptoms from exposure to covid-19 provide support to clinical diagnosis, triage and prognosis: an exploratory analysis date: 2020-11-03 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101909 sha: doc_id: 335007 cord_uid: 27a3h2lo background: symptomatic covid-19 is prevalent in the community. we identify factors indicating covid-19 positivity in non-hospitalized patients and prognosticators of moderate-to-severe disease. methods: appeals conducted in april-june 2020 in social media, collaborating medical societies and patient advocacy groups recruited 20,476 participants ≥18 years who believed they had covid-19 exposure. volunteers consented on-line and reported height, weight, concomitant illnesses, medication and supplement use, residential, occupational or community covid-19 exposure, symptoms and symptom severity on a 4-point scale. of the 12,117 curated analytic population 2,279 reported a covid-19 viral test result: 865 positive (covid+) and 1,414 negative (covid-). results: the triad of anosmia, ageusia and fever best distinguished covid+ from covid-participants (or 6.07, 95% ci: 4.39 to 8.47). covid+ subjects with bmi≥30, concomitant respiratory disorders or an organ transplant had increased risk of moderate-tosevere dyspnoea. race and anti-autoimmunity medication did not affect moderate-to-severe dyspnea risk. conclusions: the triad of anosmia, ageusia and fever differentiates covid-19. elevated risks of severe symptoms outside the hospital were most evident among the obese and those with pulmonary comorbidity. race and use of medication for autoimmune disease did not predict severe disease. these findings should facilitate rapid covid-19 diagnosis and triage in settings without testing. trial registration: clinicaltrials.gov nct04368065, eu pas register eupas36240. limited information is available concerning the symptomatology of human coronavirus disease 2019 (covid-19) outside of the hospital [1, 2] . here we follow a research model developed in collaboration with the european medicines agency that validated person-generated healthdata as a reliable method for pharmacovigilance [3] , and use established best practices for patient registries that have been particularly useful in pandemic threats [4, 5, 6] . we build on these models using community-driven research to characterize symptoms indicative of a positive covid-19 viral test result and identify risk factors for development of serious symptoms of covid-19 infection outside the hospital setting. respondent-driven sampling in the us from april 2 nd to july 14 th 2020 inclusive, yielded 20,476 adults who completed registration, demographics and symptoms forms at www.helpstopcovid19.com. participants were recruited using social media, with additional awareness raising activities undertaken by medical societies and patient advocacy groups. every state in the us is represented, with most participants coming from populous states with high infection rates: california (9%), new york (9%), florida (7%) and texas (6%). participants provided information about testing and test results; noting that only viral testing was available during this sampling timeframe and most participants reported not having been tested (70%). reported were: covid-19-like symptoms using a checklist [7] and ranked the reported symptoms on a 4-point severity scale from very mild to severe; comorbidities; presence of fever, use of prescription and non-prescription medication, vitamins and supplements; occupation as well as age, gender and ethnicity. survey respondents were invited to participate in longitudinal follow-up twice a week for four weeks and every two weeks for the following two months. participants were not required to answer every question. no remuneration was provided. a curated analytic data set (n=12,117) was created for adults who completed baseline screening of symptoms and demographics, and which excluded likely fabricated entries based on a combination of clinical flags (e.g., body mass index (bmi) <15 or >60, height < 4ft) and likely duplicates, determined by nearly identical respondent entries within 10 minutes of each other. no missing data were imputed. participants who tested positive (covid+) were compared to those who tested negative (covid-). odds ratios (or) and 95% confidence interval (ci) were used to estimate the likelihood that a symptom or characteristic (or constellation thereof) would be present given a positive test result. a multivariable logistic regression was used to estimate the or (95%ci) of developing moderate or severe 5dyspnea among covid+ participants. two models were applied -a reduced model that included demographic characteristics and a full model that added comorbidities and medication use. a total of 12,117 participants were included in the curated dataset (71% female; median age 43 years and 24% non-caucasian), out of which n=2,279 (19%) reported a covid-19 test result. baseline data are shown for 2,279 participants, including covid+ (n=863) and covid-(n=1,414). participants reporting a covid-19 test result had a mean age of 41 years, with 13% over 60 years of age, and nearly twice as many females as males; 20% of participants reported education level of "high school or less" (table 1) . fever, cough, fatigue and aches and pains were the most commonly reported symptoms, with more symptoms reported on average by covid+ than covid-participants (5.5 vs 3.4) ( triad. covid+ participants who reported anosmia or ageusia also had a mean of nine symptoms, in contrast to a mean of just two for those without either symptom. moderate or severe 6dyspnea was more frequently reported by covid+ (24%) than covid-(15%) participants. among covid+ participants the risk of moderate or severe 6dyspnea did not differ by age, gender, race, or ethnicity. particularly, risk was elevated among the obese (bmi>30) (or 2.30 95%ci 1.40, 3.78) and those taking medications for respiratory disorders (or 3.68 95%ci 2.04, 6.62). there was no strong evidence of elevated risk for 6dyspnea among participants with cardiovascular disease or those taking medications for diabetes, hypertension and autoimmune conditions (table 3) . this research program is unusual in its evaluation of symptomatology for covid-19 in the community setting [8] and may be particularly helpful in a number of travel medicine related settings, e.g. on board cruise ships and in other maritime settings, including naval vessels; during military deployments and in remote or resource poor settings [9, 10, 11, 12, 13] . anosmia and ageusia were the most likely symptoms indicative of a positive test results, and participants reporting either of these had more symptoms and of greater severity [8] . this is in line with previous findings and experimental evidence supporting involvement of the olfactory apparatus [14, 15] . the triad of anosmia, ageusia and fever provided a particularly powerful symptom constellation differentiating covid+ from covid-in the community. this triad may offer an expeditious way to identify probable covid-19 infections in the community, especially in the absence of reliable, widespread testing [9, 16, 17] the triad could be taken as pathognomonic during the pandemic and trigger anti-covid interventions in the absence of reliable nearpatient diagnostics. this may be particularly helpful in many travel medicine or community based settings including resource-poor, logistically challenged or remote settings, as well as in closed community settings e.g. the military, prisons, care homes, seagoing vessels. further support for a clinical diagnosis of covid-19 might also be a history of vomiting. although nonspecific, vomiting is in general not a feature of respiratory tract infections in the community [18, 19] . severe 7dyspnea is indicative of severe disease that may require hospitalization and may presage possible pulmonary fibrosis or other sequelae [20, 21, 22, 23] . while our findings are congruent with obesity being a known risk factor for severe disease, the association of significant 7dyspnea with obesity in a community setting raises concerns about referral thresholds. it may well be prudent to have a very low threshold for referral and admission of symptomatic obese patients. the same consideration could also apply to patients with underlying respiratory disorders. however, there was no evidence for a marked increase in risk among people who reported underlying cancer or cardiovascular disease, or those taking medications for autoimmune disease, diabetes, or hypertension. the absence of increased risk of severe disease in users of medication for auto-immune disorders is similar to previous findings indicating that use of disease modifying agents does not increase the risk of complications from seasonal influenza [24] . the findings of increased risk of severe disease in the presence of obesity were in line with existing evidence on covid-19 [25] and are somewhat in contrast with previous findings in seasonal influenza, which pointed to decreasing risk of influenza complications with increasing bmi [26] , supporting the distinct pathology and immunopathology of covid-19. our findings would be strengthened by complementary analyses of other clinical and treatment information for obese participants and those on medication for auto-immune disorders, including if and how they are being treated for these underlying conditions; a possible explanation may be that individuals with more severe conditions were underrepresented in our study, but this remains speculative. further validation may be derived from additional data collection and analysis from subsequent waves of infection, a process that has already been initiated. it is important to keep in mind that these data are voluntarily reported, are not a representative sample of the us population, and thus will not support inferences about distribution of symptoms in the us. recognizing that self-reported information has limitations, comparisons between respondents may nevertheless indicate true causal relationships and can serve to stimulate further research as the medical and scientific community seek to learn more j o u r n a l p r e -p r o o f about this infection. this methodology appears to be useful in capturing relevant real world data, particularly symptom severity, without requiring physical presentation for clinical assessment, and offers valuable perspective on the true burden of illness as well as signaling those at particularly high risk of severe symptoms and, in parallel, those unlikely to be at such increased risk. the findings may help guide diagnosis and triage in settings where there is not ready access to rapid and reliable diagnostic testing. approximately 10-12% of participants did not respond to one or more of these questions b n=852 (7%) of all participants, n=80 (9.2%) of covid+ and n=97 (6.9%) of covid-participants did not provide an answer in this section notes: shortness of breath and severity assessed at baseline. participants who reported shortness of breath, but did not report severity of the symptom were excluded from this analysis (n=11). a referent category includes participants who reported not having the condition of interest or not taking the medication of interest pathophysiology, transmission, diagnosis and treatment of coronarvirus disease 2019 (covid-19). a review prevalence of asymptomatic sars-cov-2 infection. a narrative review direct-to-patient research: piloting a new approach to understanding drug safety during pregnancy recognizing true h5n1 infections in humans during confirmed outbreaks registries for evaluating patient outcomes: a user's guide. conducted under contract no agency for healthcare research and quality investigating outbreaks of novel infectious disease: an international case study real-time tracking of self-reported symptoms to predict potential covid-19 covid-19: travel health and the implications for sub -saharan africa more than 30 coronavirus cases on pacific aircraft carrier, new ones discovered on another carrier in japan: officials coronavirus : plusieurs cas suspects à bord du porte-avions français charles-de-gaulle french aircraft carrier heads home early due to possible covid-19 cases dolfijn breekt reis af vanwege corona -nieuwsbericht -defensie.nl". defensie.nl olfactory and gustative disorders for the diagnosis of covid-19 sars-cov-2 infects and damages the mature and immature olfactory sensory neurons of hamsters van den bruel a. antibody tests for identification of current and past infection with sars-cov-2. cochrane database of systematic reviews oseltamivir effectiveness in seasonal influenza patients taking symptomatic therapy: retrospective analysis of rct data clinical features of covid-19 and influenza: a comparative study on nord franche-comte cluster. microbes and infection long term respiratory complications of covid-19 pulmonary fibrosis and covid-19: the potential role for antifibrotic therapy. the lancet covid-19 patients with pulmonary fibrotic tissue: clinical pharmacological rational of antifibrotic therapy pulmonary fibrosis secondary to covid-19: a call to arms? rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study single cell sequencing unraveling genetic basis of shared immunologic switch between severe covid19 and obesity epub ahead of print body mass index and the incidence of influenza-associated pneumonia in a uk primary care cohort. influenza and other respiratory viruses we would like to acknowledge dr. sally mcnagny for her clinical insights and alison bourke for her contributions to the data curation.funding sources: no funding was received for this work. key: cord-338136-nbtkl5cx authors: clemente, nuria sanchez; ramond, anna; turchi martelli, celina maria; brickley, elizabeth b. title: geographies of risk: emerging infectious diseases and travel health data date: 2020-06-25 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101806 sha: doc_id: 338136 cord_uid: nbtkl5cx nan the battles against these novel threats. not only do travel medicine practitioners provide counsel in the context of the imperfect and evolving information that accompanies epidemics, but also, they are often the first port of call when travellers return to their home countries with medical concerns. reflecting on the findings of petridou and colleagues, 1 describing imported zikv cases to the uk between 2016-2018, confirmed at the rare and imported pathogens laboratory, we look back to the 2015-2017 zika virus (zikv) pandemic and reflect on some of the opportunities and limitations presented by data obtained from returning travellers in enhancing understanding of emerging infectious diseases. given travellers' well-defined temporal windows of potential exposure, improved recollections of risk behaviors, and access to well-resourced travel clinic laboratories, travel health data are uniquely positioned to provide insights into the pathogenesis of emergent infectious diseases. in the case of zikv, case studies of pregnant travellers provided early evidence that asymptomatic maternal zikv infections can also result in congenital malformations. 2 data from a traveller returning to an ecological setting that does not support zikv vectors, elucidated sexual contact as a new route of transmission. 3 there are, however, noteworthy limitations to using travellers as sentinels for emerging infectious diseases. first, we can assume neither homogenous mixing between travellers and locals nor equivalent risks of exposure to pathogens. considering zikv, travellers' geographic footprint may be limited to tourist sites with enhanced vector control measures limiting the prevalence of aedes spp. mosquitoes. travellers may practice temporarily enhanced preventative behaviours, such as the daily use of insecticides, which may be inaccessible to resident populations. second, travellers and locals may have differing age distributions and underlying risk factors that could modify the clinical severity or complications of the resulting disease. third, travellers may display more health-seeking behaviour traits, be more likely to seek testing for minor symptoms, and have better access to testing laboratories. fourth, travellers and locals may differ with respect to their immunological experiences in ways that could modify testing outcomes. for instance, prior exposure to dengue virus can lead to immunological cross-reactivity that can compromise the specificity of serological testing for zikv. for all these and other reasons, it is therefore important, where possible, for studies utilizing travel data to contextualize and validate their findings with on-the-ground epidemiological investigations led by resident country experts. the sharing of data, knowledge, and expertise between travel medicine specialists and professionals working in areas with active transmission is mutually beneficial and of paramount importance for protecting the public's health in all countries. during outbreaks of emerging infectious diseases, local clinicians and epidemiologists play a critical role in describing the novel features, risk factors, and transmission patterns for emerging infectious diseases. when the epidemic of microcephaly was first identified in northeast brazil, local teams provided the first clinical descriptions of the novel congenital zika syndrome and undertook epidemiological studies that provided robust evidence of zikv as the etiological agent. while travel health data has the opportunity to build on this foundation and provide novel insights about emerging infectious agents, the fastest progress will be made through meaningful bi-directional international partnerships built on respectful collaboration, commitments to capacity building, and cooperative efforts to bolster surveillance. as evidenced by the zikv and covid-19 pandemics, we are in a new era of emerging infections, rapid research, and potential international partnerships. now more than ever, travel data and databases are becoming invaluable resources in the early stages of outbreak investigations and for on-going support of local surveillance efforts in affected areas. by working together across our shared geographies of risk, we will be best prepared to confront, contain, and mitigate the impact of emerging infectious disease pandemics. i have no competing interests to declare all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. travel medicine and infectious disease requires that all authors sign a declaration of conflicting interests. if you have nothing to declare in any of these categories then this should be stated. a conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). it may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. zika virus infection in travellers returning to the united kingdom during the period of the outbreak in the americas (2016-17): a retrospective analysis vital signs: update on zika virus-associated birth defects and evaluation of all u.s. infants with congenital zika virus exposure -u.s. zika pregnancy registry probable non-vector-borne transmission of zika virus clinical infectious diseases : an official publication of the infectious diseases society of sentinel surveillance in travel medicine: 20 years of geosentinel publications (1999-2018) travel surveillance and genomics uncover a hidden zika outbreak during the waning epidemic travel medicine and infectious disease requires that all authors sign a declaration of conflicting interests. if you have nothing to declare in any of these categories then this should be stated. a conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). it may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. none. all sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. if the study sponsors had no such involvement, this should be stated. key: cord-314607-bcocsjij authors: memish, ziad a.; assiri, abdullah m.; alshehri, mohammed; hussain, raheela; alomar, ibrahim title: the prevalance of respiratory viruses among healthcare workers serving pilgrims in makkah during the 2009 influenza a (h1n1) pandemic date: 2011-12-23 journal: travel med infect dis doi: 10.1016/j.tmaid.2011.11.002 sha: doc_id: 314607 cord_uid: bcocsjij despite the high risk of acquiring respiratory infections, healthcare workers who treat pilgrims at hajj have not been studied in previous research on respiratory diseases during hajj. the objective of this study was to determine the prevalence of different respiratory viruses among healthcare workers who treated pilgrims during hajj 2009, the year of the influenza a h1n1 pandemic. a cross-sectional study was performed just before and after hajj (25–29 november, 2009). nasal and throat swabs were tested for 18 respiratory virus types and subtypes. a total of 184 healthcare workers were examined. most were men (85%) with an average age of 41 years. before the hajj, rates of seasonal influenza vaccination were higher (51%) than rates of pandemic influenza a h1n1 vaccination (22%). after the hajj, participants reported high rates of maintaining hand hygiene (98%), cough etiquette (89%), and wearing a face mask (90%). among all the viruses tested, only two were detected: rhinovirus was detected in 12.6% and coronavirus 229e in 0.6%. rhinovirus was detected in 21% of those who had respiratory symptoms during hajj. influenza a (including h1n1), influenza b. respiratory syncytial virus, other coronaviruses, parainfluenza viruses, human metapneumovirus, adenovirus, and human bocavirus were not detected. the finding of high rates of rhinovirus infection corresponds to their frequent occurrence in adults. none of the participants had influenza a h1n1 2009, possibly because it was also infrequent among the 2009 pilgrims. the prevalance of respiratory viruses among healthcare workers serving pilgrims in makkah during the 2009 influenza a (h1n1) pandemic keywords hajj; viral; respiratory; healthcare workers; h1n1 summary despite the high risk of acquiring respiratory infections, healthcare workers who treat pilgrims at hajj have not been studied in previous research on respiratory diseases during hajj. the objective of this study was to determine the prevalence of different respiratory viruses among healthcare workers who treated pilgrims during hajj 2009, the year of the influenza a h1n1 pandemic. a cross-sectional study was performed just before and after hajj (25e29 november, 2009). nasal and throat swabs were tested for 18 respiratory virus types and subtypes. a total of 184 healthcare workers were examined. most were men (85%) with an average age of 41 years. before the hajj, rates of seasonal influenza vaccination were higher (51%) than rates of pandemic influenza a h1n1 vaccination (22%). after the hajj, participants reported high rates of maintaining hand hygiene (98%), cough etiquette (89%), and wearing a face mask (90%). among all the viruses tested, only two were detected: rhinovirus was detected in 12.6% and coronavirus 229e in 0.6%. rhinovirus was detected in 21% of those who had respiratory symptoms during hajj. influenza a (including h1n1), influenza b. respiratory syncytial virus, other coronaviruses, parainfluenza viruses, human metapneumovirus, adenovirus, and human bocavirus were not detected. the finding of high rates of rhinovirus infection corresponds to their frequent occurrence in adults. none of the participants had influenza a h1n1 2009, possibly because it was also infrequent among the 2009 pilgrims. ª 2011 elsevier ltd. all rights reserved. healthcare workers are exposed to many respiratory infections when they see patients, and they may transmit these infections to their patients or colleagues. for example, during the outbreak of severe acute respiratory syndrome (sars) in 2003, attack rates were more than 50% in healthcare workers. 1 healthcare workers who see pilgrims during hajj (the annual muslim pilgrimage to makkah) may be at higher risk of acquiring respiratory and other infections. 2, 3 because of these risks, special immunization requirements have been proposed to protect healthcare workers, 4 although healthcare workers have not been included in previous studies of respiratory diseases during hajj. 2, 5 hajj is the largest annual mass gathering in the world; it brings more than two million people from different countries together in a small, confined area. the extreme overcrowding of pilgrims during hajj reaches about 7 persons per meter; combined with fatigue and extremely hot weather during much of the year, this crowding may increase the risk of transmitting air-and droplet-borne infectious diseases, particularly respiratory viruses. 3,5e7 an estimated one in three pilgrims experience respiratory symptoms. 6 several transmissible bacterial and viral respiratory pathogens have been reported among pilgrims, notably meningococci of all serotypes, streptococcus pneumoniae, gram-negative organisms, atypical organisms, mycobacterium tuberculosis, influenza a and b viruses, rhinoviruses, respiratory syncytial virus (rsv), parainfluenza viruses, enteroviruses, and adenoviruses. 5,6,8e10 in april of 2009, a novel influenza a strain (h1n1 2009 strain) in mexico spread globally. 11, 12 the toll was particularly heavy in saudi arabia, which ranked fourth of 22 countries in the eastern mediterranean region in deaths and probable h1n1 cases. 13 the 2009 hajj took place in november, six months later, and presented a public health challenge for infection control authorities in saudi arabia. 14 several practices to minimize disease transmission among pilgrims and healthcare workers were instituted even before the beginning of hajj season, since pre-hajj data showed low acceptance rates of h1n1 vaccine among healthcare workers. 15, 16 this study evaluated the prevalence of viral respiratory pathogens among healthcare workers during the 2009 hajj which coincided with the influenza a h1n1 2009 pandemic. healthcare workers, including physicians, nurses, health inspectors, and others, who served pilgrims during the 2009 hajj season were included. three-fourths of the healthcare workers in the study were from the saudi ministry of health (moh), and the rest were from medical missions other than moh. most of the healthcare workers had treated pilgrims previously and had been practicing medicine for more than 10 years. the main religious activities of the 2009 hajj season started on 25th november 2009 with a visit to the holy kaaba and continued for 5 or 6 days at different holy sites in mina, arafat, and muzdalifa. the current study was a cross-sectional study performed in two phases. the first phase was conducted during the week before the start of hajj on november 25th, and the second phase was conducted in the week following the end of hajj on november 30th. healthcare workers were asked to answer a questionnaire and provide nasal and throat swabs both before and after hajj. the pre-hajj questionnaire was about demographics (age, sex, occupation, and nationality), medical history (chronic disease and smoking), vaccination history (including h1n1 and seasonal influenza), and knowledge of h1n1 influenza (symptoms, transmission, and prevention). the post-hajj questionnaire included questions about exposure to infections during hajj and compliance with infection control practices (hand hygiene, cough etiquette, and wearing a mask). nasal and throat swabs were collected using the same method during both phases of the study. nose and throat swabs were collected in viral transport media using dacron swabs on stainless steel wire and plastic shafts, respectively (remel, microtest m4rt, usa). immediately after collection, samples were transported to the jeddah regional laboratory where they were stored at à80 c until tested. nucleic acid was extracted using the x-tractor gene, corbett from qiagen using 25101 vx dna/rna purification protocol. the multiplex pcr using micro fluid arrays and luminex x-map system, with xtag respiratory viral panel fast assay (manufactured by luminex molecular diagnostics, inc, toronto, on, canada, distributed by abbott molecular, wiesbaden-delkenheim, germany) was used for nucleic acid testing for 18 circulating respiratory virus types and subtypes: influenza a, influenza a h1, influenza a h3, influenza b, rsv, coronavirus 229e, coronavirus oc 43, coronavirus nl63, coronavirus hku1, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, human metapneumovirus, rhinovirus, adenovirus, and human bocavirus. the xtag data analysis software for rvp fast(tdas rvp fast) analyzed the data and provided a report summarizing which viruses were present. the rvp fast detects influenza b, influenza a h1 seasonal, and influenza a h3 only. if any other subtypes are present, it will indicate the presence of influenza a matrix protein only. therefore the samples in which influenza a matrix protein was detected were run separately by a singleplex pcr to detect h1 2009 pandemic strain using artus inf/h1 lc/rg rt-pcr kit (qiagen) and for avian influenza a h5n1 (subtype asia) by lightmix kit (tib, molbiol,gmbh, berlin, germany), according to the manufacturer's instructions. any strain in which rna was not detected for these four influenza a types (i.e., h1, h3 seasonal in rvp fast and independent singleplex pcrs for h1 2009 pandemic strain, and h5n1 [subtype asia]) was labeled as unsubtypeable influenza a virus. demographics, medical history, vaccination history, knowledge of h1n1 influenza, and compliance with infection control practices are presented as frequencies. the prevalence of respiratory viruses is presented as number of viruses per 1000 healthcare workers. differences in the prevalence of respiratory viruses before and after the hajj were examined using non-parametric paired statistics a total of 184 healthcare workers who treated pilgrims during the 2009 hajj season were included in the study. of these, 161 answered the (main) pre-hajj questionnaire and 104 answered the (short) post-hajj questionnaire. a total of 120 combined nasal and throat swabs were obtained during the pre-and post-hajj periods. demographic and clinical characteristics of the sample are shown in table 1 . the majority of the healthcare workers were males (85%) with an average age of 40.9 ae 9.2 years (range 23e59 years), non-saudi (71%), physicians (75%), with more than 10 years of medical experience (60%) as well as previous experience of serving in hajj medical services (83%). most of the healthcare workers (93%) described their own health as very good to excellent. chronic disease, namely hypertension, diabetes, and asthma were present in 15% and 11% were current smokers. compliance of healthcare workers with pre-hajj vaccination and infection control is shown in table 2 . eighty four percent of them got at least one vaccine before hajj. the coverage of hepatitis b, meningococcal and seasonal influenza vaccines were relatively high (73%, 67% and 51%, respectively), while the coverage of h1n1 vaccine was considerably low (22%). the main reasons described for not getting the vaccine were worries about the side effects, (42%), non-availability (34%), and fear of developing h1n1 symptoms (22%). approximately 50% of the healthcare workers did not get seasonal influenza vaccine in the past year due to the belief of being healthy (29%), lack of knowledge about the place to get the vaccine (22%), and the assumption that influenza is not a serious illness (18%). compliance with hand hygiene was noted in 98%, cough etiquette in 89% and wearing face mask in 90% of the healthcare workers. the exposure risk as defined by being within 1 m from a person with ili was reported in 61%, handling biological specimens in 34% and examining patients in 76%. about 20% of them got sick or injured during hajj. background knowledge of the healthcare workers about h1n1 2009 is shown in tables 3 and 4 . eighty five percent believed that h1n1 is a serious disease, 80% were worried about catching h1n1 influenza during hajj and 75% were aware of the main symptoms of h1n1 influenza. the main source or vehicle of h1n1 transmission as recognized by them were contact with people infected with h1n1 (86%), contaminated fomites (72%) and air (65%). appreciable level of knowledge about measures to avoid h1n1 infection were noted as described by maintenance of hand hygiene (91%), wearing a mask (76%), cough/sneeze etiquette (76%), staying away from sick people (65%), using hand sanitizer (63%), avoiding crowds/public gatherings (62%) and taking h1n1 vaccine (58%). among the 18 circulating respiratory virus types and subtypes, only two were detected in the healthcare workers in the pre-and post-hajj period: rhinovirus (n z 21, 12.6%) and coronavirus 229e (n z 1, 0.6%) . rhinovirus was detected more before the hajj (n z 14, 11.7%) than after (n z 9, 7.5%), but the difference was not statistically significant. the only isolate of coronavirus was detected in the post-hajj period. two healthcare workers had rhinovirus detected both before and after the hajj. rhinovirus was detected in 21.1% of those who had respiratory symptoms and 30.0% of those who got sick during hajj. no other respiratory viruses were detected in any of the samples. the prevalence (per 100 persons) of respiratory viruses according to age, sex, profession, smoking, vaccine, sickness, and wearing a mask is shown in fig. 1 . the prevalence was slightly higher in healthcare workers who got sick during hajj, in nurses, and in those who did not wear masks than in smokers; however, the difference was not statistically significant. hajj, the annual pilgrimage of muslims is a time of a unique mass gathering event in makkah. around two million people are confined to small area and the chances of having infections acquired by respiratory tract are increased. al-tamami et al, 10 during the 2001 hajj, found 23 cases of meningitis of all types, mainly in indians, whose ages ranged from 1 to 70 years, and in twice as many women as men. balkhy et al, 6 in 2004, studied 500 symptomatic pilgrims, 10.8% of whom had positive viral cultures. of these, influenza b accounted for 50%, followed by herpes simplex virus (21.4%), rsv (12.9%), parainfluenza (7.4%) and influenza a (5.6%). a comparative study of respiratory tract infections in symptomatic uk and saudi pilgrims by rashid et al. in 2008 8 found infections in 25% of uk pilgrims but in only 13% of saudi pilgrims. half of the infections in uk pilgrims were due to rhinoviruses, followed by influenza virus, parainfluenza, and rsv. the saudi pilgrims had higher infection rates with influenza virus (78.5%) than with rhinovirus (21.4%). in 2009, alborzi et al. 9 also reported that 32.5% of patients tested had viral pathogens: influenza in 25 (9.8%), parainfluenza in 19 (7.4%), rhinovirus in 15 (5.9%), adenovirus in 14 (5.4%), enterovirus in 5 (2%), and rsv in 4 (1.6%) and coinfection with two viruses in 1 patient (0.4%). the current study evaluated the prevalence of respiratory viruses in healthcare workers who saw pilgrims after the h1n1 2009 pandemic had been declared. we tested for 18 respiratory virus types and subtypes in the healthcare workers and found primarily rhinoviruses and a single coronavirus 229e. rhinoviruses were more prevalent after the hajj (11.7%) than before (7.5%). none of the healthcare workers tested positive for any influenza virus, including the h1n1 2009 pandemic strain. this is explained by the fact that among more than two million pilgrims in 2009, the ministry of health reported only 100 cases of h1n1 and 5 deaths. 17 the high case-fatality ratio may be because pilgrims were committed to completing hajj and delayed seeking medical care until their condition had worsened. 17, 18 since the overall number of cases among pilgrims was low, therefore, the chances of transmitting it to healthcare workers were very small. rhinoviruses are present in about two-thirds of persons with common colds and probably are responsible for more human infections than any other agents. 19, 20 they are common in all age groups, occur throughout the year, and are present worldwide. 21 louis et al. 22 found that rhinovirus was responsible for half of the respiratory infections in residents and staff in a long-term care facility for elderly persons, although in community-dwelling elderly, they cause 63% of respiratory infections. 23 renois et al 24 found rhinoviruses to be most prevalent in cases of influenza-like illness in infections with one agent (25%) as well as in coinfections with influenza a h1n1 viruses (50%). our finding that rhinoviruses are the most prevalent viruses in healthcare workers during the 2009 hajj are consistent with the other studies of rhinoviruses in the general population, in patients with influenza-like illness, and also in pilgrims. arruda et al. 25 studied the natural history of rhinovirus infections in adults during autumn and found that among 346 persons with colds, 82% (283) had rhinovirus infections and 8% had coronavirus oc43 and 229e. these findings agree with our finding of rhinovirus as the predominantly isolated virus (12.6%), followed by coronavirus 229e (0.6%), in a group of subjectively healthy healthcare workers. arruda et al. isolated a high percentage of viruses because the subjects were symptomatic, while in our study rhinovirus was detected in 21% of participants with respiratory symptoms and in 30% who got sick during hajj. rhinoviruses spread efficiently in families, in school groups, among university students, and on military bases. 26, 27 linde et al. 28 found an increase in the proportion and number of rhinovirus diagnoses that roughly parallels a decrease in influenza diagnoses, after the summer holidays and start of schools. they hypothesize that a rhinovirus epidemic could interfere with the spread of pandemic influenza in a warm and humid climate, which decreases the spread of influenza by aerosol. a similar phenomenon may be responsible for the frequent isolation of rhinoviruses in the present study. rhinoviruses may protect the host from being infected by other viruses such as influenza a virus, parainfluenza virus, adenoviruses, coronaviruses, bocavirus, metapneumovirus, and rsv. 29 rhinovirus shedding is commonly limited to 10e14 days in immunocompetent subjects. 24 however viral rna may be present from days before symptoms occur to five or more weeks after they go away. 30, 31 the influenza a h1n1 vaccination rate in healthcare workers has been reported to be lower than the seasonal influenza vaccination rate 16, 32, 33 and was 22% versus 51% in the current study. these results are also comparable to the data obtained from the united states for the same period: where vaccination coverage for h1n1 in healthcare workers was 37% and for seasonal influenza it was 62%. 32, 33 in conclusion, we found that rhinoviruses were the most frequently isolated viruses in a group of subjectively healthy middle-aged healthcare workers who treated hajj pilgrims during the 2009 influenza a h1n1 pandemic. respiratory symptoms were present in 21% of the healthcare workers in which the virus was detected. none of the participants had influenza a h1n1 2009, despite that only 22% of them were vaccinated against h1n1 vaccine, possibly because it was also infrequently found among pilgrims. usa, dr abduraman abudawod and dr. nedal almasri for their assistance in the data collection. risk of respiratory infections in healthcare workers: lessons on infection control emerge from the sars outbreak acute respiratory tract infections among hajj medical mission personnel, saudi arabia health risks at the hajj association of national health occupational physicians (anhops) respiratory tract infection during hajj influenza a common viral infection among hajj pilgrims: time for routine surveillance and vaccination mecca bound: the challenges ahead viral respiratory infections at the hajj: comparison between uk and saudi pilgrims viral etiology of acute respiratory infections among iranian hajj pilgrims risk factors of bacterial meningitis in makkah during hajj 1421 h: a pilot study outbreak of swine-origin influenza a (h1n1) virus infection e mexico, marcheapril update: swine influenza a (h1n1) infections e california and texas world health organization. the regional office of eastern mediterranean global public health implications of a mass gathering in mecca, saudi arabia during the midst of an influenza pandemic establishment of public health security in saudi arabia for the 2009 hajj in response to pandemic influenza a h1n1 acceptance and adverse effects of h1n1 vaccinations among a cohort of national guard health care workers during the 2009 hajj season prevention of pandemic influenza after mass gatherings e learning from hajj pandemic h1n1 influenza at the 2009 hajj: understanding the unexpectedly low h1n1 burden human rhinoviruses: the cold wars resume acute respiratory symptoms in adults in general practice the seasonality of rhinovirus infections and its implications for clinical recognition rhinovirus outbreak in all long term care facility for elderly persons associated with unusually high mortality acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden rapid detection of respiratory tract viral infections and coinfections in patients with influenza-like illnesses by use of reverse transcription-pcr dna microarray systems frequency and natural history of rhinovirus infections in adults during autumn the seattle virus watch. v. epidemiologic observations of rhinovirus infections, 1965e1969, in families with young children rhinoviruses in seattle families, 1975e1979 does viral interference affect spread of influenza? do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections? persistence of rhinovirus and enterovirus rna after acute respiratory illness in children picornavirus infections in children diagnosed by rt-pcr during longitudinal surveillance with weekly sampling: association with symptomatic illness and effect of season influenza vaccination of health-care personnel: recommendations of the healthcare infection control practices advisory committee (hicpac) and the advisory committee on immunization practices (acip) should healthcare workers have the swine flu vaccine key: cord-302784-jkjdglns authors: alotaibi, badriah; bieh, kingsley; yassin, yara; mushi, abdulaziz; maashi, fuad; awam, amnah; mohamed, gamal; hassan, amir; yezli, saber title: management of hospitalized drug sensitive pulmonary tuberculosis patients during the hajj mass gathering: a cross sectional study date: 2019-07-13 journal: travel med infect dis doi: 10.1016/j.tmaid.2019.07.007 sha: doc_id: 302784 cord_uid: jkjdglns background: to document the management of drug-sensitive tb patients during the hajj and assess compliance with the saudi tb management guidelines. method: the study was conducted in hospitals in makkah during the 2016 and 2017 hajj seasons. structured questionnaire was used to collect data on relevant indices on tb management and a scoring system was developed to assess compliance with guidelines. results: data was collected from 31 tb cases, 65.4% (17/26) were saudi residents. sputum culture was the only diagnostic test applied in 67.7% (21/31) of patients. most (96.8%, 30/31) confirmed tb cases were isolated, but only 12.9% (4/28) were tested for hiv and merely 37% (10/27) received the recommended four 1st-line anti-tb drugs. guideline compliance scores were highest for infection prevention and control and surveillance (9.6/10) and identifying tb suspects (7.2/10). the least scores were obtained for treating tb (5.0/10) and diagnosing tb (3.0/10). conclusions: healthcare providers training and supervision are paramount to improve their knowledge and skill and ensure their compliance with existing tb management guidelines. however, there may be a need for the introduction of an international policy/guideline for tb control and management during mass gatherings such as the hajj to guide providers’ choices and facilitate monitoring. tuberculosis (tb) remains a global public health problem with significant morbidity and mortality. in 2017, the world health organisation (who) estimated that 10 million people developed active tb causing up to 1.6 million deaths [1] . the who's end-tb strategy aims to reduce the overall number of tb deaths by 95% and the tb incidence rate by 90% in 2035 compared with the 2015 baseline incidence and mortality figures [2] . key to achieving these targets is the early diagnosis and appropriate management of tb cases worldwide according to national and international guidelines [3] [4] [5] [6] . this includes in the context of mass gatherings such as the annual hajj in makkah, kingdom of saudi arabia (ksa), where over 2 million pilgrims, many originating from tb endemic areas, congregate in crowded settings and worship under conditions that increase the risk of tb transmission [7, 8] . in the context of the hajj, respiratory tract infection including those caused by viruses have been researched in detail [9] . however, while tb cases have been reported during the event [10, 11] , tb management approaches during this unique event remained largely undocumented, and it is unknown whether these are consistent with the ksa and international tb management guidelines. hospitals in makkah serve both hajj pilgrims as well as local residents and the hajj workforce during the mass gathering free of charge. the additional stress on these health facilities during hajj may compromise the services provided for all patients during the event, including those diagnosed with tb. this study documents the management of drug-sensitive tb patients during hajj and explores the compliance of healthcare providers with the ksa tb management guidelines in the ministry of health (moh) hospitals in makkah during the mass gathering. this cross sectional study took place in makkah, saudi arabia, and https://doi.org/10.1016/j.tmaid.2019.07.007 received 28 january 2019; received in revised form 12 june 2019; accepted 10 july 2019 included 13 hospitals comprising those serving pilgrims in hajj holy sites. the study was conducted during the hajj lunar month (1st-30th dulhija) during the 2016 and 2017 hajj seasons, corresponding to 2nd sep-1st oct 2016 and 22nd aug-21st sep 2017, respectively. all hospitalized adults (> 18 years old) diagnosed with drug-sensitive pulmonary tb (ptb) during the study period were enrolled in the study if they consented. these patients are referred to in the manuscript as "suspected tb patients" until the time they were confirmed to have tb by the healthcare facility there were admitted to. the management of tb patients was documented using a specifically designed data collection form which included patients' demographics data, underlying health conditions and tb risk factors as well as clinical data including various aspects of tb management such as patients' screening, infection prevention and control (ipc), tb diagnosis and treatment and case notification and outcome. data was collected by the study team from patient's records, attending physician and through interviews with patients. all analyses were done using spss 22.0 (spss inc., chicago, usa) and sas 9.4 (sas institute inc., nc, usa) software program. variables were characterized using frequencies and mean for the respective categorical and continuous variables. a scoring system was developed, having identified four key themes from the questionnaire and literature review which were relevant to tb management in hajj. the themes were 1) identifying tb suspect, 2) ipc and surveillance, 3) diagnosing tb and 4) treating drug-sensitive tb. for each theme, relevant indicators were identified from the questionnaire (tables 2-5) . a score of 1 was assigned for each indicator/variable that was consistent with the 2014 ksa tb management guideline [6] (latest version during study period) and 0 for inconsistency with the guideline. the indicator subscore (x) for guideline consistency was obtained as follows: x = number of cases consistent with guidelines (c)/ total number eligible of cases (d) * 10 the eligible cases summed the consistent and inconsistent responses with tb guideline and strictly excluded missing data and unknown responses. the guideline consistency score for each theme was obtained by calculating the mean of the indicator sub-scores for each theme. the study was approved by the king fahad medical city ethics committee and the institutional review board (irb log: 16-329e) and conducted in accordance with the ethics committee's guidelines. characteristics of the study population are presented in table 1 . for the two-year period, 31 confirmed drug-sensitive ptb patients were recruited for the study. the mean age of the study population was 52 years (sd = 18.1 years, range 21-83 years). most (80.6%, 25/31) were males and over half were over 50 years old (60.7%, 17/28), with only primary or no formal education (55.1%, 16/29). the tb patients were nationals of 10 countries but the majority (65.4%, 17/26) had been residing in ksa for at least one year (table 1) . over one third of the cases (37.5%, 9/24) did not complete their hajj rituals while the status of 50% (12/24) of the cases was not known. three confirmed tb cases (12.5%, 3/24) did complete their hajj rituals in individual ambulances. no mortality was recorded among the tb patients at the time when the study ended with half (14/28) having been discharged (table 1) . in relation to tb risk factors, only 6.6% (2/30) of respondents reported prior travel to high tb burden countries (pakistan and indonesia) and 27.6% (8/29) stated that they had performed hajj or umrah within the past 1 year. the majority (75%, 6/8) of the previous hajj or umrah pilgrims were saudi residents. a sizable proportion of tb cases declared that they had smoked or were current smokers of tobacco products (44.8%, 13/29) or had chronic diseases (63.0%, 17/27) especially diabetes and hypertension (table 1) . upon registration, most (76.6%, 23/30) suspected tb patients were admitted to an isolation room or ward. otherwise, the patients were either admitted into the emergency room (er [6.7%, 2/30]), icu (6.7%, 2/30), neurosurgery ward (3.3%, 1/30), orthopedic ward (3.3%, 1/30) or general ward (3.3%, 1/30). while a proportion (48.4%, 15/ 31) of suspected tb patients was separated from other patients during registration, the triaging status of 45.2% (14/31) of suspected tb patients was not reported ( table 2 ). the proportion of suspected tb patients put in isolation while waiting diagnosis was 77.4% (24/31) and rose to 96.8% (30/31) once drug-susceptible tb was confirmed. only 1 (3.2%) confirmed tb patient was managed in the er. generally, most (93.1%, 27/29) confirmed tb patients spent less than 1 day in the health facilities before they were isolated. in all cases, appropriate symptoms were sought from tb suspects, in particular, cough ≥2 weeks (64.5%, 20/31) and fever with chills/night sweat (67.7%, 21/31). the history of contact with active tb cases was obtained from 45.2% (14/31) of suspected tb cases, although the status of this variable was unknown in a further 41.9% (13/31) of the cases (table 3 ). in general, 44.8% (13/29) of the tb suspects were questioned about other tb risk factors. specifically, their country of residence, hiv status and potential occupational exposure to tb (table 3) . furthermore, in the majority of cases (67.7%, 21/31) providers used recommended screening test for active tb (chest x-ray) in case management. in terms of diagnostic period, 50% (5/10) of tb suspected patients within known health facilities visits status had > 2 visits to health facilities before appropriate screening/diagnostic tests were ordered (table 4 ). however, the period between patient registration/arrival in health facilities and order of tb screening/diagnostic test(s) was ≤12 h in 77.4% (24/31) of cases. similarly, in most cases (83.4%, 25/30), the period between ordering screening/diagnostic test(s) and confirmation of tb diagnosis was ≥2 days. in general, 62.5% (15/24) of cases were diagnosed within 2 days of arrival/registration to healthcare facilities. sputum culture was the diagnostic test utilized in the majority (67.7%, 21/31) of cases (table 4 ). xpert mtb/rif assay was not utilized for tb diagnosis. in one instance, none of the recommended diagnostic tests were ordered for the tb suspected patient. only 12.9% (4/25) of suspected/confirmed tb cases were screened for hiv. in over half of cases (58.1%, 18/31), the tb suspected patients were questioned about their tb history, although for a further 25.5% (8/31), response to this variable was unknown ( based on the duration of hajj season (around one month), the possibility of monitoring treatment completion is unfeasible in a hajj study. thus, appropriate post-hajj referral and provision of drugs to last during the referral period were proxies for estimating possible continuity of care. in most cases it was not known whether confirmed tb patients were referred for further treatment after completion of hajj (77.3%, 17/22) or were given enough anti-tb drugs to last until they arrive in their country of residence (61.6%, 11/18). in 76.7% (23/30) of cases, the confirmed tb cases were reported to the ksa moh preventive medicine department. the reporting status of the rest of the cases (23.3%, 7/30) was unknown. a proportion (44.8%, 13/29) of the confirmed tb cases was reported to the appropriate country medical missions' office. this excludes the 48.3% (14/29) of cases with unknown medical missions' reporting status. among the latter, 57.1% (8/14) were saudi residents. the confirmed tb case status of two residents of pakistan and myanmar were not reported to their respective country medical mission's office. the tb management guidelines compliance scores across the 4 identified themes are presented in table 6 . out of a maximum possible score of 10, the overall guideline compliance score was highest for the themes ipc and surveillance (9.6) and identifying tb suspects (7.2). the least scores were obtained for the themes treating tb (5.0) and diagnosing tb (3.0). some notable variations in theme's sub-scores were observed. for instance, while the overall score for the identifying tb suspects theme was high, a low score was documented for obtaining history of tb risk factors from patients. inversely, while the overall score for treating tb was average, high score was seen in relation to not starting tb treatment for patient before tb diagnosis. this study exemplifies the compliance of tertiary healthcare providers with the saudi national guidelines for tb management during the hajj. the result showed high level of compliance with the assessed tb management guidelines indices for systematic screening of tb suspects as well as ipc and surveillance, but low compliance scores were obtained for prompt tb diagnosis and use of standardized treatment regimen for drug-susceptible tb. most tb cases in the current study were males and over half were above 50 years old with primary or no formal education. this is in accordance with global and hajj-related data and established risk factors for tb [1, 7, 10, 12] . however, the prevalence of coexisting chronic diseases (63%, 17/27) among tb patients, especially diabetes, was higher than that reported internationally as well as previous studies among hajj pilgrims with tb [7, [12] [13] [14] . the presence of chronic diseases, increases the risk of tb disease, predisposes to severe illness and complicates tb treatment [1, 12] . as such, the management of comorbidities is now a key focus of the integrated, patient-centered care and prevention strategy of global tb control [2] . around 28% (8/29) of the tb cases reported being current smokers and a similar proportion (5/18) indicated that they did smoke in the past. this is higher than that reported in another study among hajj pilgrims with tb (13.3%) [7] but lower than figures from some international reports [15, 16] . other risk factors for tb such as visit to, or residence in high-burden countries and occupational exposure were uncommon among tb patients in the study and so was previous hajj or umrah performance. while the latter events are not an established risk factor for tb transmission, hajj is a risk of tb infection and both clinically-recognized or undiagnosed active tb have been reported at the pilgrimage [7, 10, 17] . the majority (65.4%, 17/26) of tb patients in this study were ksa residents. this may be explained by the fact that the study included both pilgrims and non-pilgrims and that healthcare facilities in makkah provide healthcare to pilgrims and non-pilgrims during the hajj. although saudi arabia is not a high tb burden country, tb incidence in the country show significant regional variation with the makkah region showing much higher tb incidence rates than the rest of the country and rising trend [18, 19] . in addition to the hosting of the hajj and umrah mass gatherings, this high tb incidence may also be related to the fact that around 40% of the makkah region population are non-saudis, many originate from and frequently visit high tb burden countries [18, 19] . regardless, it is evident that in addition to strategies to control imported active tb [7] , interventions to prevent transmission during hajj from locals and internal pilgrims with tb should also be developed and implemented. generally, home-based care for tb is preferred to methods of care that are based on strict hospitalization. in the ksa context, medical or mental instability and residence in congregate settings are among factors that may warrant hospitalization [6] . in this study, most of the suspected and confirmed tb patients were admitted and isolated for tb management. to the best of our knowledge, there is no standardized global protocol guiding the choice of suitable models of care-whether home based or hospitalized care-during international mass gatherings. however, considering the potential of tb transmission in such crowded settings, the constant mobility of pilgrims and challenges in verifiable or stable residences for pilgrims during hajj, hospitalization, although undesirable, seems a logical and practical choice for tb management during the mass gathering. ipc in healthcare settings is one of the key strategies for tb control [20] . however, implementation of ipc recommendations seems to be inadequate with several studies reporting poor tb infection control measures in health facilities [21] [22] [23] [24] . further, many hcws are practicing without adequate infection control training and often lack knowledge on tb infection control strategies and guidelines [24, 25] . in the current study, we report high compliance with the aspects of tb ipc [26] . early detection through systematic screening of tb suspects is key to improving tb case detection. the who recommends that persons with signs and symptoms consistent with tb should be evaluated for tb to ensure prompt diagnosis and treatment [3, 5] . similarly, the saudi tb guideline recommends that healthcare workers (hcws) should be knowledgeable about tb symptoms to facilitate the efficient identification of tb suspects for diagnosis and treatment [6] . in the current study, providers utilized presenting symptoms to correctly identify suspected tb patients in all cases. cough and fever with chills/night sweat were the most frequent symptoms among patients. this finding corroborates existing evidence that identifies cough as the most common symptom of ptb [3, 27] . further, in majority of cases (67.7%, 21/31), chest x-ray, a recommended screening tool for active tb, was conducted for the tb suspects. chest x-ray is particularly more sensitive for tb screening after a positive symptom screening [27] . however, we also found that less than half of the tb suspected cases were questioned about tb risk factors. adequate knowledge of tb symptoms and risk factors among providers are prerequisites for correct and prompt identification of suspected tb patients for screening and diagnosis [5, 6] . in view of the significant use of both symptom-based and radiological screening methods in this study, a total guideline compliance score of 7.2 out of 10 was obtained for the prompt identification and screening of tb suspects theme for tb management. delayed diagnosis of tb can enhance the transmission of infection, worsen the disease and increase the risk of death [28, 29] . in the current study, half of the tb cases had more than 2 visits to healthcare facilities before tb screening/diagnosis tests were ordered for the patients. while studies from other settings reported similar findings [30, 31] , our results are concerning, as delays in diagnosing tb during hajj may lead to significant transmission given the crowded setting during the event. similarly, sputum culture (which takes at least 2-3 weeks to produce results) was the only recommended diagnostic test applied in about 70% (21/31) of cases. the application of sputum culture as the singular diagnostic test is not consistent with approved standards for tb diagnosis [6] . as 75% (18/24) of suspected cases were confirmed to have tb by the third day of arrival in the health facility, it appears that providers relied on screening tests, such as chest x-ray, for the confirmation of tb diagnosis. this practice is inconsistent with both national and international guidelines; chest radiography is only recommended for screening purposes. the 2014 ksa tb guidelines recommended the use of xpert mtb/ rif as an initial tb diagnostic test on a conditional basis [6] . as such, the latter was not included in the scoring criteria for this study. nonetheless, xpert mtb/rif, which could detect tb and mdr-tb by proxy in the same day [32] , was not applied for tb diagnosis in this study. although available in a number of saudi hospitals and reference labs, the roll out of xpert mtb/rif has been slow and its use for pointof-care testing is limited [7, 33] . access to same day diagnosis of tb could prove valuable in a highly mobile hajj population where followup visits to the same health facility may not be guaranteed and where delays in diagnosis may increase the risk of transmission in such crowded settings. as such, ksa authorities should consider the provision of tb molecular testing capability in health facilities within the hajj areas to facilitate rapid (same-day) diagnosis of tb during the mass gatherings. due to the synergistic relationship between hiv and tb, it is recommended that all tb patients should be screened for hiv [5] . yet, only a fraction of tb patients were questioned about their hiv status (20.7%, 6/29) or tested for hiv (12.9%, 4/28) in this study. this is much lower than what is reported globally [1] . as a low prevalence setting, knowledge of hiv among healthcare workers is low in saudi arabia [34] . yet, hiv could be a more frequent comorbidity among pilgrims who arrive with active tb from areas with high hiv disease prevalence [1] . more so, a missed or delayed hiv diagnosis in a tb patient stalls the commencement of appropriate treatment and results in poor outcomes for the patient, community and health system [35] . therefore, healthcare providers in ksa ought to be trained and guided to conduct screening for hiv and other comorbidities in all suspected tb patients irrespective of their nationality. in general, because of delays in diagnosis, infrequency of hiv testing and failure to utilize the appropriate diagnostic tests for suspect tb patients, the combined score for the tb diagnosis theme was 3 out of a maximum of 10, the lowest score of all tb management themes in the current study. treatment of tb in ksa is free of charge for pilgrims and other patients and both the ksa and who guidelines for tb management recommend the use of four 1st-line anti-tb drugs in the treatment of drug-susceptible tb [5, 6] . the guideline compliance score for tb treatment in this study was average; partly because 63% (17/27) of tb patients received fewer than four 1st-line anti-tb drugs. in general, inappropriate treatment of tb is common worldwide. in a systematic review that included 37 studies from 22 countries, inappropriate treatment regimens were prescribed in 67% of the studies and the percentage of patients on inappropriate regimens varied between 0.4% and 100% [36] . poor knowledge of national and international tb management guidelines contributes to inappropriate prescription of anti-tb drugs by healthcare providers, and the use of inappropriate regimen drives the occurrence of relapse and the emergence of drugresistant tb [37, 38] . both the who and ksa tb guidelines recommend that all patients with ptb being treated with the 1st-line regimen should have their sputum samples tested by the end of the 2nd, 5th and 6th month of treatment [6, 39] . in the current study, all confirmed tb cases with known notification status were reported to the saudi health authorities. however, it is unknown whether the continuum of care was maintained for tb cases who were international pilgrims and who had to return to their home countries soon after the pilgrimage (before the end of the treatment period). any travel-related treatment interruptions could breed treatment relapse and drug-resistance and propagate community spread of tb. both national and international tb guidelines fall short of providing guidance on tb control at international mass gatherings, including procedures for ensuring access to care and support services during travel. thus, the development and dissemination of a multinational hajj and umrah and/or mass gatherings-specific tb management protocols are needed. these protocols should also include pathways for the safe transfer across borders and follow up of tb patients involved in mass gatherings. the current study is among the foremost surveys of tb management at international mass gatherings. while the small number of cases and high proportion of unknown responses for some variables constituted limitations, the tb management indices obtained was a fair representation of the compliance of providers with national and international tb guidelines in moh hospitals during the hajj. the findings provides a basis for the review of existing practices across settingsprivate and public sector vs national and foreign health facilities-and serves as a reference for the development of appropriate guideline and protocol for tb management at the hajj and umrah, as well as other settings with similar health system resources and population dynamics hosting recurrent international mass gatherings. in the short term, availability of rapid molecular diagnostic techniques for tb as we all improving hcws' knowledge regarding tb management guidelines and monitoring compliance are needed to ensure tb patients are management appropriately during hajj and that tb transmission is prevented. no conflicts of interest to declare. none to declare. the study was approved by the king fahad medical city ethics committee and the institutional review board (irb log: 16-329e) and conducted in accordance with the ethics committee's guidelines. all participants gave verbal consent before enrolment. world health organization. gear up to end tb: introducing the end tb strategy. world health organization world health organization. early detection of tuberculosis: an overview of approaches, guidelines and tools world health organization. guidelines for the treatment of drug-susceptible tuberculosis and patient care compendium of who guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis. world health organization saudi ministry of health. basics of tuberculosis control in saudi arabia. public health agency ntcp, ministry of health, kingdom of saudi arabia undiagnosed active pulmonary tuberculosis among pilgrims during the 2015 hajj mass gathering: a prospective cross-sectional study tuberculosis infection during hajj pilgrimage. the risk to pilgrims and their communities a systematic review of emerging respiratory viruses at the hajj and possible coinfection with streptococcus pneumoniae tuberculosis is the commonest cause of pneumonia requiring hospitalization during hajj (pilgrimage to makkah) clinical and temporal patterns of severe pneumonia causing critical illness during hajj tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts tuberculosis non-communicable disease comorbidity and multimorbidity in public primary care patients in south africa comorbidities in pulmonary tuberculosis cases in puducherry and tamil nadu, india: opportunities for intervention high prevalence of smoking among patients with suspected tuberculosis in south africa prevalence of smoking and its impact on treatment outcomes in newly diagnosed pulmonary tuberculosis patients: a hospital-based prospective study high risk of mycobacterium tuberculosis infection during the hajj pilgrimage tuberculosis incidence trends in saudi arabia over 20 years: 1991-2010 tuberculosis in saudi arabia: prevalence and antimicrobial resistance world health organization. who policy on tb infection control in health-care facilities, congregate settings and households a national infection control evaluation of drug-resistant tuberculosis hospitals in south africa the status of tuberculosis infection control measures in health care facilities rendering joint tb/ hiv services in "german leprosy and tuberculosis relief association" supported states in nigeria infection control and the burden of tuberculosis infection and disease in health care workers in china: a cross-sectional study assessment of knowledge and practice of health workers towards tuberculosis infection control and associated factors in public health facilities of addis ababa, ethiopia: a cross-sectional study updates on knowledge, attitude and preventive practices on tuberculosis among healthcare workers a study of the probable transmission routes of mers-cov during the first hospital outbreak in the republic of world health organization. systematic screening for active tuberculosis: principles and recommendations. world health organization the relationship between delayed or incomplete treatment and all-cause mortality in patients with tuberculosis delayed tuberculosis diagnosis and tuberculosis transmission missed opportunities to diagnose tuberculosis are common among hospitalized patients and patients seen in emergency departments time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature roadmap for rolling out xpert mtb/rif for rapid diagnosis of tb and mdr-tb evaluation of genexpert mtb/rif for detection of mycobacterium tuberculosis complex and rpo b gene in respiratory and non-respiratory clinical specimens at a tertiary care teaching hospital in saudi arabia knowledge and attitudes of doctors toward people living with hiv saudi arabia early versus delayed antiretroviral therapy for hiv and tuberculosis co-infected patients: a systematic review and meta-analysis of randomized controlled trials prevalence of inappropriate tuberculosis treatment regimens: a systematic review knowledge of tuberculosis-treatment prescription of health workers: a systematic review multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis world health organization. treatment of tuberculosis: guidelines. geneva: world health organization key: cord-325069-wxdkao69 authors: khatri, priyanka; singh, shweta r; belani, neeta kesu; yeong, yin leng; lohan, rahul; lim, yee wei; teo, winnie zy title: youtube as source of information on 2019 novel coronavirus outbreak: a cross sectional study of english and mandarin content date: 2020-03-20 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101636 sha: doc_id: 325069 cord_uid: wxdkao69 background: the current 2019 novel coronavirus outbreak is rapidly evolving. youtube has been recognized as a popular source of information in previous disease outbreaks. we analyzed the content on youtube about n-cov in english and mandarin languages. methods: youtube was searched using the terms ‘2019 novel coronavirus’, ‘wuhan virus’ and ‘武汉病毒’ (mandarin for wuhan virus) on 1st and 2nd february 2020. first 50 videos in each group were analyzed. videos in other languages, duplicate videos, those without an audio and duration >15 min were excluded .72 videos in english and 42 in mandarin were reviewed. 2 reviewers classified the videos as useful, misleading or news based on pre specified criterion. inter-observer agreement was evaluated with kappa coefficient. modified discern index for reliability and medical information and content index (mici) score were used for content analysis. results: these videos attracted cumulative 21,288,856 views. 67% of english and 50% mandarin videos had useful information. the viewership of misleading mandarin videos was higher than the useful ones. who accounted for only 4% of useful videos. mean discern score for reliability was 3.12/5 and 3.25/5 for english and mandarin videos respectively. mean cumulative mici score of useful videos was low (6.71/25 for english and 6.28/25 for mandarin). conclusions: youtube viewership during 2019 n-cov outbreak is higher than previous outbreaks. the medical content of videos is suboptimal international health agencies are underrepresented. given its popularity, youtube should be considered as important platform for information dissemination. in december 2019, a series of pneumonia cases of unknown cause were reported in wuhan city in hubei province of china [1] . a novel strain of coronavirus was isolated from the affected patients on 7th jan 2020 and the number of confirmed cases rapidly soared to 581 within 2 weeks [2] . the cases spread beyond wuhan city and on 30th jan 2020, world health organization (who) declared the 2019 novel coronavirus (2019-ncov) outbreak as "public health emergency of international concern "(pheic). as per who situation report of 6th february 2020, 28276 cases had been confirmed globally, of these 216 were outside china in 24 countries worldwide [3] . in our current digital world, online platforms are perhaps the most accessible source of health related information for the public [4, 5] . youtube is a popular video sharing website with an estimated monthly viewership of 1 billion [6] and serves as an important source of health care related information. during the ebola outbreak in 2014, relevant you tube videos were watched millions of times [7] . similar viewership was reported during the 2016 zika virus epidemic [8] . such formidable viewership makes youtube a double-edged sword in times of disease outbreaks. while appropriate youtube content may benefit the government agencies and health care organizations in allaying public anxiety and enforcing measures to control the spread of disease, dissemination of wrong information can lead to public paranoia and https://doi.org/10.1016/j.tmaid.2020.101636 received 13 february 2020; accepted 19 march 2020 failure to contain the infection [9] . the quality of information on youtube has been evaluated during previous epidemics and endemics. up to 20% of videos were reported to have misleading information about various aspects of disease during these outbreaks [8, 10, 11] we are not aware of any studies evaluating the role of youtube as a source of information on 2019 -ncov. the objectives of our study were (i) to analyze the quality of the information available on youtube about current ncov outbreak (ii) to compare the english language content with the information available in chinese mandarin henceforth mentioned as mandarin. it is the most widely spoken language in asia and official language of china. the current n-cov epidemic has affected the asia pacific region more than the west. we think that it is therefore important to review the available content in mandarin. youtube was accessed on 1st and 2 nd february 2020 from singapore using the search terms '2019 novel coronavirus' and 'wuhan virus '. search term '2019 novel coronavirus' yielded 16,4000,000 results while the term 'wuhan virus' showed 20,800,000 results. the search term used in mandarin '武汉病毒' is a translation for 'wuhan virus' and showed 58,100,000 results. we included first 50 videos from each search term for further analysis. this screening strategy is based on previous studies indicating that the users do not go beyond the first few pages of results from a search engine [12] [13] [14] . the default youtube algorithm of decreasing order of relevance was used for sorting the videos. these 150 videos were saved in a playlist for further analysis because the search results in youtube can change on a day to day basis [7] . uniform resource locators (urls) of these videos were saved separately as back up. our search methodology is in alignment with previous studies on youtube content [15] [16] [17] . of the 150 videos screened, 72 videos in english and 42 videos in mandarin were included in further analysis ( fig. 1a and b ). exclusion criterion were: videos in language other than english or mandarin, absence of audio, videos lacking information on the 2019 novel coronavirus and duration more than 15 min. an analysis of 250 top you-tube channels concluded that the optimal length for a video is 10-16 min [18] . videos with longer duration do not receive much viewership. hence we excluded those videos from our study. the videos with subtitles were included in the group of the subtitle language. all videos were reviewed and analyzed by 2 independent reviewers (wzt and yyl). both wzt and yyl have received formal education in english and chinese and are fluent in both. wzt is a haematologist and yyl is a medicine trainee. any discrepancies were resolved by a third reviewer nkb who is proficient in both english and spoken mandarin. as this study required analysis of publicly available information, institution review board approval was not required. videos were classified as useful if they contained scientifically correct information about any aspect of the disease (symptoms, treatment, prevention of disease, or measures being taken to combat the disease). the videos that contained scientifically unproven (e.g., referring to ncov as a manmade conspiracy or government propaganda) information were classified as misleading. videos uploaded by news agencies with information on current status of the disease in terms of mortality and extent of spread only, without any information on prevention, treatment, or measures to combat the disease were classified as news update. this classification has been used in evaluation of information during previous epidemics [10, 19, 20] . we used modified discern score to assess the reliability of the videos [15] . this score allocates one point each for clarity, reliable source of information, lack of bias, reference supplementation and mention of uncertainty (table 1) . a maximum score of 5 indicates highest reliability for a particular video. for evaluating the content, we used medical information and content index (mici) as previously defined by nagpal et al. during the ebola epidemic [7] . this scale uses a 5 point likert scale to assess five components of medical information included in the videos: prevalence, transmission, clinical symptoms, screening/testing, and treatment/outcomes of the disease. the study team devised set of criterion to be used for grading each component of mici score on a scale of 1-5. for example a video would be scored 5 for the treatment/outcome component if it mentions all of the following: the symptoms can be self-resolving but some cases can become dangerously ill requiring hospitalization or intensive care unit, disease can lead to death, treatment is mainly supportive, vaccinations not yet available. the full list of criterion is available as supplementary table 1 . the kappa coefficient of agreement was used to determine degree of agreement between the two researchers. source of videos was categorized into one of five groups: academic institutions or hospitals, news agencies, government agencies like regional health departments, who or independent users. the authors are aware of the uncertainties regarding this disease. for example, there is still no consensus on the source of disease outbreak or the transmissibility of the virus, exact incubation period of the virus, and the proportion of infected people who develop disease. before grading the videos, available scientific literature [21] [22] [23] and relevant information on who website was reviewed. version r 3.5.3 was used for analysis. unpaired student t-test was used to test the hypothesis of difference in means for all variables. a pvalue of 0.05 was considered to be significant. given the small sample size, univariate logistic regression was used to find the odds of posting a useful video based on source. 72 videos in english and 42 videos in mandarin were included for analysis after applying exclusion criterion (fig. 1) . the total duration of all videos was 8.45 h. these 114 videos attracted a cumulative number of 21,288,856 views and 259108 likes. the kappa coefficient of agreement regarding the usefulness of the videos was 0.72 (p value < 0.001). 60% videos were classified as useful (n = 68), 8% misleading (n = 9) and 32% as news (n = 37). baseline characteristics of the videos are summarised in table 2 . the majority of videos were uploaded by news agencies (76%, n = 86) followed by independent users (11%, n = 12). who contributed 3 videos (table 4 ). one of these videos was in english language with mandarin subtitles and had 29466 views. there were no videos by cdc. no videos were shared by academic institutions in mandarin. independent users were 7 times less likely to upload useful information than academic institutions (table 5) . despite being of similar length, misleading videos in english attracted significantly lesser number of views and likes than useful videos. conversely, misleading videos in mandarin were of longer duration than useful videos and attracted more number of views. this difference was however not statistically significant.the statements made in misleading videos are available as supplementary table 2 . more than 70% of useful videos in english contained information about the prevalence, transmission and treatment/outcomes of ncov disease. almost half of the useful videos did not address transmission or clinical symptoms ( youtube viewership of content related to the 2019 n-cov epidemic appears higher than previous disease outbreaks [10, 20] . this is evident by the much higher number of mean views/day of the useful videos in our study. this can be partly explained by the fact that we performed this analysis early in the course of disease evolution. the mean number of days since upload on youtube for useful videos was 6 in our study compared to 61 days as reported by pathak et al. during the 2014 ebola virus disease outbreak. it has been reported that the viewership of videos tends to decrease over time and that could lead to higher number of views/day in the initial days of video upload. regardless, the difference is substantial and high viewership of content in our study should be considered as a reflection of growing popularity of youtube for health related information. the higher number of views can also be explained by the global spread of this disease compared to previous outbreaks like ebola which was mainly restricted to africa. the current content on youtube in english is mostly informative. there were only 2 misleading videos amongst the included 72 videos. these results are reassuring. previous studies have reported that about 15-30% of information on youtube about a disease can be misleading [24] [25] [26] . the lower percentage of misleading videos in our study can be explained by the difference in source of these videos compared to previous studies. individual users accounted for only 11% of total videos while news agencies contributed 68%. this is not surprising given the global nature and rapid spread of this outbreak. this has attracted attention of news agencies worldwide. videos uploaded by independent users are more likely to contain misleading information than government/news agency videos [8] . the modified discern score of videos which were characterized as useful is of concern too. there was only 1 video with a perfect discern score of 5 indicating highest reliability. 20% of the useful videos had discern score of less than 3 indicating low reliability. most of the videos did not mention areas of uncertainty or additional sources of patient information. international health agencies like who only had 2 videos while cdc had none in the top 100 english videos related to this disease. under representation of international health agencies on youtube has previously been reported [8] . previous studies have focussed on analysis of youtube videos only in english. youtube is gaining popularity for its content in non-english languages too. in the first week of 2019, a total of 243,254 videos were posted on youtube, out of these 67% were in languages other than english [27] . this prompted us to evaluate the information available on youtube about ncov in mandarin and compare it to the content in english. the mean discern scores were similar in 2 groups indicating comparable reliability. similarly, comparable but very low mean total mici scores were noted in both groups, suggesting overall paucity of good quality scientific information on n-cov outbreak. the information pertaining to screening and testing was worst with mean mici scores of 0.95 and 0.31 in english and mandarin groups respectively. under representation of government agencies was noted in mandarin videos as well. news updates constituted most of the mandarin videos too, however compared to english new agencies, the narrators of news clips in mandarin often commented on how chinese government could have acted differently to contain this epidemic early. no videos were shared by academic institutions and hospitals in mandarin which contributed to slightly higher percentage of misleading videos in mandarin. contrary to the english videos, the misleading videos in mandarin were more popular than useful videos, as evidenced by higher mean number of likes. the misleading information in native language at epicentre of outbreak might have led to undue public distress during early phase of outbreak. youtube thus should play a more active role in our study has many limitations. this study presents only a cross sectional snapshot of the available information. the viewership and content on youtube change on a daily basis. we are unable to comment on how the viewership and content regarding 2019 ncov will change as the outbreak evolves. we did not analyze other video sharing platforms such as health sharing websites or news channel websites. in addition, youtube is not accessible from china. instead, a platform called youku is used for video sharing. this affects the applicability of results in china which is the epicentre of this disease outbreak. restriction of youtube in china also explains the relative lesser number of views of mandarin language videos compared to those in english. nonetheless, mandarin remains the widest spoken language in asia pacific region and videos in this language serve as an important source of information to native mandarin speakers in this region. another limitation of our study is the possibility of inter and intra observer bias though we used the kappa coefficient to ensure that the results were not too different. our search was limited to first 50 videos for each keyword. it has previously been explained in multiple studies that most internet users do not look beyond the first 50 search results [16, 28, 29] for the search in conclusion, the available information on youtube about 2019 n-cov outbreak attracted high viewership. this clearly establishes youtube as a popular platform for information seeking in the current n-cov epidemic. as the current outbreak evolves, international health agencies and academic institutions should release more videos with information about screening and testing of this disease. youtube should consider screening and removing videos with misleading information to prevent public paranoia in current state of emergency. no funding was required to conduct this study. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. table 4 source wise distribution of different video types. situation report 9th situation report 17th the internet as a source of health information and services use of the internet as a health information resource among french young adults: results from a nationally representative survey youtube videos as a source of medical information during the ebola hemorrhagic fever epidemic are internet videos useful sources of information during global public health emergencies? a case study of youtube videos during the 2015-16 zika virus pandemic panic, paranoia, and public health -the aids epidemic's lessons for ebola youtube as a source of information on the h1n1 influenza pandemic analysis of youtube as a source of information for west nile virus infection are video sharing web sites a useful source of information on hypertension? is youtube useful as a source of information for sjogren's syndrome? youtube for information on rheumatoid arthritis -a wakeup call youtube as source of patient information on abdominal aortic aneuryms a quality analysis of disc herniation videos on youtube youtube as an information source for femoroacetabular impingement: a systematic review of video content is youtube an accurate and reliable source of yellow fever information during outbreaks youtube as a source of information on ebola virus disease early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with 2019 novel coronavirus in wuhan a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster is youtube useful as a source of information for sjogren's syndrome? youtube for information on rheumatoid arthritis -a wakeup call are video sharing web sites a useful source of information on hypertension? popular youtube channels produced a vast amount of content, much of it in languages other than english youtube tm as an information resource for orthognathic surgery lingual orthodontic treatment: a youtube tm video analysis travel medicine and infectious disease xxx (xxxx) xxxx supplementary data related to this article can be found at https:// doi.org/10.1016/j.tmaid.2020.101636. key: cord-340942-oatf59k0 authors: magalhães, jurandy júnior ferraz de; mendes, renata pessoa germano; silva, caroline targino alves da; silva, severino jefferson ribeiro da; guarines, klarissa miranda; pena, lindomar title: epidemiological and clinical characteristics of the first 557 successive patients with covid-19 in pernambuco state, northeast brazil date: 2020-09-21 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101884 sha: doc_id: 340942 cord_uid: oatf59k0 background: south america is the current epicenter of covid-19 pandemic. yet, the epidemiological and clinical features of the disease have not been described in brazil, the third most affected country in the world. methods: in this retrospective study, we describe the demographics, epidemiology and clinical features of the first 557 consecutive patients positive for sars-cov-2 living in pernambuco state, northeast brazil. results: the first covid-19 cases occurred in the high income population. the age of infected patients ranged from 27 days to 97 years with a median of 47 years. the ratio of males to female in the sars-cov-2-infected group was 0.83:1. the most common symptom was cough (74.51%), followed by fever (66.79%), dyspnea (56.01%), sore throat (28.19%) and o(2) saturation <95% (24.42%). 86.44% of the lethal cases were patients older than 51 years. the median time from illness onset to diagnosis was 4.0 days (range 0–39 days) severe patients diagnosed after 14 days of symptoms onset had higher viral load than patients with mild disease. conclusions: our study provides important information about covid-19 in the tropics and will assist physicians and health officials to face the current pandemics as sars-cov-2 continues to spread in the human population. in late december 2019, a cluster of severe pneumonia cases of unknown origin was reported in wuhan, hubei province, china [1] . the disease, later named coronavirus disease 2019 (covid19) , was caused by a novel coronavirus identified as severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [2, 3] . similar to other highly pathogenic coronaviruses (covs -sars-cov and middle east respiratory syndrome cov (mers-cov), sars-cov-2 belongs to β genus within the coronaviridae family and emerged from bats. the rapid spread of sars-cov-2 around the world caused the world health organization (who) to declared covid-19 as a pandemic on march 11, 2020 [4] . china was the first epicenter of pandemic, followed by europe, the usa, and now south america. on february 26, 2020, brazil reported the first case in latin america in a são paulo patient returning home after a work trip to italy from february 9th to 21st. the patient had a mild respiratory disease characterized by coryza, dry cough, and sore throat [5] [6] [7] . since then, the number of covid-19 cases in brazil has increased steadily and the country has become the third most affected in the world after the usa and india. given the paucity of diagnostic tests in developing countries, the actual incidence of covid-19 in brazil is heavily underestimated. for instance, while the usa has done 282,114 tests per million inhabitants, brazil has performed only 68,143 tests/million people (https://www.worldometers. info/coronavirus/). as of september 15, 2020, brazil has confirmed 4.3 million covid-19 cases and 132,297 deaths (https://www.wor ldometers.info/coronavirus/). pernambuco is one of the most affected state in brazil with 137.869 cases and 7914 deaths [8] . the emergence of sars-cov-2 caused a profound change in the global scenario and recruited public health authorities and research groups from different parts of the world to fill knowledge gaps in the biology and pathogenesis of this devastating pathogen. although the epidemiological and clinical presentation of covid-19 has been well documented in several countries of the northern hemisphere, information regarding the clinical features of covid-19 in latin america, especially in brazil, remains scarce and limited. thus, an updated analysis of cases could help to significantly improve our knowledge and consequently provide insights into covid-19 in this region of the planet, given its unique climate, social dynamics, population genetics and political scenario [9] . here, we describe for the first time the clinical, epidemiological and demographic features of the first 557 laboratory-confirmed covid-19 cases in pernambuco state, northeast brazil, who were diagnosed between march 12 and april 22, 2020. a total of 557 patients living in pernambuco state with a positive sars-cov-2 nucleic acid test were included in this study. patients were considered to have confirmed covid-19 infection if they had at least one positive rt-qpcr test for sars-cov-2. this study was approved by the upe institutional review board under protocol caae: 27607619.0.0000.5207 and was performed in accordance with relevant guidelines e regulations, including the brazilian national health council (cns) resolution 466/2012. the requirement for informed consent study was waived based on the nature of this observational retrospective study, in which patient identifying information were kept confidential. patient epidemiological information, demographic and clinical characteristics, including medical history, signs and symptoms, laboratory findings, underlying co-morbidities, and date of disease onset were obtained from electronic medical records of the pernambuco central public health laboratory (lacen) and analyzed. patient outcome data were obtained from march 12 to 22 april 2020, the final date of followup. all covid-19 patients enrolled in this study were diagnosed according to world health organization interim guidance [10] . laboratory confirmation was performed at the pernambuco lacen, which is one of the designated laboratories for the diagnosis of sars-cov-2 in this state. nasopharyngeal and oropharyngeal swabs were collected from patients presenting respiratory signs of disease compatible with covid-19. after sample collection, viral rna was extracted using the reliaprep viral tna miniprep system kit (promega, madison, wi, usa), according to the manufacturers' instructions and the rna was used for rt-qpcr following the protocol for sars-cov-2 detection established by corman and coworkers [11] . spatial analysis were done by georeferencing only the addresses of individuals residing in recife (n = 306), capital of the state of pernambuco and city with the largest number of confirmed cases of covid-19 at the time of this analysis. for that, the qgis software (https://qgis. org/en/site/) was used to plot home addresses and the kernel density estimation method was applied to identify the neighborhoods with the highest concentration of covid-19 cases. we also calculated the incidence of infection in the neighborhoods and that concentration of cases were displayed on a heat map. the location of the georeferenced addresses was produced on a scale of 1:215,000, which means that on the map, the location of the addresses presents an error of approximately 0.4 mm (40 m on the real scale). therefore, the addresses of individuals are located in an area of approximately 2500 m 2 . as recife is an urbanized city, ethical concerns are not applicable because it is not possible to verify the exact location of each residence. the cartographic base used was acquired in shapefile format at the website of the brazilian institute of geography and statistics (ibge) in the geocentric reference system for the americas (sirgas) 2000. in addition, we built a graduated map with information on the income of households in the neighborhoods from the city of recife and we classified the neighborhoods based on the amount of minimum wages received to correlate the distribution of covid-19 cases within the different ranges of household income of the studied population. we used data on minimum wages and average monthly nominal income per household from the last brazilian census (http://censo2010.ibge.gov.br/). microsoft office excel (version 2010) was used to build a database with patient's information. data process and analysis were made using the graphpad prism version 6.0 for windows (graphpad software, la jolla, ca, usa). continuous variables were expressed as medians and interquartile ranges, as appropriate. categorical variables were summarized as counts and percentages. a chi-square test was used to investigate the level of association among variables. statistically significant differences were defined as p < 0.05. from 12 march to april 22, 2020, a total of 2772 suspected cases-1616 females (58.30%) and 1156 males (41.70%) -were collected and tested for sars-cov-2 at the pernambuco lacen by rt-qpcr. from total cases, 557 (20.09%) were positive for sars-cov-2. these were the first covid-19 cases reported in the state. fig. 1 illustrates the epidemic distribution in pernambuco state. the highest number of cases (n = 304, 54.58%) occurred in the city of recife, capital of pernambuco, followed by the metropolitan cities jaboatão dos guararapes (n = 43, 7.72%), olinda (n = 43, 7.72%), paulista (n = 30, 5.39%), são lourenço da mata (n = 23, 4.13%), and camaragibe (n = 16, 2.87%). the first 304 cases of covid-19 in recife were georeferenced using the kernal density estimate. the highest case numbers were concentrated in the neighborhoods of casa amarela, parnamirim, rosarinho, encruzilhada, espinheiro, graças, torre, madalena, and boa viagem (fig. 1a ). the rosarinho neighborhood had the highest incidence of covid-19 (12.26/10 4 inhabitants) and also had the highest number of cases per square kilometer (20/km 2 ), while the guabiraba neighborhood had the lowest incidence (1.58/10 4 inhabitants) and a lower number of cases per square kilometer (0.02/km 2 ). regarding the distribution of covid-19 cases in the different household income ranges (fig. 1b) , we found that sars-cov-2 infections occurred in neighborhoods with greater purchasing power. of the nine neighborhoods highlighted on the heat map, seven had households with earnings greater than 10 minimum wages, demonstrating that the first covid-19 cases in pernambuco target the high income population. fig. 1a shows the spatial distribution of covid-19 cases in recife, pernambuco capital as heat map. the kernel density estimate was used to show the areas with the highest concentration of cases associated with the incidence of the disease in some neighborhoods. fig. 1b shows a graduated map with information on the average nominal monthly household income converted into the amount of minimum wages. fig. 1c shows the cities with covid-19 positive cases in the state of pernambuco. pernambuco was notified on march 12, 2010. during the first week, 29 (5.20%) cases and 2 (3.38%) deaths were registered. the fourth week (from 7 to 14 april) registered the greatest increase in the number of cases and deaths. a total of 354 (63.55%) cases and 29 (49.15%) deaths were recorded in that period, which corresponded to 501 (89.94%%) accumulated positive cases and 58 (98.30%) deaths. the age of sars-cov-2 infected patients ranged from 27 days to 97 years with a mean of 48.57 years and a median of 47 (interquartile range [iqr], 32 to 68). the ratio of males to female in the sars-cov-2infected group was 0.83:1 (45.42% males/54.58% females; chi-square test, p = 0.46), showing a slight higher incidence in females than males. the highest number of cases occurred in patients aged 31-40 years old (n = 128, 22.98%), followed by the 41-50 years age group (n = 121, 21.72%), and the group embracing patients from 51 to 60 years old (n = 101, 18.13%). during the study period, a total of 59 deaths occurred. among these, 51 (86.44%) were patients older than 51 years. although the incidence was more elevated in females, the number of deaths tended to be higher in males (55.93% versus 44.06%), despite the difference not reaching statistical significance (chi-square test, p = 0.87). the mean age of deceased patients was 66.06 years and the median was 65 (interquartile range, 51.5-82.5). the highest mortality rate was observed in patients in the 61-70 years age group (n = 18, 30.50%), followed by the 51 to 60 age group (n = 11, 18.64%) (fig. 2b) . fig. 3a summarizes the main symptoms presented at the time of patient notification. the most common symptom was cough (n = 415, 74.51%), followed by fever (n = 372, 66.79%), dyspnea (n = 312, 56.01%), sore throat (n = 157, 28.19%) and o 2 saturation <95% (n = 136, 24.42%). some patients also presented myalgia (n = 28, 5.03%), headache (n = 24, 4.31%), running nose (n = 20, 3.59%), diarrhea (n = 17, 3.05%), and vomiting (n = 9, 1.62%). fig. 3b shows the symptoms according to age groups. the most prevalent symptom in patients aged less than 20 years old were fever, cough and dyspnea. in addition to these symptoms, sore throat, myalgia, headache, diarrhea, vomiting and runny nose were more common in people aged over 20 years old. the highest rate of patients with saturation <95% was found in individuals aged over 61 years. the average time from the symptoms onset to notification date was 4.85 days while among deceased patients this number was 4.52 days. we next sought to investigate the virus shedding pattern in patients at the time of diagnosis. information on the quantitation cycle (cq) was available for 388 patients. the cq value was used to estimate the viral load of patient's nasopharyngeal specimens, in which lower cq values indicate higher amount of virus. the median cq of the patients was 26.3 (sd = 5,7) and ranged from 13.3 to 39.3. to evaluate sars-cov-2 shedding patterns in this cohort, the data were further stratified according to the day of symptoms onset at the time of sampling. the median time from illness onset to diagnosis was 4.0 days (sd = 4,7), with a range of 0-39 days (fig. 4a) . we then compared the viral load of severe cases (patients that were admitted to icu and the ones that have died) with mild cases at different days since symptoms onset (fig. 4b) . there was no statistically significant difference in viral load at the time of diagnosis of patients with mild or severe covid-19 up to 14 days of symptoms onset. however, patients with severe disease diagnosed after 14 days of symptoms onset had higher viral load than patients with mild disease (p = 0.0218). the clinical evolution of patients reported up to the date of notification (april 22nd, 2020) indicated that 50.63% (282/557) were in selfisolation, 26.93% (150/557) were in general hospital wards, 5.38% (30/ 557) required intensive care unit (icu) care, 6.46% (36/557) fully recovered from the disease and 10.59% (59/557) of the patients evolved to death (table 1) . information on comorbidities was available to 116 patients. a total of 72.27% of the patients reported comorbidities. the most common comorbidity was arterial hypertension (26.72%), followed by diabetes mellitus (16.38%), cardiovascular diseases (13.79%), asthma (6.89%), lung disease (4.31%), obesity (2.59%), and kidney disease (0.87%) (fig. 5) . brazil remains the third most affected country after the usa and india. after its initial detection on february 26, 2020, sars-cov-2 has spread to all its 26 states and the federal district. yet, the epidemiological and clinical profile of covid-19 in brazil has not been reported in the literature. here, we described for the first time the epidemiological and clinical characteristics of the first 557 consecutive patients diagnosed with sars-cov-2 in the state of pernambuco between 12 march and april 22, 2020. the first patients diagnosed with sars-cov-2 in pernambuco were an elderly couple (71-year-old man and 66-yearold woman) returning from rome, italy on 29 february and whose diagnostic was confirmed on 12 march. the couple lived in the boa viagem, a high-income neighborhood located in the southern region of the city (fig. 1) . this couple had returned from a trip to italy and sought medical treatment on march 5, 2020, when italy already had 3858 confirmed cases of covid-19 (who). on march 17, pernambuco reported local transmission of sars-cov-2 for the first time and since then the number of new cases has increased steadily first in the metropolitan area and then spreading to inland cities. the state capital, recife had the highest number of covid-19 cases in the study period. as shown in fig. 1b , the first sars-cov-2 cases were concentrated in neighborhoods with a higher nominal monthly household income, such as the rosarinho, espinheiro, and boa viagem neighborhoods that had average earnings above 10 brazilian minimum wages. our data is in agreement with a study done in rio de janeiro, brazil in which the highest rates of covid-19 were observed in the wealthiest regions [12] . despite the epidemiological evidence and the first detection of sars-cov-2 in the boa viagem neighborhood with subsequent spread mainly to high income neighborhoods, it is not possible to say with certainty that sars-cov-2 infections in pernambuco started from these places. for that, robust phylogeography analyses based on sars-cov-2 genomic sequences from these patients would be necessary to definitely understand the its transmission dynamics and associate it with clinical and epidemiological data. nevertheless, individuals with high household income are more likely to take costly international trips and are therefore expose themselves to the risk of acquiring an infection overseas. in fact, the index covid-19 case in brazil was diagnosed in são paulo in patient returning from a trip from italy. phylogenetic analyses of the first patients in são paulo coupled with travel history information confirmed multiple independent importations from italy and local spread during the initial stage of sars-cov-2 transmission in the country [13] . our results highlights the importance of emerging diseases strengthening programs and preventing people who have traveled to different locations in the world from returning to their countries without undergoing quarantine and testing upon return to their home country. the median age of the patients included in this study was 47 years (iqr 32 to 68), ranging from 27 days to 97 years. however, the median age of deceased patients was 65 years. in our study, only 14 cases (2,51% of total) were reported in patients aged less the 20 years, whereas a large proportion of cases (44,70% of total) were in patients aged 31-50 years old. lethal cases in this cohort were concentrated in patients older than 51 years, which accounted for 86.44% of total deaths. our data is in agreement with a study conducted by guan et al. where the median age of sars-cov-2 infected patients was 47 years (iqr: 35 to 58) and only 0.9% of patients were under 15 years old [14] . in another study carried out in china, the most affected patients were in the 50-59 years age group, whereas fatal cases were concentrated in the 70-79 years group [15] . in our study, a higher proportion of women sought medical attention upon suspecting of a respiratory disease (58.30% females and 41.70% males) and sars-cov-2 positivity was higher in female (54.58%) than males (45.42%). the data is in agreement with 102,646 cases of covid-19 cases reported in canada to date, in which 56% occurred in females [16] . this sex discrepancy in our studyt might be due to lifestyle behavior in which women are more likely to seek medical care at the first signs of disease than men. the covid-19 lethality in this study showed a higher tendency in males than females (55.93% versus 44.06%), although it not reached statistical significance. in general, the men to women ratio of covid-19 prevalence is the same, but men with covid-19 tend have higher risk of developing the severe forms of the disease and die from it [17, 18] . we found that cough, fever and dyspnea were the most common symptoms. the main symptoms showed in our study were also reported by others [19] [20] [21] [22] . wan et al., 2020 demonstrated that fever (88.9%) and cough (76.5%) were also the most common symptoms, however, dyspnea was present in only 13.3% of patients [23] . gastrointestinal manifestations were less prevalent. lower frequency of gastrointestinal symptoms is also shown in other studies [14, 20] . the virus shedding pattern in patients at the time of diagnosis was investigated in this study. our data demonstrated that the median time from symptoms onset to viral rna shedding was 4 days, ranging from 0 to 39 days. this data is in agreement with a study in wuhan in which the longest duration of viral shedding in survivors was 37 days [21] . comparison of the sars-cov-2 load of severe cases with mild cases at different days since symptoms onset did not find a statistically significant difference up to 14 days of symptoms onset, but lately diagnosed patients (after 14 days) had higher viral load than patients with mild disease (p = 0.0218). recently, liu and co-workers studied the viral dynamics in mild and severe cases of covid-19 and found that patients with severe disease had about 60 times higher viral load than that of mild cases [24] , irrespective of the day of symptoms onset. in this cohort, 10.59% of the patients died from covid-19. the high case-fatality rate may be overestimated in this cohort may be due scarcity of testing in brazil compared to developed countries. for instance, brazil has performed only 68,143 tests per million people, whereas this rate in developed countries is over 100 thousand per million inhabitants. as of september 15, 2020, the case-fatality rate of covid-19 is about 3.15%, with 936,651 deaths and 29,648,872 confirmed cases worldwide (https://www.worldometers.info/coronavir us/). a significant proportion of cases (72.27%) in this cohort reported comorbidities and arterial hypertension was the most common condition associated with covid-19 infection followed by diabetes mellitus. our findings is in accordance with a study investigating the first 1000 consecutive patients in new york [25] and also in other regions of the world [26] . sars-cov-2 continues to spread in brazil causing unprecedented challenges to the country's health system. herein, we described the epidemiological and clinical manifestations of the first 557 successive covid-19 patients in pernambuco state, northeast brazil. our study provided important information about the demographics, clinics and epidemiology of covid-19 in the tropical world and will assist physicians and health officials to face the current pandemics and be better numbers between parentheses indicate percentage of patients in each age group. prepared to counteract future incursions of highly transmissible respiratory pathogens in the human population. the authors declare no conflict of interest. clinical features of patients infected with 2019 novel coronavirus in wuhan, china a novel coronavirus from patients with pneumonia in china a pneumonia outbreak associated with a new coronavirus of probable bat origin covid-19) -situation report -51 brasil confirma primeiro caso de infecção pelo novo coronavírus. 2020. htt ps://www.paho.org/bra/index.php?option=com_content&view=article&id=6 113:brasil-confirma-primeiro-caso-de-infeccao-pelo-novo-coronavirus&itemi d=812 covid-19 in latin america: the implications of the first confirmed case in brazil what are the factors influencing the covid-19 outbreak in latin america boletim epidemiológico covid-19. recife. pernambuco: state health department covid-19 in brazil: "so what? clinicalmanagement-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr effect of income on the cumulative incidence of covid-19: an ecological study importation and early local transmission of covid-19 in brazil clinical characteristics of coronavirus disease 2019 in china estimates of the severity of coronavirus disease 2019: a model-based analysis coronavirus disease 2019 (covid-19): epidemiology update 2020 impact of sex and gender on covid-19 outcomes in europe gender differences in patients with covid-19: focus on severity and mortality epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of 140 patients infected with sars-cov-2 in wuhan, china. allergy clinical features and treatment of covid-19 patients in northeast chongqing viral dynamics in mild and severe cases of covid-19 characterization and clinical course of 1000 patients with coronavirus disease 2019 in new york: retrospective case series covid-19 and comorbidities: a systematic review and meta-analysis supplementary data to this article can be found online at https://doi. org/10.1016/j.tmaid.2020.101884. key: cord-307464-66eqh79t authors: hwang, grace m.; mahoney, paula j.; james, john h.; lin, gene c.; berro, andre d.; keybl, meredith a.; goedecke, d. michael; mathieu, jennifer j.; wilson, todd title: a model-based tool to predict the propagation of infectious disease via airports date: 2012-01-13 journal: travel med infect dis doi: 10.1016/j.tmaid.2011.12.003 sha: doc_id: 307464 cord_uid: 66eqh79t epidemics of novel or re-emerging infectious diseases have quickly spread globally via air travel, as highlighted by pandemic h1n1 influenza in 2009 (ph1n1). federal, state, and local public health responders must be able to plan for and respond to these events at aviation points of entry. the emergence of a novel influenza virus and its spread to the united states were simulated for february 2009 from 55 international metropolitan areas using three basic reproduction numbers (r(0)): 1.53, 1.70, and 1.90. empirical data from the ph1n1 virus were used to validate our seir model. time to entry to the u.s. during the early stages of a prototypical novel communicable disease was predicted based on the aviation network patterns and the epidemiology of the disease. for example, approximately 96% of origins (r(0) of 1.53) propagated a disease into the u.s. in under 75 days, 90% of these origins propagated a disease in under 50 days. an r(0) of 1.53 reproduced the ph1ni observations. the ability to anticipate the rate and location of disease introduction into the u.s. provides greater opportunity to plan responses based on the scenario as it is unfolding. this simulation tool can aid public health officials to assess risk and leverage resources efficiently. influenza transmission; susceptible-exposedinfectious-recovered (seir) disease-spread modeling; public health aviation screening; pandemic response; points of entry summary epidemics of novel or re-emerging infectious diseases have quickly spread globally via air travel, as highlighted by pandemic h1n1 influenza in 2009 (ph1n1). federal, state, and local public health responders must be able to plan for and respond to these events at aviation points of entry. the emergence of a novel influenza virus and its spread to the united states were simulated for february 2009 from 55 international metropolitan areas using three basic reproduction numbers (r 0 ): 1.53, 1.70, and 1.90. empirical data from the ph1n1 virus were used to validate our seir model. time to entry to the u.s. during the early stages of a prototypical novel communicable disease was predicted based on the aviation network patterns and the epidemiology of the disease. for example, approximately 96% of origins (r 0 of 1.53) propagated a disease into the u.s. in under 75 days, 90% of these origins propagated a disease in under 50 days. an r 0 of 1.53 reproduced the ph1ni observations. the ability to anticipate the rate and location of disease introduction into the u.s. provides greater opportunity to plan responses based on the scenario as it is unfolding. this simulation tool can aid public health officials to assess risk and leverage resources efficiently. ª 2012 elsevier ltd. all rights reserved. as the world's population becomes ever more closely connected and as the numbers of international flights and air passengers continue to increase, so too has the spread of communicable diseases of public health concern via air travel. 1 novel infectious diseases have emerged and rapidly spread around the globe during the modern jet travel era. examples include the severe acute respiratory syndrome (sars) outbreak that started in southern china in 2002 2 and the pandemic influenza a (ph1n1) virus that was first reported in mexico in 2009. 3 recent evidence, including analyses of the spread of ph1n1, 4e6 has demonstrated how quickly transmissible diseases can be spread by air travelers. 7, 8 due to these health issues, the dramatic increase of international aviation travel and security concerns, the term "border" no longer denotes a static, fixed entity that begins and ends at political boundaries, but instead has been extended virtually to include pre-and post-travel geotemporal space. 9 because of this global interconnectedness, adverse health consequences and economic and travel disruptions can result from the emergence of rapidly spreading novel communicable diseases anywhere in the world. 1 whenever global or regional public health threats emerge, countries predictably implement mitigation measures at their international points of entry. 4,10e12 anticipating how such events will emerge and unfold is the essence of preparedness planning, and a critical practice for public health authorities who wish to mitigate the impact of such events. 13 previous aviation point of entry modeling studies have evaluated the potential effectiveness of some measures for mitigating global outbreaks of communicable disease, such as improving the timeliness of diagnostic testing for epidemic diseases, 14, 15 and rapidly developing and distributing sufficient quantities of pharmaceutical countermeasures, such as vaccines and antimicrobial drugs. 6,16e18 post-ph1n1 airport-based public health interventions including traveler screening have been described. 19 while collectively these reports remain useful in analyzing the potential value of public health interventions at airports, to our knowledge no studies have used modeling to provide operational planning guidance assumptions for policy makers and public health authorities who would implement such measures. for this paper, and as part of pre-pandemic preparedness planning, we estimated the geo-temporal components of disease spread between city pairs via air travel. more specifically, we examined the time-course for infectious air travelers to arrive in the united states (u.s.) from international cities with the highest u.s.-bound flight traffic for the month of february. previous u.s. modeling and planning efforts for point of entry response to pandemic influenza assumed a system-wide "all or nothing" initiation of traveler screening, aligned with world health organization phases. temporal and geographical risk-based response stratification was underrepresented in those analyses, while spatial considerations and disease epidemiological characteristics guided most airport response planning. this paper describes a method that would allow for a more flexible approach, which could be applied to threats other than pandemic influenza. we used a traditional susceptible-exposed-infectious-recovered (seir) model 20, 21 and an illustrative scheduled-flight dataset, to demonstrate how public health authorities could prioritize the allocation of responseresources in the u.s. at point of entry in response to a novel disease that was spreading rapidly outside of north america. to characterize possible patterns and rates of spread for an emerging infectious disease that could enter north america from various geographic points of origin, a prototypical novel pandemic influenza virus was simulated as an example of a human-to-human transmissible disease that is known to spread rapidly via air travel. the model propagates disease based on population sizes from metropolitan areas using calculations that estimate the dynamics of disease spread within each city and by air travel of individuals from one city to another, as previously described and calibrated by epstein et al. and bobashev et al. 20, 21 the simulated population is mutually assigned into one of the following disease states: susceptible (s), exposed (e), symptomatically infectious (i_s), asymptomatically infectious (i_a), and recovered (r). these disease states are illustrated in fig. 1 . a person can move from being susceptible, to exposed, then to either asymptomatically or symptomatically infectious prior to recovery. the model is implemented such that people in the infectious state have a 66.67% chance of being symptomatic and a 33.33% chance of being asymptomatic. 18 people who transition to the recovered state would no longer be susceptible and remain in the recovered state for the duration of the simulation. unlike prior implementation of this model, people in the infectious states were disallowed from entering a dead state in part to maximize person-to-person spread in the early stages of a pandemic and to create an upper boundary for this modeling study. as such the case-fatality proportion was intentionally set to zero. the model was propagated so that a susceptible person could become exposed, on average for 1.2 days. the exposed person could then become symptomatically infectious or asymptomatically infectious on average for 4.1 days, with a maximum infectious duration of 6 days. our seir model does not differentiate symptomatic and asymptomatic infection in the average infectious period calculation, nor does the model account for enhanced level of infectivity which could for example occur during early figure 1 mutually exclusive, allowable disease states of the model: susceptible (s), exposed (e), asymptomatically infectious (i_a), symptomatically infectious (i_s), and recovered (r). stages of influenza while a person is asymptomatic. the simulation evolved in discrete units of 1 day. selected parameters used in this model are given in supplemental table s1 . unlike prior implementations of the model 20e22 which permitted only asymptomatically infectious people to travel, the present implementation permitted both asymptomatically and symptomatically infectious people to travel. in addition, the model includes 177 major metropolitan areas (see supplemental table s2 ) around the world, including the 100 largest airports, the 100 largest cities worldwide, 20,21 and 35 cities in the u.s. (supplemental tables s3 and s4 ). this approach led to some parts of the globe being sparsely represented, commensurate with the level of direct aviation traffic those regions send to the u.s. all estimates of population data were from sources released in 2007 or later. 23e25 international metropolitan population data were taken from united nations estimates and the world gazetteer. u.s. metropolitan population data were based on us census estimates for the 35 metropolitan statistical areas, totaling 126 million people. points of origin were selected on the basis of the numbers of actual flights between international metropolitan areas and the u.s. during february 9e13, 2009. the study used the top 55 points of origin, which accounted for approximately 94% of all international air passengers traveling to the u.s. america's neighbor countries, mexico and canada, each have numerous ground border crossings with the u.s., many of them heavily trafficked; therefore it has been assumed that infectious diseases that originated in mexico or canada would quickly propagate to the u.s. through these ground channels. in fact, in the recent ph1n1 pandemic, the virus spread rapidly into the u.s. from mexico through multiple points of entry. 3 for this reason in the points of origin analysis presented here, mexico, canada and the u.s. have been treated as a single world region, and we have not calculated times required for an infectious disease to propagate to the u.s. from points of origin in canada or mexico. in contrast, honolulu was treated as an international point of origin because the state of hawaii has limited nonaviation links to the rest of the world, including the u.s. in fact, public health authorities watching for the spread of disease to north america from east asia consider honolulu an important sentinel site for surveillance. 26 thus, honolulu's role in the model closely resembles that of other points of origin outside north america. to populate the disease-spread model, weekly direct flight data were extracted from scheduled flights listed in a market intelligence source for aviation industry data (i.e., diio ò llc 27 ) for one week of february 2009, because the 1918 and h1n1 pandemics emerged in late winter. database extraction included origins and destinations from 272 airports in 177 metropolitan areas (supplemental table s4 ). weekly seats for flights between different airports in the same city pair were combined. if the summed seats between a city pair differed in directionality, the average seat counts were applied. weekly seat counts were converted to daily seat counts and then multiplied by 70% to obtain enplanement estimates for all city pairs. the 70% load factor is consistent with information reported by the bureau of transportation and statistics for the average of scheduled and non-scheduled flights (http://www.bts.gov). the flight matrix used in this study is available upon request. since this study focused on forecasting and predictions, best available scheduled flight data were used, with the understanding that not all flights into the u.s. were recorded in scheduled flight databases (e.g., chartered flights and unscheduled flights were not represented). known assumptions for pandemic influenza are summarized in supplemental table s1 . model output included how quickly the disease reached the u.s. via the global airline transportation network and also which u.s. metropolitan areas the disease reached first. time to reach the united states, referred to as "early disease arrival time," was defined as the number of days it took for the tenth symptomatically infectious person from anywhere in the simulated worldwide network to appear in u.s. metropolitan areas. it is important to note that the "early disease arrival time" includes the period of time during which the virus is spreading person-to-person but unknown to public health authorities. the 10-person threshold was selected on the basis of a 2005 report by the u.s. department of homeland security's national infrastructure and simulation analysis center, which showed that the arrival of as few as 10 infected people would be sufficient to propagate a disease in the u.s. for simulations seeded with an attack rate of 25% or greater. 28 in this case, "attack rate" referred to the cumulative number of people infected at the peak of the pandemic, normalized by the population at the start of the pandemic. in a given simulation, the 10 symptomatically infectious people used to determine the early disease arrival time could be 10 infectious travelers arriving in the u.s., or a combination of infectious travelers and people within the u.s. who became infected following contact with an infectious traveler. in addition to modeling an r 0 of 1.53 which best approximates the 2009 ph1n1, we selected two additional r 0 's, 1.7 and 1.9, to simulate based on evaluations of r 0 values from all actual 20th century influenza pandemics. 8, 17, 29, 30 although r 0 values for some of these pandemics have been estimated as being greater than 1.9, 6, 17, 20, 29 research has shown that mitigation measures such as point of entry interventions may be less effective at such high r 0 values. 29, 31 for the purpose of pandemic response planning, we assumed that well over 100 exposed persons at each point of origin was a realistic scenario. 32 the model accounted for seasonality by assuming that cities within the tropics have the same viral transmission year round, while cities outside the tropics exhibit transmission rates that vary sinusoidally with peak transmission occurring on january 1 in the northern hemisphere and july 2 in the southern hemisphere. although the model can be implemented with flight data files reflecting true traveler patterns across city pairs for each simulated increment in time, we choose to use representative data from the month of feb. 2009 for the purpose of this prepandemic baseline study. clearly, the analysis presented in this paper would depend on the granularity of the actual data used by the model. all simulation outputs were interactively accessed via a visualization tool, written in anylogic 6, xj technologies, st. petersburg, russian federation. we vertically grouped points of origin by world regions, as follows: (1) central america, caribbean, south america, (2) africa, (3) europe including russia, (4) asia, (5) southeast asia with india, (6) near east including north african arab states and middle east mediterranean states, and (7) oceania (see supplemental table s2 for world region classification). results are shown in the left-, middle-, and right-hand panels of fig. 2 respectively for the three reproduction numbers modeled: r 0 z 1.53, 1.7, and 1.9. gray-scale raster plots represent the trial-average number of symptomatically infected people over time as a fraction of the aggregate simulated u.s. metropolitan populations. a solid red dot was superimposed onto each aggregate wave to indicate the median early disease arrival time across all trials for a given point of origin. a green bar illustrating the minimum and maximum range of the early disease arrival time was also superimposed on each aggregate wave. to determine which airports have the highest probability of being affected by disease spread via air travel, we computed the number of times a particular u.s. airport received any of the first ten symptomatically infectious passengers for all points of origin and for points of origin segregated by their respective world regions. the time-course of disease entry into the u.s is presented in fig. 2 as aggregate pandemic waves from all points of origin seeded for three r 0 's. for response planning purposes, we are most interested in the time leading up to the day in which ten infectious people appear in the u.s. (red dot). it is apparent that at least two clusters of median early disease arrival times appeared for each panel of fig. 2 . the separation in clusters was most pronounced from the r 0 z 1.53 simulation, followed by a decrease in separation as the r 0 values increased (see fig. 3a ). more specifically, median early disease arrival times in the 25th and 75th percentile were under and over 25 days, respectively (see table 1 ). this observation suggests that response planning could be conducted differently for points of origin depending on their respective quartile and r 0 classifications. when points of origin were grouped by their respective world regions (see table 2 ), median early disease arrival times from central america, the caribbean, south america, europe, the near east, and oceania (honolulu) were shorter than those from asia, africa, southeast asia including india, and oceania (australia). fig. 3b , in which median early disease arrival times into the u.s were plotted in decreasing magnitude for each point of origin and r 0, further elucidates this trend. a summary examination of how u.s. airports would be affected by the first ten symptomatic people entering the u.s. revealed that new york, miami, newark, atlanta, los angeles would experience the earliest impact (fig. 4a) . further, detailed examinations of how these airports would be affected by points of origin from specific world regions are also presented: central america, caribbean, or south america (fig. 4b) , africa (fig. 4c) , europe (fig. 4d) , asia and southeast asia (fig. 4e and f) , near east (fig. 4g) and oceania (fig. 4h ). our analysis indicated that los angeles and san francisco airports would experience the earliest impact for disease originating from asia, southeast asia and oceania, while new york and atlanta airports would experience one of the earliest impacts for diseases originating from all other world regions. unlike our points of origin analysis, when we validated our model based on data from the 2009 ph1n1, we did not treat the u.s. and mexico as one mixing body. rather, we used mexico city as a proxy for the village of la gloria, veracruz, mexico, from where some of the earliest ph1n1 cases were reported. 3 in addition, we replicated the mean u.s. incidence rate of 0.997%, as reported by the cdc for ph1n1 cases in the u.s. between april and july 23, 2009 33 based on the u.s. cities used in the model (listed in supplemental table 2 ). in order to replicate the mean incidence rate of 0.997%, we evaluated two parameters: 1) the basic reproduction number, which represents a measure of the average number of people in a totally susceptible population to whom one infected individual transmits a disease, was allowed to vary between 1.4 and 1.7 in increments of 0.01. 2) the number of days it takes the model to predict the targeted mean incidence rate which best matches july 23, 2009, i.e., the 165th day after feb 15th, 2009. we confirmed that our model generated a u.s. incidence rate of 1.0482% (standard deviation of 0.0067%) on the 165th day after disease onset for an r 0 of 1.53; these parameters are very close to the reported mean incidence rate of 0.997% by july 23, 2009. an r 0 of 1.53 is well within published estimates of r 0 for the 2009 ph1n1 which ranged from 1.4 to 1.6. 3,34 since the 1968 h3n2 (hong kong) influenza pandemic, global air travel has nearly increased by a factor of ten, from 261 million passengers 35 worldwide to more than 2.5 billion passengers in 2010. 36,37 air travel contributes greatly to the rapidity of communicable disease transfer across international borders and thus federal, state, and local public health authorities must understand and plan for aviation point of entry response to these threats. 5, 9, 13 the model results presented here resemble those from related modeling studies in that they suggest an important influence of geographic origin of the outbreak on the timing and location of disease introduction into the u.s. during an emerging disease event. 38 in this respect, the range of public health tools available for point of entry intervention (observation, health information distribution, health questionnaires, individual screening, illness response, contact investigations, isolation and quarantine, etc.) could be activated based on anticipated city-to-city spread of the disease in question, rather than being "turned on" systemwide unnecessarily, at great potential cost to taxpayers and need for use of government resources. our model output shows how quickly the disease reached the u.s. via the global airline transportation network and which u.s. metropolitan areas the disease reached first. we found variance in arrival times and locations of infectious passengers from origin points at different global locales. model results indicated that a staggered "turn on" of point of entry responses according to strategic risk assessments, resources available, and time required to mount an effective response, would be feasible and should guide response planning. the model, as well as the actual events during the sars and ph1n1 outbreaks of the past decade, reinforced that a short time window would be available to implement measures at points of entry that could be effective in mitigating disease spread. 13 as occurred during ph1n1, the initial outbreak and subsequent spread could go undetected for weeks or even months before the first cases were figure 2 predicted disease spread time-course. simulations were based on 100 exposed people from each international metropolitan point of origin across three reproduction numbers: 1.53, 1.7, and 1.9. the y-axis displays origins that are first grouped by continent and then sorted alphabetically. the x-axis denotes time in days relative to the start of the disease-spread simulation. gray-scale raster plots represent the number of infected people across time as a fraction of the aggregate u.s. metropolitan population size employed by the model. each row shows the median disease spread for all suprathreshold trials (out of 40) in which at least 10 symptomatically infectious people appeared in the united states. in the r 0 z 1.53 simulations, early disease arrival times varied from about 5 days to slightly under 225 days from disease emergence in a population. approximately 95% of origins resulted in median early disease arrival under 75 days, with 85% of those origins resulting in median early disease arrival in less than 50 days. in the r 0 z 1.7 simulations, early disease arrival time ranged from about 5 days to approximately 100 days. approximately 95% of origins resulted in median early disease arrival in less than 50 days, with 37% of those origins resulting in median early disease arrival in less than 25 days. in the r 0 z 1.9 simulations, early disease arrival time varied from about 5 days to slightly under 80 days. approximately 96% of origins resulted in median early disease arrival under 50 days, with 53% of those origins showing median early disease arrival in less than 25 days. identified and laboratory-confirmed, 32 drastically curtailing the time and options available to respond effectively. since the u.s. essentially serves as a global hub for aviation travel with 88 international arrival and departure points for regularly scheduled commercial flights 27 ; with an additional 113 u.s. airports that received passengers from international charter, private and/or air ambulance flights in 2010, 39 it is not surprising that once a novel infectious disease emerges and begins person-to-person spread near international transportation hubs anywhere in the world, that novel disease will in all likelihood appear in the u.s. within days or, at most, a few weeks' time. spurred by a rise in global traveler numbers and favorable changes in aviation regulations in many countries, the dramatic increase in the sheer number of aviation international arrival and departure points located within geographically and politically distinct entities, 9 has resulted in the creation of new pathways for passengers e and diseases e to enter into local communities worldwide. our model could prove useful for those countries with multiple entry points to consider when planning for a pandemic. although this paper describes new data for policy makers and planners to use for planning of public health interventions at point of entry, the effectiveness of point of entry interventions should be examined closely so that resources are not diverted from community infection control and prevention efforts, where they could have greater impact. point of entry interventions for influenza have been questioned, for example, because of the many travelers who could be infected but not symptomatic at the time of entry (thus avoiding detection), greatly reducing the efficacy of any public health intervention. computer simulations have demonstrated that even drastic travel restrictions (e.g., border closure) would achieve only limited delays in the introduction of a severe novel influenza virus, for example, into the u.s. during the early stages of an outbreak. 17,20,30,40e42 indeed, the world health organization (who) discouraged point of entry screening measures both before and during ph1n1, 43e45 and the who director-general margaret chan asserted very early in the pandemic that travel restrictions would be counterproductive and "serve no purpose". 37, 46 however, prudence dictates planning for such a contingency as one possible component of a comprehensive and coordinated public health response to an emerging disease threat. there are many drivers behind the decision to screen aviation travelers during novel communicable disease outbreaks spreading regionally or globally; despite recommendations to the contrary, and known and potential limitations to aviation traveler screening activities for novel influenza, many countries mounted broad screening efforts at their borders during ph1n1 19 nonetheless. in calibrating an effective public health response, knowing the "where" is just as important as knowing the "what" and the "when." thus, the unique geospatial characteristics of specific originating locations and regions need to be identified to accurately assess risk and develop effective response plans for point of entry interventions. for example, if a rapidly unfolding outbreak were taking place in central america, it would make sense to anticipate higher need for public health resources focused on direct flights coming to the u.s. from high-volume contributors such as managua and guatemala city. although other passengers from central america may come to the u.s. via connecting flights, these travelers would be so low in number as to present minimal risk, and to expend resources to address them initially may divert from more effective efforts with the bulk of travelers arriving on direct flights at a few u.s. locations. our analysis of 2009 flight data revealed that, by volume, the airports most affected by flights from central this approach seems intuitive, but others have observed that this risk-based, targeted approach to bolstering surveillance and response capacities at key airports has been the exception rather than the norm, and that careful planning for public health response at key points of entry can be more effective than the usual first response of implementing travel restrictions. 13, 41, 47 in light of current global economic uncertainties and the overall decline of resources for public health in the u.s. and other countries, current planning and future point of entry interventions for global disease outbreaks must optimize the resources that are available, quickly and accurately assess risks and prioritize efforts to maximize impact of intervention efforts. 48 the "node-to-node" approach embodied in our model will allow public health officials to preserve resources for longer-term, community-based mitigation and prevention activities by targeting response to those points of entry likely to be affected earliest. although scientific modeling and simulation have proven to be effective tools for visualizing and planning responses to outbreaks of infectious diseases, in particular for influenza pandemics, 28, 42, 49 these analyses should not be the only drivers for planners or policy makers when anticipating future outbreaks. 50e52 as with other studies reported in the literature, this model shows that the speed with which a communicable disease spreads to the u.s. will depend on the r 0 of the disease in question. g this finding could represent a limitation of using the model for planning, since r 0 is quite difficult to determine for an emerging disease. further, the model employed in this study is not agentbased, and the attack rates reported by agent-based models cannot be computed identically using this equation-based model. this is because the total number of people who became infectious during a complete model run cannot be tallied without modeling each person as an agent. although we used the well-known and accepted assumptions of a prototypical pandemic influenza virus to examine early disease arrival times, the recent ph1n1 pandemic makes it clear that novel viruses do not always behave as expected. some disease-specific assumptions and outcomes of the model may therefore not be useful in planning for future disease outbreaks. since this study focused on forecasting and predictions, future scheduled nonstop flights for a single month were utilized as the basis for estimating travel for a simulated period of one year. this approach simplifies the complex phenomenon of international travel. a rigorous comparison between scheduled seats and actual enplanements (which would include, among other things, chartered flights and actual load factors), was not conducted in part because such data for non-u.s. cities were not readily available. the spread of disease during travel from infectious passengers to susceptible passengers was not modeled separately from spread in the general population. variation in travel based on seasonality was not included and thus the analysis presented in this study only applies to a disease that spread in the month of february 2009 based on travel in that month. finally, this approach neglects travel between cities that does not take place via nonstop flights on the same day e in particular, connecting flights through gateway cities, or non-aviation means such as car or train for nearby cities such as paris, france, and amsterdam, the netherlands. thus, new analyses should be conducted periodically, and especially as an event is unfolding which may require point of entry intervention. policy makers and public health authorities must always consider aviation points of entry as potential foci for interrupting or slowing the global spread of disease. therefore, future modeling should consider how to maximize effectiveness of public health interventions while minimizing passenger delays and travel disruptions, by analyzing the efficacy and cost of specific interventions such as dispensing antivirals at points of entry, health questionnaires with real-time data entry using handheld devices, and fever detection using technology such as thermal imaging. further analysis and reporting of worldwide government responses to the emergence of ph1n1 and other regional disease outbreaks would help to fill in some of the information gaps regarding point of entry interventions. future models should also examine various pathogens (e.g., smallpox, pneumonic plague, a sars-like virus) and their rates of spread. the rate of global spread from specific geographic locations around the world should also be studied using various known assumptions and pathogen characteristics. those results could usefully be compared with the ph1n1 and sars experiences. our findings indicate that time to disease entry to the u.s. during the early stages of an emerging pandemic would vary and can be predicted based on point of origin and point of entry into the u.s. this ability to anticipate the rate and location of disease introduction into the u.s. provides greater opportunity to plan responses based on the scenario as it is unfolding. this simulation tool can aid public health officials to assess risk and leverage resources efficiently via targeted and scalable border mitigation measures, especially at key u.s. airports that would be most expected to bear the initial brunt of an international outbreak. the findings and conclusions in this paper are those of the author(s) and do not necessarily represent the views of the centers for disease control and prevention, the federal aviation administration (faa), or the u.s. department of transportation (dot). the united states government, the faa, and the dot make no any warranty or guarantee, expressed or implied, concerning the content or accuracy of these views. approved for 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pandemic mitigation strategies for pandemic influenza in the united states who consultation on priority public health interventions before and during an influenza pandemic: working group two: public health interventions nonpharmaceutical interventions for pandemic influenza, national and community measures forecast and control of epidemics in a globalized world a framework for public health action: the health impact pyramid modeling targeted layered containment of an influenza pandemic in the united states dynamically modeling sars and other newly emerging respiratory illnesses: past, present, and future population-based simulations of influenza pandemics: validity and significance for public health policy large-scale spatial-transmission models of infectious disease all authors have confirmed that they have no conflict of interest either financially or via personal relationships as defined by travel medicine and infectious disease. supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.tmaid.2011. 12.003. key: cord-341187-jqesw4e8 authors: yu, xinhua title: modeling return of the epidemic: impact of population structure, asymptomatic infection, case importation and personal contacts date: 2020-08-27 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101858 sha: doc_id: 341187 cord_uid: jqesw4e8 background: proactive interventions have halted the pandemic of coronavirus infected disease in some regions. however, without reaching herd immunity, the return of epidemic is possible. we investigate the impact of population structure, case importation, asymptomatic cases, and the number of contacts on a possible second wave of epidemic through mathematical modelling. methods: we built a modified susceptible-exposed-infectious-removed (seir) model with parameters mirroring those of the covid-19 pandemic and reported simulated characteristics of epidemics for incidence, hospitalizations and deaths under different scenarios. results: a larger percent of elderly people leads to higher number of hospitalizations, while a large percent of prior infection will effectively curb the epidemic. the number of imported cases and the speed of importation have small impact on the epidemic progression. however, a higher percent of asymptomatic cases slows the epidemic down and reduces the number of hospitalizations and deaths at the epidemic peak. finally, reducing the number of contacts among young people alone has moderate effects on themselves, but little effects on the elderly population. however, reducing the number of contacts among elderly people alone can mitigate the epidemic significantly in both age groups, even though young people remain active within themselves. conclusion: reducing the number of contacts among high risk populations alone can mitigate the burden of epidemic in the whole society. interventions targeting high risk groups may be more effective in containing or mitigating the epidemic. : flowchart of the epidemic model the above flowchart is applied to both young (age <65) and old populations (age>=65). we assume there is cross infection between younger and older age groups. the combined flowcharts can be modeled in differential equations (with index t suppressed and subscript y for young people, s for old people) as follows: table1: detailed parameter estimates and ranges. all rates are set as daily rates in a region with population size of 1,000,000. range and references f 1 importing rate for susceptible population, proportional to the size of population 10 people per day, only for young people arbitrary, net travel inflow of 2-20 people per day for a city of a million. f y2 , f s2 importing rate for exposed and infectious persons, proportional to the size of population note: 1) the infecting rate per contact per day is based on the basic reproductive number and serial interval between case generations. early reports suggested a r 0 of 2.2 (range 1.5-3), and a serial interval range of 3-9 days. however, several recent studies found the r 0 was greater than 3, one reported as high as 5.7. in this study, we took a conservative estimate of 2.6 and a moderate serial interval: 6 days for young people, 4 days for old people. based on simple sir model, the reproductive number is k*b*t, where k is contact rate, b is infecting probability per contact, and t is serial interval. assuming k=10 contacts per person per day for young people, and the infecting probability is b1= 0.043 for a symptomatic young people. for mild or asymptomatic cases, we assume 50% less infectious than symptomatic cases, thus b2 = 0.021 for young undiagnosed people. for older people, the parameters are set to higher than young people, with fewer contact and shorter serial interval. 2) the base rate per day is based on disease duration such as incubation period, diagnosis delay, hospitalization delay, hospitalization stay and recovery duration. we assumed an exponential distribution of duration, i.e., daily rate is 1-exp(-1/duration). j o u r n a l p r e -p r o o f 7 we investigate the impact of population structure, case importation, asymptomatic cases, and the number of contacts on a possible second wave of epidemic through mathematical modelling. methods: we built a modified susceptible-exposed-infectious-removed (seir) model with parameters mirroring those of the covid-19 pandemic and reported simulated characteristics of epidemics for incidence, hospitalizations and deaths under different scenarios. have detected virus shedding in nasopharyngeal swap samples among asymptomatic cases [11] . a few case reports have shown some cluster of cases initiated by asymptomatic cases [6, 8, 10] . researchers have postulated that asymptomatic and pre-symptomatic cases may play a significant role in sustaining the community transmission [7] . second, government leaders have been pressed to allow people to return to normal work and life to avoid economic recession. after social activities are restored, both international and domestic j o u r n a l p r e -p r o o f travel ban will be lifted. social and work-related gatherings are restored. imported symptomatic and asymptomatic cases may kindle a second wave of epidemic in the community [7] . the us, the mortality rate for age 50 or younger is below 1%, while the mortality rate increases to more than 10% among people aged 80 or above [15] . finally, as demonstrated in the 2009 h1n1 flu pandemic [16] , a pandemic with lower hospitalization and mortality rates has less impact on the society than those with higher hospitalization and mortality rates, though it may still have heavier impact on the economy. epidemic model simulation has been used extensively to estimate essential epidemic parameters, in this study, we will build a modified susceptible-exposed-infectious-removed (seir) model [27] to simulate the covid-19 pandemic and investigate the impact of population structure, asymptomatic cases, case importation, and the number of contacts on the epidemic progression. we will explicitly evaluate the changes of hospitalizations and mortality under various scenarios for young and elderly people. our analysis will provide theoretical evidence for possible strategies to prepare for a second wave of epidemic. the covid-19, like many other respiratory infectious diseases such as influenza, often has an incubation period during which the exposed persons cannot transmit the virus to others. after the incubation period, there is an infection period during which cases may or may not have symptoms but are able to infect other people. the infectivity may also vary at different time points of the infection period. as in the covid-19 pandemic, the highest infectious points are 1-2 days around the symptom onset [28] . after the infection period, the patients are recovered or removed from the infectious pool. in addition, various controlling measures may be implemented j o u r n a l p r e -p r o o f during the epidemic, notably the case isolation, quarantine of high risk people through contact tracing, and also social distancing. all these measures will change the transmissibility of virus during a contact between an infectious person and a susceptible person. therefore, the modified seir model as shown in figure 1 is appropriate (also see the modeling framework section in supplemental documents for details). the seir model and its variants have been used in many previous studies for modeling the covid-19 pandemic [23, 25] . briefly, we divide the population into the susceptible population (s), self-quarantined susceptible people (q), exposed we also assume a dynamic population in which the numbers of imported susceptible persons and assumptions that will be discussed later and also in the supplemental document. to account for population heterogeneity, we also apply the basic framework (figure 1 ) to both young (age < 65) and elderly (age >=65) populations. the two flowcharts are connected through cross-infection due to mutual contacts. the combined flowcharts can be translated into a set of ordinary differential equations (see supplemental document). the key equations relevant to the drive of pandemic and cross-infection between two age groups are for the change of exposed people at time t (subscript y for young, and s for elderly people, with time indicator t suppressed): specifically, the first equation models the exposure dynamics among young people. it includes imported exposed people (f y2 n y ), newly exposed people through contacting within the young people ( + ) and contacting between young susceptible and infected elderly people ( + ). then some percent of exposed young people become symptomatic cases ( ), and some become asymptomatic cases ( ). a fixed percent of exposed people will die of other diseases ( ). the second equation for the exposure dynamics among elderly people can be interpreted similarly. the model involves many parameters. their definitions, default values, and ranges are listed in the supplemental document (supp. the default model is set on a region with 1 million residents, consisting of 20% elderly people and 20% of total population with past infection (or immunized). there is no existing symptomatic or asymptomatic case, and no person in self-quarantine in the region. we assume only one imported young exposed case every two days for 20 days (i.e., 10 imported cases). analyses are performed based on the ranges of parameter estimates. we vary one parameter at a the r package epimodel is used for simulating the deterministic epidemic models [40] . the r codes for simulating the modified seir epidemic models are available (http://github.com/xinhuayu/returnepidemic/). this study is deemed exempt from ethics approval as the research involves no human subjects and we use publicly available data. no informed consent is needed. under the default model setting, all epidemic measures reflect the model parameters satisfactorily (table 2 , also refer to supplemental table 1 ). that is, the resulting epidemic j o u r n a l p r e -p r o o f measures from the default model such as the disease incidence, epidemic peak, and duration of the epidemic are reasonable and mirror those reported in the literature. for example, starting with ten imported infectious persons and assuming 40% asymptomatic cases at the peak of epidemic, the epidemic reaches peak quickly within 73 days and lasts 172 days. it is ten days quicker among elderly people than among young people ( table 2 ). the epidemic curves for incident cases (symptomatic and asymptomatic), hospitalizations and deaths by age groups are typical (supplemental figure 2 ). the modeling results in an overall hospitalization rate of 14.1%. the in-hospital mortality rate is 5.0% for young and 20.3% for elderly people, with an overall mortality rate of 1.9%, similar to those empirical measures in the covid-19 pandemic in the early epidemic of the us. therefore, the default model represents the current covid-19 pandemic sufficiently well. as summarized in table 3 , the size of region and a small percent change of self-quarantined susceptible people do not change the epidemic progression significantly except for the total number of cases. a smaller percent of elderly slows down the epidemic, while a much higher percent of elderly does not change the epidemic curve significantly. as expected, when over 60% people have prior infections, the epidemic takes very long to reach the peak and results in substantial fewer cases. the effects are similar in both young and elderly people (supplemental both the percent and infectivity of asymptomatic cases were investigated (table 3 ). an increase of the percent of asymptomatic cases from 10% to 30% postpones the epidemic peak by 12 days j o u r n a l p r e -p r o o f due to less infectivity of asymptomatic cases, and results in significantly fewer hospitalizations and deaths. on the other hand, a higher infectivity of asymptomatic cases (e.g., 100% of symptomatic cases) results in a fast developing and narrow epidemic curve which reaches the peak within 60 days. there are more hospitalizations and deaths at the epidemic peak compared with the default model, both assumed 40% asymptomatic cases. in addition, a change of the percent of asymptomatic cases among elderly people leads to larger changes in hospitalizations and deaths than that of young people (supplemental table 2a & 2b) . for example, comparing 60% with 40% asymptomatic cases, the total hospitalizations are reduced only by half among elderly people, while it is a two third decrease among young people. furthermore, when the effects of the percent and infectivity of asymptomatic cases are combined, for example, in a low risk epidemic with 60% asymptomatic cases but with a lower (30%) infectivity, the epidemic reaches its peak slower for both young and elderly people with peak hospitalizations almost half of the default model (assuming 40% asymptomatic cases and 50% infectivity) (supplemental figure 3) . this epidemic model is initiated by imported infectious persons (may be asymptomatic or presymptomatic cases). the number of imported cases is in absolute sense, regardless of the size of population. a daily arrival of two infectious people speeds up the epidemic by 8 days compared with one case every two days in the default model ( table 3 ). the magnitudes of epidemic are similar between different importation scenarios. in addition, a longer importing duration shifts the epidemic only slightly. finally, if we assume all the imported cases are asymptomatic cases, the epidemic curves are not significantly different from that of default model (supplemental figure 4) . respectively, all significantly lower than those of default model ( table 2 ). the times to the epidemic peaks are also postponed in both curves. when both young and elderly people reduce contacts to 3 per day, such as under the stay-at-home rule, the epidemic curves on hospitalizations are significantly mitigated in both age groups (figure 2d ). finally, we consider two extreme scenarios: 1) high risk scenario: assuming one imported case per day continuously throughout the epidemic, 30% asymptomatic cases at the epidemic peak, and the same infectivity between symptomatic and asymptomatic cases; 2) low risk scenario: assuming one imported case every two days for twenty days, 60% asymptomatic cases, and asymptomatic cases have only 30% infectivity of symptomatic cases. in both scenarios, limiting contacts among elderly people alone still has significant impact on hospitalizations in both age j o u r n a l p r e -p r o o f groups, and a larger relative difference in the low risk scenario than high risk scenario ( figure 3 and supplemental figure 7 ). we with growing availability of detection kits during the covid-19 pandemic, more asymptomatic or mild symptomatic cases are identified. ultimately, an optimal view is asymptomatic cases may account for 60% of infections. however, recent research and case reports have confirmed that asymptomatic or pre-symptomatic cases can shed enough quantify of virus to be infectious [6] [7] [8] [9] 11] . furthermore, if the infectivity of asymptomatic cases is similar to that of symptomatic cases, a faster epidemic will occur. despite more asymptomatic cases at the peak of epidemic, there are also significantly more hospitalizations and deaths, which may overwhelm the health care system. with a lower infectivity (30% infectivity) among asymptomatic cases, the epidemic reaches its peak later and results in half of hospitalizations at the peak compared with the default model (supplemental figure 3) . in addition, a closely related issue is case importation [25] . imported cases are often pre-symptomatic, asymptomatic or with mild symptoms. they seed of a second outbreak, even with just a few cases. therefore, proactively identifying asymptomatic j o u r n a l p r e -p r o o f cases, isolating them and tracing their contacts thereafter will prevent the occurrence of an epidemic [22] . our study has some strengths. we have devised a modified seir model to incorporate both symptomatic and asymptomatic cases. we emphasize population heterogeneity such as age structure in the model. we include a self-quarantined group who will not infect other people if they are infected with the virus. naturally, these settings can be extended to represent other high risk or special groups with revised parameters. in addition, we separate hospitalization and death from other removed compartments to explicitly estimate the impact of an epidemic on hospitalizations and deaths. from the health impact point of view, severe cases that lead to hospitalizations and deaths are more important than mild cases, as demonstrated in the 2009 h1n1 pandemic [16] . furthermore, we explored a few key determinants of epidemic explicitly, leading to many insights on epidemic prevention strategies. there are a few limitations in our study. as inherent in all modeling studies, simulation interpretations are heavily dependent on model assumptions and parameter estimations. our epidemic model is a population model. although we take account of population heterogeneity such as age in the current model, our age group is overly broad. a more detailed age grouping scheme, including children, young adults, middle age group, and elderly, may reflect the agespecific epidemic more realistically. other factors may also be included, and additional compartments such as pre-symptomatic stage may be modeled. however, more sophisticated models require more assumptions and may not necessarily provide more insights about the epidemic process. instead, in this study, in addition to ensuring the mathematical correctness of the models, we prioritize the epidemiological concepts and clinical relevance in setting up the models rather than model complexity. nevertheless, our findings do not intend to provide j o u r n a l p r e -p r o o f definitive advice to design a new policy but rather gain insights of the epidemic process and provide theoretical support for a possibly more effective prevention strategy based on approaches targeting high risk populations. in addition, we assume random mixing within and between age groups. as a population model, we cannot assess the impact of individual behaviors such as the way of reducing contacts, social distancing and travelling. furthermore, it ignores clustering within the population such as senior group living, community gatherings (e.g., churches, community centers), worksites and schools. these clusters are hotbeds for superspreading events which may lead to a sudden increase of new cases and overwhelm the healthcare system unexpectedly. furthermore, the quarantine compartment in the model is not contact tracing based. modeling contact tracing based quarantine is more relevant to public health interventions [42] . therefore, the goal of our future research is to exploring the effect of these factors with stochastic simulations of individual behavior [24, 43] and network analysis [44] . additionally, our model is set on a mid-size region with 1 million residents. we do not intend to model an pandemic, as all prevention strategies are ultimately local. our study only examines a small subset of scenarios during the epidemic. multi-interventions and more stringent controlling measures are more effective in mitigating a pandemic but are likely less sustainable in the long run. after the initial epidemic ends, society will return to normal, and only one or two most effective interventions such as social distancing may be practiced, often partially. thus, one parameter analysis under various scenarios is important for evaluating the probability of a second epidemic. finally, one critical issue in preparing for and preventing a second wave of pandemic is vaccinating the susceptible people, which 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epidemics networks and epidemic models clinical characteristics of non-critically ill patients with novel coronavirus infection (covid-19) in a fangcang hospital the peak self-quarantined is 2% of the susceptible population but changes with the prevalence of disease. the hospitalization rate is 5% for young, and 30% for old symptomatic cases, respectively. the mortality rate is 5% for hospitalized young people and 20% for hospitalized elderly. there are no prior symptomatic or asymptomatic cases or quarantined people in the total population the x. yu is solely responsible for the conceptualization, data collection, analysis, report writing and reporting writing of this study. key: cord-341101-5yvjbr5q authors: hashem, anwar m.; alghamdi, badrah s.; algaissi, abdullah a.; alshehri, fahad s.; bukhari, abdullah; alfaleh, mohamed a.; memish, ziad a. title: therapeutic use of chloroquine and hydroxychloroquine in covid-19 and other viral infections: a narrative review date: 2020-05-06 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101735 sha: doc_id: 341101 cord_uid: 5yvjbr5q the rapidly spreading coronavirus disease (covid-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (sars-cov-2), represents an unprecedented serious challenge to the global public health community. the extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. while approved specific antiviral drugs against sars-cov-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for covid-19 infected patients. recent publications have re-examined the use of chloroquine (cq) and/or hydroxychloroquine (hcq) as a potential therapeutic option for these patients. in an attempt to explore the evidence that supports their use in covid-19 patients, we comprehensively reviewed the previous studies which used cq or hcq as an antiviral treatment. both cq and hcq demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. while few clinical trials have suggested some beneficial effects of cq and hcq in covid-19 patients, most of the reported data are still preliminary. given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in covid-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of covid-19. 6 a receptor for cell entry, suggesting a possible similar effect of cq on sars-cov-2 at this step of virus replication [40] . cq can also affect early stage of virus replication by inhibiting virus-endosome fusion, likely via increasing endosomal ph [41] . covs such as sars-cov were shown to be able to enter target cells via ph-dependent mechanism in which the acidic ph of the lysosome triggers fusion of the viral and endosomal membranes resulting in viral particle uncoating and subsequent release of viral nucleic acid into the cytoplasm [42] . cq can also impair posttranslational modifications of viral proteins through interfering with proteolytic processes [43] and inhibition of glycosylation via specific interactions with sugarmodifying enzymes or glycosyltransferases [28] . cq can also hamper lysosomal protein degradation and lysosomal fusion with autophagosomes [44] [45] [46] . moreover, it has been suggested that cq has the ability to affect the cytotoxic mechanisms and works as antiautophagy agent in vitro [47] . cq works as anti-inflammatory agent through reducing tumor necrosis factor (tnfα) release and suppressing tnf receptors on monocytes [26, 28] . on the other hand, hcq has a similar effect to cq in interfering with the glycosylation of ace2, blocking virus/cell fusion and inhibiting lysosomal activity by increasing ph [22] . hcq can also impede major histocompatibility complex (mch) class ii expression which inhibits t cell activation, expression of cd145 and cytokines release [48] [49] [50] . furthermore, hcq has been shown to impair toll-like receptors (tlrs) signaling through increasing endosomal ph and interfering with tlr7 and tlr9 binding to their dna/rna ligands thereby inhibiting transcription of pro-inflammatory genes [51] [52] [53] . the aforementioned immunomodulatory properties of cq and hcq have raised the interest in using these drugs in covid-19 patients at risk of cytokines release syndrome (crs) [22] . 7 the fact that both cq and hcq are considered for the management of covid-19 patients clearly highlights the need to better understand their pharmacokinetics (pk) parameters. however, a full understanding of these parameters has been challenging despite the numerous reported studies. generally, pk parameters for cq and hcq are comparable (table 1) [54, 55] . following oral administration of cq and hcq, their bioavailability can reach up to 80% with plasma peak time around 2-4 hours [56] [57] [58] . thus, parenteral administration, if available, might be a better route especially that oral administration has shown huge interpatient variability [56, 59, 60] . the long half-life of both cq and hcq which could range from 30 to 60 days is likely attributed to their large volume of distribution (200 to 800 l/kg) and extensive tissue uptake [61] [62] [63] [64] [65] [66] [67] [68] . cq and hcq are metabolized via cyp-450 enzymes to other active compounds, which are responsible for the extended pharmacological actions and increased toxicity [61, 69] . up to 60% of cq and hcq is primarily excreted renally as unchanged or metabolized forms, and the remaining (40%) is usually cleared through the liver, feces and skin or stored in other lean body tissues [54, [69] [70] [71] [72] [73] [74] . it's important to note that cq and hcq have a chiral center, which produces two enantiomers r(−) or s(+) forms or isomers [75] , in which little is known about the differences in their pharmacological activity and their corresponding metabolites. most clinically used cq and hcq exist as a racemic mixture (50:50) of both isomers which complicates the understanding of their pk and associated toxicity as they could behave differently inside the body [57, [75] [76] [77] . the most common cq and hcq adverse effects are gastrointestinal symptoms such as nausea, vomiting and abdominal discomfort [78] , and uncommonly worrisome fulminant hepatic failure [79] , toxic epidermal necrolysis (ten) [80] and cardiotoxicity that could 8 manifest with qt abnormality [81] [82] [83] . nevertheless, over the years cq and hcq have maintained a good safety profile when used in several chronic diseases such as ra and sle. despite some animal experiments suggesting that hcq is probably less toxic than cq, there is a lack of high quality evidence from clinical trials supporting this claim [74, [84] [85] [86] [87] . these toxicities could be related to the very long half-life and the large volume of distribution of both drugs. one of the significant toxic effects of cq and hcq is the possible ocular pigmentation due to their binding to melanin, which could lead to damage in different parts of the eye including the cornea, ciliary body and retina [88] . notably, the incidence of such ocular toxicity is usually rare. for instance, it was shown that only 0.5% out of ~400 patients treated with hcq (≤6.5 mg/kg/day) for 6 years due to ra or sle had developed ocular related complications [89] . most studies have shown that such complications might only occur with long term treatment of chronic diseases which extends for more than 5 years with doses above or equal to 6.5 mg/kg/day [90, 91] . however, ocular toxicity and changes could still occur with shorter treatments. other complications such as development of proximal myopathy associated with respiratory failure have also been reported in patients treated with either cq or hcq [92] [93] [94] [95] . nonetheless, most of these complications were seen in elderly patients with an average age of 70 years suffering from chronic ra or autoimmune diseases. both cq and hcq were also shown to be associated with rare but life-threatening cardiomyopathy [96] [97] [98] . other less reported cq and hcq toxicities include urticaria [99] , ototoxicity [100, 101] and some neurological effects [102, 103] . the antiviral effects of cq were suggested at least 50 years ago [23, 25] . since then, several studies have tested the ability of cq and hcq to inhibit the replication of a wide range of covs and non-cov viruses in vitro as shown in tables 2 and 3 , respectively. the majority of 9 these studies have revealed a substantial ability of cq and hcq as well as some of their derivatives to inhibit viral replication with no to low toxicity. specifically, cq has been shown to inhibit the replication of different covs including sars-cov, mers-cov and sars-cov-2 among others in several studies (table 2) [37, [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] . only two studies showed no significant inhibitory effects of cq on mers-cov and mouse hepatitis virus (mhv4) [116, 117] . other cq derivatives such as amodiaquine (amd), ferroquine (fq), hydroxy ferroquine (hfq) have been also shown to exerts some antiviral activity [105, 106] . interestingly enough, while hcq does not seem to have a significant effect in reducing sars-cov and feline cov replication [106] , it was recently shown to have a potent in vitro inhibitory effect against sars-cov-2 replication [112, 116] . similarly, these compounds have shown excellent in vitro antiviral activity against several non cov (mostly rna viruses) with low toxicity in most cases (table 3) . for instance, hiv was shown to be inhibited by cq alone or in combination with hcq, hydroxyurea (hu1), didanosine (ddi), zidovudine (zdv), indinavir (idv), saquinavir (sqv) or ritonavir (rtv) [106, [118] [119] [120] [121] [122] . while other derivatives such as hcq and hfq have been also shown to inhibit hiv replication [106, 123, 124] , one study showed no effect of hcq and fq on hiv [106] . similarly, it was found that cq could enhance epstein-barr virus replication [125] . furthermore, another study has suggested possible enhanced hiv replication with cq treatment through protection of tat protein from proteolytic degradation [126] . influenza a and b viruses have also been shown to be inhibited by cq [27, [127] [128] [129] [130] [131] although contradicting results have been seen for some subtypes and strains such as avian h7n3 strains (a/mallard/it/43/01 and a/ty/it/220158/02) [106, 130] . several other studies have also reported in vitro inhibitory effect of cq on multiple viruses such as chikungunya virus (chikv) [41, 132, 133] , zika virus (zikv) [134] [135] [136] , ebola virus (ebov) [137] [138] [139] , dengue viruses (denv) in mammalian cells [43, 140, 141] but not insect cells [141] as well 10 as several others [43, 139, [142] [143] [144] [145] [146] [147] [148] [149] [150] . nonetheless, some reports failed to observe antiviral activity of cq, hcq and fq on several other viruses including polio virus, reovirus, respiratory syncytial virus (rsv), herpes simplex viruses, coxsackie virus, vesicular stomatitis virus (vsv), vaccinia virus, sindbis virus, parainfluenza-3 virus and punta toro virus [106, 151] . there are limited studies established to investigate the possible antiviral effect of cq or hcq in animal models (table 4 ). in general, studies showed no significant effect of cq on covs including sars-cov and feline infectious peritonitis virus (fipv) replication or clinical scores in mice and cats, respectively [105, 110] . however, it has been found that cq significantly reduced hcov-oc43 dissemination and replication in mice central nervous system (cns) after cq administration [152] and increased the survival rate of hcov-oc43 infected newborn mice when their mothers treated by cq most probably through placental and maternal milk transfer [108] . on the other hand, cq administration has shown contradicting outcomes when used against non-covs rna viruses in different animal models. some studies have demonstrated antiviral efficacy of cq in influenza a virus h5n1, zikv and ebov infected mice [29, 134, 139] . interestingly, cq was effective against zikv in both wild type and ifnar deficient mice, and protected infected suckling pups from infection and microcephaly when given to their mothers [29, 134, 136] . however, several other studies showed no significant antiviral effect of cq against influenza a h1n1 and h3n2 viruses in mice and ferrets, respectively [129] . similarly, cq was ineffective against ebov in guinea pigs, mice and hamsters [137, 138] , nipah virus (niv) in ferrets and hamsters [148, 153] , hendra virus (hev) in hamsters [148] , 11 chikv in cynomolgus macaques [133] , lassa virus (lasv) in mice [139] and semliki forest virus (siv) in mice [154] . importantly, most of these previous in vivo studies showed toxicity in animals [129, 133, 137, 138, 154] . furthermore, it was shown that cq could lead to disease exacerbation correlating with increased type i ifn response and delayed immune responses in chikv infected macaques [133] , increased mortality rate of sfv-infected mice [154] and niv or hev infected hamsters [148] . there are very limited published clinical trials that studied the possible antiviral effect of cq or hcq in cov and non-cov infected patients (table 5 ). these published clinical trials have clearly shown no significant benefit of using cq in the prevention or treatment against influenza, denv or chikv infections in patients [133, [155] [156] [157] [158] . in fact, in one study, patients treated with cq were more likely to develop adverse effects such as arthralgia at day 200 post-treatment [157] . on the other hand, few studies have reported that hcq could decease hiv-1 viremia, stabilize cd4 t cell count and reduce il-6 and igg levels in infected patients [159] , although others showed contradicting finding of increased hiv rnaemia in hcq treated patients [160, 161] . interestingly, while few clinical studies have suggested that the use of hcq alone or with azithromycin (azt) could be beneficial for covid-19 patients as it reduces viral shedding and time to clinical recovery [162] [163] [164] , others have reported no effect in infected patients [165, 166] . however, it is important to note that most of these studies have several limitations in study designs with small sample sizes. nonetheless, around 104 clinical trials are ongoing in different countries to asses and evaluate the therapeutic and prophylactic effects of both cq and/or hcq in covid-19 patients (table 6 ). the covid-19 pandemic has spread out of control and has caused considerable morbidity and mortality in several countries. in this unprecedented situation, clinicians have tried all kinds of treatments in an effort to stem the progression of this disease. one treatment that has received huge attention was the empirical use of anti-malarial cq/hcq. while there is no strong and enough scientific and clinical data to support their use, several countries have already included cq/hcq in covid-19 treatment protocols [167, 168] , not only as a treatment option for severely ill patients but also as a prophylactic measure. in this comprehensive review of the antiviral effects of cq and hcq on sars-cov-2 as well as other viruses, we show a broad variation in the research outcomes. both cq and hcq demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. while few clinical trials have suggested some beneficial effects of cq and hcq in covid-19 patients, most of the reported data are still preliminary [20, 162] , [163] . furthermore, at least 7 of the ongoing trials were canceled or stopped and it is not yet clear if this was due to possible adverse effects, ineffectiveness or other reasons. there are several toxicities associated with these drugs [78] [79] [80] , the one that is foremost concerning is the possibility of qt prolongation and the risk of torsades de pointes, which is a potentially life-threatening arrhythmia [81] [82] [83] . nevertheless, while our literature review showed that this is quite rare, it is not yet evident whether there would be any additive or possible synergistic risk when these drugs are combined with other medications such as azt [83] . in fact, it is challenging to base a treatment decision in the absence of a complete research cycle and a clear vision of drug efficacy and safety. given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in 13 covid-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of covid-19. this work was funded by king abdulaziz city for science and technology (kacst) grant number 09-1, which is a part of the targeted research program (trp). azt: azithromycin; vit c: vitamin c; vit d: vitamin d; lst: losartan; rdv: remdesivir; ifß-1a: interferon ß-1a; nivo: nivolumab; tcz: tocilizumab; lev: levamisole; bud: budesonide; form: formoterol; sof: sofosbuvir; ldv: ledipasvir; otv: oseltamivir; atv: atazanavir; cobi: cobicistat; tdf: tenofovir disoproxil fumarate hrct: pulmonary inflammation resolution time, imv: invasive mechanical ventilation; hcw: healthcare workers; ; ars: acute respiratory syndrome spo2/fio2: oxygen saturation/fraction of inspired oxygen ratio icu: intensive care unit; crp: c-reactive protein * the same study was registered in isrctn registry (registration no. isrctn50189673) with a total number of 5000 patients ); the european union isrctn registry /) and the australian new zealand clinical trial registry (anzctr) comparative therapeutic efficacy of remdesivir and combination 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covid-19 patients with at least a six-day follow up: a pilot observational study a pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (covid-19) no evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe covid-19 infection covid-19: us gives emergency approval to hydroxychloroquine despite lack of evidence indian council for medical research. recommendation for empiric use of hydroxychloroquine for prophylaxis of sars-cov-2 infection the antiinflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis hydroxychloroquine treatment of patients with human immunodeficiency virus type 1 the effect of chloroquine on immune activation and interferon signatures associated with hiv-1 key: cord-327063-ea7a1xfl authors: dhama, kuldeep; patel, shailesh kumar; sharun, khan; pathak, mamta; tiwari, ruchi; yatoo, mohd iqbal; malik, yashpal singh; sah, ranjit; rabaan, ali a.; panwar, parmod kumar; singh, karam pal; michalak, izabela; chaicumpa, wanpen; martinez-pulgarin, dayron f.; bonilla-aldana, d. katterine; rodriguez-morales, alfonso j. title: sars-cov-2 jumping the species barrier: zoonotic lessons from sars, mers and recent advances to combat this pandemic virus date: 2020-08-02 journal: travel med infect dis doi: 10.1016/j.tmaid.2020.101830 sha: doc_id: 327063 cord_uid: ea7a1xfl coronavirus disease 2019 (covid-19), caused by sars-cov-2 (severe acute respiratory syndrome coronavirus-2) of the family coronaviridae, appeared in china in december 2019. this disease was declared as posing public health international emergency by world health organization on january 30, 2020, attained the status of a very high-risk category on february 29, and now having a pandemic status (march 11). covid-19 has presently spread to more than 215 countries/territories while killing nearly 0.62 million humans out of cumulative confirmed infected asymptomatic or symptomatic cases accounting to almost 15 million as of july 22, 2020, within a short period of just a few months. researchers worldwide are pacing with high efforts to counter the spread of this virus and to design effective vaccines and therapeutics/drugs. few of the studies have shown the potential of the animal-human interface and zoonotic links in the origin of sars-cov-2. exploring the possible zoonosis and revealing the factors responsible for its initial transmission from animals to humans will pave ways to design and implement effective preventive and control strategies to counter the covid-19. the present review presents a comprehensive overview of covid-19 and sars-cov-2, with emphasis on the role of animals and their jumping the cross-species barriers, experiences learned from sarsand mers-covs, zoonotic links, and spillover events, transmission to humans and rapid spread, and highlights the new advances in diagnosis, vaccine and therapies, preventive and control measures, one health concept along with recent research developments to counter this pandemic disease. in the 21 st century, we have faced a few deadly disease outbreaks caused by pathogenic viruses such as bird flu caused by avian influenza virus h5n1, swine flu caused by reassorted influenza virus h1n1 pandemic 2009 (h1n1pdm2009), severe acute respiratory syndrome (sars) caused by sars-cov (coronavirus), the middle east respiratory syndrome (mers) caused by mers-cov [1] [2] [3] , ebola [4] , zika [5, 6] , nipah virus infections, and the most recent threat [7] , coronavirus disease 2019 (covid19 ) that has been posed by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) of the family coronaviridae, genus betacoronavirus [8] [9] [10] [11] [12] [13] [14] . the sars-cov-2 virus emerged from the city of wuhan, hubei province, china, during december 2019, was declared as public health international emergency by the world health organization (who) on january 31, 2020. consequently, it was categorized in a high-risk category on february 29, 2020, and gained the pandemic status on march 11, 2020 . the disease emerged from wuhan, china, as its epicentre, which moved later to italy, then the usa, and brazil. subsequently, within a short time interval of six months, it has affected nearly 215 countries/territories and claimed near to 0.62 million human deaths out of cumulative confirmed infected asymptomatic or symptomatic cases accounting to almost 15 million. sars-cov-2 has very adversely affected the usa, brazil, india, russia, south africa, peru, mexico, chile, spain, the united kingdom (uk), iran, pakistan, saudi arabia, italy and other countries. the disease incidences are lower in children than adults but exhibit all symptoms of a disease like adults [15] . the lessons learned from earlier threats of sars, mers and the present covid-19 pandemic situations warrants designing and implementing some modified plans and strategies to combat emerging and zoonotic pathogens that could pose pandemic threats/risks while taking away many human lives [11, [16] [17] [18] [19] [20] [21] [22] . researchers and health agencies across the world are putting high efforts to contain/restrain the spread of this deadly disease. they are pacing to develop potential vaccines and therapeutics/drugs [23, 24] . evidence from the initial outbreak indicates earlier cases had links to huanan wholesale seafood market in china [25] and further isolation of sars-cov-2 from different samples of the area (people, animals, birds, discharges, soil, structures) suggests the involvement of intermediate hosts [26] . recently, a literature of review has pointed out the possible potential role of the animal-human interface, zoonotic links and spillover events towards the origin of sars-cov-2/ covid-19 [11, 20, [27] [28] [29] [30] [31] . in the past couple of decade's animal origin viral diseases, especially bats-linked, have increased many folds in humans with noted cross-species transmissions. although many of the illnesses are linked with bats still information on their ecological behaviour, molecular aspects are limited, which could lead to more viral outbreaks shortly [32] . the ongoing covid-19 pandemic has emphasized the importance of understanding the evolution of natural hosts in response to viral pathogens. in a recent study on ace2 receptors, the gene was found under intense selection pressure in bats and positive selection in other selected mammalian hosts [33] . the sars-cov-2 is also thought to have originated from bats, just like sars-cov and mers-cov. civets and dromedary camels are considered as the intermediate host of sars-and mers-cov, respectively, from where they were transmitted to humans [34] . the understanding of genomic signatures of sars-cov-2 with other covs is must for strategic planning through identifying natural or intermediate hosts. using genomic and protein data in a natural vector method (alignment-free approach), phylogenetic analysis revealed the possible transmission path originates from bats to pangolins to humans [35] . however, the likely source of virus origin and the intermediate host of sars-cov-2 are yet to be identified. initially, when the novel virus emerged in china, a hypothesis was put forward, claiming the recent recombination event as the cause of the sars-cov-2 emergence . nevertheless, the phylogenetic and recombination analysis performed within the subgenus of sarbecovirus demonstrated that the novel virus shows discordant clustering with bat-sars-like coronavirus (ratg13) sequences thus rejecting the possibility of a recent recombination event [36] . previously, it was found that the continuous passaging of mers-cov in non-susceptible cells that express viral receptors led to the accumulation of mutations in the spike protein gene. this paid attention to the potential of coronaviruses like mers-cov to undergo mutations that enhance viral entry into novel animal species, thus resulting in cross-species transmission [37] . the covid-19 outbreak is still associated with several unanswered questions like the possibility of shedding of the virus before the onset of clinical signs, whether the transmission is limited to only through respiratory droplets, the possibility of an intermediate host that is responsible for zoonotic spillover, and the possible transmission characteristics [20, 38] . hitherto studies report that the spillover risk remains high from zoonotic viruses and on the same lines a study from north america proposed a hypothesized conceptual model demonstrating sars-cov-2 spillover from humans to naive wildlife host species through the gastrointestinal route where stool from covid-19 infected patient contaminates water bodies and reaches to wildlife hosts [39] . besides, the pandemic imposed a massive blow on the chinese economy, which is not going to heal soon [40] . instead of the current situation, singapore's prime minister lee hsien loong rightly said that the virus might have started in china. however, it does not respect nationality or race. it does not check your passport before it goes into your body, and anybody can be infected. hence, all suspected people need to be tested and quarantined [41] . further research exploring the sars-cov-2 associated zoonosis and mechanisms accounting for its initial transmission from animals to humans, will lead to sort out the spread of this virus as well as design and develop appropriate prevention and control strategies to counter covid-19. the present comprehensive manuscript presents an overview on covid-19, an emerging sars-cov-2 infectious disease while focusing mainly on the events and circumstantial evidences with regards to this virus jumping the species barriers, sharing a few lessons learned from sars-and mers-covs, zoonotic spillover events (zoonosis), acquiring transmission ability to infect humans, and adopting appropriate preventive and control measures [42] . it also highlights the recent advances in sars-cov-2 diagnosis (see supplement material s1), vaccine, drugs and therapies (see supplement material s2), which could aid to counter and restrain this emerging virus at the face of pandemic situations, as well as prevention and control (see supplement material s3). sars-cov-2 is an enveloped virus measuring approximately 50-200 nm in diameter with a single strand positive-sense rna genome ranging from 26 to 32 kilobases in length [43, 44] . it has club-shaped glycoprotein spikes in the envelope, giving it a crown-like or coronal appearance [25] . the genome sars-cov-2 is comprised of 5′ untranslated region (5′ utr) that includes 5′ leader sequence, open reading frame (orf) 1a/b (replicase genes), spike (s) protein, envelop (e) protein, membrane/matrix (m) protein, and accessory proteins (orf 3,6,7a, 7b, 8 and 9b), nucleoprotein (n), and 3′ untranslated region (3′ utr) in their sequence [45] . it has a 50% genetic identity to mers-cov and 80% to sars-cov [43, 46] . the receptor-binding domain (rbd) of virus spikes helps in binding to cellular receptor angiotensin-converting enzyme 2 (ace-2) [47, 48] . orf and rbd of sars-cov-2 may have a role in elucidating cellular interactions and cross-species transmission mechanisms [49] . receptor binding motifs (rbm) have a role in interaction with human receptors, human to human transmission, and cross-species transmission as gln493 provides favourable interaction, and asn501 shows compatibility with human ace-2 [47] . besides, sars-cov-2 has superior transmission competence in comparison to the sars-cov, leading to a continuously increasing number of confirmed cases [50] . sars-cov-2 has the potential to survive in the environment for several days [51] . though believed to be sensitive to environmental factors and alcohol-based sanitizers, bleach, and chloroform, the sars-cov-2 can survive in wet surroundings for days and in closed air conditions up to 12 hours [26, 52] . survival of sars-cov-2 varies with the nature of the surface (glass, fabric, metal, plastic, or paper), environment, and virus load. it can survive on surfaces for hours to several days. it can survive in aerosols for up to 3 hours and on plastic for up to 72 hours [26, 53] . the initial clinical picture of the covid-19 was pneumonia of unknown origin as the first clinical cases were presented with signs of pneumonia [38] . later it was diagnosed as sars-cov-2 infection that was associated with severe pneumonia. hence, initially named as novel coronavirus pneumonia (ncp) [54] . as the outbreak proceeded, a series of cases were produced, developing a wide range of clinical signs with few remaining asymptomatic being in the early incubation stage of the disease. thus covid-19 is characterized by three major patterns of the clinical course of infection, including mild illness producing upper respiratory signs, non-life-threatening pneumonia, and severe pneumonia with acute respiratory distress syndrome (ards) [55, 56] . initially, mild signs appear for 7-8 days, followed by rapid deterioration and ards. it can be mild to moderate in 80% of affected cases, including pneumonia and non-pneumonia cases. in comparison, 13.8% are severe cases, including dyspnea, respiratory distress, hemoptysis, gastrointestinal infection, liver, central nervous system, and lung damage cases [57, 58] . critical cases account for 6.1% and include respiratory failure, septic shock, and multiple organ failure/dysfunction cases. few cases remain asymptomatic and include cases that can become any of the above during infection [26] . thus, the symptoms can be nonspecific and can range from no symptoms (asymptomatic) to severe pneumonia [26] . in this context, a study concluded that the covid-19 is probably overestimated, as around 2.6 million people succumb to respiratory diseases every year in comparison to approximately 400,000 deaths due to the sars-cov-2 infection [59] . the typical clinical signs of covid-19 are fever, chills, cough, fatigue, and chest distress [60, 61] . fever and cough are considered as the most common symptoms in covid-19 patients [62] , followed by headache, dyspnea, sore throat, hemoptysis, myalgia, diarrhoea, nausea, and vomiting are also observed [61, 62] . some patients have shown rhinorrhea, chest pain [25] , nasal congestion [26] , anorexia, pharyngalgia, and abdominal pain [63] . furthermore, neurological symptoms like anosmia and ageusia are also reported as significant clinical symptoms of covid-19 [64] . the characteristic of covid-19 is attacking the lower respiratory tract and producing signs of upper respiratory distress, including rhinorrhea, sneezing, and sore throat [49] . the clinical presentation of individuals infected with sars-cov-2 revealed upper respiratory tract infection, viremia, viral shedding from the nasopharynx, and stool along with the development of nausea, vomiting or diarrhoea after antiviral treatment [65] . on diagnostic imaging using computed tomography (ct scan) and radiography (x-ray) bilateral pneumonia, ground-glass opacity, multiple mottling, pneumothorax, infiltration, consolidation or bronchoinflation sign has been noted in many cases of covid-19 [25, 49, 66] . previously, sars-cov was found to infect the brainstem heavily [67] . even though fever is considered as the most common symptom associated with covid-19 infection, a large proportion of the patients do not express fever during the initial hospital admission [68] . the different transmission routes of sars-cov-2 infections have not yet been entirely ascertained, and are still under investigation. both direct and indirect pathways of transmission are being explored [69] . similar to sars and mers, sars-cov-2 is predominantly spread via the respiratory route [70] . person to person transmission is the main reason for community and global spread. the initial estimated reproduction number (rovalue) of covid-19 was assessed to be from 0.8 to 2.4 in december 2019, which later has been increased to a mean value of 2.6 (range 2.1-5.1) [71] . human-to-human transmission is by face-to-face contact with a sneeze or cough, or from contact with secretions of infected people [56, 70] . nevertheless, the infectivity of other secretions and excretions are not fully understood and may require further study [45] . aerosol and plastic surfaces can sustain virus for hours to days [53] . travelling of infected people is considered as the main reason for the global spread of covid-19 [20, 56] . although the asymptomatic and mild cases are the major hurdle in the evaluation of the real number of infected people, the genuine data on travellers returning from affected countries or areas may prove crucial in estimating the disease incidence [72] . the possible occurrence of super-spreading events is very high at large gatherings, and suspension of gathering during a pandemic may prove crucial in reducing the overall transmission [73] . close contact with any person within 6 feet of the covid-19 patient or anyone having direct contact with secretions of covid-19 patients [74] may set up the infection. unlike sars-cov, most transmissions in covid-19 are during the prodromal period when the infected individuals produce large quantities of virus in the upper respiratory tract, move/travel, and usually work thus spreading virus before illness develops [56] . the rapid spread of covid-19 among the susceptible population can be due to the wide variation in illness degrees that results in a missed diagnosis. heavy viral load in asymptomatic cases and nosocomial transmission is spreading covid-19 unknowingly [75] . recently, high viral load was detected in the sputum of convalescent patients, pointing out the possibility of prolonged shedding of sars-cov-2 even after recovery. this finding, along with the fact that asymptomatic persons can also act as the potential source of infection, may warrant a reassessment in the transmission dynamics of the covid-19 outbreak [76] . the presence of viral nucleic acids in faeces is an important finding, thereby increasing the possibility of faecal-oral transmission. however, symptoms may or may not be manifested [77] . this was found to be the unique feature of covid-19 and was lacking in the previous sars and mers outbreaks. in a study conducted by the chinese cdc, it was found that the majority of patients (80.9%) infected with covid-19 infection were either asymptomatic or had mild pneumonia [56, 66] . furthermore, all forms of sexual contacts have been reported to pose a significantly high risk of disease transmission through respiratory aerosols and fomites. however, to date, no evidence of sexual transmission is available, and further investigation is required in this direction [78] . disease severity is higher in older individuals, especially males with immunocompromised conditions and comorbidities like diabetes, asthma, or cardiovascular diseases [26, 66] . these are considered to be vulnerable to the sars-cov-2 infection. predisposition increases under risk environments where transmission of the virus from affected persons or contaminated fomites to unaffected ones becomes feasible. it was earlier noted that covs are not common to affect immunocompromised patients like other some viral infections (influenza, rhinovirus, adenoviruses, to name a few). the current pandemic has shown sars-cov-2 to affect more lethally than young patients, mainly destroying the lung tissues [79] . till now, evidence regarding the higher susceptibility of pregnant women in comparison to non-pregnant women lacks in covid-19. also, there is no evidence of vertical transmission (mother to fetus/baby transmission) of covid-19 infection [80] . a case study reporting the birth of a healthy infant by a sars-cov-2 infected woman suggests that mother-to-child transmission is unlikely in the case of covid-19. the study also pointed out that on the delivery day, all the samples tested negative except for sputum, which proved positive [81] . however, as per one most recent report, neonates have been found positive for sars-cov-2, indicating the possibility of vertical transmission from infected mothers to their progeny, thus rendering newborns into a high-risk group owing to their immature immune system [82] . individuals harbouring sars-cov-2 may remain asymptomatic for the incubation period [83] . different from sars-cov and mers-cov infection, the median incubation period of covid-19 was found to be four days [68] . the median period from the development of signs to death was 14 days [84] . the case fatality rate (cfr) of covid-19 was found to be lower than mers and sars [62] . however, current disease dynamics with the involvement of many more countries or areas may change the future mortality rate. the recent analysis suggests that the total fatality rate of covid-19 is calculated at 3.46% [75] . however, italy experienced the worst cfr of more than 9% with older people and males suffering from multiple comorbidities as primary victims [85] . sars-cov-2 has shown characteristics of efficient replication in the upper respiratory tract, causing the less abrupt onset of clinical signs just like the common cold and unlike sars-cov [70] . it can also replicate in the lower respiratory tract as has been noted in cases without pneumonia but having lesions in the lungs on radiological examination [70] . the pathogenesis mechanisms of covid-19 are yet to be fully elucidated. however, both cellular and humoral immune responses against sars-cov-2 or its antigenic structures like spike protein (s) are believed to be of importance [86, 87] with disturbed levels of inflammatory mediators playing a mediating role [66] . following receptor binding with angiotensin-converting enzyme 2 (ace2) through receptor binding motif (rbm) of the receptor-binding domain (rbd) of s1 subunit of the sars-cov-2 spike glycoprotein (s), virus gains entry in host cells [47, 88, 89] . s2 subunit helps in the fusion of viral and hosts cell membranes [47, 90] . sars-cov-2 produces cytopathic effects in respiratory and gastrointestinal surface epithelial cells [91] . these include multinucleated syncytial cells, abnormally enlarged pulmonary cells, infiltration with mononuclear cells, lymphocytes infiltration in pulmonary organs, fibrinous exudation, and hyaline deposition [66] . cytokine storm is believed to be involved in this inflammatory pathophysiology of the covid-19 patients producing lung lesions and systemic symptoms [66] . elevated levels of tnf-α, il1b, ifnγ, ip10, gcsf, mip1a, and mcp1, may have stimulated t-helper-1 (th1) cells leading to this inflammatory cascade [66] . however, levels of anti-inflammatory mediators (il4, il10) were also increased, indicating t-helper-2 (th2) stimulation, which suppresses inflammation, unlike what happens in sars [66] . a study documented that the nucleic acid of sars-cov-2 detected in the faecal samples was as accurate as of that of pharyngeal samples obtained from infected patients. moreover, the patients tested positive for sars-cov-2 in stool showed no gastrointestinal symptoms and had no relation to the severity of lung infections [92] . one of the significant clinical signs of covid-19 patients during the initial presentations was gastrointestinal symptoms. hence, the involvement of git in pathogenesis needs to be explored. the significant laboratory findings include lymphopenia, increased values of erythrocyte sedimentation rate, c-reactive protein, lactate dehydrogenase, and decreased oxygenation index [61] . an increase in proinflammatory cytokine and a decrease in antiinflammatory cytokines have also been noted [66] . viral isolation has been achieved from bronchoalveolar lavage of affected persons; however, in the case of pregnant women, serum, faeces, urine, breast milk, umbilical cord blood, placenta, and amniotic fluid were found to be negative for sars-cov-2 [81] . at the same time, the sputum was tested positive [82] . the presence of abnormal coagulation parameters in patients with severe novel coronavirus pneumonia was associated with poor prognosis. the non-survivor patients had higher levels of d-dimer, and fibrin degradation product (fdp) along with longer activated partial thromboplastin time and prothrombin time compared to survivors at the time of admission [93] . though clinical manifestations, pathological changes, and diagnostic laboratory findings can unravel the disease nature helping in devising therapeutic modalities, however, for epidemiological aspects and future prevention and control, simultaneous tracing of the origin and explaining the spillover events can prove beneficial. the sars-cov-2 has first been reported from the pneumonia patients of the wuhan city in hubei province of china. these patients were involved in trading at a wet animal market in the huanan area. it is believed that sars-cov-2 is introduced from the animal kingdom to human populations during november or december 2019, as revealed from the phylogeny of the genomic sequences from the initially reported cases [94] . the spillover of sars-cov-2 from animals to humans took place at the beginning of december 2019 [56] , and the clinical cases appeared around ending december [46, 95] . genetic analysis showed that this novel virus is closely related to bat covs and is similar but distinct from the sars virus [43] . several evidences based on genome sequences, the homology of the ace2 receptor, and the presence of single intact orf on gene 8 indicate bats as a natural reservoir of these viruses. however, an unknown animal is yet to be unravelled as an intermediate host [43, 46, 47, 49, 56] . initial investigations on animal source origin of sars-cov-2 have inconclusively revealed snakes [27] , pangolins, and turtles [96] . the rapid spread of covid-19 followed the initial animal to human spillover through human-to-human transmission. genetic epidemiology had revealed that the spread from the beginning of december when the first cases were retrospectively traced in wuhan was mainly by a human-to-human transmission and not due to continued spillover [56] . these species cross jumping, spillover, and rapid transmission events are linked to viral characteristics, host diversity, and environmental feasibility. coronaviruses being rna viruses have high mutation rates that, besides creating new strains, enable them to adapt to a wide range of hosts. hence, based on genome sequences, all known human covs have emerged from animal sources [97] . this seventh member of the human cov has also been isolated initially from the pneumonia patients who were having direct or indirect links to the huanan seafood market in wuhan china, wherein other animals were also being sold [98] . these include a 49-year-old lady retailer in this wet animal market, a 61-year-old frequent visitor to this market, and a 32-year-old man [74, 98] . further, isolation of the sars-cov-2 from the environmental samples around this market, including people, animals, soil, discharges, or structures, strengthens the claims of involvement of hosts either as a reservoir or intermediate [26, 52, 99] . recently, a pomeranian dog as a probable intermediate host was identified; however, such reports are yet to be validated, and research is underway to explore the emergence of this infectious disease at the animal-human interface [29, 99] . multiple substitutions were observed in ace2 receptors of a dog [96] . in this context, the pomeranian dog of the infected owner found positive for covid-19 suggest the permissiveness of the species for sars-cov-2 as a result of species jumping [99, 100] . among the fifteen dogs tested from different households with confirmed human covid-19 cases in hong kong sar, two dogs were found to be infected with sars-cov-2. the diagnosis was made using quantitative rt-pcr, serology, and viral genome sequencing. virus isolation was also done from the samples obtained from one dog. the genetic sequences of viruses obtained from the two dogs were identical to the ones that were detected from their human cases indicating human-to-dog transmission [101] . moreover, a study reported that the sars-cov-2 might infect the cats and further transmitted by the infected cat to other cats [102] . one cat was tested positive for sars-cov-2 in france that showed mild respiratory and digestive signs. the cat was tested positive by rt-qpcr on the rectal swab, and serological analysis identified the presence of antibodies against sars-cov-2. genome analysis further confirmed that the sars-cov-2 isolated from the cat belongs to the phylogenetic clade a2a seen in french human indicating humanto-animal transmission [103] . this is not the first time that a domestic cat has been found susceptible to zoonotic coronavirus. during the 2003 sars-cov outbreak, domestic cats were tested positive for sars-cov that were living near sars infected humans [21, 104] . even though experimental evidence indicates the possibility of sars-cov-2 transmission from infected to a susceptible cat close, sars-cov-2 transmission between cats or cat-tohumans are not reported under natural conditions [21] . furthermore, along with dogs and cats, the zoo animals like tigers and lions were also reported to get the sars-cov-2 infection and exhibit clinical signs such as vomiting, diarrhoea, dry cough, breathing difficulty and wheezing [105, 106] . spillover of sars-cov-2 was also reported in mink farms of netherlands, further increasing the concern of transmission to humans. outbreaks of sars-cov-2 were reported in two mink farms holding 12,000 and 7500 animals. the virus is suspected to be introduced by a farmworker having covid-19 [107, 108] . host-pathogen interactions and pathogenesis determine the severity and expression of disease [30, [109] [110] [111] . adaptation over time reduces the severity of infection as happened with hcovs; however, the emergence of novel viruses or strains due to genetic alterations or recombinations can enhance hardness producing novel diseases like covid-19 [111, 112] . evolutionarily, the balance of viral-human interaction and immune response against virus enables adaptation, thereby persistence in a host without severe or symptomatic disease when the aggravated pathogenesis results in mortality. hence, loss of sustainable hosts and transmission to novel hosts becomes inevitable for future sustainability [111, 112] . a pathogen cannot kill all its hosts, and for future sustainability, it adapts to some suitable host or spills over to a new host. sars-cov-2 has been implicated to be originated from animals, and associated with animal linkages, spillover events, cross-species barrier jumping and zoonosis [9, 20, 27, [29] [30] [31] 113] . since the beginning of 2002 till the end of 2019, three coronaviruses viz. sars-cov, mers-cov, and sars-cov-2 have caused havoc in the human population globally and will continue to do so. earlier identified betacoronaviruses (sars-cov and mers-cov) were reported in guangdong province of china in november 2002 and saudi arabia in 2012, respectively [114] . sars-cov-2 is the third zoonotic betacoronaviruses recognized in this century. however, the cfr of the sars-cov-2 is lower to date when compared with sars and mers. it should not be overlooked as many asymptomatic cases may remain undiagnosed due to the unavailability of diagnostic kits in china. with nearly 0.62 million deaths till the preparation of the manuscript, sars-cov-2 is proven to be deadliest as far as the number of deaths is concerned in comparison with sars-cov and mers-cov with 774 and 858 associated deaths, respectively [115, 116] . earlier, covid-19 was linked with the exposure to the huanan seafood market. however, individuals with no history of exposure above were also diagnosed with the illness, further supporting the human to human spread through droplets produced by cough and sneeze [66] . the spread of covid-19 that occurred with a high pace and lack of transparency in reporting the disease by the chinese health ministry and failure in the timely implementation of preventive measures has been considered as the primary contributor as stated earlier in sars [19, 117] . both sars-cov and sars-cov-2 showed prominent similarities in their pathogenesis and epidemics. in both cases, bats were considered as the natural host, and the cold temperature and low humidity in cold, dry winter provided conducive environmental conditions that promoted the survival of the virus in the environment [62] . further, moriyama et al. [118] assessed the significance of the environmental factor on host immune system targeting innate and adaptive both responses in the respiratory tract. zoonotic spillover is the transmission of pathogens to humans from vertebrate animals [119] . at present, these spillovers are of significant concern as in the past, many spillovers in the form of nipah, hendra, ebola, sars, mers, and ongoing covid-19 involving many animal species like pigs, horses, monkeys, camels, civets, among others, were documented. bovine covs have been reported to infect children and thus possess zoonotic potential [9, 13, 120, 121] . spillover is governed by the interaction of viral-specific proteins like s protein and host ace2 receptor [30, 31, 111, 112] . these s proteins have rbd in covs, which contain receptor binding motifs (rbm) that help in specific binding to host ace2 receptors [47, 122] . mutations in amino acid sequences of rbds results in a change in specificity of a receptor, interaction and binding, hence alteration in transmissibility, pathogenicity and cross-species jumping with a predisposition to novel and more severe diseases [110, 123] . in the case of sars-cov-2, rbd of s protein has 10-15 times affinity ace2r [88, 110] . it has furin recognition sequence "rrar" at the s1-s2 cleaving site that represents a functional site for the cellular serine protease tmprss2 thus increasing the efficiency of transmission and contagiousness [88, 90, 110] . in addition to enhanced binding affinity, electrostatic complementarity and hydrophobic interactions are critical to enhancing receptor binding and escaping antibody recognition by the rbd of sars-cov-2, thereby further increasing transmission capability and contagiousness [110] . a detailed investigation regarding the emergence of new coronavirus, host range, and transmissibility is crucial to understand such pandemics shortly. the literature revealed that before the appearance of sars-cov and mers-cov, human coronavirus (hcov) strains like hcov-nl63, hcov-229e, hcov-oc43, and hcov-hku1 were the covs strains producing mild infections in humans. however, their natural ancestral hosts were of animal origin, like bats for hcov-nl63, and hcov-229e and rodents were natural hosts for hcov-oc43 and hku1. these four hcovs were initially of low pathogenicity. to enhance the pathogenicity, they used intermediate hosts such as cattle for hcov-oc43 (natural host was rodent), and alpacas for hcov-229e (bats were natural host) and this way acquired the ability to infect human beings with serious health hazards [124] . added to the involvement of bats and pangolins, the recent reports revealing sars-cov-2 infection in cats, dogs, tigers, lions and minks have raised concerns over this virus affecting multiple animal species, and also points out towards the incidences of reverse zoonosis [31, 102, 106, 108, 125, 126] . the ferrets, cats, and primates are suggested to be good candidates for susceptibility to sars-cov-2 [123, 127] . covid-19 research and surveillance in companion and pet animals, livestock animals, zoo animal species, wildlife animal species as well as their handlers, veterinarians, and owners need to be enhanced during the pandemic, which would help to follow better integrated one health strategies [128] and appropriate preventive and mitigation to counter sars-cov-2 effectively [29, 126, [129] [130] [131] [132] [133] . significance of covid-19 monitoring and implementation of suitable public health measures among workers involved in meat and poultry processing facilities/industries has been emphasized, which would protect them as well as aid in preserving the critical meat and poultry production infrastructure and the meat products [134] . the involvement of intermediate hosts in maintaining and transmitting the virus to susceptible host predisposes humans to novel covs leading to the emergence of new diseases in humans. the currently ongoing sars-cov-2 / covid-19 pandemic has put on hold the entire world [111, 135] . the covs have frequently been associated with animal and human diseases and have a zoonotic interface [97, 111] . usually, one or more types of animal hosts are involved in the transmission cycle of covs to humans [30, 97] . that can be natural host, reservoir host, intermediate host or definitive host [31] . bats have been the natural hosts for human covs of alphacoronavirus (hcov-nl63, hcov-229e) and betacoronavirus (sars-cov, mers-cov, sars-cov-2) genera whereas for betacoronavirus members hcov-oc43 and hcov-hku1, rodents are the natural hosts. genome sequence analysis has revealed bats as a natural host for sars-cov-2 [30, 97] . in natural or reservoir hosts, covs adapts well, however, being unstable rna viruses, they keep multiplying continuously without producing disease thereby enabling persistence or survivability and accumulation of mutations over the time resulting in the emergence of newer and novel strains of viruses [97, 111, 136] . these unique strains or viruses occasionally spill over to other species including animals or humans, adapting to their body systems and hence broaden the biological host range for evolutionary sustainability; however, results in epidemiological widening of disease sphere as well [25, 31] . this transmission and adaptation scenario initiates a host-pathogen response resulting in the novel usually severe diseases that can at times be fatal in initial stages or over extended periods until virus pathogen adapts to host or the host develops sufficient immune defence [137, 138] . it has been reported that almost all hcovs have originated from animals like bats (sars-cov, mers-cov, hcov-nl63, and hcov-229e) and rodents (hcov-oc43 and hku1) [139, 140] . additionally, covs have been reported to infect several species of domestic and wild animals either clinically or subclinically [27, 28, 30, 141] . cattle, horses, camels, swine, dogs, cats, birds, rabbits, rodents, ferrets, mink, bats, snakes, frogs, marmots, hedgehogs, malayan pangolin along with other wild animals may serve as a reservoir host of coronavirus [9, 27, 44, 124, [142] [143] [144] [145] [146] [147] . in the context of sars-cov-2, snakes, pangolins and bats have been suspected as intermediate hosts since the first cases of covid-19 had links to huanan sea food market where different animals, birds, and wild animals were being sold along with seafood items [27, 28, 43, 109, 147, 148] . coronaviruses have been reported to cause salivary, enteric and respiratory infections in laboratory animals (mice, rat, guinea pig, and rabbit) and urinary tract infection, respiratory illness and reproductive disorder in poultry [9, 142] . in bovine, canine, feline and swine covs infections have resulted in diarrhoea, enteritis, respiratory illness, gastro-intestinal affections and nervous symptoms [120, 121, [149] [150] [151] . coronavirus, namely-sw1, has been reported in captive beluga whale using a panviral microarray method [152] . among all the assumptions on animal hosts as the intermediate host, genomic and evolutionary information from pangolins reveals the highest closeness to the sars-cov-2 than any other host covs isolates [153] . the spike protein, the main target of many studies searching for a cure of covid-19, has been found highly similar to sars-cov-2 and, thus, could serve as a surrogate system for further evaluations [153] . bats are the natural reservoir host of many covs. as reported earlier, 7 out of 11 alphacoronaviruses and 4 out of 9 betacoronaviruses as per the international committee on taxonomy of viruses (ictv) classification were solely originated from bats [97, 154] . according to the literature, bats have been regarded as a potential wildlife reservoir whereas civets and dromedary camels as intermediate hosts of sars-cov and mers-cov, respectively [155, 156] . the bat coronavirus, batcov ratg13, has shown higher relatedness to sars-cov-2 at the whole genome level and spike gene in particular [153] . coexistence and frequent recombination between highly diversified and prevalent bat sars-related coronaviruses (sarsr-cov) and coronaviruses may suggest the probable emergence of novel viruses shortly [157, 158] . benvenuto et al. [159] analyzed the whole genome sequences of different covs using fast unconstrained bayesian approximation (fubar) to understand the evolutionary and molecular epidemiology of sars-cov-2. the authors concluded that sars-cov-2 clustered with sequences of bat sars-like covs with a few mutations in nucleocapsid and spike glycoprotein, suggesting its probable transmission from the bats [159] . bats, especially horseshoe bats (rhinolophus spp.), are considered to be the known reservoirs of sars-related covs. since the bat origin, covs have always caused outbreaks in humans, studying the diversity and distribution of coronavirus populations in the bats will help to mitigate future outbreaks in humans and animals [160] . interestingly, bats play a crucial role in all the spillovers mentioned above, indicating their importance in the emergence of new viruses. the reason behind the emergence and broad host range of covs in the past and present might be due to unstable rna-dependent rna polymerase (rdrp), lack of proof-reading ability, high frequency of mutations in the receptor-binding domain of spike gene and genetic recombination [140, 161, 162] . bat covs have high diversity and great potential of spillover in different animal species, as reported earlier in civet cat and dromedary camel, leading to well-known pandemics sars and mers, respectively along with the recent spillover in pigs resulted in swine acute diarrhoea syndrome (sads). however, spillover resulted in the emergence of sads-cov, which showed a 95% genomic identity with bat coronavirus, which led to severe mortality with 24,693 deaths in neonatal piglets [160] . fortunately, it did not excel in the form of the third pandemic, and no human cases were reported till date. the spillover responsible for ongoing covid-19 is still under investigation and a matter of great concern for the researchers all around the globe. based on resampling similarity codon usage (rscu), snakes (bungarus multicinctus and naja atra) were suggested as wildlife reservoirs of sars-cov-2 and reported to be associated with the cross-species transmission [27] and later it was disapproved by other researchers [163, 164] . unfortunately, to date, the intermediate host of the sars-cov-2 is abstruse what results in its escalation in the human population around the globe. in this context, analyzing the interaction between the asn501 site in rbd of spike glycoprotein of sars-cov-2 and the residue at 41 sites of ace2 receptor of different hosts (pangolins, turtle, mouse, dog, cat, hamster and bat) revealed that tyrosine has higher receptor binding affinity than histidine suggesting pangolins and turtle be closer than bats to humans and maybe the probable intermediate hosts of sars-cov-2 [96] . however, this hypothesis was also contradicted by li et al. [28] based on an insertion of the unique peptide (prra) in the sars-cov-2 virus, which was lacking in covs from pangolins. moreover, sars-cov-2 showed higher similarity to the betacov/bat/yunnan/ratg13/2013 compared to the ones that were isolated from the pangolins, thereby denied the direct link of the virus from pangolins. however, further studies are required to confirm the role of pangolins in sars-cov-2 spread to humans. the receptor-binding domain of the spike protein of sars-cov interacts with the host receptor ace2 facilitating its potential of cross-species, as well as human-to-human transmission [47] . similarly, the spike protein of sars-cov-2 was reported to recognize ace2 receptors expressed in fish, amphibians, reptiles, birds, and mammals and has a more robust binding capacity (affinity) in comparison to sars-cov [89] . this suggests their involvement as probable natural and intermediate hosts [161] , which may further help in the selection of animal models for epidemic investigation and preventing its spread [47] . bat origin covs have been found to cross the species barrier that favoured their transmission via recombination/mutations in the rbd. the evidence of a virus outbreak that occurred in chinese pig farms suggests its possible cross-species [160, 165] . also, murine cells were found permissive for sars-cov after substitution of his353 with lys353 in the ace2 receptor of a mouse, which suggests the role of residue changes in the cross-species and human-to-human transmission [166] . mutation in residues at position 479 and 487 of receptor binding motif (rbm) of sars-cov was reported to play a role in civet-to-human and human-to-human transmission, respectively [167, 168] . the covs are more prone to recombination and mutations leading to variable host range, and resemblance of receptors in various hosts results in cross-species jumping [31, 112, 169] . genetic divergence due to these genetic alterations results in the evolution of newer viral strains having altered virulence, tissue tropism, and host range [170, 171] . moreover, the presence of threonine at position 487 was reported to enhance the binding affinity of rbm for the ace2 receptor of civet and humans [172] . however, many sarsrelated coronaviruses (sarsr-cov) have been reported in bats and used ace2 receptors for entry into a host cell, which showed its potential to infect humans directly without any intermediate host [173] . in addition to this, no direct transmission of sarsr-cov is reported from bats to humans to date. however, seropositivity on a serological investigation of individuals without prior exposure to sars-cov residing near bat caves in china revealed likely infection of humans by bat sarsr-cov and related viruses [174] . besides, the interspecies transmission potential of sarsr-covs is due to the orf8 gene [175] . as per reports, the sars-cov emerged via recombination of bat sarsr-covs, was transmitted to farmed civets along with other mammals, and these infected civets spread the virus to market civets. the virus was reported to undergo mutations in infected market civets before its spillover to humans. similarly, the mers-cov circulated for 30 years in camels before the pandemic [97, 176] supporting the hypothesis that after species jumping the exogenous viruses opted for adaptation to the environment and host before spillover to humans [177] . moreover, the possible spillover of other circulating bat sarsr-covs to humans from mammalian hosts soon is highly anticipated. the cross-species jumping and adaptation are determined by the presence of specific receptors on host tissues (like ace 2 receptor for hcov-nl63, sars-cov and sars-cov-2, dipeptidyl peptidase-4 for mers-cov, human aminopeptidase n for hcov-229e, 9-oacetylsialic acids for hcov-oc43, hcov-hku1) which help in binding and entry of the virus into host cells [30, 31] . these receptors are present in various body systems in animals and humans, including respiratory and gastrointestinal systems [30] . reservoir host animals including bats and rodents possess these receptors which are similar to those present in camels, masked palm civets (paguma larvata), or bovines, that act as an intermediate host for different covs [30, 110, 111] . presence of some of these receptors in humans like ace2 or dpp4 makes them vulnerable to cov infection like sars-cov and mers-cov causing sars and mers infections, respectively [31, 168] . the mers-cov spike was found to possess the capacity for adapting to species variation in the host receptor dpp4 [37] . the mechanism expressed by mers-cov in adapting to infect cells of new species might be present in the other coronaviruses. ace2 has also been found as a binding receptor for sars-cov-2 [47] . the species-specific variations in the host receptors limit the interaction with cov spike protein, and this is responsible for the development of the species barrier that prevents spillover infection. snakes, civets, and pangolins are considered as the potential intermediate hosts of covid-19. however, further confirmation is required by tracking the origin of the virus. this is critical for preventing additional exposure to this fatal virus [178] . the probability of the sars-cov-2 spread during incubation and convalescent period has been suggested [76] . as per reports, presence of covs has been observed in respiratory droplets, body fluids and inanimate objects with the ability to remain infectious for nine days on contaminated surfaces resulting in its risk of self-inoculation via mucous membranes of the eyes, mouth or nose [179] [180] [181] . nosocomial, as well as human-to-human transmission, have been reported to occur via virus-laden aerosols, contaminated hands or surfaces, and close community contact with an infected person [66, 182, 183] . the ocular route has been reported in the human-to-human transmission of sars-cov-2, as observed in sars-cov, suggesting the involvement of different ways other than the respiratory tract [184, 185] . later on, the probability of the faecal-oral route for potential transmission of the virus was also suggested [186] . the metatranscriptome sequencing of sars-cov-2 in the bronchoalveolar lavage fluid (balf) of infected individuals resulted in polymorphism in few intra-hosts variants, suggesting the in vivo evolution of the virus thereby affecting its virulence, transmissibility, and infectivity [187] . an overview of coronaviruses jumping the cross-species barriers, zoonotic covs transmitted from bats to animals before spillover to humans, and possible prospects for further transmission to mammalian hosts is depicted in figure 1 . the first two decades (2000-2020) of 21 st century have proven a nightmare for the countries around the globe considering the coronavirus zoonosis, including the ongoing crisis of covid-19 which has involved entire fields of global [188, 189] . the countries affected severely by previous covs were even not evolved entirely from the effects of sars and mers when the covid-19 struck almost the entire world. novel coronavirus sars-cov-2 has shaken all the sectors of the countries irrespective of being developed or underdeveloped including healthcare system, economics, trade, infrastructure, service and production sectors [190, 191] . being a zoonotic disease with still unknown intermediate host, undisclosed features of a novel viral pathogen, unclear modes of transmission and ecological aspects, less explored pathogenesis and substantial morbidity and considerable mortality, the safety of all is a matter of great concern, and thus the involvement of various authorities was sought since the inception of disease [26, 31, 192, 193] . the first time the need for one health concept has risen to a level that authorities in various countries implemented coordinated approaches between medical, veterinary, public health, wildlife, food safety, environmental departments and so on [193] [194] [195] . that involved acquiring suggestions, diagnosis and prevention and treatment measures and their implementation in collaboration. non-medical staff in association with the medical staff was employed for initial screening, quarantine, contact tracing when the expertise of molecular biologists or technicians from various disciplines was used in the laboratory diagnosis. medical staff provided the cure and management of the patients when the public health departments, including public health engineering, municipality, food and supplies ensured sanitation, hygiene, food supply and safety. imposing of lockdown was provided by security personnel's and the transport department facilitated the movement of stranded people. thus, this crises management strategy involved various agencies directly or indirectly. however, as the animal, human and environmental health is linked to one another, the prime and future efforts should primarily focus on all these aspects. in addition to regular hand hygiene, respiratory etiquette, social/physical distancing, use of personnel protective equipment (ppe) and food safety recommendations, one health approach encompasses the role of veterinary, medical and environmental specialists for the prevention and control of current covid-19 crises and investigating the animal origin of covid-19, regulating and limiting the sale and farming of wildlife species for food and taking a one health approach to food systems feeding the world for the prevention of future pandemics [193, 196, 197] . considering the contagiousness of the virus, discouraging the working of affected individuals, public health hygiene strategies, and social distancing has been recommended as preventive measures [26, 198] . food hygiene and safety, as recommended by oie [193] and usda [199] , should be followed. as the viral survivability has been demonstrated on various surfaces [53] hence disinfection by using recommended disinfectants is necessary [200] . environmental hygiene and cleanliness are also essential [200] . interaction with animals and improper utilization of animal products during an outbreak should be avoided [193] . though the one health involves mainly public health, animal health and environmental experts, however, for the successful management of current crises and future prevention and control requires the participation of all concerned sectors having a role in public health measures, identifying clinical cases, diagnosis, contact tracing, proper infection control in various settings, isolation, quarantine, cure and management, public awareness, facilitation of infrastructure and other facilities through local administrations [26, 195] . as the human covid-19 cases are on the rise due to efficient human-to-human transmission, there is a subsequent rise in the natural infections of covid-19 among the companion and wild animal species owing to the spillover. this is mainly because of the specific biological and virological characteristics of coronaviruses that gives them the ability to easily cross-species barriers [130] . even though animal-to-human transmission is not reported in covid-19, 'one health' approach is necessary to control this pandemic virus a schematic illustration of covid-19 clinical signs, modes of transmission, important diagnostic methods, and advances in vaccine development along with salient prevention and control strategies are presented in figure 2 . with the rising number and worldwide spread of covid-19, the need for global efforts rely heavily on the investigations carried out at infection sites to trace different aspects of this novel coronavirus outbreak. one of the critical facets and the earliest research must involve determining the root cause, origin, and source of this emerging infectious disease. shreds of evidence have revealed various cross-species jumping or spillover from animals to humans of these zoonotic coronaviruses. detailed serological investigation of all domestic and wild animals residing in the proximity to humans is of utmost necessity to know and prevent likely spillover of many other bat-related covs in the future. rapid detection of spillovers above will only be possible by the implementation of an effective and robust surveillance system for circulating viruses with high zoonotic potential in animals. besides, detection of a pathogen while crossing the species barrier to start circulation among humans and prevention of human-to-human transmission in early-stage may prove crucial in termination of a probable epidemic or pandemic. application of 'one health' concept involving medical, veterinary, wildlife, public health, and other related professionals may help in infection tracing, exploring risk factors and predisposition, minimizing risk to susceptible ones, and finally devising better prevention and control strategies. in the initial stages of the covid-19 outbreak, the steps taken for implementing stringent control and 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