key: cord-271277-z0o7bhzr authors: lee, jacob title: covid-19 screening center: how to balance between the speed and safety? date: 2020-04-16 journal: j korean med sci doi: 10.3346/jkms.2020.35.e157 sha: doc_id: 271277 cord_uid: z0o7bhzr nan can minimize exposure to the virus, and the medical staff can allocate time for ventilation and environmental sterilization. in order to minimize cross-contamination during the process of specimen collection, aprons and gloves should be worn in addition to personal protective equipment, and the apron and gloves should be changed for each patient. the disadvantage is that it is difficult for medical staffs to work outdoors for long durations when the weather is very cold, hot or windy. if the medical staff responsible for collecting samples is not sufficiently trained, cross-contamination may occur while wearing the apron and gloves. medical staffs should be assigned specimen collection only after adequate training. the dt screening center needs a large space and can only be used by people with vehicles. the wt screening center can be installed in a relatively small space and is intended for patients visiting on foot. 3 in the wt screening center, fixed gloves are not changed for each testee, and these rubber gloves cannot be easily disinfected. disposable vinyl or polyethylene gloves are also worn to prevent contamination of the fixed gloves, but they can be contaminated while wearing as well. there is no way to preserve patient safety and prevent sample contamination unless the gloves fixed to the booth are changed for every patient. the inner surfaces of the booth should be wiped with a disposable disinfecting tissue or a piece of cloth and a disinfectant solution. after disinfection, a ventilation period of at least 30 minutes should be observed. 4 however, most wt screening centers allow only 10-15 minutes of ventilation. in order to increase the speed of sample collection at the wt screening centers, the number of booths should be increased. in conclusion, it is difficult to use wt screening centers safely without improving the gloves and the environmental sterilization process. these screening centers are probably dealing with patients like specimens being handled on a bench in a laboratory. the closed booth wt screening center risks the possibility of cross-contamination due to fixed gloves, in addition to the ventilation issues after environmental sterilization, thus leading to the creation of an outdoor wt screening center. this kind of screening center was created in order to screen immigrants at incheon international airport. this method has the advantages of both the dt and wt screening centers with its facilities for outdoor specimen collection and multiple booths. specimen collection booths should be installed at intervals of 5-6 m and no pedestrians should be allowed around the sampling booth as droplets can spread during the specimen collection process. drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak mass prophylaxis dispensing concerns: traffic and public access to pods walk-through screening center for covid-19: an accessible and efficient screening system in a pandemic situation world health organization. laboratory testing for 2019 novel coronavirus (2019-ncov) in suspected human cases disadvantages, like those faced with the dt screening centers, can be experienced due to external weather conditions. gloves and aprons must be replaced for every patient.due to the covid-19 pandemic, various screening centers are being set up in korea. regardless of the type of screening center you are trying to build, remember that patient safety is the top priority. key: cord-282554-hlcgutzf authors: yoo, jin-hong title: the fight against the 2019-ncov outbreak: an arduous march has just begun date: 2020-01-30 journal: j korean med sci doi: 10.3346/jkms.2020.35.e56 sha: doc_id: 282554 cord_uid: hlcgutzf nan this virus is a positive sense single stranded rna virus belonging to the family coronaviridae. most coronaviruses cause only mild upper respiratory infections, but sometimes they cause fatal respiratory disease and outbreaks, as experienced in cases of sars-cov or mers-cov. this disaster has been warned until recently that new mutants of coronavirus can occur anytime. 5, 6 the emergence of these mutants is caused by species jumping between human and other animals. therefore, it is likely to occur in an environment where human and animals are in close contact. the current outbreak is also suspected of being caused by mutants from species spillover in wuhan's wild animal market. the 2019-ncov is rapidly spreading throughout china and around the world in a relatively short period of time. as of 29 january 2020, a total of 6,140 cases were confirmed in 19 countries, including korea, of which 132 died (in china only) and had a mortality of 2.1%. 7 as much as the 2015 mers-cov outbreak, we are also learning a lot of lesson from this disaster. because epidemic is a national disaster, not only medical institutions but also governments have to be active. hence, honesty and transparency are, above all, the virtues that governments should have. our country is excellent at coping with this disaster, thanks to the experiences that we have gained during the 2015 mers-cov outbreak. 8 our defense system is at least more solid and faster than it used to be. what do you expect this ncov outbreak to be in the future? based on the sars epidemic precedence, the outbreak is expected to last at least three months. and this outbreak is expected to have a greater amount of transmission than the 2015 mers-cov. recently, the possibility of transmission by asymptomatic infected people has also been raised carefully although its evidence is unclear. therefore, we should also prepare for the spread to communities by asymptomatic infections. 9,10 after the mers-cov outbreak in 2015, there was a self-tormenting expression in the medical profession society: 'patients die, hospitals die, and civil servants are praised.' but the bad memories of the past should never be repeated. in fact, at present, cooperation between community health centers and private hospitals is not always harmonious. the government needs to be more active, not just to leave everything to the medical staffs. after all, the responsibility for the controlling nationwide epidemics lies with health authorities of the government. the korea center for disease control and prevention (kcdc) must be the control tower of the present disaster in korea and all other central or local governmental organizations must cooperate with the kcdc. toward the end of the 2019-ncov outbreak we must go on a march of arduousness. health workers, the government, and the people will need to unite to overcome this disaster. a novel coronavirus from patients with pneumonia in china clinical features of patients infected with 2019 novel coronavirus in wuhan world health organization. who issues best practices for naming new human infectious diseases surveillance case definitions for human infection with novel coronavirus (ncov) a sars-like cluster of circulating bat coronaviruses shows potential for human emergence origin and evolution of pathogenic coronaviruses tracking coronavirus: map, data and timeline clinical and epidemiologic characteristics of spreaders of middle east respiratory syndrome coronavirus during the 2015 outbreak in korea key: cord-304345-efic9sqh authors: kym, sungmin title: fast screening systems for covid-19 date: 2020-04-14 journal: j korean med sci doi: 10.3346/jkms.2020.35.e153 sha: doc_id: 304345 cord_uid: efic9sqh nan walk-through (wt) screening is also being tried out. 2 the advantage of the wt system over the dt system is that it has the same benefits of saving time, manpower, and ppe, but in addition, it is available to people who do not drive. but one main shortcoming of the wt system is the costs required in building negative pressured booths (cost of 2.8 to 3 million korean won per one wt booth). safe and effective disinfection of the booth is another issue to be counted. another screening system, globe-wall (gw) system, would have medical testers be stationed inside the negative pressured booths. the testers would collect respiratory specimens from people who stay outside the booth. this system may have some advantages over others in that it would only require a minimal level of ppe for the testers. but the aforementioned issues of booth construction costs and disinfection still exist in this system. in spite of several issues remaining unsolved at present, these creative new methods for collecting respiratory specimens for covid-19 tests have achieved great credibility in terms of time saving. however, it is believed that a couple of the issues still need to be addressed more actively in order to prove the systems' merits. first, there needs to be greater evaluation of the possibility of covid-19 patients infecting medical personnel and/or other testees in line with them. so far, there has been no report of a proven case of an individual contracting covid-19 from participating in the fast screening process. and all daily reports of pcr tests on wt system booths have come out negative even though 2 covid-19 patients have been detected by the wt test system. 2 however, more properly designed evaluations, such as pcr tests on the booth and ppe for the testers immediately after collection of respiratory specimens from already confirmed patients, and their follow up pcr tests after disinfection, are required. second, outdoor setup at well-ventilated spaces need to be considered another option for collecting respiratory specimens via covid-19 tests. in fact, this method is the recommended alternative for pulmonary tuberculosis or pneumonic plague tests' sputum collection when a negative pressured sputum collection booth is not available. 3,4 the outdoor system of respiratory specimen collection has a clear advantage of saving construction costs of negative pressured booths. but the system may not apply for small open spaces that have no sufficient air circulation. to conclude, safe and fast ways of collecting respiratory specimens are mandatory in cases of widespread outbreak of transmissible respiratory infections such as the current covid-19. although the dt, wt, and gw systems have been tried and are gathering creditability, more thorough evaluations of their safety are warranted. moreover, the outdoor collection system is believed to have potential as another option for respiratory specimen collection of covid-19 tests. drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak walk-through screening center for covid-19: an accessible and efficient screening system in a pandemic situation core curriculum on tuberculosis: what the clinician should know world health organization. how to safely collect sputum samples from patients suspected to be infected with pneumonic plaque key: cord-268907-cv0mkpzd authors: kim, jung heon; bae, wonjun; kim, jiyeon; hwang, eung soo title: an urgent need for global preparedness against the reemergence of “forgotten” infectious diseases in korea date: 2018-04-04 journal: j korean med sci doi: 10.3346/jkms.2018.33.e125 sha: doc_id: 268907 cord_uid: cv0mkpzd nan the authors have no potential conflicts of interest to disclose. 2016. 1 hav infection was not an important pathogen until the 1970s-1980s because almost all persons were infected in early ages with low sequelae by poor hygienic environment. they had immunity to hav and there was no need for vaccination at those time. however rapid increases of hav from 1,197 cases in 2012 to 4,679 cases in 2016 were reported with an outbreak with 5,521 cases in 2011. 1 some of hav cases were imported from overseas by abroad travelers. what's next? measles, pertussis, and more? we should not make these infectious diseases as "never-ending stories," and comprehensive global preparedness for preventing outbreaks is needed urgently. we already know that vaccine program pursues high rate of vaccination. according to the report from korean centers for disease control and prevention (kcdc) in 2016, vaccination rates between 0 and 3-year-old children for national essential vaccination were over 90%; bcg 97.8%, hepb 97.3%, dtap 96.2%, ipv 97.6%, mmr 97.8%, var 97.5%, je 92.7%. 2 the vaccination rate in nip was reported in young ages but there is little nation-wide survey data of their appropriateness of immune formation to prevent infection after vaccination. we do not know why mumps and varicella are continuously and increasingly prevalent in spite of high vaccination rates. is it from a vaccine procedure failure or genetic changes of causative agents? it is impossible to answer this question immediately because there is little basic background data in korea. we habitually adopt the data of infection status, seroepidemiological data from other advanced countries when an outbreak occurs without our own continuous and routine investment for the basic infection data. if they were utilized without global understanding or analyzed without the comparison with our own data, it would not always help to resolve our need because the situation of each country is different from each other. we already know changes much in genetic characteristics of many causative pathogens, nutrition, individual and herd immunity, ways of domestic and international transportation, socioeconomical and environmental situation from the past ones. therefore, it is imperative that a global and comprehensive preparedness mechanism be implemented, not only for the emerging infectious diseases but also re-emerging, "forgotten" ones. the kcdc is the sole entity responsible for the control of legal reporting of communicable diseases in the country, but it has limited resources and faces an uphill battle in realizing complete preparedness for all infectious diseases. we have already learned a difficult lesson from the dearth of infectious diseases specialists during the influenza epidemic in 2009 and the middle east respiratory syndrome-related coronavirus (mers-cov) outbreak in 2015. it is true that, in response to these crises, the korean government has reformed the structure of kcdc and increased its workforce to more effectively control emerging infectious diseases. however, old-fashioned infectious diseases, scarlet fever, mumps, hepatitis a, varicella, and zoster are in resurgence. it is necessary to gain a comprehensive understanding of the characteristics of pathogens, hygiene levels, immunity status and changes in each age group, environmental alterations, dietary nutrition, vaccine supply, treatment modalities, international relationship of diseases, so on. in order to make and keep korea safe from infectious diseases, we must expend every effort to go beyond the current fragmented approaches to institute a more balanced framework predicated on a mutually-reinforcing, cross-sectoral network of stakeholders. this would necessitate, inter alia, strengthening the planning and implementation capacities of korean government including kcdc, enhancing the participation of regional government bodies, supporting academic research at universities, infectious disease institutes and related entities. references 1. ministry of health and welfare national childhood vaccination coverage among children aged 3 years in korea the research was performed using literature and services at the seoul national university college of medicine. key: cord-304526-hoybp1h6 authors: kwon, ki tae; ko, jae-hoon; shin, heejun; sung, minki; kim, jin yong title: drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak date: 2020-03-16 journal: j korean med sci doi: 10.3346/jkms.2020.35.e123 sha: doc_id: 304526 cord_uid: hoybp1h6 as the coronavirus disease 2019 (covid-19) outbreak is ongoing, the number of individuals to be tested for covid-19 is rapidly increasing. for safe and efficient screening for covid-19, drive-through (dt) screening centers have been designed and implemented in korea. herein, we present the overall concept, advantages, and limitations of the covid-19 dt screening centers. the steps of the dt centers include registration, examination, specimen collection, and instructions. the entire service takes about 10 minutes for one testee without leaving his or her cars. increased testing capacity over 100 tests per day and prevention of cross-infection between testees in the waiting space are the major advantages, while protection of staff from the outdoor atmosphere is challenging. it could be implemented in other countries to cope with the global covid-19 outbreak and transformed according to their own situations. a dt screening center should be located in an area remote from a populated area. a large parking lot with enough space is preferred but it can be implemented even in a small parking area if it is operated by a reservation system. the entrance and exit should be strictly guided and movement also should be controlled at every dt step. the brief flow of the dt center is as follows: entrance -registration -examination -specimen collection -instructions -exit (fig. 1) . the entire service is provided to the testees without leaving their cars. all communication can be made by mobile phone except for the specimen collection. the use of an electronic payment system allows minimal contact between the testees and staff. either an open tent or temporary building can be used for work booths. while an open tent type has the advantages of low cost and natural ventilation, it is vulnerable to the outdoor environment, including weather conditions. a temporary building type is more secure for healthcare workers (hcws) and equipment within the facility against outdoor conditions. however, it requires higher initial cost. a temporary building type can be used as either a clean or contaminated zone, depending on the design of the process. personal protective equipment (ppe) of inner and outer gloves, n95 respirator, eye-shield/face shield/goggles, and hooded coverall/gown is required for the hcws who may have direct contact with testees. nitrile or latex gloves are preferred to vinyl or polyethylene gloves by virtue of their better durability. composition of ppe can be adjusted depending on the level of contact with the testees and/or supply capacities. 5 continuous work over 4 hours wearing a n95 respirator should be avoided. 5,6 after the entrance, testees answer the questionnaire containing personal information, epidemiologic factors, and related symptoms. at the examination booth, body temperature is measured using a contactless thermometer. the doctor asks additional questions based on the questionnaire. if covid-19 is strongly suspected at this stage, the testee is transferred to a designated hospital after specimen collection. it is preferred that the examination is done without direct contact with the testee using mobile phone or electronic record system, so the hcws can do their jobs without wearing a n95 respirator for a relatively longer time. it 2/4 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e123 registration & questionnaire examination specimen collection drive-through covid screening center is important since the examination work requires professionalism among all the dt stages, and this manpower pool is sparse during an outbreak situation. the examination step can be omitted for the testees with negligible risk of covid-19 (e.g. screening for asymptomatic cases). when arriving at the specimen collection booth, the window nearest the testee is to be open a few inches and nasopharyngeal and oropharyngeal swabs are taken by hcws through this space for an upper respiratory tract specimen. 7 during this process, the car ventilation mode should be kept as internal circulation. sputum samples are collected in the testees' cars by themselves with the windows closed. to minimize the contact between testee and contaminated ppe of hcws, hcws wear an additional disposable apron gown and gloves over their ppe and change them for every testee in addition to hand disinfection with 70% alcohol. at the instruction booth, the testees are informed 1) how to get the test results, 2) of home quarantine until the notification of test results, 3) how to contact the healthcare authorities in case of worsening symptoms. the dt screening center for covid-19 was suggested by one of the authors and first implemented on february 23, 2020 at kyungpook national university chilgok hospital, daegu, korea where the huge covid-19 outbreak occurred. as it proved to be safe and efficient for covid-19 screening, the dt system was adopted by 68 covid-19 screening centers among 577 centers in korea (as of march 12, 2020). it took about 10 minutes per one test, which is one third shorter than the conventional screening process. the main timeconsuming factor in the conventional covid-19 screening system is the time required for ventilation and cleaning of the specimen collection room. designed as an airborne infection isolation room with 12 air changes/hour, it takes around 30 minutes to achieve airbornecontaminant removal efficiency over 99%, and even longer if surface disinfection with sodium hypochlorite is performed. 8 however, this time for ventilation and cleaning is not required for the dt screening system because testees' cars are used as specimen collection rooms. at dt screening centers, around 100 tests can be done per day and about four to eight persons are required depending on the design of workflow. the flow can be simplified as two booths of registration/questionnaire/examination/instruction and specimen collection, which requires minimized manpower and ppe consumption. in addition to the improved efficiency, the dt screening system can also exclude the risk of cross-infection between testees at the waiting space of conventional screening centers, for testees' own cars work as isolation units throughout the test course. based on our experience, the limitations of dt screening centers includes the followings. first, a possibility of specimen contamination by the hcws' ppe would be a concern because hcws do not change conventional ppes for every testee. to avoid such possibility, hcws wear an additional disposable apron gown and gloves in addition to the alcohol-based hand disinfection for every test. definitely, conventional ppe should be changed if there is visible contamination in ppe. second, in case of an outbreak during the winter season, protection of hcws' from the outdoor atmosphere would be challenging. in this case, we recommend placing a warming source near the hcws working space. also, dehydration may matter in the case of long working time wearing ppe. we recommend rotating work every one or two hours, if possible. third, prompt subsequent management for the medically unstable testees may be limited if the dt screening center is located far from hospitals. this should be fully communicated to the public, that the testees with unstable condition should visit the conventional screening center affiliated with a hospital. fourth, only testees with their own cars can visit the dt screening center. fifth, as the barrier is lower than the conventional screening centers, some people may visit different dt screening centers to get unnecessary repeated tests, resulting in waste of resources. this issue should be solved by public education because test history cannot be shared between screening centers due to privacy issues. dt screening centers have been implemented in korea for safer and more efficient screening for covid-19. it could be implemented in other countries to cope with the global covid-19 outbreak and adjusted according to the regional situations. this system may also evolve into a dt respiratory clinic, when rapid diagnostic kit, oral treatment options, and/or vaccines for covid-19 are available in the future. world health organization for antimicrobial therapykorean society for healthcare-associated infection control and preventionkorea centers for disease control and prevention mass prophylaxis dispensing concerns: traffic and public access to pods drive-through medicine: a novel proposal for rapid evaluation of patients during an influenza pandemic rational use of personal protective equipment for coronavirus disease 2019 (covid-19) respirator tolerance in health care workers laboratory testing for 2019 novel coronavirus (2019-ncov) in suspected human cases guidelines for environmental infection control in health-care facilities. recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) we greatly appreciate the members of the policy committee for emerging infectious diseases who helped conceptualize the dt screening system, and all the members of the korean society of infectious diseases (ksid) who are coping with the current global outbreak situation together. we also thank the korean centers for disease control & prevention and the ministry of health and welfare for providing the overall number of dt screening centers in korea. key: cord-320022-e3ti4doi authors: lee, jin; kim, ki hwan; kang, hyun mi; kim, jong-hyun title: do we really need to isolate all children with covid-19 in healthcare facilities? date: 2020-07-22 journal: j korean med sci doi: 10.3346/jkms.2020.35.e277 sha: doc_id: 320022 cord_uid: e3ti4doi nan while such methods are being enforced for strict infection control at the national level in response to covid-19, most countries-including the united states and many in europeallow people who are asymptomatic or those with mild symptoms be placed under selfisolation for at-home treatment ( table 1) . [5] [6] [7] [8] [9] the policies in korea do not allow infected people who are asymptomatic or those with mild symptoms to choose where he or she will be placed under isolation, which could raise human rights issues. moreover, unnecessarily prolonging the length of a hospital stay until they satisfy the criteria for discharge from isolation could cause a relative decrease in the healthcare capacity for severe and critical patients. therefore, reasonable allocation of hospital beds must be considered to reduce covid-19-related mortality rate. isolation is considered an unavoidable measure for controlling infectious diseases, especially emerging infectious diseases. however, adverse psychological effects that entail such advantages of effective infection mitigation should not be neglected. according to a recent literature review, signs of post-traumatic stress symptoms, confusion and anger after isolation/quarantine were found in numerous studies, and such signs tended to become worse as the duration of isolation/quarantine increased. 10 the disease control authorities in each country must put forth the effort to have clear indications for isolation and minimize the duration of isolation. furthermore, it is already known that a higher percentage of children confirmed with covid-19 are asymptomatic or show mild symptoms, and the disease at their age tends to be less severe compared to adults. 11 children experience a growth stage when their personality is formed through relationships with others, and they have a high dependency on their parents. in particular, when a child below primary school age is placed in an isolation unit at a healthcare institution, it creates a situation of requiring an uninfected stressful adult guardian to be isolated together to take care of the child. 12 it is also important to pay special attention to the psychological and emotional support for children and parents (or primary caregivers) who have to be separated from each other. to minimize these disadvantages in children, home isolation should be adopted as early treatment sites like many other countries. although the previous korean isolation release criteria relied only upon pcr test results, the recently updated criteria, which references the world health organization guideline 5 enabling a shorter isolation period, includes both symptom-based and test-based criteria. with respect to the recently updated korean isolation release criteria, 4,5 asymptomatic cases can be released from isolation if they 1) develop no clinical symptoms for 10 days after being confirmed, or 2) receive two consecutive negative pcr test results taken at least 24 hours 2/4 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e277 for symptomatic patients: 10 days after symptom onset, plus at least 3 days without symptoms (without fever and respiratory symptoms). the decision of location should be made on a case-bycase basis and will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household. for asymptomatic patients: 10 days after test positive. hospitalization, ambulatory setting or at home (selfisolation) the decision to monitor a patient in the inpatient or outpatient setting should be made on a case-bycase basis. this decision will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and the ability of the patient to self-isolate at home. options include a symptom-based, a time-based, or a test-based strategy. -symptom-based strategy: ≥ 3 days (72 hours) since recovery (no fever without the use of fever-reducing medications and improvement in respiratory symptoms) and, ≥ 10 days since symptoms onset -time-based strategy: (persons with laboratory-confirmed covid-19 who have not had any symptoms) ≥ 10 days since the date of their first covid-19 positive test and have had no subsequent illness. -test-based strategy: resolution of fever, improvement in respiratory symptoms and two negative nasopharyngeal swabs, ≥ 24 hours apart the symptom-based, time-based, and test-based strategies may result in different timeframes for discontinuation of isolation post-recovery. for all scenarios outlined above, the decision to discontinue isolation should be made in the context of local circumstances. apart after 7 days since the date of their first covid-19 positive test. symptomatic cases can be released from isolation 1) after 10 days have passed since the onset of illness and are afebrile without antipyretics for at least 72 hours while showing improvement of clinical symptoms, or 2) after 7 days have passed since the onset of illness and are afebrile without antipyretics while showing improvement of clinical symptoms, plus two consecutive negative pcr test results taken at least 24 hours apart ( table 1) . meanwhile, epidemiological investigations and laboratory analyses on re-positive covid-19 cases of people who test positive after recovery show no concrete evidence that they have infectivity. 13 rather, in these cases, more weight is given to the potential of sars-cov-2 viral rna detection rather than sars-cov-2 with infectivity. therefore, considering the recovery processes of respiratory viruses, avoiding policies that delay the return to society after isolation will help overcome the covid-19 era. furthermore, in asymptomatic people including children, using test-based strategies for discharge from isolation can cause unnecessarily long isolation periods that will eventually have negative impact on both individuals and the society. under the uncertain circumstances of when the covid-19 pandemic will come to an end, people who are asymptomatic or those with mild symptoms need to be allowed to stay at home after evaluation. we therefore propose a change in the current policy that prioritizes isolation in healthcare institutions and residential treatment centers, to providing an isolation environment for pediatric patients to make a smooth recovery and emotionally/ psychologically overcome the threatening covid-19. to make this possible, the following things should be considered: a separated area for sleep and taking meals for the patient and guardian, the guardian must not be a high risk for covid-19, and channels of communication that allow the patient's status to be communicated to a medical institution or to health authorities as needed. telemedicine (telephone/video visits, etc.) and medical staff visits are key elements fundamental to the infrastructure of medical care support in the home isolation of children. to summarize, the aggressive response to covid-19 executed by the korean disease control system has been effective in managing the situation so far. however, after several months of experience in combating covid-19, it is necessary to make efforts to further reduce the isolation period based on scientific research data that is continuously being updated-taking into consideration disease severity, human rights, and normalization of individuals and society. we suggest that hospitalization should not initially be required in people who are asymptomatic or those with mild clinical presentations and believe that many patients will be able to manage their illness at home under close medical observation. coronavirus disease-19, republic of korea as of infectious disease control and prevention act. no. 16101, article 41 infectious disease control and prevention act. no. 16101, article 2 response guidelines against covid-19 clinical management of covid-19: interim guidance discontinuation of isolation for persons with covid-19 not in healthcare settings: interim guidance discontinuation of transmission-based precautions and disposition of patients with covid-19 in healthcare settings interim clinical guidance for management of patients with confirmed coronavirus disease (covid-19 stay at home: guidance for households with possible or confirmed coronavirus (covid-19) infection the psychological impact of quarantine and how to reduce it: rapid review of the evidence epidemiology of covid-19 among children in china psychological impact of quarantine on caregivers at a children's hospital for contact with case of covid-19 korean center for disease control and prevention. findings from investigation and analysis of re-positive cases the authors have no potential conflicts of interest to disclose. key: cord-286930-c1zkjdgf authors: park, won-ju title: seroprevalence of respiratory syncytial virus igg among healthy young adults in basic training for the republic of korea air force date: 2014-09-02 journal: j korean med sci doi: 10.3346/jkms.2014.29.9.1325 sha: doc_id: 286930 cord_uid: c1zkjdgf this investigation enrolled 570 healthy young males gathered from all over the country for military service at the republic of korea air force boot camp. it confirmed rsv igg seroprevalence by utilizing the enzyme immunoassay method just prior to undergoing basic training. the mean age of this study was 20.25±1.34 yr old. the results of their immunoassay seroprofiles showed that 561 men (98.4%) were positive, 2 (0.4%) were negative and 7 (1.2%) were equivocal belonging to the grey zone. it was confirmed that rsv is a common respiratory virus and rsv infection was encountered by almost all people before reaching adulthood in korea. nine basic trainees belonging to the rsv igg negative and equivocal grey zone categories were prospectively observed for any particular vulnerability to respiratory infection during the training period of two months. however, these nine men completed their basic training without developing any specific respiratory illness. graphical abstract: [image: see text] respiratory infections in the military service are the most common inflictions in the military healthcare area, yet they are problems not easy to unravel. they may cause death to military personnel often through complications, such as pneumonia and meningitis. such events could induce a setback in the military schedule affecting military capability and sustaining an enormous loss. immunity is easily compromised in an ambience of high physical and psychological stress, as well as the dense population of the military training camp. they cause numerous respiratory infections. the results of studies conducted up to now revealed that primary etiologic pathogens included adenoviruses, influenza a and b viruses, epstein-barr virus, coronavirus, and rhinoviruses, as well as streptococcus pneumoniae, streptococcus pyogenes, chlamydia pneumoniae and mycoplasma pneumoniae (1) . recent studies revealed that respiratory syncytial virus (rsv) would also be a significant pathogen that causes respiratory infection and an outbreak of febrile illness in the military (2, 3) . rsv belongs to the family of paramyxoviridae, and is classified in the genus pneumovirus. rsv is the most common cause of fatal acute respiratory tract infection in infants and young children. rsv infects virtually everyone by 4 yr of age, and reinfection occurs throughout life, even among the elderly (4-6). adults infected with rsv tend to have more variable and less distinctive clinical findings than children, and the viral cause of the infection is often unsuspected (7) . this study attempted to verify the seroprevalence of rsv igg among healthy young adults in their early twenties who had just been admitted to the korea air force basic training camp. subjects with an rsv igg seronegative outcome were prospectively observed for vulnerability to respiratory infection, especially during the period of basic training. military recruits admitted to the air force boot camp were required to undergo a basic health examination which includes a blood sampling test. in this investigation, rsv igg immunoassay was added to the basic blood test. all subjects were admitted to the training camp on june 26, 2012. they underwent a blood test on june 27, 2012, which was a day after resting without training on the day of admission. the total number of recruits was 570 and all of them underwent an rsv igg test. institutional review boards of the ministry of national defense (irb no. afmc-12-irb-014). air force physicians themselves explained the purpose, method and precautions of this study, and tests were conducted after obtaining an informed consent from each subject. the mean age of subjects was 20.25 ± 1.34 yr old with a range of 18.5-28.0 yr old. the immunoassay seroprofiles showed that 561 men (98.4%) were positive, 2 (0.4%) were negative, and 7 (1.2%) were equivocal belonging to the grey zone ( table 1 , fig. 1 ). with the exception of 7 recruits in the grey zone, seropositive subjects were 99.6% (561/563). there were no significant differences in rsv igg titer among variables such as their hometown, size of city or age (p > 0.1; anova; spss ver. 15.0, chicago, il, usa). nine basic trainees belonging to the rsv igg negative or equivocal grey zone categories were prospectively observed. any particular vulnerability to respiratory infection was confirmed by checking their visits to the military medical clinic for two months during the training period. however, all of these nine recruits did not utilize the military medical facilities during the basic training period of two months. the result of this study showed that the rsv igg seropositivity of subjects in their twenties was 99.6%. it is difficult to compare the result directly because there exist the different methods or kit for detection of antibody and the criteria of each method. however, such result of seropositivity was similar to that of the us. military personnel, which was 97.8% (8) . even in several previous studies, all children older than 5 yr old were known to have experienced an rsv infection (9, 10) . this investigation also confirmed that almost all healthy young military recruits in their early twenties were rsv igg positive in the republic of korea. in an effort to verify the increased vulnerability to respiratory infection for the rsv igg negative or equivocal grey zone recruits during the training period, the medical records for all 570 subjects were verified in the basic training camp. however, the numbers of trainees with a seronegative result were small while there were totally no records of their utilization of medical facilities for symptoms relating to any respiratory infection, making a statistical analysis impossible. in the meanwhile, the outcome of not experiencing any particular respiratory infection for nine trainees with an rsv igg negative or an equivocal result during the training period of two months can lead to a notion that young adults with an rsv igg negative result may not be a risk factor for a respiratory infection in a collective group environment. nevertheless, such deduction would require further studies for verifications in the days ahead. immunity to rsv is incomplete, protective immunity against rsv infection is complex and the importance of serum antibody is controversial (11) (12) (13) . a study targeting on infants demonstrates that rsv specific maternal igg has a protective effect against severe infections. nevertheless, such studies on adult groups are inadequate (14, 15) . although there does not appear to be a defect in humoral immunity, there is evidence that the cd8+ t-cell immunity may be impaired with age (15) . deficient rsv f-specific t-cell responses contribute to susceptibility to severe rsv disease in elderly adults (16) . the significance of this study is the aspect that seroprevalence of rsv igg of healthy young adults in the republic of korea was verified for the first time. the greatest merit of this study is the fact that the subjects were collectively gathered together from all over the country at the same time and may represent healthy young male adults in the republic of korea. rsv infections occur primarily in seasonal epidemic. rsv infection occurred predominantly in the fall and winter in the republic of korea (6, 17) . therefore, our data is limited. however, as seen from the results of previous studies overseas, it was confirmed that rsv is a common respiratory virus and rsv infection was encountered by almost all people before reaching adulthood in korea. it is very important to accumulate the basic sero-epidemiological data of every infectious agent. it is anticipated that this study may provide the basic data for rsv related studies in the republic of korea in the future. frequently, an rsv infection in the military may be unsuspected. nevertheless, rsv is a common cause of respiratory illness and often causes outbreaks in particular adult groups (18, 19) . in an effort to prevent respiratory infections in the military, further rsv studies and challenges regarding diagnosis of rsv infection would be necessary. there are no financial or other issues that might lead to conflict of interests. respiratory diseases among u.s. military personnel: countering emerging threats respiratory syncytial virus: an important cause of acute respiratory illness among young adults undergoing military training symptomatic respiratory syncytial virus infection in previously healthy young adults living in a crowded military environment medical microvirology epidemiology of respiratory viral infection using multiplex rt-pcr in clinical and epidemiological comparison of human metapneumovirus and respiratory syncytial virus in seoul respiratory syncytial virus and parainfluenza virus serosurvey of bacterial and viral respiratory pathogens among deployed u.s. service members seroprevalence of anti-rsv igg in thai children aged 6 months to 5 years large-scale seroprevalence analysis of human metapneumovirus and human respiratory syncytial virus infections in beijing protective and disease-enhancing immune responses to respiratory syncytial virus relationship of serum antibody to risk of respiratory syncytial virus infection in elderly adults role of neutralizing antibodies in adults with community-acquired pneumonia by respiratory syncytial virus the level and duration of rsv-specific maternal igg in infants in kilifi kenya prevalence of respiratory syncytial virus igg antibodies in infants living in a rural area of mozambique adults 65 years old and older have reduced numbers of functional memory t cells to respiratory syncytial virus fusion protein epidemiological characterization of respiratory viruses detected from acute respiratory patients in seoul respiratory syncytial virus infection in adult populations risk factors for respiratory syncytial virus illness among patients with chronic obstructive pulmonary disease key: cord-282293-pdhjl508 authors: park, wan beom; kwon, nak-jung; choe, pyoeng gyun; choi, su-jin; oh, hong sang; lee, sang min; chong, hyonyong; kim, jong-il; song, kyoung-ho; bang, ji hwan; kim, eu suk; kim, hong-bin; park, sang won; kim, nam joong; oh, myoung-don title: isolation of middle east respiratory syndrome coronavirus from a patient of the 2015 korean outbreak date: 2016-01-14 journal: j korean med sci doi: 10.3346/jkms.2016.31.2.315 sha: doc_id: 282293 cord_uid: pdhjl508 during the 2015 outbreak of middle east respiratory syndrome coronavirus (mers-cov) in korea, 186 persons were infected, resulting in 38 fatalities. we isolated mers-cov from the oropharyngeal sample obtained from a patient of the outbreak. cytopathic effects showing detachment and rounding of cells were observed in vero cell cultures 3 days after inoculation of the sample. spherical virus particles were observed by transmission electron microscopy. full-length genome sequence of the virus isolate was obtained and phylogenetic analyses showed that it clustered with clade b of mers-cov. middle east respiratory syndrome coronavirus (mers-cov) is a betacoronavirus causing a severe acute respiratory infection (1, 2) . it was first isolated from the sputum of a patient with severe pneumonia in saudi arabia in 2012 (3) . since then, 26 countries have reported 1,618 laboratory-confirmed cases of infection with mers-cov to the world health organization (who), including 579 fatalities (4) . the korean outbreak of mers-cov was initiated in may 2015 by a business man returning from the middle east (5) . the transmission of mers-cov continued until early july, resulting in 186 cases with 38 deaths. one of the most important characteristics of the korean outbreak was 4 large clusters of cases due to superspreading event at hospitals, accounting for > 80% of the total cases. another characteristic was that many cases of second-and third-generation of transmission occurred (5, 6) . this finding is quite contrast to the previous studies suggesting limited person-to-person transmissibility of mers-cov (7, 8) . to better understand transmissibility and assess epidemic risk, characterization of mers-cov of the korean outbreak would be of paramount importance (9) . here, we report the mers-cov isolated from a patient of the korean outbreak. a 39-year-old healthcare worker was admitted to the hospital because of fever and cough. on may 27, 2015, he was unknowingly exposed to the index case (designated as patient number 14 by korea ministry of health and welfare) of the hospital outbreak of middle east respiratory syndrome coronavirus (mers-cov) at emergency department of a hospital (10) . two days later, he developed fever and dry cough. on june 2, he was diagnosed with mers-cov infection as sputum sample was positive on real-time reverse transcriptase polymerase chain reaction (rt-pcr) assay, and admitted to the isolation unit of the mers-designated hospital by the government. he had a history of cough variant asthma, but did not take any regular medication, and otherwise healthy. on admission (june 2, 2015), the physical examination revealed a body temperature of 38.8°c, a respiratory rate of 22 breaths per minute, a pulse of 78 per minute, and a blood pressure of 118/71 mmhg. chest radiography showed patchy consolidation in the upper zone of the left lung. his pneumonia progressed, and on june 8, he developed shortness of breath, his arterial oxygen saturation decreased below 90%, requiring oxygen supplementation, and chest radiography showed multiple consolidations in the both lungs. on june 10, he was intubated and mechanical ventilation was started. his hypoxemia worsened rapidly, and veno-venous extr acorporeal membrane oxygenation support was started since june 11. on july 2 (day 35 of his illness), real-time rt-pcr for mers-cov turned negative, and was removed from the isolation unit. he recovered gradually. the patient's oropharyngeal samples were obtained by using utm tm kit containing 3 ml of viral transport media (copan di-agnostics inc., murrieta, ca, usa). the samples were stored at -70°c until assays. we inoculated m onolayers of vero cells with the samples and cultured the cells at 37°c in a 5% carbon dioxide atmosphere. cytopathic effects consisting of rounding and detachment of cells were observed 3 days after the inoculation of the sample taken on day 11 of his illness ( fig. 1a and b) . the rna titer in the sample was 5.80 × 10 7 copies/ml for upe gene and 4.97 × 10 7 copies/ml for orf1a gene. in order to observe virus particles, vero cell monolayer showing the cytopathic effects was fixed as previously described (11) . it was cut on ultramicrotome (rmc mt-xl) at 65 nm. ultrathin sections were stained with saturated 4% uranyl acetate and 4% lead citrate before examination with a transmission electron microscope (jem-1400; jeol usa inc., peabody, ma, usa) at 60 kv. spherical particles ranging 77 to 131 nm in diameter were observed within the cytoplasm of infected cells (fig. 1c and d) . for full-length genome sequencing of the virus isolate (mers-cov hu/kor/snu1_035/2015), vero cell monolayer showing cytopathic effects was harvested and used for rna extraction. rna was extracted by using qiaamp viral rna mini kit (qiagen, valencia, ca), according to the manufacturer's instructions. the rna was used for cdna synthesis using su-perscript iii reverse transcriptase (invitrogen, ma, usa) by each specific rt primer as described previously (12) . finally, about 2.5 kb pcr products were amplified by each primer pair (table 1) , and the amplicons were sheared by covaris s2 according to the 200 bp target bp condition (covaris, ma, usa). to generate the next generation sequencing (ngs) library, the fragments were ligated with adapter and index (barcode) using truseq nano dna ht library prep kit (illumina, ca, usa), and the library was sequenced by miseq (illumina, ca, usa). the ngs data were aligned to mers-cov, nc_019843, used for binary sequence alignment/map (bam) file generation, and genome assembly. in order to evaluate genetic relationship between this isolate and homo sapiens and camelus dromedaries mers-cov sequences reported from other countries, phylogenetic analyses were conducted using the whole genome, the s gene and the ofr1a gene. the full-length genome sequence (30,119 bp) of the virus isolate was obtained and deposited in the genbank (accession no. ku308549). the genome sequence of the virus had high level of nucleotide identity (97.80%-99.95%) to those of mers-cov reported previously ( fig. 2a) . of note, the closest ones were korea/seoul/035-1-2015 and 035-2-2015 (genbank accession no. , that were directly sequenced from sputum of the same patient as ours (13) . a previous study about s gene of mers-cov reported from korea showed that a culture isolate from patient number 002 contained two nonsynonymous variants (s137r and v530l) (14) . these variants were not found in our isolate and there was no difference in amino acids of s protein between our isolate and directly sequenced ones (kt374054-5). this difference can be explained by cell culture-adaptation in that our culture isolate was obtained before passage whereas one with nonsysnonymous variant was from the third passage in vero cells. phylogenetic analyses of the whole genome showed that this virus closely clustered with those reported from korea (gen-bank accession nos. kt029139, kt374050-kt374057), china (genbank accession no. kt006149.2) and saudi arabia in 2015 (genbank accession no. kt026453-6). phylogenetic analyses based on orf1ab genes revealed that this virus fell into the group 3, but those based on s genes showed that this virus belongs to the group 5 along with other viruses reported from korea ( fig. 2b and c) . these findings are compatible to a previous study (15) . in summary, we isolated mers-cov from a patient with severe pneumonia who had been infected during the korean outbreak in 2015. we also obtained full-length sequence of the the evolutionary history was inferred by using the maximum likelihood method based on the tamura-nei model (16) . evolutionary analyses were conducted in mega6 (17 middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease middle east respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia world health organization. middle east respiratory syndrome corona saudi arabia: disease outbreak news middle east respiratory syndrome coronavirus outbreak in the republic of korea transmission characteristics of mers and sars in the healthcare setting: a comparative study interhuman transmissibility of middle east respiratory syndrome coronavirus: estimation of pandemic risk transmission and evolution of the middle east respiratory syndrome coronavirus in saudi arabia: a descriptive genomic study what needs to be done to control the spread of middle east respiratory syndrome coronavirus? middle east respiratory syndrome coronavirus superspreading event involving 81 persons, korea processing tissue and cells for transmission electron microscopy in diagnostic pathology and research full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus microevolution of outbreak-associated middle east respiratory syndrome coronavirus variations in spike glycoprotein gene of mers-cov origin and possible genetic recombination of the middle east respiratory syndrome coronavirus from the first imported case in china: phylogenetics and coalescence analysis estimation of the number of nucleotide substitutions in the control region of mitochondrial dna in humans and chimpanzees mega6: molecular evolutionary genetics analysis version 6.0 we thank ms. myoung im shin (department of pathology, seoul national university hospital) for her technical assistance in electron microscopy. the authors have no potential conflicts of interest to disclose. key: cord-349646-imv0sc9y authors: lee, yonghyun; min, pokkee; lee, seonggu; kim, shin-woo title: prevalence and duration of acute loss of smell or taste in covid-19 patients date: 2020-05-06 journal: j korean med sci doi: 10.3346/jkms.2020.35.e174 sha: doc_id: 349646 cord_uid: imv0sc9y initially, acute loss of smell (anosmia) and taste (ageusia) was not considered important symptoms for coronavirus disease 2019 (covid-19). to determine the prevalence of these symptoms and to evaluate their diagnostic significance, we (approximately 150 physicians of the daegu medical association) prospectively collected data of cases of anosmia and ageusia from march 8, 2020, via telephone interview among 3,191 patients in daegu, korea. acute anosmia or ageusia was observed in 15.3% (488/3,191) patients in the early stage of covid-19 and in 15.7% (367/2,342) patients with asymptomatic-to-mild disease severity. their prevalence was significantly more common among females and younger individuals (p = 0.01 and p < 0.001, respectively). most patients with anosmia or ageusia recovered within 3 weeks. the median time to recovery was 7 days for both symptoms. anosmia and ageusia seem to be part of important symptoms and clues for the diagnosis of covid-19, particularly in the early stage of the disease. with an explosive increase in the number of new patients, hospital bed shortage was a great challenge to the healthcare system. 1 we developed and employed a remote telephone severity scoring system (daegu severity score for covid-19) for assigning priority for hospitalization and arranging for facility isolation ("therapeutic living centers") starting on february 29, 2020. 1 fifteen centers were operated for the 3,033 admissions to covid-19 therapeutic living centers. 1 approximately 150 physicians of the daegu medical association (dma) voluntarily participated in this study and checked the status of patients who were staying at home on a daily basis. 1 they reported the interview results to the team arranging hospitalization or facility isolation in daegu. during the interviews, several dma physicians found that a significant number of the patients stated experiencing acute loss of smell (anosmia) or loss of taste (ageusia). acute smell and taste disorders are related to a wide range of respiratory viral infections. 2,3 covid-19 is characterized by a variety of clinical manifestations. 4 in a typical case, a high fever appears after dry cough; in some cases, viral pneumonia develops and progresses, resulting in shortness of breath. 4,5 common symptoms among patients with covid-19 include fever, dry cough, shortness of breath (dyspnea), muscle ache (myalgia), confusion, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea/vomiting, conjunctival congestion, nasal congestion, sputum production, fatigue (malaise), hemoptysis, and chills. 4,6-9 a literature review revealed a few published articles on the importance of anosmia or ageusia as symptoms of covid-19. 10-13 from march 8, 2020, dma physicians prospectively questioned patients newly diagnosed with covid-19 who were awaiting hospitalization or facility isolation regarding the presence of anosmia or ageusia; they also provided counseling on a daily basis for these symptoms until admission to hospitals or therapeutic living centers. the data collected on anosmia or ageusia during the telephone severity scoring performed from march 8, 2020 to march 31, 2020, were analyzed retrospectively for the evaluation of the diagnostic significance of anosmia or ageusia in covid-19. additional telephone calls were made after admission to assess the duration of symptom persistence among those who reported that anosmia or ageusia persisted until hospitalization or facility isolation. we analyzed the collected data using descriptive statistics and kaplan-meier analysis for the evaluation of factors associated with the recovery from anosmia or ageusia. statistical analyses were performed using r statistics version 3.5. approximately 15% (15.3%, 488/3,191) patients had anosmia or ageusia in the early stage of covid-19 ( fig. 1) . among patients with asymptomatic-to-mild disease severity (2,342 patients), 367 (15.7%) had anosmia or ageusia. the basic characteristics of the patients with or without anosmia or ageusia are summarized in table 1 . anosmia or ageusia was significantly more common among females and younger individuals (p = 0.01 and p < 0.001, respectively) ( table 1) the duration of these two symptoms was ascertained based on the daily interviews conducted by dma physicians during the waiting period for hospitalization or facility isolation and by follow-up telephone interviews with 232 (for anosmia) and 196 (for ageusia) patients. recovery from anosmia is expressed using a survival curve ( fig. 2a) . kaplan-meier graphs with log-rank tests were generated using data on recovery from anomia based on demographic variables including age of > 50 years and sex. no significant differences were observed in log-rank tests. the median time to recovery from anosmia was 7 days, and the recovery time pattern is depicted in fig. 2b time pattern is shown in fig. 2c . most patients with anosmia or ageusia recovered within 3 weeks (fig. 2b and c) . young age, particularly the age group of 20-39 years, showed a tendency to be associated with a longer persistence of anosmia (fig. 2d) . recovery from ageusia was similar to that from anomia (supplementary fig. 1) . recently, anosmia was reported in a small cross-sectional survey study of covid-19. 11 this article did not report follow-up information and included a relatively small number of patients (59 patients). our data were derived from 3,191 patients, among whom 232 (anosmia) and 143 (ageusia) were followed up regarding the persistence of these symptoms. smell and taste disorders are related to a wide range of viral infections. 2,3 infection of the upper respiratory tract can cause acute-onset anosmia or ageusia because of viral damage to the olfactory epithelium. 3 moreover, viruses that can use the olfactory nerve as a route into the central nervous system include influenza a virus, herpesviruses, poliovirus, rabies virus, parainfluenza virus, adenoviruses, and japanese encephalitis virus. 2 in mouse models, sars-cov demonstrated transneuronal penetration through the olfactory bulb and its infection resulted in the rapid, transneuronal spread of the virus to connected areas of the brain. in covid-19, headache may not only be a constitutional symptom but also be a symptom induced by invasion of the central nervous system. human angiotensin-converting enzyme 2 is a functional receptor for sars-cov-2. 10,12 damage to the olfactory nerve during invasion and multiplication of sars-cov-2 may explain anosmia observed in the early stage of covid-19. therefore, anosmia or ageusia may be more frequently observed in the covid-19 patients than other respiratory viral infections. ageusia may be a secondary result of olfactory dysfunction. however, the angiotensinconverting enzyme 2 receptor, which is the main host cell receptor of sars-cov-2 for binding and penetrating cells, is widely expressed on epithelial cells of the oral mucosa. 15 damage of mucosal epithelial cells of the oral cavity may explain ageusia observed in the early stage of covid-19. this evidence may explain the pathogenetic mechanism underlying anosmia and ageusia in covid-19. high transmissibility of covid-19 before and immediately after symptom onset was reported with a recent epidemic study. 16 early diagnosis is important for the control of covid-19, recognition of early signs such as anosmia or ageusia might be very helpful for the diagnosis covid-19 and isolation of the patients. this telephone severity scoring system had a limitation regarding the accuracy of the assessment of patients. however, anosmia and ageusia are not ambiguous symptoms. our report had a relatively large number of patients and focused on the time pattern on the recovery of these symptoms. in conclusion, anosmia and ageusia seem to be part of important symptoms and clues for the diagnosis of covid-19, particularly in the early stage of the disease. the acute anosmia or ageusia need to be recognized as important symptoms of the covid-19 infection. among patients with asymptomatic-to-mild disease severity, the presence of anosmia or ageusia may be an important differential presentation for the suspicion and diagnosis of covid-19. and these symptoms may recover within 3 weeks. association dmdaegu medical association. a brief telephone severity scoring system and therapeutic living centers solved acute hospital-bed shortage during the covid-19 outbreak in daegu the olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system smell and taste disorders clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of coronavirus disease 2019 in china clinical features of patients infected with 2019 novel coronavirus in wuhan, china clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus 2 infection: a preliminary report of the first 28 patients from the korean cohort study on covid-19 olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid-19): a multicenter european study self-reported olfactory and taste disorders in sars-cov-2 patients: a cross-sectional study sudden and complete olfactory loss function as a possible symptom of covid-19 olfactory and taste disorder: the first and only sign in a patient with sars-cov-2 pneumonia severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace2 the authors would like to thank all physicians of daegu medical association who volunteered to interview and counsel patients with covid-19 in daegu, korea. key: cord-269885-r8molh8c authors: jeong, soo young; sung, se in; sung, ji-hee; ahn, so yoon; kang, eun-suk; chang, yun sil; park, won soon; kim, jong-hwa title: mers-cov infection in a pregnant woman in korea date: 2017-08-08 journal: j korean med sci doi: 10.3346/jkms.2017.32.10.1717 sha: doc_id: 269885 cord_uid: r8molh8c middle east respiratory syndrome (mers) is a lethal respiratory disease — caused by mers-coronavirus (mers-cov) which was first identified in 2012. especially, pregnant women can be expected as highly vulnerable candidates for this viral infection. in may 2015, this virus was spread in korea and a pregnant woman was confirmed with positive result of mers-cov polymerase chain reaction (pcr). her condition was improved only with conservative treatment. after a full recovery of mers, the patient manifested abrupt vaginal bleeding with rupture of membrane. under an impression of placenta abruption, an emergent cesarean section was performed. our team performed many laboratory tests related to mers-cov and all results were negative. we report the first case of mers-cov infection during pregnancy occurred outside of the middle east. also, this case showed relatively benign maternal course which resulted in full recovery with subsequent healthy full-term delivery without mers-cov transmission. middle east respiratory syndrome (mers) is a lethal respiratory disease caused by mers-coronavirus (mers-cov) and occurs mostly in the middle east, initially by camel-to-human transmission, and then by human-to-human transmission. however, the disease was spread to other continents, probably by an index case, with subsequent pandemic outbreaks through human-to-human transmission through droplets and contact. during these respiratory viral outbreaks, pregnant women can be expected as highly vulnerable candidates for infection (1) . a mers outbreak occurred in korea in 2015 with 186 infections, including 38 deaths (2, 3) . we experienced a case of a korean pregnant woman who was confirmed for a mers-cov infection via a polymerase chain reaction (pcr) test. this is the first case of a mers-positive pregnancy reported outside the middle east and is also the first case of having been exposed and confirmed on 3rd trimester of pregnancy with full-recovery and successful full-term delivery. on may 27, 2015, the patient's mother was exposed to the 14th mers patient, had a fever starting from june 3 and was diagnosed with mers on june 7. while febrile, she had been in close contact with her daughter, a 39-year-old pregnant woman (gravida 2 para 1). on june 8 (35 weeks and 4 days of gestational age [ga]), this pregnant woman visited the emergency room complaining of mild myalgia. based on this contact history with a mers patient and her symptoms, a mers-cov pcr test was performed and the result was found to be positive on june 9. starting from june 9, the patient developed dyspnea and sputum production. although chest auscultation was normal, the oxygen saturation (spo2) was 95% in room air and chest radiography showed diffuse opacity in the left lower lung area compared to a previously obtained radiographic image. the laboratory findings included a leukocyte count of 5,570/mm 3 (normal range 4,000-10,000/mm 3 ), with a differential of 71.4% segmented neutrophils, 20.5% lymphocytes, and 7.9% monocytes; and c-reactive protein level of 1.95 mg/ dl (normal range 0-0.3 mg/dl). she was given supplemental oxygen for hypoxia and conservative treatment, with hydration and pain control. the antiviral agents used in other severe mers-cov patients were not used in this patient, because her symptoms and laboratory findings were not severe. also, there was no evidence of any potential harm to the fetus and pregnant woman related to those drugs. after several days, her dyspnea and myalgia improved. the spo2 was 98% in room air and chest radiography showed interval improvement. on june 19 and 21, mers-cov pcr was performed and the results were negative. she had no symptoms related to mers. on june 23, the patient manifested abrupt vaginal bleeding with rupture of membranes. a fist-sized blood clot was found through speculum examination and she had abdominal pain. fetal cardiotocography showed no deceleration, but a variability of fetal heart rate changed from moderate to minimal. with an impression of placental abruption, her obstetrical team decided on emergent cesarean delivery. a 3,140 g male newborn was delivered at 37 weeks and 5 days of gestation. apgar scores at 1 and 5 minutes were 9 and 9, respectively. as expected, about 10% placental abruption was found (fig. 1) . after delivery, the baby was immediately moved to the airborne infection isolation room (aiir) and received an initial care with all health care personnel (hcp) completely protected according to the centers for disease control and prevention (cdc) guidelines (4). mers-cov pcr tests and antibody tests were performed with umbilical cord blood and placenta, and all results were negative. a systematic testing procedure for coronavirus infection, including chest radiograph and serial reverse transcription (rt)-pcr assays with peripheral blood and nasopharyngeal swab, did not demonstrate the presence of mers-cov in the newborn. mers-cov antibody tests were performed with mother and newborn sera on june 16 and june 28, respectively (5). in the mother's serum, immunoglobulin g (igg) was detected, albeit weakly, (0.302) via enzyme-linked immunosorbent assay (elisa; euroimmun ag, luebeck, germany), and via indirect immunofluorescence test (iift; euroimmun ag) with a titer of 1:100. igm and iga were not detected through elisa and the plaque reduction neutralization test (prnt) result was below the cutoff value. however, mers antibodies for igg, igm, and iga were not detected in the newborn's blood samples ( table 1) . the patient and her newborn baby were discharged in stable condition on june 30 with no clinical abnormalities on followup at the outpatient clinic. mers-cov was first isolated from a patient who died from a severe respiratory illness in jeddah, saudi arabia in june 2012 (6) . since then, more than 1,698 confirmed cases were reported to https://doi.org/10.3346/jkms.2017.32. 10.1717 the world health organization (who). clinical features of mers are variable, and infected patients can be asymptomatic or have an acute febrile illness, upper respiratory tract disease, or even multiple organ failure resulting in death (7) (8) (9) (10) (11) . however, there are limited data about the clinical features of mers-cov infection during pregnancy and the perinatal outcome of patients diagnosed with mers-cov infection. to our best knowledge, there have been 9 reported cases in which pregnant patients had positive laboratory results for mers-cov including this case (12) (13) (14) (15) (table 2) . unlike other cases, this case is not only the first mers-cov infection during pregnancy occurred outside of the middle east, but also the first case of mers confirmed on 3rd trimester of pregnancy showing good outcome of both mother and baby. currently, an exposure time to this virus during pregnancy and a severity of maternal disease could be expected to affect the perinatal outcome. however, there is limited knowledge about the clinical implications of mers-cov infection on the maternal, fetal, and placental aspects of pregnancy. from the maternal aspect, there is no epidemiologic data regarding whether pregnant women are more susceptible to mers. also, it is unknown whether mers-cov infected pregnant women have a more severe disease course compared with the non-pregnant population. in our case, she showed a mild disease course. she had low level of igg antibody by elisa and iift but not detectable neutralization activity by prnt. it has been suggested that neutralizing antibodies are produced at low levels and are potentially short-lived after mild or asymptomatic mers-cov infection (16, 17) . from the fetal aspect, it is unclear whether mers was a causative factor in the stillbirth or preterm birth. fetal specimen and/or placenta were not available for evaluation in the previous cases. as pregnancy alters maternal pulmonary function and consumes more oxygen, severe respiratory illness during pregnancy results in maternal hypoxemia. maternal hypoxemia can be associated with poor fetal oxygenation, which eventually could lead to preterm birth or stillbirth. also, altered immune responses during pregnancy could affect the fetal outcome (13) . from the placental aspect, there have been no reports of mers causing pathology of the placenta including infarction, insufficiency, or villus placentitis. our case showed placenta abruption clinically, which can be caused by maternal infection. there is no evidence of a relationship between mers-cov and placenta disorder. however, the possibility that this virus may be a cause of placenta abruption should be of concern. lastly, the remaining question was whether the virus could cross the placenta causing significant infection in the fetus, and whether mers could cause vertical transmission. camel-tohuman transmission, and human-to-human transmission via contact, droplet, and possibly airborne routes are the known modes of transmission (18, 19) . however, there are no data about perinatal transmission of mers-cov. moreover, if the mother mounts an appropriate immune response to produce enough neutralizing antibodies without serious conditions, passive antibodies transferred from mother to fetus may have a protective effect on the fetus. there is only one case reporting the mother's serologic data previously (15) , in which stillbirth occurred at approximately 5 months of gestation, although the mother had mers-cov antibody by elisa (titer 1:1,600) , immunofluorescent antibody (ifa), and microneutralization titer assay (titer 1:80). in our case, although the mother had igg antibody (titer 1:100 by iift), antibody was not detected in neonatal serum. this finding may provoke different interpretations in regard to the role of maternal antibodies in the fetus or to transmission of maternal antibodies, necessitating more data in the future. to know whether prenatal transmission of mers-cov can occur, collection of samples including amniotic fluid, placenta, and umbilical cord is needed from an infected pregnant patient. further studies with a larger sample size will help in understanding of the pathophysiology and perinatal outcome of mers during pregnancy and the optimal mode of delivery. the effect of asian influenza on the outcome of pregnancy mers-cov outbreak following a single patient exposure in an emergency room in south korea: an epidemiological outbreak study middle east respiratory syndrome coronavirus (mers-cov) nosocomial outbreak in south korea: insights from modeling interim infection prevention and control recommendations for hospitalized patients with middle east respiratory syndrome coronavirus (mers-cov) serologic evaluation of mers screening strategy for healthcare personnel during a hospital-associated outbreak isolation of a novel coronavirus from a man with pneumonia in saudi arabia characteristics and outcomes of middle east respiratory syndrome coronavirus patients admitted to an intensive care unit in jeddah, saudi arabia clinical presentation and outcomes of middle east respiratory syndrome in the republic of korea mers outbreak in korea: hospital-to-hospital transmission better understanding on mers corona virus outbreak in korea case definition and management of patients with mers coronavirus in saudi arabia impact of middle east respiratory syndrome coronavirus (mers-cov) on pregnancy and perinatal outcome middle east respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from saudi arabia middle east respiratory syndrome coronavirus during pregnancy stillbirth during infection with middle east respiratory syndrome coronavirus transmission of mers-coronavirus in household contacts persistence of antibodies against middle east respiratory syndrome coronavirus middle east respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control the emergence of the middle east respiratory syndrome coronavirus we thank dr. christian drosten and dr. marcel a. muller in institute of virology, university of bonn medical center for performing immunoglobulin a (iga) enzyme-linked immunosorbent assay (elisa) and plaque reduction neutralization test (prnt). we also thank prof. kyong ran peck in division of infectious disease, department of medicine, samsung medical center, sungkyunkwan university school of medicine for providing the reagent and practical help for us to obtain the antibody test results. the authors have no potential conflicts of interest to disclose. jong-hwa kim https://orcid.org/0000-0003-4356-0561 key: cord-289370-3n56low4 authors: kim, hong nyun; lee, jang hoon; park, hun sik; yang, dong heon; jang, se yong; bae, myung hwan; cho, yongkeun; chae, shung chull; lee, yong-hoon title: a case of covid-19 with acute myocardial infarction and cardiogenic shock date: 2020-07-08 journal: j korean med sci doi: 10.3346/jkms.2020.35.e258 sha: doc_id: 289370 cord_uid: 3n56low4 a 60-year-old male patient with coronavirus disease-2019 showed new onset st-segment elevation in v1–v2 leads on electrocardiogram and cardiac enzyme elevation in intensive care unit. he had a history of type 2 diabetes mellitus, hypertension, and dyslipidemia. he was receiving mechanical ventilation and veno-venous extracorporeal membrane oxygenation treatment for severe hypoxia. two-d echocardiogram showed regional wall motion abnormalities. we performed primary percutaneous coronary intervention for acute myocardial infarction complicating cardiogenic shock under hemodynamic support. he expired on the 16th day of admission because of cardiogenic shock and multi-organ failure. active surveillance and intensive treatment strategy are important for saving lives of covid-19 patients with acute myocardial infarction. since the first report of coronavirus disease 2019 in hubei province, china in december 2019, it has been spreading rapidly worldwide, and the world health organization declared a pandemic on march 11, 2020 . in daegu, korea, there was rapid increase in covid-19 patients following the first outbreak on february 18, 2020. the pandemic of covid-19 acted as a significant burden on the medical capacity of local medical institutions, and local medical institutions concentrated a large number of personnel and facilities to prevent and treat covid-19 infection. therefore, in such a pandemic, it is very difficult to properly deal with emergency situation such as acute myocardial infarction (ami). we herein present our first case of percutaneous coronary intervention (pci) for patients with covid-19 infection who developed ami with cardiogenic shock during hospitalization in intensive care unit. a 60-years-old male visited the emergency room for general weakness and poor oral intake for 10 days on march 18, 2020. he had a history of type 2 diabetes mellitus, hypertension for 20 years, and dyslipidemia for 10 years. initially, he did not complain of respiratory symptoms such as cough, sputum, dyspnea, or febrile chilling sensation. his initial vital signs were pertinent for a blood pressure of 160/100 mmhg, a heart rate of 90 beats/min, a body temperature 36.8°c, a respiratory rate of 20 breaths/min, and peripheral o 2 saturation of 94% on room air. however, the chest x-ray demonstrated bilateral patchy infiltration (fig. 1) . he had a history of close contact with a covid-19 patient during medical practice as a physician on february 25, 2020. accordingly, a real-time reverse transcriptase polymerase chain reaction test for covid-19 was done and confirmed covid-19 positive on march 19, 2020. although an antiviral agent (lopinavir/ritonavir) and antibiotics were administered immediate after admission, his condition continued to deteriorate during hospitalization. intubation and mechanical ventilation was applied on the 5th day of admission. continuous renal replacement therapy was started on the 6th day of admission and veno-venous extracorporeal membrane oxygenation (v-v ecmo) was applied on the 13th day of admission. on the 14th day of hospitalization, his vital signs became unstable. chest x-ray revealed peribronchial ground glass opacities and nodular opacities in both lung fields (fig. 1) . on the electrocardiogram (ecg), st elevation in v1-v2 leads and t wave inversion in v3-v6 leads were newly observed (fig. 2) . laboratory testing demonstrated elevated cardiac troponin i of 46.1 ng/ml (reference range ≤ 0.045 ng/ml) and n-terminal pro-b-type natriuretic peptide of 1,971.5 pg/ml (reference range ≤ 125.0 pg/ml). transthoracic two-d echocardiogram (tte) revealed severe decreased left ventricular ejection fraction of 30%, and regional wall motion abnormalities at apex and apical septal segments. despite the use of inotropes and v-v ecmo, blood pressure and peripheral o 2 saturation gradually decreased. therefore, we decided to perform urgent coronary angiography (cag). a negative pressure isolation chamber was used to minimize possible infection in the patient transfer process. a minimum number of staffs including three cardiologists, a nurse, and an x-ray technician was allowed to participate in procedure. before the patient entered the catheterization room, medical personnel entered the room first wearing level d personal protective equipment including powered air purifying respirators (fig. 3) . baseline cag revealed multivessel disease. there was 80% diameter stenosis in the mid and distal portion of the left anterior descending artery (lad), 90% diameter stenosis in the proximal ramus intermedius coronary artery (pri), 90% diameter stenosis in the proximal left circumflex artery (plcx), and 95% diameter stenosis in the proximal and distal right coronary artery (rca) (fig. 4) . it was difficult to distinguish the culprit lesion by ecg, tte, and cag. we decided to perform complete revascularization for multivessel coronary lesions because his vital signs were unstable. first, pre-balloon angioplasty using a 2.5 × 20 mm balloon was done and drug eluting stent (3.5 × 32 mm) was implanted in the proximal rca lesion. second, plain old balloon angioplasty (poba) using a 2.5 × 20 mm balloon on the plcx lesion was done. third, poba using a 2.5 × 20 mm balloon was done at the pri lesion. fourth, pre-balloon angioplasty using a 2.5 × 20 mm balloon was done and a drug eluting stent (3.0 × 28 mm) was implanted in the mid lad lesion. finally, we obtained thrombolysis in myocardial infarction (timi) grade 3 flow in lad, lcx, and ri, separately, and timi grade 2 flow in rca (fig. 5) . the total amount of contrast media used was 150 cc and total procedural time was 72 minutes. there were no specific complications during the procedure. immediately after pci, v-v ecmo was converted to veno-arterial ecmo for hemodynamic support. despite maximum medical therapy, the patient's condition gradually deteriorated and he did not recover from the cardiogenic shock. one day after the pci, an intra-aortic balloon pump was applied in anticipation of improvement of cardiogenic shock. however, unfortunately, he expired the next day (16th day of admission) because of cardiogenic shock and multi-organ failure. the study protocol was reviewed and approved by the institutional review board of school of medicine, kyungpook national university (irb no. 2020-06-034). since the first confirmed cases of covid-19 occurred on february 18, 2020, in daegu, korea, the number of confirmed cases increased sharply up to 6,704 cases, and 115 deaths occurred by april 1, 2020. this is the first case of a patient with covid-19 who underwent pci for ami complicating cardiogenic shock. in our case, there are two noteworthy lessons regarding the covid-19 pandemic. first, there are significant associations between cardiovascular risk factors and mortality in covid-19. cardiovascular comorbidities are common in patients with covid-19 infection. however, in previous studies, relative frequency of cardiovascular risk factors or underlying cardiovascular conditions in available covid-19 cohorts was quite variable. 1 hypertension was presented from 6.5% to 38.6% and diabetes mellitus presented from 7.3% to 19.5% of confirmed cases. the prevalence of cardiovascular disease in covid-19 patients was also variable from 4.0% to 14.6%. therefore, it remains uncertain whether hypertension, diabetes mellitus, and cardiovascular disease are causally linked with covid-19 infection. however, the patients who develop severe disease are more likely to be vulnerable because of comorbid disease such as hypertension, diabetes mellitus, and cardiovascular disease. covid-19 mainly affects the respiratory system, including the lung, but affects multiple organs, especially the cardiovascular system. 2,3 in previous reports, cases of pericarditis, 4 myocarditis, 5 stress induced cardiomyopathy, 6,7 and arrhythmia occurred in patients with covid-19, 8 and cases of pulmonary thromboembolism, 9 coronary artery thrombosis, 10 and stemi were also reported. 11,12 however, studies on how covid-19 affect ami is limited. the patient suffered from diabetes mellitus and was suspected of diabetic ketoacidosis with serum glucose of 655 mg/dl, hemoglobin a1c of 11.4%, and ketone body of 4.9 mmol/l (reference range ≤ 0.6 mmol/l) at the time of admission. 13 in addition, he had a high risk of ami due to severe respiratory failure and renal failure during hospitalization. although it is not understood how covid-19 affects development of ami, severe respiratory failure and multi-organ failure may directly or indirectly affect the development of ami. 14 in particular, the risk of ami may increase in patients with underlying conditions such as old age, hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease. therefore, it is necessary to closely observe and properly test ecg, cardiac enzymes, and tte (if suspected) in patients with cardiovascular risk factors or underlying cardiovascular conditions during the covid-19 pandemic. second, significant time delay between diagnosis and procedure may occur in covid-19 patients. reduction of reperfusion time is crucial for system of care in patients with ami. this treatment principle of ami is not significantly different even in covid-19 confirmed patients. 15, 16 however, in real-world practice, it is possible to have a significant time delay between ami diagnosis and the actual procedure because the primary pci of a covid-19 patient is accompanied by the possibility of covid-19 transmission in hospital facilities, medical staff, and other patients. therefore, there must be a policy for patient transportation and facility isolation in advance. in addition, there must be a standard sterilization processes for the facility after the procedure. first of all, the most important thing is that sufficient personal protection equipment for all medical staff are provided during the whole procedure process. in our case, although he had ami with cardiogenic shock, primary pci was performed at the end of the scheduled procedures to minimize exposure of other patients. therefore, several hours of time delay occurred between the pci decision and actual pci implementation. we should make an effort to reduce transportation and personal protectionrelated time delay in covid-19 patients. finally, when ami with cardiogenic shock is accompanied by covid-19, a patient's recovery is very difficult. therefore, we should remember that active surveillance and intensive treatment strategy without time delay are important for saving lives even in covid-19 patients with ami. cardiovascular considerations for patients, health care workers, and health systems during the covid-19 pandemic clinical features of patients infected with 2019 novel coronavirus in wuhan, china covid-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options cardiac tamponade secondary to covid-19. jacc case rep subacute perimyocarditis in a young patient with covid-19 infection typical takotsubo syndrome triggered by sars-cov-2 infection sars-cov-2, a novel virus with an unusual cardiac feature: inverted takotsubo syndrome novel coronavirus 19 (covid-19) associated sinus node dysfunction: a case series covid-19 complicated by acute pulmonary embolism and right-sided heart failure multivessel coronary thrombosis in a patient with covid-19 pneumonia st-elevation myocardial infarction in patients with covid-19: clinical and angiographic outcomes st-segment elevation in patients with covid-19 -a case series acute hyperglycemic crises with coronavirus disease-19: case reports inflammation, immunity, and infection in atherothrombosis: jacc review topic of the week the european society for cardiology. esc guidance for the diagnosis and management of cv disease during the covid-19 pandemic management of acute myocardial infarction during the covid-19 pandemic key: cord-259906-9em5tjya authors: park, ji young; han, mi seon; park, kyoung un; kim, ji young; choi, eun hwa title: first pediatric case of coronavirus disease 2019 in korea date: 2020-03-16 journal: j korean med sci doi: 10.3346/jkms.2020.35.e124 sha: doc_id: 259906 cord_uid: 9em5tjya the large outbreak of coronavirus disease 2019 (covid-19) that started in wuhan, china has now spread to many countries worldwide. current epidemiologic knowledge suggests that relatively few cases are seen among children, which limits opportunities to address pediatric specific issues on infection control and the children's contribution to viral spread in the community. here, we report the first pediatric case of covid-19 in korea. the 10-year-old girl was a close contact of her uncle and her mother who were confirmed to have covid-19. in this report, we present mild clinical course of her pneumonia that did not require antiviral treatment and serial viral test results from multiple specimens. lastly, we raise concerns on the optimal strategy of self-quarantine and patient care in a negative isolation room for children. hospital. from february 2, 2020, self-quarantine was resumed by the remaining five family members. although the patient's father, aunt and cousin stayed in separate rooms, the patient shared the same room with her mother. on february 5, 2020, her mother was confirmed with covid-19. because the patient closely contacted her uncle and her mother, she was screened for covid-19, and three screening tests for severe acute respiratory syndrome coronavirus 2 (sars-cov-2) were all negative on day 1 and 4 since her uncle's diagnosis (february 1) and day 2 from the last exposure (february 5) to her mother. she remained well without subjective symptoms until the 13th day from the last exposure when she developed slightly elevated temperature of 37.3°c, which led to a confirmed diagnosis of her covid-19 on february 18, 2020. a small amount of sputum for the previous three days was later reported. no other symptoms such as diarrhea or vomiting were reported. on admission, she was not dyspneic nor cyanotic with a body temperature of 37.7°c. initial laboratory results were as follows: white blood cell count 4,080/μl (37.3% lymphocytes), hemoglobin 13.5 g/dl, platelet count 251,000/μl, and c-reactive protein < 0.40 mg/dl. real-time reverse transcription polymerase chain reaction (rt-pcr) for sars-cov-2 (supplementary data 1) was serially tested for the samples from nasopharynx, throat, saliva, serum, stool, and urine. viral tests were positive in the samples from nasopharynx, throat, and stool ( fig. 2a) . serum, saliva, and urine tested negative on hospital days 3 and 8. because the rt-pcr was developed for the qualitative assay, the cycle threshold values of rt-pcr could not be converted to viral load kinetics in this report. it is noteworthy, however, that stool samples were positive until the 17th day since symptom onset. no infiltrations were noted on the initial and 3 follow-up chest x-ray images (fig. 2b) . however, chest computed tomography (ct) showed patchy or nodular consolidations with peripheral ground glass opacities in subpleural areas of the right lower lobe (fig. 2c) . the patient had no underlying disease and the only symptoms she presented with were low-grade fever and a small amount of sputum. although chest ct showed mild pneumonia, antiviral therapy was not required. this 10-year old girl took care of herself during the first 7 days spent alone in a negative isolation room. when her mother was discharged from her own negative isolation room, her mother joined her for care. she was transferred to a cohorting facility on the 15th hospital day to allow her isolation room to be used by another confirmed case in a more severe condition. very little research on covid-19 in children has been published in china or elsewhere. most of the covid-19 cases in children resulted from close contacts with covid-19 cases or were found among family cluster cases. 5, 6 most of the infected children had mild or difficult to recognize symptoms and some were even asymptomatic. fever and cough were the most common symptoms, and some had runny nose, or gastrointestinal symptoms such as diarrhea, or vomiting. all of the cases improved, and no deaths have been reported so far. we do not fully understand why children are less infected and less ill. low infection rate and mild symptoms in children have also been observed in the previous sars epidemic in 2003 and the middle east respiratory syndrome (mers) since 2012. 7-9 one of the explanations of covid-19 sparing the pediatric populations might be because children are less exposed to the virus in the first place. children are less likely to be exposed to the virus because this novel virus is initially transmitted among travelers and their close contacts. children might also have fewer chances to be tested for sars-cov-2 because they only present mild symptoms similar to common cold. meanwhile, the role of innate immunity to respiratory tract infection is greater in early life because the adaptive immune response is underdeveloped in young children. 10 given that both young children and adults lack adaptive specific immunity to this novel virus, mild clinical course in young children may be explained by their dominant innate immune response compared to adults. weaker ability to trigger an acute inflammatory response to sars-cov-2 might also contribute to the children's better outcome. this, however, does not completely rule out the possibility of severe cases and even death especially in children with underlying diseases, as observed in the previous mers epidemics. 8, 9 korea is now experiencing significant outbreaks and became the most-affected country after china. 2 the nation's biggest cluster has connections to shincheonji religious group in daegu. another worrisome cluster has been linked to the patients hospitalized in daenam hospital in cheongdo. 11 viral tests are being run on massive scales in korea. thus, we may be able to diagnose more pediatric cases compared to other countries and have a unique opportunity to define the clinical features of covid-19 in the pediatric population and the role of children in the transmission in child-care settings, schools and the community. starting from several imported cases from wuhan in january 2020, subsequent human-to-human transmissions occurred initially among their close contacts and family members. however, as the community spreads progress, we will see more cases among children. among 3,526 confirmed cases, as of march 1, 2020, 164 children and adolescents under 20 years of age were diagnosed with covid-19, comprising approximately 4.7% of the total confirmed cases. 11 the percentage of the confirmed child cases in korea is higher than that in china and has risen from 1.5% to 4.7% in just one week. these findings are worrisome. it is well known that children contribute to the community spread of seasonal influenza by introducing influenza to the family and by disseminating influenza in the community. 12 to mitigate community spread of covid-19, all school closures are justified in the current situation in korea. to provide a scientific evidence for the effectiveness of school closures, we should not miss the opportunity to learn children's role in spreading sars-cov-2 to the community. it is interesting to note that although this case had mild symptoms only, patchy or nodular consolidations with peripheral ground glass opacities were observed on chest ct. a recent study in china analyzed the ct images of 15 children with covid-19, 10 of whom were asymptomatic and 5 had fever. 13 among the 15 children, pulmonary inflammatory lesions were observed in 9. small nodular ground glass opacity was the most common finding and subpleural patchy opacities were also observable, with all lesions limited to a single lung segment. adults generally have ground-glass and consolidative opacities in both lungs at chest ct. 14 chest ct is a highly sensitive diagnostic tool to detect pneumonia and the sensitivity for covid-19 is reported to be 97.5%. 15 however, considering the favorable clinical course in children with covid-19, the necessity of performing ct scans on children should be judged with consideration of the potential health risks of radiation. meanwhile, one of the issues regarding pediatric patients with covid-19 is quarantine. while in self-quarantine, the present patient shared the same room with her mother who was soon confirmed with covid-19. ideally, any close contacts should stay at home in a separate room and refrain from going out. however, unlike adults, self-isolating young children by themselves is almost impossible because infants and young children must be taken care of by their caregivers. considering the circumstances, the korean centers for disease control and prevention and the korean society of pediatric infectious diseases recommend one of the family members to be assigned as a caregiver for infants and young children who are suspected or confirmed with covid-19, and the caregiver not to contact other family members. 16 most importantly, caregivers should take all possible precautions to avoid being exposed to the virus. thus, further pediatric-specific guidelines on the isolation and adequate personal protective equipment for caregivers should be prepared. this 10-year old girl is the first pediatric case of covid-19 in korea. as this is only a single case, we cannot say much about clinical manifestations of childhood covid-19 and viral load as a whole but can provide a model to pediatricians on which samples to test and what to consider in caring for children with covid-19. as the number of confirmed cases surges in korea, data on pediatric patients need to be comprehensively analyzed to further describe the clinical findings and to learn the role of children in a covid-19 pandemic. seoul national university bundang hospital institutional review board approved this study (no. b-2003-603-701) and written consent was waived because the patient and her mother were isolated in a negative-pressure room and her father was in self-quarantine. the patient and her mother agreed to the publication of this report. a novel coronavirus from patients with pneumonia in china world health organization. coronavirus disease (covid-19) situation report-41 world health organization. coronavirus disease (covid-19) situation report-39 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern china severe acute respiratory syndrome coronavirus pathogenesis, disease and vaccines: an update middle east respiratory syndrome coronavirus disease in children middle east respiratory syndrome coronavirus in children innate immunity to respiratory infection in early life korea centers for disease control & prevention. the updates of covid-19 in the republic of korea modification of an outbreak of influenza in tecumseh, michigan by vaccination of schoolchildren analysis of ct features of 15 children with 2019 novel coronavirus infection ct imaging features of 2019 novel coronavirus (2019-ncov) correlation of chest ct and rt-pcr testing in coronavirus disease 2019 (covid-19) in china: a report of 1014 cases korean centers for disease control and prevention. management guideline for children and adolescents on covid-19 we would like to thank all the staff and their families at the isolation unit and the office of infection control in the seoul national university bundang hospital for their tireless efforts. we appreciate the hard work of all the members at gyeonggi infectious disease control center. we thank professor hoan jong lee for his critical comments on this report. we also thank all the members of the korean society of pediatric infectious diseases for their valuable advice on the management of this case. lastly, we would like to thank the korea key: cord-320669-7acoduj3 authors: park, peong gang; kim, chang hyup; heo, yoon; kim, tae suk; park, chan woo; kim, choong-hyo title: out-of-hospital cohort treatment of coronavirus disease 2019 patients with mild symptoms in korea: an experience from a single community treatment center date: 2020-03-31 journal: j korean med sci doi: 10.3346/jkms.2020.35.e140 sha: doc_id: 320669 cord_uid: 7acoduj3 the outbreak of coronavirus disease 2019 (covid-19) caused a worldwide pandemic. less than 6 weeks after the first confirmed cases in korea, the patient number exceeded 5,000, which overcrowded limited hospital resources and forced confirmed patients to stay at home. to allocate medical resources efficiently, korea implemented a novel institution for the purpose of treating patients with cohort isolation out of hospital, namely the community treatment center (ctc). herein, we report results of the initial management of patients at one of the largest ctc in korea. a total of 309 patients were admitted to our ctc. during the first two weeks, 7 patients were transferred to the hospital because of symptom aggravation and 107 patients were discharged without any complication. although it is a novel concept and may have some limitations, ctc may be a very cost-effective and resource-saving strategy in managing massive cases of covid-19 or other emerging infectious diseases. with mild symptoms are already occupying the hospital for the purpose of preventing disease transmission, patients with severe symptoms may not receive proper treatment. in korea, the first confirmed cases were identified on january 20. for the first 4 weeks after the initial outbreak, the disease spread slowly with less than 100 confirmed cases, with all the confirmed patients being admitted to negative pressure isolation rooms in hospitals. 3 however, the number of patients rapidly surged after that, exceeding 5,000 within 6 weeks, most of them in the daegu and gyeongbuk regions. this surge overcrowded regional hospital resources and forced some confirmed patients to stay at home. 3, 4 there was even a report of an out-of-hospital death on february 27 of a patient with confirmed covid-19 infection awaiting admission due to shortage of hospital resources. to allocate medical resources efficiently, a novel institution with the purpose of treating patients with cohort isolation out of the hospital, namely the community treatment center (ctc), was designed and implemented in korea. the ctc is an independent building outside a hospital based on the concept that patients with mild symptoms do not require advanced medical resources, although they require isolation to prevent transmission and active surveillance in case they develop more severe symptoms. utilizing ctcs has several advantages compared to isolating patients at home: strict isolation with active surveillance of patients is possible; it also lowers the risk associated with collecting viral specimens and the possibility of cross-infections. as of march 18, a total of 12 ctcs are operating in korea, and more ctcs in other regions are preparing to open shortly. herein, we report the initial management and treatment results of patients at gyeongbuk-daegu 7 ctc, one of the largest ctcs in korea. the building currently being utilized as gyeongbuk-daegu 7 ctc, located in gumi, gyeongbuk, was previously a dormitory building owned by a private company and is now renovated as a ctc. healthcare providers currently working at the center consist of 7 physicians, 5 nurses and 1 radiologic technician from kangwon national university hospital; 7 public health doctors from the ministry of health and welfare; and volunteer healthcare providers (12 nurses and 12 nursing assistants). physicians worked on a two-shift system, taking charge of active surveillance of patients and collecting viral specimens from patients. nurses worked on a three-shift system and assisted physicians with such tasks. the clean zone, where healthcare providers work, is separated from the patients' zone, where patients reside, to prevent cross-infection between healthcare providers and patients ( fig. 1) . healthcare providers are required to wear personal protective equipment (ppe) of inner and outer gloves, n95 respirator, goggles, and hooded coveralls when entering the patients' zone. 5 patients were also instructed to stay in their rooms to prevent cross-infection between patients. in the patients' zone, two negative pressure rooms for a mobile radiograph imaging facility and a doctor's office was installed to examine patients with symptoms of coronavirus. candidates for ctc admission were confirmed covid-19 patients with real-time reverse transcriptase polymerase chain reaction (rrt-pcr) method and considered by authorities as patients without severe symptoms using guidelines from the korea centers for disease control and prevention (kcdc). 6,7 exclusion criteria were as follows: patients with underlying chronic severe medical conditions such as heart failure or chronic kidney disease and patients with high fever or dyspnea -all of whom likely required advanced medical treatment. patients admitted were initially checked for their symptoms and underlying diseases; patients 55 years of age or older received routine chest radiographs to rule out asymptomatic pneumonia. after their admission, their body temperature was monitored twice a day. to minimize access of healthcare providers to the patients' zone and to communicate more effectively, we encouraged patients to install a specialized mobile application (inphr ® , softnet, seoul, korea) to report their body temperature, of which adherence reached more than 80% (fig. 2) . patients who were inexperienced in using a mobile application were instead encouraged to use telephone communication. although the center is strictly not a medical institution, we used a digital health information system, as well as a picture archiving and communication system provided by kangwon national university hospital and acted as if patients were admitted to a special hospital ward to communicate orders and laboratory/radiological test results. medications for symptomatic treatment such as antipyretics were prescribed using this method, although antiviral agents were not prescribed. if patients developed worsening respiratory symptoms or fever, chest radiograph and pulse oximetry were performed. patients were transferred to the hospital equipped for specialized treatment if a pneumonia-like lesion on chest radiography or desaturation was detected. patients routinely received viral testing weekly. upper respiratory tract specimens were obtained from the nasopharyngeal and oropharyngeal swab, as was recommended by the kcdc, and rrt-pcr was employed to detect the virus using the published sequences. 7, 8 if the test came out negative for a patient, the following test was conducted 24 hours later. if the second test also produced a negative result, the patient was then discharged, as was recommended by the kcdc. 7 all healthcare providers monitored themselves for their body temperatures and respiratory symptoms twice a day. three hundred and nine patients were admitted on march 9, all of whom were confirmed with covid-19 but were isolated in their home due to the shortage of hospital beds. 124 (40.1%) of them were male. their median age was 31 (range: 7-77) and 12 patients (3.9%) were 18 years old or younger. 125 (40.4%) patients used solitary rooms and 184 (59.6%) used shared space with a separate room, of whom 32 (10.4%) were relatives. the patients were admitted to the ctc after a median of 7 (range: 3-14) days since the diagnosis of covid-19. patients presented with various symptoms such as cough (50 patients, 16.2%), rhinorrhea (49 patients, 15.9%), sputum (39 patients, 12.7%), sore throat (24 patients 7.8%), and chest discomfort (12 patients, 3.9%). 176 (57.1%) patients were asymptomatic at the time of admission. psychiatric symptoms including depression, anxiety, and insomnia increased as the treatment progressed and we introduced remote counseling services using the mobile application in cooperation with psychiatrists at kangwon national university hospital. other unusual symptoms include epistaxis and musculoskeletal pain. there were no reports of symptoms requiring emergent medical care such as altered mental status, syncope, or severe dyspnea. 7 (2.3%) of the patients were transferred to the hospital after a median 3.5 (range: 0-7) days of admission. two patients due to pneumonia, 1 due to suspicious chronic obstructive pulmonary disease, 1 due to unremitted high fever, 1 patient due to severe psychiatric compliant including suicidal ideation, and 2 patients transferred to the hospital on their own will. of them, two patients were transferred to the hospital shortly after admission, due to chest radiograph abnormalities at the initial screening. all patients received viral tests 3 or 4 days after their admission. among them, 101 (32.7%) patients received negative results. 69 (22.3%) patients received consecutive negative results and were discharged a median of 13 (range: 8-23) days after their initial diagnosis. secondary viral testing was obtained 8 days after admission and 85 (27.5%) patients received negative results. 38 (12.3%) of them received consecutive negative results and were discharged a median of 18 (range: 15-23) days after their initial diagnosis. as of the end of the second week since the first admission of patients, there were no reported cases of cross-infection of healthcare providers. there were many limitations regarding the installation and the operation of ctc. firstly, this facility does not have a negative-pressure air conditioning system and we divided the clean zone and the patient's zone arbitrarily, anticipating natural ventilation effects. secondly, the standard recommended protocol of changing ppes between every testing of patients, to prevent cross-infection among patients and specimen contamination, were not strictly adhered to due to the lack of resources. 5 in fact, a considerable number of patients received negative results initially but then got positive results on the consecutive test. these results may be due to window periods of virus infection, but the possibility of cross-infection among patients during sample collection or contamination of specimens cannot be excluded. also, due to the limitations of the original facility, not all patients could receive solitary rooms, although they used separate bedrooms and bathroom inside the shared space and were promptly reassigned to solitary rooms as soon as other patients were discharged and solitary rooms became available. if more ctcs are to be operated, as is expected, this problem will be ameliorated. also, as we selected and admitted patients under the criteria limited to their age and a simple questionnaire, the risk factors and the severity of the disease of each patient were not fully understood, although we could identify and transfer some high-risk patients using the initial chest radiograph. as more about the nature and risk factors of covid-19 are being identified, it would become easier for us to identify the risk and severity of the patients admitted to ctc. nevertheless, in terms of the efficient allocation of medical resources in a pandemic status such as this case, ctc is thought to be a novel, cost-effective and resource-saving strategy. in many countries, hospital beds are outnumbered by covid-19 patients with mild symptoms, which in turn hinders more severe patients from being hospitalized that may lead to fatalities of patients awaiting hospitalization. 1 this system, in which healthcare providers examine patients and immediately transfer patients in need of advanced care to hospitals while successfully preventing the transmission of infection, will be applicable to other countries or any other emerging infectious diseases in addition to covid-19. ctcs can be a very cost-effective alternative since facilities and centers that are already in place in the regional community can be utilized. after korea implemented ctcs on march 2, the number of patients infected with covid-19 who had no other choice but to be isolated at home due to the shortage of hospital beds have dropped from 3,000 to less than 300 on march 18, as ctcs could accommodate most of them. 3 all 12 ctcs, which are currently operating, are performing the role of controlling the source of infection and screening for patients with severe conditions. however, the criteria and the method of the screening, admission, and discharge of patients varies widely between centers and our management method does not represent overall ctcs. as more data and experiences are accumulated, ctcs are expected to provide more standardized evaluation and treatment. data from other ctcs, including the transportation system of patients with aggravating symptoms, need to be comprehensively analyzed to further describe advantages and challenges of ctcs in managing the covid-19 pandemic. world health organization middle east respiratory syndrome coronavirus (mers-cov) outbreak in south korea, 2015: epidemiology, characteristics and public health implications korea centers for disease control and prevention. the updates of covid-19 in the republic of korea report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from rational use of personal protective equipment for coronavirus disease 2019 (covid-19) laboratory testing for 2019 novel coronavirus (2019-ncov) in suspected human cases guideline for management of covid-19 detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr the authors have no potential conflicts of interest to disclose. we appreciate won sub oh md, phd who established the system of infection control for this ctc. we would like to thank all of the staff at gyeongbuk-daegu 7 ctc for their dedicated efforts and kangwon national university hospital for its unsparing support of human and material resources. we also deeply appreciate lg display co., ltd. for their support of facilities and commodities for healthcare providers. lastly, we would like to thank the korea centers for disease control and prevention and the ministry of health and welfare for their administrative support, including the transportation system of patients with aggravating symptoms. key: cord-260310-0gkoanrg authors: kim, jin yong; ko, jae-hoon; kim, yeonjae; kim, yae-jean; kim, jeong-min; chung, yoon-seok; kim, heui man; han, myung-guk; kim, so yeon; chin, bum sik title: viral load kinetics of sars-cov-2 infection in first two patients in korea date: 2020-02-20 journal: j korean med sci doi: 10.3346/jkms.2020.35.e86 sha: doc_id: 260310 cord_uid: 0gkoanrg as of february 2020, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) outbreak started in china in december 2019 has been spreading in many countries in the world. with the numbers of confirmed cases are increasing, information on the epidemiologic investigation and clinical manifestation have been accumulated. however, data on viral load kinetics in confirmed cases are lacking. here, we present the viral load kinetics of the first two confirmed patients with mild to moderate illnesses in korea in whom distinct viral load kinetics are shown. this report suggests that viral load kinetics of sars-cov-2 may be different from that of previously reported other coronavirus infections such as sars-cov. values of rrt-pcr was converted into rna copy number of sars-cov-2. the detection limit of quantitative pcr reaction was 2,690 copies/ml. detailed methods and values for the tests are presented in the supplementary data 1 and supplementary tables 1 to 3. a 35-year-old chinese woman from wuhan, china was confirmed to be first sars-cov-2 infected case in korea. the detailed exposure history and a clinical course of this patient is described in previous report. 7 viral load kinetics of patient 1 is shown in fig. 1a (viral rna copies) and supplementary fig. 1 (reverse ct value). briefly, she was quarantined at the airport due to fever (38.3°c) at the entry inspection on january 19, 2020. she had no significant exposure history and developed fever, chills, and myalgia one day before the entry to korea (january 18, 2020, day 1 of symptom onset). the virus was detected from urt specimens on day 2 of symptom onset. as she did not have significant respiratory symptoms, lrt specimen (spontaneous sputum) was obtained with airway clearance techniques of percussion on day 3. although any infiltration was not noticed on her chest x-ray (cxr) on the same day, lrt specimen was positive for sars-cov-2. on day 4, high resolution computed tomography (hrct) was taken and multiple ground-glass opacities were observed in both sub-pleural spaces. 7 on day 5, the viral load was increased from day 3 in lrt specimen and she required oxygen supplement via nasal cannula (3 l/min). she eventually developed cough on day 7, and infiltration was observed on cxr from the next day. however, it appeared that the viral loads already started to decrease from around day 7 in both urt and lrt specimens. rrt-pcr continued to be positive at low level until day 13 (lrt specimens) and 14 (urt specimens). on day 12, her cxr was worsened with increase in oxygen requirement up to 10 l/min, while the viral loads dropped significantly from the initial values. therefore, by the time when the significant infiltration was visible on a plain chest radiography, the viral load might be already on its lower end of detection. from day 14 (lrt specimen) and day 15 (urt specimen), rrt-pcr became undetectable for two consecutive days, respectively. she had mild loose stool from day 4 to day 19. although rdrp and/or e gene were detected occasionally from urine and stool specimens collected from day 5 to 12, none of specimen satisfied conditions for positivity. only one serum sample collected on day 8 showed positive rrt-pcr result, but the ct value was adjacent to the cut-off value for positivity. her symptoms, oxygen requirement, and cxr findings significantly improved from day 17 and she was discharged on day 20 of symptom onset (february 6, 2019). patient 2 was a 55-year-old korean man, who had been working at wuhan, china, arrived in korea via shanghai on january 22, 2020. the detailed exposure history and a clinical course of this patient is described in supplementary data 1. briefly, he did not have any significant exposure history and developed sore throat and intermittent myalgia since january 10 which was controlled by nonsteroidal anti-inflammatory agent. he was tested on january 23, 2020, confirmed with sars-cov-2 infection next day and hospitalized on the same day. therefore, his admission day (january 24) was considered to be the day 15 of symptom onset. his cxr on day 15 showed infiltration and chest hrct on day 16 showed bilateral groundglass opacity (supplementary fig. 3a) . the viral load kinetics are shown in fig. 1b (viral rna copies) and supplementary fig. 2 (reverse ct value). in this patient, the initial test was performed on day 14 of symptom onset and sars-cov-2 was detected in both urt and lrt specimens. however, the initial viral loads were relatively lower (49,047 copies/ml for urt and 391,243 copies/ml for lrt) than those of patient 1 (46,971,053 copies/ml for urt and 9,171,220 copies/ml for lrt) in whom the test was performed on day 2 of symptom onset. sars-cov-2 was detected a few more times during hospitalization from both urt and lrt specimens at low levels. as he had just mild cough with little or no sputum, lrt specimens in patient 2, the exact fever duration could not be estimated because he had taken non-steroidal anti-inflammatory agent to control his myalgia and sore throat before hospitalization. when his physician discontinued the medication, the fever was observed; b) patient 2 experienced loose stool after taking lopinavir/ ritonavir. were available only a few times. from d18 (urt specimen) and d20 (lrt specimen), rrt-pcr became undetectable for two consecutive days, respectively. on day 25, rdrp (ct value of 36.69) and e (ct value of 33.18) genes was detected again from the urt sample of day 25, it was interpreted as negative due to high ct value of rdrp gene. from his plasma and stool specimens, only e genes were once detected on day 17 and it was also interpreted as negative result. his cxr improved from day 19 and he was discharged on day 27 (february 5, 2020). this study presents the viral load kinetics of the first two confirmed patients in korea in whom distinct viral load kinetics are shown. although the viral load and cxr findings in these two patients may not represent the whole spectrum of sars-cov-2 illness, our report will provide many important findings and opportunity to understand this newly discovered virus infection in human. in patient 1, we observed one example of moderate disease (shortness of breath and oxygen requirement up to 10 l/min) with corresponding radiograph findings and viral loads. we could observe her clinical presentation from day 2 of symptom onset and the whole clinical picture was captured with viral loads. there are several important implications from this observation. first, unlike sars-cov infection, 8 we found that viral load was highest during the early phase of the illness (3-5 days from first symptom onset, fever and myalgia were the only symptoms in patient 1) and continued to decrease until the end of the second week. while she developed cough as well as shortness of breath and infiltration appeared on cxr at the end of first week of illness, the viral load already started to decrease at this phase. this may have a very important implication to determine the optimal time point for antiviral treatment intervention to prevent progression to severe disease. second, the virus was detected from lrt specimens even before the development of lrt symptoms (cough, shortness of breath, and oxygen requirement) or visible infiltration on cxr. this may suggest that although the patient does not complain of any lrt symptoms, the virus is already there and causing insidious pathology, ultimately leading to lrt symptoms and chest infiltration later. however, the viral load starts to decrease in both urt and lrt specimens at the same time, which may puzzle the clinicians. third, unlike in mers-cov revealing higher concentration of virus in lrt specimens, 9 viral loads were similar in both urt and lrt specimens. fourth, low concentration of genetic materials, especially e gene, was detected in urine and stool from the end of the first week until the patient recovered from the infection. however, rrt-pcr results did not meet the criteria for sars-cov-2 positivity. further studies need to be performed in non-respiratory specimens such as urine and stool samples. in patient 2, we observed one example of mild disease with corresponding radiograph findings and viral loads. this may represent many real-world mild cases who may present to medical facility late in their disease course. therefore, this patient's information has also some important implications. first, even in a patient with mild disease (sore throat only), visible infiltration on cxr was observed at the end of second week. second, even in a patient with mild disease, if visible infiltration on cxr is observed, virus is still detected in both urt and lrt specimens even at the end of second week after symptom onset. viral loads of urt were similar with and sometimes higher than lrt specimens, and virus was detectable for longer period in urt specimen. this could be also probably because the patient did not have significant cough and had little amount of spontaneous sputum insufficient for testing. there are also limitations in our report. since we only presented two patients (mild and moderate), the information from these patients may not be generalizable to many other cases, especially severe cases. second, lopinavir/ritonavir was used in both patients on day 5 and day 17 from symptom onset, but its role cannot be determined in viral load reduction or clinical improvement. in addition, since they received lopinavir/ritonavir which can also cause diarrhea, how much of gastrointestinal tract symptom was in fact related to sars-cov-2 or drug side effect. third, we cannot estimate the time point when these patients were exposed to virus and when they started to shed the virus from their respiratory secretions. these data are also urgently needed to understand this virus better and to implement the control strategies as early as possible. finally, the virus has not been readily cultured from these specimens, yet, although we are still trying. it is not clear whether there was not viable virus (possibly infectious) or we were not successful to culture this newly discovered virus in the beginning. therefore, knowing the virus load that can give a positive culture result is important in the future. there is scarce information on viral load kinetics in sars-cov-2 infected patients throughout the illness. therefore, although our report is based on observation from only two patients, this will provide valuable insight to understand the nature of this virus. in conclusion, we report a unique pattern of sars-cov-2 viral kinetics in urt and lrt specimens from first two patients diagnosed in korea. while two cases were different in disease course, these data will provide valuable insight to understand the nature of this virus. the clinical data and images are presented under agreement of the patients. severe acute respiratory syndrome-related coronavirus: the species and its viruses -a statement of the coronavirus study group. biorxiv early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia a novel coronavirus from patients with pneumonia in china the-second-meeting-of-the-international-healthregulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov) laboratory testing for 2019 novel coronavirus (2019-ncov) in suspected human cases detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr the first case of 2019 novel coronavirus pneumonia imported into korea from wuhan, china: implication for infection prevention and control measures clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study importance of specimen type and quality in diagnosing middle east respiratory syndrome we greatly appreciate the efforts of all the hospital employees and their families at the incheon medical center and national medical center, who are working tirelessly during this outbreak. we thank to yoonju oh, sung hee kim, yoon soog kang, and kwang sil kim (incheon medical center) for collecting and preserving clinical specimens. we thank hyun mee park (department of radiology, national medical center) for the obtainment of excellent radiologic study result safely. we also thank to yunyoung jang, and eunhee kim for the dedication to protect healthcare workers of national medical center by infection control. we sincerely appreciate the discussion and critical feedback from dr. janet a englund (seattle children's hospital, seattle, wa, usa). lastly, we thank all the members of the korean society of infectious diseases (ksid), the groups of korean emerging infectious diseases (koeid) application, and korea national clinical management network (kncmn) for covid-19, who are coping with the current global outbreak situation together. table 3 estimated number of viral copy of respiratory specimens key: cord-270922-7z0n78ja authors: lee, you hyun; kim, yu cheol; shin, jae pil title: characteristics of ocular manifestations of patients with coronavirus disease 2019 in daegu province, korea date: 2020-09-01 journal: j korean med sci doi: 10.3346/jkms.2020.35.e322 sha: doc_id: 270922 cord_uid: 7z0n78ja background: the coronavirus disease 2019 (covid-19) has reportedly affected almost 23 million people, with more than 800 thousand deaths globally. there have been a few reports on the ocular manifestations of covid-19 patients in china but no reports in korea. the present study aimed to examine ocular manifestations of covid-19 patients in korea. methods: covid-19 patients admitted from march 2020 to april 2020 at keimyung university dongsan hospital and keimyung university daegu dongsan hospital were reviewed retrospectively for ocular manifestations. during the period of hospitalization, ocular symptoms as well as blood test results were noted and analyzed. patients were then divided into the first-episode and relapsed group and ocular symptoms were analyzed in the groups. results: a total of 103 patients were included in this study. among them, 71patients were in the first-episode group and 32 patients in the relapsed group. no significant differences were determined in terms of positivity of ocular symptoms between the first-episode group (12 patients, 16.9%) and the relapsed group (10 patients, 31.3%, p > 0.05). symptoms of positive upper respiratory infection and lower creatine phosphokinase were determined to be related to positive ocular symptoms. conjunctival congestion was noted in seven patients. in the subgroup analysis, the conjunctival congestion-positive patients exhibited higher positivity of upper respiratory infection symptoms (100%) as compared with those in the negative group (40%, p = 0.017). conclusion: positive upper respiratory infection symptoms and lower creatine phosphokinase were determined to be related to ocular symptoms in covid-19 patients. among these patients, positive upper respiratory infection symptoms were associated with conjunctival congestion. the novel coronavirus disease 2019 (covid-19) was first reported in wuhan, china, in december 2019, and it has been declared as a public health emergency of interest by the world health organization in january 2020. to date, covid-19 has reportedly infected almost 23 million people, with more than 800 thousand deaths globally. however, ocular manifestations were not reported in the initial clinical reports. 1-3 in china, guan et al. 4 have reported that 9 of the 1099 cases have conjunctival congestion; furthermore, chen et al. 5 demonstrated various ocular symptoms in covid-19 patients such as conjunctival congestion, dry eyes, blurred vision, and foreign-body sensation. wu et al. 6 also reported conjunctivitis as an ocular finding in covid-19 patients, demonstrating a positive correlation with higher white blood cell and neutrophil counts and higher levels of procalcitonin, c-reactive protein, and lactate dehydrogenase in hubei, china. similar to hubei province, daegu has also recorded a high number of covid-19 cases in korea. however, to the best of our knowledge, no study on the ocular manifestations of covid-19 patients has been reported in the country. here, we evaluated the characteristics of ocular manifestations of patients with covid-19 in daegu. this study was designed as a retrospective, comparative case series conducted in two hospitals (keimyung university dongsan hospital and keimyung university daegu dongsan hospital). the study adhered to the tenets of the declaration of helsinki. we retrospectively reviewed the electronic medical records of covid-19 patients who were admitted from march to april 2020. patients who were transferred from other hospitals were excluded. the patients were divided into two groups: the first-episode group and relapsed group. differences in terms of laboratory results and the prevalence of ocular symptoms were examined by groups. among the ocular symptom-positive patients, we also performed a subgroup analysis of conjunctival congestion-positive and -negative patients. demographic characteristics, including age, gender, total duration of hospitalization, presence of hypertension, diabetes, cerebrovascular attack, and hyperlipidemia, were assessed. we also confirmed any positive upper respiratory infection (uri) symptoms (at least one of the following: runny nose, coughing, sore throat, and fever ≥ 38°c) and pneumonia at the time of covid-19 diagnosis. data on ocular symptoms (ocular discomfort, ocular pain, conjunctival congestion, visual disturbance, epiphora, and itching sensation) were obtained each day through an ophthalmologist via telephone and recorded in the electronic medical record. for patients with conjunctival congestion, a nurse took a photograph of the eye and forwarded it to the ophthalmologist for confirmation. blood test results on the day of admission, including complete blood cell count, procalcitonin, c-reactive protein, creatine phosphokinase, lactate phosphokinase, lactate dehydrogenase, sodium, potassium, chloride, calcium, inorganic phosphorus, glucose, blood urea nitrogen, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate phosphatase, and alanine transaminase, were also included in this study. statistical analysis was performed using spss version 12.0 (ibm, armonk, ny, usa). between-group differences in age, total duration of hospitalization, and blood test results were compared using an independent t-test or mann-whitney u test. categorical variables such as gender, positive uri symptoms or pneumonia,and the presence of systemic diseases such as diabetes, hypertension, and hyperlipidemia were compared using a chi-square test or fisher exact test. p values of less than 0.05 were considered statistically significant. the protocol of the current study was reviewed and approved by the institutional review board of keimyung university dongsan hospital (approval no.2020-06-109). because of the retrospective and noninvasive study design, the requirement for informed consent was waived by the board. a total of 103 patients were included in this study. among them, 71 patients were in the firstepisode group and 32 patients in the relapsed group. demographics and laboratory results have been summarized in table 1 . the mean patient age was 49 ± 18 years in the first-episode group and 44 ± 16 years in the relapsed group, a difference that was deemed not statistically significant (p = 0.18). in total, 15 patients (21.1%) in the first-episode group and 8 patients (25.0%) in the relapsed group were male. the total hospitalization period was found to be significantly longer in the first-episode group than in the relapsed group (34 ± 18 vs. 13 ± 7 days, p < 0.01). the presence of pneumonia was significantly different between the two groups (first-episode group versus relapsed group: 49.3% vs. 21.9%, p < 0.01). there was also a significant difference in positive uri symptoms (first-episode group versus relapsed group: 46.5% vs. 15.6%, p < 0.01). there was no difference in systemic diseases such as hypertension, diabetes mellitus, and hyperlipidemia between the two groups (p > 0.05). blood test results indicated significantly higher values of procalcitonin, neutrophil count, monocyte count, c-reactive protein, lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, and alanine transaminase in the first-episode group compared to the relapsed group (p < 0.05). other test results showed no differences between the two groups (p > 0.05) ( table 1) . table 2 compares ocular manifestations between the two groups. there were no significant differences in the positivity of ocular symptoms between the first-episode group (12 patients, 16 .9%) and relapsed group (10 patients, 31.3%, p = 0.18). conjunctival congestion was visible in six patients (8.5%) in the first-episode group and one patient (3.1%) in the relapsed group. complaints of ocular discomfort were noted in two patients (2.8%) in the first-episode group and three patients (9.3%) in the relapsed group. ocular pain was noted in one patient (1.4%) in the first-episode group and in two patients (6.3%) in the relapsed group. visual disturbance was reported in four patients (5.6%) in the first-episode group and two patients (6.3%) in the relapsed group. epiphora was shown in one patient (1.4%) in the first-episode group and one (3.1%) in the relapsed group. two patients (2.8%) in the first-episode group and two (6.3%) in the relapsed group reported itching sensation. all of the above ocular table 3 summarizes the demographics and laboratory results of the ocular symptom-positive group and -negative group. the occurrence of positive uri symptoms was significantly greater in the ocular symptom-positive group (13 patients, 59.1%) than in the ocular symptom-negative group (25 patients, 30.9%, p = 0.02). creatine phosphokinase was also observed to be significantly lower in the ocular symptom-positive group (61 ± 33 vs. 93 ± 80 u/l, p = 0.02). other factors such as age; total duration of hospitalization; gender; presence of pneumonia, diabetes, or hypertension; and other blood test results showed no significant difference between the ocular symptom-positive and -negative groups (p > 0.05). table 4 presents the demographics and laboratory results of the conjunctival congestionpositive and -negative groups. a higher rate of positive uri symptoms was observed in the conjunctival congestion-positive group (7 patients, 100%) than in the conjunctival congestion-negative group ( duration of hospitalization; symptom onset from diagnosis; gender; presence of pneumonia, diabetes, or hypertension; and other blood test results showed no significant difference between the conjunctival congestion-positive and -negative groups (p > 0.05). there are already a few studies reporting on the ocular symptoms or signs of covid-19; however, most of these studies have been performed in china. 5, 6 the present study retrospectively analyzed the ocular manifestations of covid-19 patients in korea. the comparison between the first-episode group and relapsed group showed longer total hospitalization period, higher incidence of pneumonia, higher incidence of uri symptoms, and higher levels of procalcitonin, neutrophil count, c-reactive protein, creatinine phosphokinase, lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, and alanine transaminase. it has already been determined that elevated levels of procalcitonin, aspartate transaminase, and lactate dehydrogenase are related to the severity of covid-19. 7, 8 several studies have reported that a positive covid-19 test result in discharged patients is due to the prolonged viral shedding that is close to the limit of detection. 9,10 based on these studies, the relapsed group in the present research might have resulted from the low viral shedding that is barely detected and the blood test results that show low disease severity. the commonly reported ocular manifestations of covid-19 are itching, red eye, tearing, foreign body sensation, and chemosis. 11 these symptoms and signs were also included in the present study. one previous study reported that 31.6% of covid-19 patients showed that ocular abnormalities and higher procalcitonin level, white blood cell count, neutrophil count, c-reactive protein level, and lactate dehydrogenase level have a correlation to ocular symptoms. 6 in our study, 31.25% of the relapsed group and 16.9% of the first-episode group were determined to have ocular symptoms. the factors associated with the ocular symptoms were positive uri symptoms and creatine phosphokinase. possible explanations for these discrepancies include the fact that the relationship between ocular symptoms and blood test results is not yet fully understood and that the mental status of covid-19 patients might have affected their subjective reports of ocular symptoms. kitazawa et al. 12 reported that anxiety and depression were associated with the subjective symptoms of dry eye disease. there have been no studies regarding depression and anxiety in relapsed covid-19 patients; however, it is estimated that patients who have been hospitalized and recovered from covid-19 will manifest persistent psychiatric disorders such as anxiety and depression. 13,14 relapsed covid-19 patients might be more vulnerable to these psychiatric disorders as they are being requarantined, resulting in a higher prevalence of subjective ocular symptoms. further studies are required to confirm the correlation between the subjective ocular symptoms and psychiatric health status in patients with covid-19. subgroup analysis revealed that the conjunctival congestion-positive group had a significantly greater incidence of positive uri symptoms. it was determined that patients with viral conjunctivitis typically have had recent contact with a sick person or a recent history of uri. 15 we did not perform a slit-lamp examination in this study; therefore, other causes of conjunctival congestion could not be ruled out. however, considering that no patient experienced ocular pain, it is more likely that viral conjunctivitis was the cause of conjunctival congestion. colavita et al. 16 reported a case of bilateral conjunctivitis with uri symptoms in a female patient with covid-19 in italy. one previous study demonstrated one positive covid-19 conjunctival swab among three conjunctival hyperemia patients. 6 conjunctival swab was not performed in this study; thus, further research performing conjunctival swab in a large number of conjunctival congestion-positive covid-19 patients is needed. the present study has some limitations. first, the sample size is small, and no healthy population was included in this study as a control. second, a comprehensive ophthalmologic evaluation was not performed because covid-19 patients were isolated. regardless, these results can be valuable to ophthalmologists worldwide in an effort to evaluate ocular manifestations in covid-19. in conclusion, positive uri symptoms and decreased creatine phosphokinase levels were determined to be associated with ocular symptoms in covid-19 patients. among these patients, positive uri symptoms are associated with conjunctival congestion. clinical features of patients infected with 2019 novel coronavirus in wuhan, china epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical characteristics of coronavirus disease 2019 in china ocular manifestations and clinical characteristics of 534 cases of covid-19 in china: a cross-sectional study characteristics of ocular findings of patients with coronavirus disease 2019 (covid-19 clinical characteristics of 161 cases of corona virus disease 2019 (covid-19) in changsha procalcitonin levels in covid-19 patients pcr assays turned positive in 25 discharged covid-19 patients positive rt-pcr tests among discharged covid-19 patients in shenzhen, china ocular findings and proportion with conjunctival sars-cov-2 in covid-19 patients the relationship of dry eye disease with depression and anxiety: a naturalistic observational study the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science viral conjunctivitis. treasure island (fl): stat pearls publishing sars-cov-2 isolation from ocular secretions of a patient with covid-19 in italy with prolonged viral rna detection key: cord-284879-sjkni2uc authors: song, suk-kyoon; lee, duk-hee; nam, jun-ho; kim, kyung-tae; do, jung-suk; kang, dae-won; kim, sang-gyung; cho, myung-rae title: igg seroprevalence of covid-19 among individuals without a history of the coronavirus disease infection in daegu, korea date: 2020-07-16 journal: j korean med sci doi: 10.3346/jkms.2020.35.e269 sha: doc_id: 284879 cord_uid: sjkni2uc background: seroprevalence studies of coronavirus disease 2019 (covid-19) from many countries have shown that the number of undiagnosed missing cases is much larger than that of confirmed cases, irrespective of seroprevalence levels. considering the strategy of korea entailing massive testing and contact tracing from the beginning of epidemic, the number of undiagnosed missing cases in korea may be negligible. this study was conducted to estimate the seroprevalence of covid-19 among individuals who were never diagnosed with covid-19 in daegu, the epicenter of covid-19 epidemic in korea. methods: serologic testing for immunoglobulin g antibody based on immunochromatographic assay was conducted in 103 patients and 95 guardians aged 18 to 82 years without any history of covid-19 diagnosis, who visited outpatient clinics of a single university-affiliated hospital from may 25 to june 5, 2020. results: the estimated seroprevalence was 7.6% (95% confidence interval, 4.3%–12.2%) with 15 positive cases. among them, only one had a polymerase chain reaction (pcr)-confirmed case among their close contacts and 13 did not experience covid-19-related symptoms. seroprevalence was similar between patients and guardians. based on this figure, the number of undiagnosed missing cases in daegu was estimated to be a dozen times more than the number of confirmed cases based on pcr testing. conclusion: despite the limitation of a small and unrepresentative sample, this is the first study on seroprevalence of covid-19 in korea. our study suggested that the number of undiagnosed missing cases was substantial even with the stringent strategy adopted in korea, similar to that of other countries. korea has successfully controlled the coronavirus disease 2019 (covid-19) epidemic with relatively few confirmed cases and deaths numbering 11,719 and 273, respectively, as of june 6, 2020. 1 however, daegu, the fourth-largest city in korea with about 2.5 million population, experienced an explosive increase in the number of covid-19 patients in late february. 2 approximately 60%-70% of confirmed cases and deaths in korea were recorded in daegu. 1 during an epidemic of infectious diseases, seroprevalence studies are important in demonstrating the widespread and undiagnosed infection in the general population. 3 public policies against infectious diseases can vary depending on the results of seroprevalence studies. 3 seroprevalence studies reported to date from several countries have shown that the seroprevalence levels are highly variable by region and time. 4-15 however, a significant fraction of the population has developed antibodies against severe acute respiratory syndrome coronavirus 2 (sars-cov-2), suggesting that the infection is much more pervasive than implied by the number of confirmed cases. the korean strategy against covid-19 consisting of massive testing, contact tracing, and quarantine has gained the attention of many countries as a model to control the covid-19 pandemic. in particular, the rapid and extensive testing for coronavirus is a key element. in this sense, it is plausible that the size of undiagnosed missing cases in korea may be substantially smaller than that of other countries. alternatively, it is possible that the number of undiagnosed missing cases is substantial in spite of the korean strategy due to the high proportion of asymptomatic and mildly symptomatic patients and the high transmission rate of covid-19. 16 , 17 although the epidemic of covid-19 in korea started on january 20, 2020, 1 no seroprevalence data are available yet. seroprevalence data provide an opportunity to evaluate the effectiveness of strategy containing covid-19 via massive testing, contact tracing, and quarantine. therefore, this preliminary study was performed to estimate the seroprevalence among individuals without previous history of covid-19 diagnosis, who visited outpatient clinics of one hospital in daegu, the epicenter of covid-19 epidemic in korea. this study was performed at daegu catholic university hospital, a tertiary care medical center in daegu, korea. the study involved 198 cases who were recruited from patients and their guardians visiting outpatient clinics from may 25 to june 5, 2020 using bulletin boards and banners in the hospital. inclusion criteria were: 1) subjects who were never diagnosed with covid-19, 2) subjects who do not currently have any covid-19-related symptom such as fever or cough, and 3) subjects who live in daegu. we collected 3 ml of blood via antecubital vein. after centrifugation, serum was preserved at −70°c and defrosted upon testing. diakey covid-19 immunoglobulin (ig)m/igg rapid test kit was used to perform the solid immunochromatographic assay (shin jin medics inc., goyang, korea). this device is preembedded with recombined covid-19 envelop antigens including nucleocapsid (n) protein and rbd domain of spike (s) protein expressed by escherichia coli. the specificity and sensitivity of antibody testing, obtained from 60 polymerase chain reaction (pcr)-positive specimens and 30 pcr-negative specimens, were estimated as 92% and 100%, respectively. serum (10 µl) was infused into the test kit, and the results were obtained 15 minutes after the addition of buffer. two doctors independently interpreted results by visual inspection. when both diagnosed the kit as positive, it was confirmed as positive case. a self-administered questionnaire was used to collect information on age, gender, body weight, height, smoking history, history of doctor-diagnosed diabetes or hypertension, reason of current hospital visits, history of covid-19 pcr test, history of covid-19 related symptoms during the previous 5 months, and presence of covid-19 confirmed cases among family, friends, or coworkers. first, the seroprevalence was determined among all subjects and the exact binomial 95% confidence interval (ci) was calculated from the test for one proportion using z-statistics. next, we compared seroprevalence among subgroups stratified by characteristics of study subjects, including age (< 40, 40-59, ≥ 60 years), gender, body mass index (bmi) (< 25, ≥ 25 kg/m 2 ), smoking history (current, previous, never), history of doctor-diagnosed diabetes or hypertension (yes, no), reason for the current hospital visit (patient, guardian), and the presence of covid-19 confirmed cases among close contacts (yes, no). associations between seroprevalence and characteristics of study subjects were evaluated using χ 2 tests or fisher's exact tests. all statistical analyses were performed using spss 25 (ibm corp., armonk, ny, usa) and p < 0.05 was considered as statistically significant. finally, we roughly estimated the number of undiagnosed missing cases in daegu. instead of considering age and gender-specific seroprevalence due to the limitation of study sample, we used the seroprevalence among all subjects based on the total population size of daegu, which was estimated at 2,438,031 according to 2019 statistics of resident registration. although a total of 6,886 cases were confirmed by pcr as of june 6, 2020, the number of undiagnosed missing cases was similar whether or not the number of confirmed cases was considered. the present study protocol was reviewed and approved by the institutional review board of daegu catholic university hospital (approval no. cr-20-103) and written informed consent was obtained from all study participants. table 1 lists the general characteristics of study subjects. the number of patients was 103 while that of guardians was 95. only 3.5% of study subjects reported the presence of confirmed covid-19 cases among close contacts such as family, friends, or coworkers. subjects with a history of pcr testing or covid-19-related symptoms during the previous 5 months were 7.1% and 9.1%, respectively. the age range was from 18 to 82 years and the mean age was 51.7 years. half of the study subjects included men; 70.7% had a bmi < 25 kg/m 2 , and 23.2% comprised current smokers. subjects with a history of diabetes or hypertension constituted 9.6% and 18.7%, respectively. there were 15 positive igg cases among 198 subjects who were never diagnosed with covid-19 ( of diabetes. seroprevalence of never smokers (2.6%) was significantly lower than that of current smokers (15.2%) or ex-smokers (14.3%) (p = 0.01). diabetic patients (21.1%) also had a higher seroprevalence than those with non-diabetes (6.1%) (p = 0.02). neither obesity nor hypertension status was related to seroprevalence. based on the seroprevalence in all subjects, the number of people with positive igg in daegu was estimated to be roughly 185,290 (95% ci, 104,835-297,439). as the total number of confirmed cases reported at daegu as of june 6 were only 6,886, it was estimated that the number of undiagnosed missing cases may be 27-fold higher than the number of confirmed cases based on pcr testing in daegu. among subjects who were never diagnosed with covid-19 in daegu where demonstrated the epidemic peak in late february, the seroprevalence was 7.6%. most of the igg positive cases were asymptomatic during the epidemic. also, only one case had a pcr-confirmed case among their close contacts. although this study was conducted with a small size and unrepresentative sample, our finding suggests that the number of undiagnosed missing cases may be at least tenfold higher than the total number of confirmed cases based on pcr testing. since the onset of the pandemic, korea adopted a test-track-trace approach utilizing largescale pcr tests and expansive tracing technology. in this scenario, a general belief is that there may be few undiagnosed missing cases. however, even under this stringent strategy of detecting all positive cases regardless of symptoms, a large number of missing undiagnosed cases was apparent. the missed undiagnosed cases may be related to the characteristics of sars-cov-2, especially the high proportion of infected patients who are asymptomatic or have only mild symptoms and the high transmission rate. 16, 17 our study suggests that any containment strategy may have a limited value with sars-cov-2 even though it is effective in flattening the epidemic curve. 18 the accuracy and reliability of antibody tests for sars-cov-2 have been disputed. 19, 20 the use of serological testing at the individual level such as immune passport, selecting vaccination target, and collecting therapeutic plasma is risky due to false-positive and false-negative cases. 19,20 however, different from the applications at the individual level, it is important to note that the estimated average seroprevalence at the population level is acceptable even with moderate sensitivity and sepcificity. 3 among many available serological methods, immunochromatographic assays are reported to show relatively lower sensitivity compared to other tests such as enzyme-linked immunosorbent assay (elisa) or chemiluminescence immunoassay (clia). 21 in fact, seroprevalence data are important to understand the scale and spread of the pandemic and predict the probability and timing of future waves of recrudescence. 3 also, it can address public health questions, such as the safety of relaxing stay-at-home orders or school closures and evaluations of alternative interventions. 3 often, seroprevalence data are linked to the concept of herd immunity, the minimum level of population immunity required to halt the spread of infection in the community. 22 assuming a basic reproduction number (r0) of 3 for sars-cov-2, the herd immunity threshold is estimated to be approximately 60%-70%. 23 judging from this threshold of herd immunity, the seroprevalence data worldwide including ours is far from the threshold of herd immunity. however, the most widely cited threshold of herd immunity was calculated based on unrealistic and simple assumption of homogeneous population susceptibility. 24 when individual variation in susceptibility or exposure to sars-cov-2 was factored in a model, the threshold of herd immunity is much lower, closer to 10%-20%. 24 one of the most important factors contributing to the heterogeneity of susceptibility of a population may involve exposure to other coronaviruses such as common cold, which is known as cross-immunity. 25 a recent study clearly demonstrated that about half of blood samples collected before covid-19 epidemic had t cell-mediated immunity against sars-cov-2. 26 cross-immunity may be one reason underlying the low mortality of covid-19 in many asian countries, where most coronavirus-related epidemics such as severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) originated. this study has several limitations. first, the study subjects were recruited from outpatients and their guardians at a single hospital, limiting the generalizability of the current finding to daegu. also, the sample size was small. second, the accuracy and reliability of serology assay are disputed due to the possibility of false-positive cases because of cross-reaction with another coronavirus such as common cold. conversely, there can be false-negative cases as well. in a recent meta-analysis comparing several serological methods, 21 the sensitivity of immunochromatographic assays was lower than that of elisa or clia, but all methods yielded high specificity closer to 99%. third, the situation in daegu may differ from that of other places in korea due to the outbreak during a short period. although a large number of symptomatic and asymptomatic cases were detected in daegu through massive pcr testing, contact tracing of confirmed cases was not performed as meticulously as at other places. therefore, the current results may not be generalized to korea. in conclusion, this study suggests that the actual number of individuals infected with sars-cov-2 in daegu, korea greatly exceeds that of the pcr-confirmed number of cases. although a large study based on a representative sample is required to confirm the current findings, even the stringent strategy of korea designed to detect and quarantine all positive cases regardless of symptoms may not be successful in containing the covid-19 pandemic. korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from serology for sars-cov-2: apprehensions, opportunities, and the path forward seroprevalence of covid-19 virus infection in guilan province performance characteristics of the abbott architect sars-cov-2 igg assay and seroprevalence in repeated seroprevalence of anti-sars-cov-2 igg antibodies in a population-based sample from estimation of seroprevalence of novel coronavirus disease (covid-19) using preserved serum at an outpatient setting in kobe, japan: a crosssectional study estimation of sars-cov-2 infection fatality rate by real-time antibody screening of blood donors cluster of covid-19 in northern france: a retrospective closed cohort study serological tests facilitate identification of asymptomatic sars-cov-2 infection in wuhan herd immunity is not a realistic exit strategy during a covid-19 outbreak infection fatality rate of sars-cov-2 infection in a german community with a super-spreading event repeated population-based surveys of antibodies against sars-cov-2 in southern brazil neutralising antibodies to sars coronavirus 2 in scottish blood donors -a pilot study of the value of serology to determine population exposure covid-19 antibody seroprevalence in presumed asymptomatic carrier transmission of covid-19 high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 can we contain the covid-19 outbreak with the same measures as for sars? will antibody tests for the coronavirus really change everything? first antibody surveys draw fire for quality, bias antibody tests in detecting sars-cov-2 infection: a meta-analysis herd immunity: understanding covid-19 herd immunity -estimating the level required to halt the covid-19 epidemics in affected countries individual variation in susceptibility or exposure to sars-cov-2 lowers the herd immunity threshold t cells found in coronavirus patients 'bode well' for long-term immunity targets of t cell responses to sars-cov-2 coronavirus in humans with covid-19 disease and unexposed individuals key: cord-011782-hz0rtgd1 authors: hong, sung-tae; youn, ho shik title: status of editing and publishing of scholarly journals by academic societies of science and technology in korea date: 2020-06-01 journal: j korean med sci doi: 10.3346/jkms.2020.35.e208 sha: doc_id: 11782 cord_uid: hz0rtgd1 background: the present study analyzed publishing data of scholarly journals which were published in 2018 by academic societies of science and technology in korea to observe journal editing and publishing status. methods: a total of 346 regional journals (59 natural science, 118 engineering, 44 agriculture, fisheries, and oceanography, and 125 medical and pharmacy) and 141 international journals (32 natural science, 43 engineering, 12 agriculture, fisheries, and oceanography, 54 medical and pharmacy) were included in this analysis, which applied the journal review by the korea federation of science and technology. websites of the journals and the submitted publication data in 2019 were reviewed. results: except for a few journals, all of the journals were published by academic societies. basic information of journals was well displayed by both offline and online. most of the 346 regional journals were published in korean language or mixed with english but 77 (22.3%), mostly medical, were in english. one-third (n = 104) journals published less than 40 articles while 9 published over 200, and 261 journals (75.4%) received less than 100 submissions in 2018. most (n = 298, 86.1%) of them were enlisted in the korean citation index (kci). editorial board members performed manuscript editing in 171 (49.4%) journals, and most of the journals paid < 50,000,000 won for publishing costs. of 141 international journals, 138 (97.9%) were published in english and all of them published overseas submissions. forty-one (29.1%) journals accepted < 20% of submissions but 58 (41.1%) accepted 100%. of them, 124 (87.9%) were indexed in the kci, 93 (66.0%) in the web of science, 120 in scopus, and 62 in pubmed. editorial board members in 38 (27.0%) journals took responsibility of manuscript editing. publishing cost of 79 (56.0%) journals was < 50,000,000 won. only 157 (32.2%) of total 487 journals, mostly medical, documented gendered innovation in their instruction to authors. conclusion: most of the korean science and technology journals keep global standard of editing and publishing. their offline and online visibility is acceptable but most regional journals are small and of low academic impact while international journals are globally indexed and acknowledged. korean scholarly journals should invite more and better articles to keep quality publication. publication of articles in scholarly journals is one of basic activities of scientific research. therefore, most academic societies publish journals of their own scopes, which must be encouraged for science progress. in the journal database of the korea research foundation, 5,630 journals are registered, but only 2,194 of them are korea citation index (kci) indexed and 324 index candidates. 1 the korean federation of science and technology societies (kofst) is an organization to enforce academic activities of science and technology societies in korea, which are categorized natural science, engineering, agriculture, fisheries & oceanography, medicine & pharmacy, and complexed sciences. 2 the kofst plays many roles of supporting or boosting academism in science and technology categories by several programs. one of the kofst programs is financial support for journal publication by academic societies, which is grouped for regional, international, and pre-international journals. the international journals are indexed ones in the web of science or scopus and the regional journals are those not indexed by either of the 2 global databases. 2 the journal supporting program selects 70%-80% journals among the applicants after peer review and supports < 50% of publication cost with limitation of 40,000,000 won. a peer review system is established and announced through the website of kofst. the journal review system is composed of 5 essential and 9-10 grading items which represent editing or publishing quality and scientific contribution. 3 to overview journal publishing status and quality, the present study analyzed publishing and editing status of scholarly journals of science and technology in korea. the data of journal editing and publishing in 2018 were submitted by journals to kofst for peer review in 2019. the submitted data were used for the peer review to choose journals of financial support, and additionally the present analysis included additional basic information on their websites. the present study was not a subject of review by the institutional review board because it did not include human subjects, materials, or data. data of editing and publishing items of 346 regional journals are summarized in table 3 some items are missing in some journals which makes different total numbers by items. table 3 . (continued) publishing status of regional journals by korean academic societies in 2018 a were in english and the others were in korean or mixed of korean and english. most of the journals of natural science, engineering, and agricultural & marine science published articles in korean but 53 (42.4%) of 125 medical scope journals were published in english. about half (178 of 346) of the journals published 4 or less issues per year and 34 (9.8%) published 12 issues. among the 118 engineering journals, 24 (20.3%) published 12 issues and 34 (28.8%) published over 100 articles. the numbers of publication issues were correlated with the number of publications in a year. most of the journals received small number of submissions as 261 (83.1%) of 314 data-supplied journals received less than 100 per year. according to the small number of submissions, accept rate of the regional journals was rather high as 100% in 239 (76.4%) of 313 data-supplied journals. most of the journals published articles with digital object identifier (doi) linkage and online, and only 4 did not publish online. most of them had their own websites for online publication, and 135 journals published full texts by hyper-text mark-up language (html) file only while 117 by both of html and the portable document file (pdf) and 91 by pdf only. of the 342 data-supplied journals, 197 (57.6%) are open access (oa), and 71.0% of medical journals were oa but it was about 50% in journals of other categories. regional journals which documented gendered innovation in their instruction to authors were 13 (22.0%), 3 (2.5%), 2 (4.5%), and 89 (71.2%) in natural science, engineering, agricultural & marine science, and medicine, respectively. the editorial board members did manuscript editing after accept in half (n = 171) of the journals, and the remaining half did it by journalhired manuscript editors (n = 68), outsourcing for professional service (n = 57), or printing publishers (n = 44). the annual budget for journal publishing is less than 50,000,000 won in most of the journals. the numbers of journals by categories and items are introduced in detail in table 3 . the editing and publishing metrics of international journals are summarized in table 4 . their numbers by journal categories are 32 natural science, 43 engineering, 12 agricultural & marine science, and 54 medicine. almost all of the journals, 138 (97.9%) of 141, are published in english, and all of the journals in natural science and medicine are in english. frequencies of the journals varied from 2 to 52 issues in the year 2018; 59 published 5-6 issues and 47 did 3-4 issues. the 11 journals of 43 in engineering published 12 issues. the numbers of total publications per journal were less than 100 in 89 (63.1%) journals, but one natural science and 3 engineering journals published over 500 articles. annual submissions were less than 100 in 84 (59.6%) journals but 5 journals received submissions over 1,000. forty-one (29.1%) journals accepted manuscripts < 20% while 58 (41.1%) accepted 100%. almost all of the journals published articles authored by foreign researchers, which meant their role of international academic communication. most of them, 124 indexed and 12 candidates, were kci journals. for global indexing databases, 93 were included in the web of science, 120 in the scopus, and 62 in pubmed. most of them had eissn and doi link. twenty-two were copublished by two or more academic societies. as a whole, 83 (58.9%) were oa journals, and 86 had own websites of online journals while 48 used publisher websites. most of them were visible by hlml or by both html and pdf. two of them were assessed of their journal impact factor (jif) 2017 by the web of science over 5.0 but most of their jif were < 2.0. none of them showed self-citation rate over 50% and 45 showed < 10%. international journals which had gendered innovation in their instruction to authors were 4 (12.5%), 4 (9.3%), 1 (8.3%), and 41 (75.9%) in natural science, engineering, agricultural & marine science, and medicine, respectively. the manuscript editing was done by journal-hired staffs in 25, most of korean scholarly journals which applied the kofst program are enlisted on the kci as indexed or index candidates. a total of 2,518 journals are kci enlisted by january 23, 2020, and 1,749 are in category of arts & humanities and social science while 769 are in science and technology ( table 1) . there may be more journals unlisted by the korea science foundation but it is hard to estimate exact numbers. in a word, numerous and diverse scholarly journals are published by korean academic societies, which suggests active research and academic publication activities. however, most of them are rather small according to divided specialties, especially in the category of arts & humanities and social science. publishing too many small journals is eventually linked to sustainability problems by insufficient submissions and financial shortage. we have to consider seriously how to co-publish journals of related scopes to keep their critical mass. only one-third of the kci enlisted journals are in the scope of science and technology, total 769. of the 769 journals, only 487 applied the review process by kofst in 2019. most of the remaining 282 journals may not meet the basic criteria of the application, such as timely publication, well-established peer review system, well-prepared instruction or guidelines for contributors, open display of basic publishing information, and global publication networking by doi. 2 of the 487 applied journals, 346 applied regional, and 141 international journal programs ( table 2) . the numbers of journals were more in engineering and medicine than those in natural science, agriculture, and fisheries & oceanography, which suggest that numbers of academic societies and researchers are more in the engineering and medicine than those in other science fields. regional journals publish articles mainly in korean, which means they target korean audience. all of the articles in korean were published in korean text with english title, authors and affiliations, abstract, tables, figures, and references following global guidelines for non-english journals. contrary to this, all of international journals published english articles except one. only one is published in korean but indexed by the global databases. most of the regional journals were small and received insufficient submissions, and thus their accept rates were rather high. many of 141 international journals were small either, but 26 of them published 12 or more issues and 20 published over 200 articles in 2018. those journals received many submissions including overseas submissions and contributed much to global science. four regional journals had no platforms for online publication, which means they published offline (paper-print) only. however, all of other regional or international journals provided platforms at journal specific websites or at publisher's websites. some of them were online only but most of them were both offline and online journals. a total of 197 (56.9%) regional journals were oa, but medical journals showed higher proportion (70.4%) while oa journals in 3 remaining category journals were around 50%. this pattern of oa was same in international journals, 83 (58.9%) of 141 journals were oa with 48 (88.9%) of 54 medical journals. in korea, most of medical journals are oa but those in other categories are not. medical journals publish more english articles with oa than those in other scopes, and this means that most of medical journals even regional journals intend to target global audience. all of the oa journals displayed cc-by or cc-by-nc (https://creativecommons.org/licenses/ by/4.0/) following the creative commons' recommendation which is global norm of oa. being indexed in journal databases is critical for scholarly journals. of the 346 regional journals, 31 were not, and 5 of 141 international journals were not indexed in the kci, the national journal index in korea. the present kci index data suggest that most of the applying journals for kofst review are indexed and officially endorsed for proper management of editing and publishing practice. the 141 international journals were indexed either by the web of science (93 journals) or scopus (120 journals). the highest jif in 2018 was 5.571 by the journal of stroke, which is published by the korean stroke society. by the jif, most of the journals were distributed between 1.0 and 2.0 and in the position at q3 or q4 among indexed journals in their scientific specialties by the web of science (table 4) . to raise the jif and the position of journals in their categories, journals must be more reader friendly and invite more good quality articles with academic impacts. many international journals have established stable system of editing and publishing to invite global authors and readers. they are upgraded slowly and steadily. one medical journal, journal of korean medical science (jkms), which is published by the korean academy of medical sciences, is published weekly. 4 the journal publishes about 300 articles a year and is indexed by the kci, web of science, scopus, and pubmed. it plays the role of flagship journal for editing and publishing in korea. in the ongoing period of coronavirus disease 2019 (covid-19) pandemic, jkms is publishing many articles on covid-19 by rapid editing, mostly within one week from submission. manuscript editing (me) is a final process of editing or revising of accepted manuscripts, which includes keeping formats, correcting typographic errors, grammars, or any required amendment before publication. this final me is important for quality publication but it is a tedious technical process. it is ideal for journals to perform me by well-trained professional manuscript editors, either as journal staff or via service company. in about half of the korean scholarly journals, editorial board members are responsible for this me process, but this is not a job of the editorial board members. the academic societies that publish scientific journals must exempt editorial board members doing me. the board members should focus on contents of manuscripts by reviewing, selecting, and ensuring science. this is the priority for public financial supports to upgrade journals. the sager guideline for gendered innovation was published in 2016 and has been recommended to all biomedical journals. 5 the guideline was accepted by the international committee of medical journal editors (icmje) and included in the icmje recommendations. 6 the recommendation is to design the research to minimize gender or sex influence by subjecting equal number of humans, animals or cells of different sex or gender as possible. the articles should clearly document subject numbers by sex, which is responsible for all journals that publish research articles subjecting humans, animals, or cells. the present analysis confirmed that many korean journals did not document the gendered innovation guideline and most of published articles did not describe it. a total of 107 (30.9%) of regional journals and 50 (35.5%) of 141 international journals documented this guideline in their instruction to authors. most of them were medical journals, 89 (71.2%) of 125 regional and 41 (75.9%) of 54 international journals. only 5% journals in natural science, engineering, and agriculture, fisheries & oceanography documented it. it is strongly recommended to accept it in editing and publishing for all journals which publish articles on humans, animals, or cells. summarizing the journal publishing, most of the korean science and technology journals keep their global standard editing and publishing by both offline and online. their online visibility is acceptable but most regional journals are small and of low academic impact while many international journals are globally indexed and acknowledged. korean journals should invite more and better articles to keep quality publication. research societies and the kci statistics by the korea citation index korean federation of science and technology societies (kofst) national electronic solution for s&t academic activities (nest) sex and gender equity in research: rationale for the sager guidelines and recommended use recommendations for the conduct, reporting, and publication of scholarly work in medical journals the authors thank members of the directorate for academic promotion, korea federation of science and technology, for their contribution of collection of journal editing and publishing information. researchers of the center for gendered innovation in science and technology research, korea, are appreciated for analysis of documented gendered innovation in journal instructions. key: cord-269440-6x19xuy3 authors: seo, min young; seok, hyeri; hwang, sun jin; choi, hee kyoung; jeon, ji hoon; sohn, jang wook; park, dae won; lee, seung hoon; choi, won suk title: trend of olfactory and gustatory dysfunction in covid-19 patients in a quarantine facility date: 2020-10-20 journal: j korean med sci doi: 10.3346/jkms.2020.35.e375 sha: doc_id: 269440 cord_uid: 6x19xuy3 background: olfactory and gustatory dysfunction has been reported as characteristic symptoms of coronavirus disease 2019 (covid-19). this study evaluated olfactory and gustatory dysfunction in mild covid-19 patients using validated assessment methods. methods: a prospective surveillance study was conducted for mild covid-19 patients who were isolated at the gyeonggi international living and treatment support center (ltsc), korea. olfactory function was assessed using the korean version of the questionnaire of olfactory disorders (qod) and cross-cultural smell identification test (cc-sit). gustatory function was assessed using an 11-point likert scale and 6-n-propylthiouracil, phenylthiocarbamide, and control strips. all patients underwent nasal and oral cavity endoscopic examination. results: of the 62 patients at the ltsc, 15 patients (24.2%) complained of olfactory or gustatory dysfunction on admission. four of 10 patients who underwent functional evaluation did not have general symptoms and 2 were asymptomatic. the mean short version of qod-negative statements and qod-visual analogue scale scores were 13 ± 6 and 4.7 ± 3.6, respectively. the mean cc-sit score was 8 ± 2. no patients showed anatomical abnormalities associated with olfactory dysfunction on endoscopic examination. the mean likert scale score for function was 8 ± 2, and there were no abnormal lesions in the oral cavity of any patient. conclusions: the prevalence of olfactory and gustatory dysfunction was 24.2% in mild covid-19 patients. all patients had hyposmia due to sensorineural olfactory dysfunction, which was confirmed using validated olfactory and gustatory evaluation methods and endoscopic examination. olfactory and gustatory dysfunction may be characteristic indicators of mild covid-19. since the first report of coronavirus disease 2019 in wuhan, china in december 2019, the disease has become widespread and global threat. 1 during this ongoing covid-19 pandemic situation, several studies regarding virology, clinical characteristics, and transmission have been reported. the main clinical manifestations of covid-19 are symptoms of upper and lower respiratory infection, including fever, cough, sputum, and fatigue, and range in severity, from asymptomatic to severe respiratory failure. 2 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is different from other viruses in coronaviridae because it can cause asymptomatic infections and show high viral loads during the early phase, which leads difficulty in controlling the disease. 3, 4 this led us to consider methods for the early diagnosis of asymptomatic or mild infection, which account for the majority of covid-19 infections. other characteristic symptoms of covid-19 infection are olfactory and gustatory dysfunction. although olfactory and gustatory dysfunction were initially not recognized as symptoms of covid-19, they were seen in a case series of confirmed patients and data from korea have reported anosmia or ageusia in 30% of 2,000 patients. 5, 6 subsequent studies have reported that olfactory and gustatory dysfunction may be characteristic symptoms of covid-19 infection, but there are limitations in assessments by validated methods. 6-11 in a study by moein et al., 12 the university of pennsylvania smell identification test (upsit) was used in the assessment of smell dysfunction, and olfactory and gustatory dysfunction were identified in 90% (59/60) and 25% (15/60) of covid-19 patients, respectively. however, the olfactory test was performed in the recovery period and the severity of the disease was heterogeneous. therefore, this study was designed to assess olfactory and gustatory dysfunction in mild covid-19 patients using validated olfactory and gustatory evaluation methods and endoscopic examination. this prospective surveillance study included mild covid-19 patients who were isolated at gyeonggi international living and treatment support center (ltsc) after confirmed diagnosis of covid-19 by sars-cov-2 real-time reverse transcription polymerase chain reaction (rt-pcr) using respiratory samples; all patients were interviewed daily regarding changes in olfactory and gustatory symptoms and their medical records were reviewed. all patients were korean nationals who had returned from foreign countries and quarantined on arrival at the airport in april 2020. the ltsc is a korean community-based isolation and treatment facility for mild covid-19 patients. all patients were assessed for symptoms including olfactory and gustatory dysfunction at the time of ltsc admission. olfactory and gustatory evaluations and nasal endoscopic evaluation via portable endoscopic smartphone systems were performed in patients complaining of olfactory and taste disorders. the olfactory and gustatory function tests and nasal endoscopic examinations were performed by one rhinologist who was wearing personal protective equipment. subjective olfactory function was evaluated using the korean version of the questionnaire of olfactory disorders (qod). 13 the qod was originally developed by thomas hummel and johannes frasnelli in 2005, and the korean version was validated by choi et al. in 2018. 13,14 for subdomains of the qod, we performed assessments using the qod-visual analogue scale (qod-vas) and the short version of qod-negative statements (sqod-ns). the qod-vas, composed of five questions, is a measure to record the severity of symptoms using the vas scale for each question, and the validated korean version uses an 11-point likert scale instead of the vas scale. the sqod-ns is composed of seven questions including social, eating, annoyance, and anxiety and assessed using a 4-point likert scale (0-3). a higher score means better olfactory specific qol. 9 additionally, we performed the cross-cultural smell identification test (cc-sit; sensonics international, haddon heights, nj, usa) for odor identification as an objective measurement of olfactory function. 15 the cc-sit is composed of 12 items (banana, chocolate, cinnamon, gasoline, lemon, onion, paint thinner, pineapple, rose, soap, smoke, and turpentine) based on items from the upsit, with the answer for each question chosen from a possible of four answers. according to the criteria, anosmia was defined as a score of 0-4, hyposmia as a score of 5-10, and normosmia as a score of 11-12. 13 subjective gustatory function was evaluated using an 11-point likert scale (0-10), and objective gustatory function was evaluated using 6-n-propylthiouracil (prop), phenylthiocarbamide (ptc), and control strips (sensonics international). prop and ptc showed a significant positive relationship with other bitter compounds used for detecting bitter compounds in screening for ageusia. 16-18 endoscopic nasal and oral cavity examinations were performed using a 4-mm 30° endoscope, which was connected to a galaxy s8 smartphone (samsung electronics, suwon, korea) using the smart scope system (karl storz, tuttlingen, germany). during the endoscopic examination, we checked for sinonasal diseases such as chronic rhinosinusitis with or without nasal polyps, deviated nasal septum, nasal turbinate hypertrophy, and any tumorous condition. the olfactory fissure area was also specifically examined. this study protocol was approved by the institutional review board of the korea university ansan hospital (2020as0122). written informed consent was obtained from each study participant. sixty-two mild covid-19 patients were assessed on april 28, 2020. at the time of admission, cough, sore throat, sputum, and headache were identified in 20 (32.3%), 19 (30.6%), 9 (14.5%), and 9 (14.5%) patients, respectively. rhinorrhea and nasal congestion were identified 10 (16.1%) and 7 (11.2%) patients, respectively. fever was identified in 3 patients, and 16 patients were asymptomatic. fifteen patients (24.2%) complained of acute olfactory dysfunction. a total of 10 patients participated in this study, except for 5 patients whose symptoms improved after admission. the demographic and clinical characteristics of the study population are shown in table 1 . the mean patient age was 33 ± 12 years (interquartile range [iqr], 20-62 years), and 7 of 10 patients were female (70%). at initial surveillance, all the 10 patients reported no fever and 2 patients had no symptoms, except olfactory or gustatory symptoms. six patients complained of respiratory symptoms including cough, sputum, and sore throat. of the 10 patients, 4 patients complained of both subjective olfactory and gustatory symptoms, and 6 patients had only olfactory symptoms without gustatory dysfunction. the mean time between the diagnosis of covid-19 and the olfactory evaluation was 12 ± 9 days (iqr, 7-19 days). all patients had no previously experienced olfactory or gustatory dysfunction before covid-19, although 4 patients had a history of allergic rhinitis and 1 patient had chronic rhinosinusitis. the mean sqod-ns and qod-vas scores were 13 ± 6 (iqr, 9-18) and 4.7 ± 3.6 (range, 1.5-7.9), respectively. the mean cc-sit score was 8 ± 10 (iqr, 7-9), and all patients were classified as having hyposmia according to the cc-sit. no patients had signs of suspicious sinusitis or nasal polyps in nasal endoscopic findings. a large septal perforation was observed in 1 patient (patient number 10) and the olfactory fissure area could not be examined in 1 patient (patient number 8) because of high septal deviation. nine patients who underwent endoscopic evaluation of the olfactory fissure area showed no anatomical abnormalities (fig. 1) . the mean likert scale score for gustatory function was 8 ± 2 (iqr, [8] [9] [10] . in the initial questionnaire, 4 patients reported gustatory dysfunction, but an objective gustatory function test showed abnormal findings in 6 patients. no patients showed abnormal lesions of the oral cavity or tongue in the oral endoscopic examinations. to our knowledge, this study is the first to assess both olfactory and gustatory function with validated methods, with simultaneous nasal and oral endoscopic examination in mild covid-19 patients. we were able to evaluate whether olfactory and gustatory dysfunction were associated with anatomical abnormality using endoscopy. in our study, the prevalence of olfactory dysfunction was 24.2% in mild covid-19 patients and all patients were classified as having hyposmia. in the recent studies by yan et al., 10 patients, respectively. in our study, the prevalence of olfactory dysfunction was markedly low, probably because the study population consisted of only mild covid-19 patients. further, 4 of 10 patients who complained of olfactory or gustatory dysfunction had no systemic symptoms and 2 patients were asymptomatic, which suggests olfactory or gustatory dysfunction may be possible indicators of covid-19. the perception of smell requires stimulation of olfactory neurons in the olfactory epithelium, which are located in the olfactory fissure. olfactory disorders are largely divided into two types-quantitative and qualitative disorders. 18 quantitative disorders refer to decreases in the degree of smell and are subdivided according to severity into hyposmia (reduced olfaction) and anosmia (absent olfaction). qualitative olfactory disorders refer to distortion in odor quality and are subdivided into parosmia (distortion of an odor perception) and phantosmia (perception of an odor in the absence of a stimulus). 20 currently, the olfactory disorders in covid-19 have been reported to be quantitative disorders. quantitative olfactory disorders have two etiologies, which show either conductive or sensorineural olfactory dysfunction. conductive olfactory dysfunction occurs when the smell cannot reach the olfactory epithelium because of nasal mucosal edema after viral infection or underlying chronic rhinosinusitis, with or without nasal polyps. in our study, we were able to exclude conductive olfactory dysfunction by examining the olfactory fissure area using nasal endoscopy in all patients, except 1 patient who could not be tested because of high septal deviation. thus, we concluded that all patients had the sensorineural type of olfactory dysfunction. sensorineural olfactory dysfunction is a common form of post-infectious olfactory dysfunction (piod), which occurs after viral infection of the upper respiratory tract, including infection by coronaviruses. 21 it may involve the olfactory neurons related to the central nervous system or non-neuronal olfactory epithelial cells. 10, 22 when the viral infection occurs in olfactory neurons, permanent olfactory dysfunction may occur and even if there is recovery, it may take a long time. therefore, the location of olfactory neurons with sensorineural olfactory dysfunction can be inferred through the clinical course. yan et al. 10 have suggested that sars-cov-2 invades the non-neuronal olfactory epithelium because the majority of patients recover rapidly. however, they assessed olfaction with a non-objective method without long-term follow-up. our study complemented previous studies by performing objective assessment using both olfactory and gustatory function tests. further studies and long-term follow-up observations are needed. the limitations of our study are as follows. first, the study population was small; hence, the results might be biased. anosmia was not identified by the cc-sit in this study. when we consider random responding, the expected minimum score is only 3 (multiple choice from 4 answers means that 25% of all answers should be correct). 15 currently, the most validated olfactory function test is to assess the odor threshold, discrimination, and identification and then sum the results of the 3 tests to give the threshold-discrimination-identification (tdi) score. however, this test kit is too bulky and non-disposable; hence, it is difficult to use for isolated covid-19 patients. thus, the cc-sit was optimal for testing covid-19 patients as it can be disposed and quickly performed. second, we assessed objective gustatory function using ptc and prop strips. although these strips were used for screening tests for gustatory function, approximately 15%-30% of normal people are genetically non-tasters for these compounds. 2325 the possibility of underestimation must be considered. furthermore, we could only detect patients did not have the sense of taste with this test; hence, we could not evaluate the mildly deteriorated patients. third, the study population was composed of mild covid-19 patients and has limitations in the application of the results. further research is needed to reflect the disease severity. a novel coronavirus from patients with pneumonia in china clinical characteristics of coronavirus disease 2019 in china transmission of 2019-ncov infection from an asymptomatic contact in germany presymptomatic sars-cov-2 infections and transmission in a skilled nursing facility isolated sudden onset anosmia in covid-19 infection. a novel syndrome? anosmia and ageusia are emerging as symptoms in patients with covid-19: what does the current evidence say? clinical characteristics of 140 patients infected with sars-cov-2 in wuhan, china sudden and complete olfactory loss of function as a possible symptom of covid-19 olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid-19): a multicenter european study association of chemosensory dysfunction and covid-19 in patients presenting with influenza-like symptoms olfactory and gustatory dysfunction in a covid-19 patient with ankylosing spondylitis treated with etanercept: case report smell dysfunction: a biomarker for covid-19 reliability and validity of the korean version of the questionnaire of olfactory disorders olfactory dysfunction and daily life olfaction and taste disorder in covid-19 development of the 12-item cross-cultural smell identification test (cc-sit) the relationship between phenylthiocarbamide (ptc) and 6-n-propylthiouracil (prop) taster status and taste thresholds for sucrose and quinine comparison of bitterness of caffeine and quinine by a time-intensity procedure sweetness of sucrose, neohesperidin dihydrochalcone, and saccharin is related to genetic ability to taste the bitter substance 6-n-propylthiouracil prevalence and duration of acute loss of smell or taste in covid-19 patients clinical diagnosis and current management strategies for olfactory dysfunction: a review identification of viruses in patients with postviral olfactory dysfunction evidence of the covid-19 virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings ptc taste blindness and the taste of caffeine detection thresholds for quinine, ptc, and prop measured using taste strips in conclusion, the prevalence of olfactory dysfunction was 24.2% in mild covid-19 patients and all patients had hyposmia due to sensorineural olfactory dysfunction, which was confirmed using validated olfactory and gustatory evaluation methods and endoscopic examination. of the patients who complained of olfactory and taste dysfunction, 20% had no symptoms other than olfactory and taste disorders, and 40% had no systemic symptoms; this means that olfactory and gustatory dysfunction may be characteristic indicators of asymptomatic or mild covid-19. further studies are needed on the association of disease severity and long-term outcomes in covid-19 patients with olfactory and gustatory dysfunction in more patients. key: cord-297681-m0cckidw authors: na, joo-young; noh, sang jae; choi, min sung; park, jong-pil title: [secondary publication] standard operating procedure for post-mortem inspection in a focus on coronavirus disease-19: the korean society for legal medicine date: 2020-08-13 journal: j korean med sci doi: 10.3346/jkms.2020.35.e302 sha: doc_id: 297681 cord_uid: m0cckidw coronavirus disease 2019 (covid-19) is a respiratory syndrome caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and emerged in wuhan, china, in late 2019. it resulted in a worldwide pandemic, and spread through community transmission in the republic of korea (rok). in the rok, sars-cov-2 is categorized as a first-degree infectious disease of the legal communicable disease present. the korean society for legal medicine (kslm) is the sole official academic association of forensic professionals in the rok. as such, this society has played an important role in forensic medicine and science in the rok. therefore, kslm suggests a standard operating procedure for the postmortem inspection in a focus on covid-19. this article includes the background of this suggested standard operation procedure, basic principles for postmortem inspections of individuals suggested of having an infectious disease, and specific procedures according to the probability level of sars-cov-2 infection. post-mortem inspection is an external examination of a dead person and is performed to determine the cause and manner of death. although identifying unnatural death is the main objective of a post-mortem inspection, natural death also accounts for a large percentage of actual post-mortem inspection cases. in general, patients who die from infectious diseases, including coronavirus disease-19 (covid-19), are not subject to post-mortem inspection because they passed away while being treated in medical institutions. however, if the cause and manner of death of the patient with confirmed covid-19 cannot be determined, the cause and manner of death needs to be clarified, and post-mortem inspection should be conducted. furthermore, patients with suspected covid-19 or limited clinical information and a history of exposure to covid-19 may be subject to post-mortem inspection, and quarantine and preventive measures should be taken to prevent infection and transmission from latent covid-19. as covid-19 has become a global pandemic, and community transmission continues, undiagnosed or latent covid-19 cannot be ruled out in post-mortem inspection cases. vulnerable groups, such as those with chronic diseases, those living alone, and the elderly, account for a large proportion of the post-mortem inspection cases. therefore, post-mortem inspection guidelines for infection prevention, including covid-19, should be prepared in advance. the korean society for legal medicine, a highly specialized organization responsible for post-mortem examination and death investigation, aims to protect multiple staff-related post-mortem examinations and prevent the spread of covid-19 in medical institutions and communities to improve social stability through this guideline for covid-19 post-mortem inspections. currently, in the republic of korea, post-mortem inspection is conducted at the death scene, emergency room, or morgue. the risk of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection during post-mortem inspection of a dead body is relatively lower than that in the case of medical procedures or treatments because dead bodies do not cough and spread droplets. however, an examination of the nostrils and oral cavity is essential during post-mortem inspection. infectious materials like body fluids can be spilled from nostrils, mouth, and anus of the dead body, and can be existing around it. the house of a dead person and the field at which post-mortem inspection is performed can be contaminated. furthermore, doctors who perform post-mortem inspections interview the family or the persons who closely contacted the deceased, so the risk of infection surely exists during post-mortem inspection. infectivity persists for a certain period after the death of the host in most infectious diseases. for example, hiv-infected bodies should be considered infectious for at least two weeks after death. hepatitis b virus (hbv) in the environment is also hardy. hbv in human plasma retains infectivity one week after drying and exposure to an ambient environment. 1 postmortem infection of sars-cov-2 has not been reported; however, the exact post-mortem infectivity remains unknown. furthermore, the stability of sars-cov-2 was similar to that of sars-cov-1 when tested under experimental conditions. sars-cov-2 remained viable in aerosol for three hours. it was more stable on plastic and stainless steel than on cooper and cardboard, with a viability of 72 hours after application to these surfaces. thus, aerosol and fomite transmission of sars-cov-2 is plausible since the virus can remain viable and infectious in aerosol for hours and up to days on surfaces (depending on the inoculum shed). 2 moreover, sars-cov-2 can be detected in anal swabs and blood. the number of positive anal swabs was more than the number of positive oropharyngeal swabs in the later stage of the infection, suggesting shedding and thereby transmission through the oral-fecal route. 3 the persistence of sars-cov, which belongs to the family coronaviridae, the same as sars-cov-2, was observed in feces, urine, and water. in vitro experiments showed that the virus was viable for two days in hospital wastewater, domestic sewage, and dechlorinated tap water, three days in feces, fourteen days in phosphate buffer saline (pbs), and seventeen days in urine at 20°c. 4 middle east respiratory syndrome coronavirus (mers-cov) can be detected in the nasal swab of an infected human cadaver (three days following death). in the case of patient death, the deceased should be treated as infectious and as having the ability to transmit the infection. 5 the analysis of 22 studies reveals that human coronaviruses such as sars coronavirus, mers coronavirus or endemic human coronaviruses can remain viable on inanimate surfaces such as metal, glass, or plastic for up to nine days. 6 therefore, the possibility of infection during postmortem inspection of a dead person who is suspected to be infected by sars-cov-2 should be kept in mind and is important to prevent a post-mortem transmission of sars-cov-2 considering the principles for living patients of sars-cov-2. covid-19 has spread worldwide, and major international organizations and health authorities in developed countries have prepared and reported guidelines for post-mortem examination of dead bodies with a high risk of infection. 7-11 however, the post-mortem investigation system differs among countries. the principles and methods of both the clinical approach and post-mortem investigation of covid-19 are also different among countries. therefore, it is impossible to accept these guidelines for the republic of korea, and these guidelines should be used as a reference. we used both guidelines for living patients of sars-cov-2 and international guidelines for the post-mortem investigation of sars-cov-2 as references. in almost all cases of unnatural death, medical history and traces of the past activity are unknown. the doctor is at risk of getting infected while performing a post-mortem inspection. therefore, post-mortem inspection should be performed under the following basic principles to protect human resources and the local community from post-mortem infection resulting from post-mortem inspection procedures. for all unnatural deaths during an epidemic or a pandemic, a post-mortem caretaker wearing personal protective equipment (ppe) must cover the body following corpse handling guidelines. the external surfaces of the body bag must be sanitized and placed into a second bag for double sealing, and the bodies must be transported to the public morgue, which has safe facilities for protecting the local community from infection. before post-mortem inspection is performed, infectious diseases must be diagnosed. post-mortem inspection is performed by professionals according to the result of the diagnosis of infection. this standard operating procedure distinguishes bodies according to the possibility of infection, considering the current situation in which human resources, systems, and facilities are inadequate in the republic of korea. the laboratory test for diagnosis of covid-19 was conducted according to the decision of the doctor and investigating professionals. however, the following conditions should be fulfilled to protect the post-mortem caretaker and the local community from post-mortem infection; a public morgue which has safe facilities; diagnosis of infection for all unnatural deaths before post-mortem inspection; right to inquire the past medical history of the deceased from the doctor who performs a postmortem inspection. bodies related to covid-19 can be divided into three categories: bodies confirmed as covid-19; bodies that may be infected; and bodies with no or insufficient information related to death, including covid-19 (fig. 1) . to classify patients according to the likelihood of infection, sars-cov-2 evaluation must first be performed. due to the nature of postmortem inspection, in most cases, there is no or insufficient ante-mortem information, so collaboration with investigative agencies, local governments, and relevant public health centers is essential to determine the possibility of sars-cov-2 infection. identification of the deceased should be preceded, and based on this, it is necessary to check whether he or she was registered as a subject to manage patients in a local health center. additionally, investigations of the past and current medical history, as well as the people who surrounded the deceased, should be conducted. if a diagnosed patient dies from covid-19, it is not subject to post-mortem inspection. however, if it is not possible to determine whether the patient died of covid-19, or if the patient died from a cause of death other than covid-19, especially if the death was following the unusual death guidelines published by the korean society for legal medicine, postmortem inspection should be carried out. -underwater bodies and deaths associated with fire accidents -death in custody, including taking to a police station, detention, interrogation, detention centers and prisons -deaths in collective welfare accommodations such as mental health facilities and orphanages -deaths of young and old people who seemed to be healthy but died suddenly -deaths of infants, children, and adolescents who are not being treated by medical institutions -deaths suspected due to acute poisoning -deaths of unknown cause at a medical institution 1) subject: the deceased who was confirmed according to the diagnostic criteria for covid-19 (virus isolation and sars-cov-2 gene polymerase chain reaction test) regardless of clinical features. 2) post-mortem inspection should be conducted with minimum manpower, comprising one medical doctor and one member of an investigative agency, and the additional necessary personnel is decided according to the situation. 1) subject: the deceased who was managed as a suspected patient, a patient under investigation and a person in contact with suspected patients before death. each definition is as follows. a. suspected patient: a person who displayed clinical symptoms (fever of more than 37.5°c or respiratory symptoms such as cough and dyspnea) within 14 days of contact with a confirmed covid-19 patient b. patient under investigation: • c. person in contact with confirmed patients: a person who has been in contact with a confirmed patient, and has been confirmed through an epidemiological investigation at the local public health center. 2) after confirming the identity of the deceased, if it is necessary to confirm whether he or she has the possibility of infection with covid-19, request confirmation to the public health center. 3) in principle, a coronavirus test is referred to the local public health center and postmortem inspection should be performed according to the results. 1) after confirming the identity of the deceased, if it is necessary to confirm whether he or she has the possibility of infection with covid-19, request confirmation to the public health center through the police in charge, and proceed with the post-mortem inspection. 2) before the post-mortem inspection is started, the possibility of infection should be confirmed through interviews with relatives and close contacts of the deceased. 3) if covid-19 cannot be ruled out reliably, the deceased should always be considered as a corpse that may be infected with covid-19, and post-mortem inspection should be carried out while wearing appropriate ppe. a. wear equipment for appropriate respiratory protection (medical mask), full body protection (gloves, a disposable waterproof long sleeve gown), and eye protection (goggles or a face shield). b. be cautious about wearing ppe, as there is a possibility of self-containment through epidemiological investigations if the deceased is found to be an infected person after postmortem inspection (based on the work standard of medical staff contacting covid-19 patients, the recommended monitoring is self-monitoring level because medical personnel wearing all the recommended protective equipment have a low exposure risk when handling or contacting the patient's secretions and feces). 14 c. in the process of post-mortem inspection, if the body is found to be or seem to be infected, immediately report it to the public health center through the police in charge and, if necessary, fill out an infectious disease report. 13 • if you did not wear adequate protective equipment, report it to the public health center and enter quarantine. • if the test result of the deceased is negative, immediately discontinue the quarantine, and if positive, maintain quarantine for 14 days (even if there are no symptoms, the test is conducted on the 13th day of containment to confirm that it is negative, the person is released on completion of the 14-day containment). (1) if it is determined during the post-mortem inspection that testing for covid-19 is necessary, report it to the public health center for cooperation with the health authority and the investigative agency. (2) if samples are to be taken from the corpse, follow the covid-19 guidelines for safe sampling and handling of samples published by the korea centers for disease control and prevention (kcdc). 15 1) upper respiratory tract specimens can be collected during post-mortem inspection. samples from both the nasopharynx and oropharynx are placed in the same transport tube with viral transport medium, and sent for analysis with test request form. 16 a. nasopharyngeal swab: gently insert a sterile swab through the nostril parallel to the nasal mid-turbinate. rub and roll the swab. leave the swab in place for a few seconds to absorb the nasal secretion. slowly rotate the swab and extract it. b. oropharyngeal swab: gently insert a sterile swab into the oropharynx, rub the swab over the posterior oropharyngeal wall, and avoid contamination from the tongue and other areas of the oral cavity. 2) all samples for covid-19 testing should be packaged and transported following covid-19 guidelines for safe sampling and handling of samples published by the kcdc. sample packaging and transportation are handled by the public health center and the police. (1) medical wastes such as protective equipment should be disposed off in a separate waste bag and notified to the public health center if post-mortem inspection and specimen sampling are performed in the residence of a deceased person. (2) use the waste disposal facility within the medical institution, if the post-mortem inspection and specimen sampling are performed at a hospital (example, an emergency room or a morgue). (3) waste should be handled according to the general guidelines of the kcdc. 17 it is reasonable to focus primarily on the prevention, diagnosis and treatment of living patients when new infectious diseases are prevalent. however, to improve the quarantine and preventive system, proper management of the deceased person with known or suspected covid-19 should be done, and appropriate protection and diagnosis should be taken during the post-mortem inspection. in republic of korea, unusual death cases are managed by the judiciary system, not by medical professionals or the health authority, and quarantine is overlooked during the post-mortem examination process. therefore, these guidelines will improve the preventive and quarantine process. biosafety considerations for autopsy aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 molecular and serological investigation of 2019-ncov infected patients: implication of multiple shedding routes study on the resistance of severe acute respiratory syndrome-associated coronavirus case report: detection of the middle east respiratory syndrome corona virus (mers-cov) in nasal secretions of a dead human persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents infection prevention and control for the safe management of a dead body in the context of covid-19 collection and submission of postmortem specimens from deceased persons with known or suspected covid-19 european centre for disease prevention and control. considerations related to the safe handling of bodies of deceased persons with suspected or confirmed covid-19 international committee of the red cross (icrc): general guidance for the management of the dead related to covid-19 international federation of red cross and red crescent societies, international committee of the red cross, world health organization. covid-19 interim guidance for the management of the dead in humanitarian settings covid-19 guidelines (for local government) enforcement decree of infectious disease control and prevention act covid-19 guidelines for funeral of the dead covid-19 guidelines (for local government) covid-19 guidelines (for local government) key: cord-270083-gm8i9olj authors: jang, jong geol; hur, jian; choi, eun young; hong, kyung soo; lee, wonhwa; ahn, june hong title: prognostic factors for severe coronavirus disease 2019 in daegu, korea date: 2020-06-02 journal: j korean med sci doi: 10.3346/jkms.2020.35.e209 sha: doc_id: 270083 cord_uid: gm8i9olj background: since its first detection in december 2019, coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus 2 infection has spread rapidly around the world. although there have been several studies investigating prognostic factors for severe covid-19, there have been no such studies in korea. methods: we performed a retrospective observational study of 110 patients with confirmed covid-19 hospitalized at a tertiary hospital in daegu, korea. demographic, clinical, laboratory, and outcome data were collected and analyzed. severe disease was defined as a composite outcome of acute respiratory distress syndrome, intensive care unit care, or death. results: diabetes mellitus (odds ratio [or], 19.15; 95% confidence interval [ci], 1.90–193.42; p = 0.012), body temperature ≥ 37.8°c (or, 10.91; 95% ci, 1.35–88.36; p = 0.025), peripheral oxygen saturation < 92% (or, 33.31; 95% ci, 2.45–452.22; p = 0.008), and creatine kinase-mb (ck-mb) > 6.3 (or, 56.84; 95% ci, 2.64–1,223.78, p = 0.010) at admission were associated with higher risk of severe covid-19. the likelihood of development of severe covid-19 increased with an increasing number of prognostic factors. conclusion: in conclusion, we found that diabetes mellitus, body temperature ≥ 37.8°c, peripheral oxygen saturation < 92%, and ck-mb > 6.3 are independent predictors of severe disease in hospitalized covid-19 patients. appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of covid-19. coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) was first reported in december 2019 in wuhan, hubei province, china. 1 this disease has spread rapidly to other regions around the world, including the western pacific, europe, eastern mediterranean, americas, and southeast asia. the world health organization declared covid-19 a pandemic on march 12, 2020. by april 19, 2020, approximately 2.28 million cases had been diagnosed with 155,124 deaths worldwide. although 81% of covid-19 cases are mild, 14% are severe, and 5% are critical. the fatality rate is about 50.0% in critical cases. 2 a number of factors associated with severe covid-19 have been identified from china. older age, male sex, presence of comorbidities, low oxygen saturation, and abnormal lab findings (high lactate dehydrogenase [ldh] , high procalcitonin, low cd4 cell count, low albumin level) were shown to be risk factors for severe however, patient-and disease-related factors vary from region to region, and these factors may be associated with the clinical severity of covid19. there have been no studies regarding prognostic factors for severe disease in covid-19 patients in korea. this study was performed to identify prognostic factors for severe disease in patients with covid-19 in daegu, korea. this was a retrospective observational study of 110 patients with confirmed covid-19 at yeungnam university medical center, daegu, korea, from february 19, 2020 to april 15, 2020 . during the study period, all adult patients (age ≥ 18 years) with covid-19 who were hospitalized via the emergency room or outpatient department were eligible for inclusion. demographic, clinical, laboratory, treatment, and outcome data were collected from the electronic medical records of the participants. demographic and clinical data included age, sex, comorbidities, symptoms and vital signs on admission, and treatment in the hospital. laboratory data consisted of complete blood count, blood biochemistry, and infection-related biomarkers. peripheral oxygen saturation was measured by pulse oximetry immediately on hospitalization of the patient. in-hospital case fatality rate was monitored until the final date of follow-up. the data were collected and analyzed by all authors. severe disease was defined as a composite outcome of acute respiratory distress syndrome (ards), intensive care unit care, or death. ards was diagnosed according to the berlin definition. 9 sars-cov-2 infection was confirmed by real-time reverse transcription polymerase chain reaction assay of nose and/or throat swap samples. continuous variables are expressed as means ± standard deviation and were compared by student's t-test or the mann-whitney u test. categorical variables are described as number (%) and were compared by the χ 2 test or fisher's exact test. univariable logistic regression analysis was performed to identify prognostic factors of severe covid-19. multivariable logistic regression analysis was conducted with variables that showed p < 0.05 in univariable analysis. we excluded variables from the univariable analysis if the number of events was too small for calculation and if there was no marked difference between two groups. in all analyses, two-tailed p < 0.05 was taken to indicate statistical significance. all statistical analyses were performed using spss software (ver. 24.0; spss inc., chicago, il, usa). this study was conducted in accordance with the tenets of the declaration of helsinki and was reviewed and approved by the institutional review board (irb) of yeungnam university hospital (yuh irb 2020-03-057). the requirement for informed consent was waived because of the retrospective study design. the final follow-up date was april 15, 2020. after excluding seven patients who were transferred to other hospitals, 110 hospitalized patients with confirmed covid-19 were included in this study (fig. 1) . baseline characteristics of all patients are summarized in table 1 . the mean age was 56.9 ± 17.0 and 62 patients (56.4%) were women. forty-nine patients (44.5%) had comorbidities, of which hypertension was the most common (33.6%) followed by diabetes mellitus (26.4%). the most frequently presenting symptoms were fever (56.4%) and cough (52.7%). the patients in the severe group were significantly older than the patients in the non-severe group (68.0 ± 11.9 vs. 53.9 ± 17.0, respectively, p < 0.001). the severe group was significantly more likely to have diabetes mellitus (60.9% vs. 17.2%, respectively, p = 0.001) and hypertension (52.2% vs. 28.7%, respectively, p = 0.033). on admission, body temperature (37.9°c ± 1.0°c vs. 37.3°c ± 0.7°c, respectively, p = 0.002) and respiration rate (23.1 ± 4.7 vs. 20.4 ± 1.7 breaths per minute, respectively, p = 0.013) were significantly higher in the severe group than the non-severe group. peripheral oxygen saturation was significantly lower in the severe group than the nonsevere group (87.7 ± 7.4 vs. 95.8 ± 3.6, respectively, p < 0.001). it was difficult to detect meaningful differences in radiologic findings between patients in the severe group and those who were not. laboratory findings on hospital admission are summarized in table 2 . in complete blood counts, white blood cell count (8.2 ± 3.4 vs. 6.3 ± 3.2, respectively, p = 0.017) and neutrophil count (7.1 ± 3.4 vs. 4.1 ± 3.0, respectively, p < 0.001) were higher in the severe group than the non-severe group. lymphocyte count (0.7 ± 0.3 vs. 1.6 ± 0.7, respectively, p < 0.001) and platelet count (184.7 ± 75.3 vs. 259.8 ± 104.6, respectively, p = 0.002) were significantly lower in the severe group than the non-severe group. with regard to blood chemistry, albumin level was significantly lower in the severe group than the non-severe group (3.1 ± 0.4 vs. 3.9 ± 0.5 g/dl, respectively, p < 0.001). concentrations of aspartate aminotransferase, total bilirubin, blood urea nitrogen, ldh, and creatine kinase-mb (ck-mb) were significantly higher in 3/10 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e209 severe group (n = ) non-severe group (n = ) patients hospitalized with covid patients were enrolled . % transferred out the severe group than the non-severe group. with regard to infection-related markers, c-reactive protein level was significantly higher in the severe group than the non-severe group (15.5 ± 8.8 vs. 3.3 ± 6.2 mg/l, respectively, p < 0.001), although procalcitonin level was not significantly different between the two groups (2.2 ± 5.6 vs. 0.1 ± 0.1 ng/ml, respectively, p = 0.094). three cases of bacterial co-infection (2 cases of klebsiella pneumonia, 1 case of clostridium difficile) were identified in the non-severe group. duration of viral shedding was not different between the two groups. multivariable analysis using variables with p < 0.05 in univariable analysis ( table 4 ). the rates of severe disease increased for patients with diabetes mellitus, body temperature ≥ 37.8°c, peripheral oxygen saturation ≤ 92%, and ck-mb > 6.3 (fig. 2) . the likelihood of development of severe covid-19 increased with increasing number of prognostic factors (p < 0.001, test for trend) (fig. 3) among the 110 patients with covid-19, 23 (20.9%) had severe disease and the in-hospital case fatality rate was 7.3% in this study. we showed that the presence of diabetes mellitus, body temperature ≥ 37.8°c, peripheral oxygen saturation < 92%, and ck-mb > 6.3 were independent predictors of severe disease in hospitalized covid-19 patients. to our knowledge, this is the first study to evaluate the prognostic factors of severe covid-19 in korea. diabetes mellitus is a major public health issue, with an estimated global prevalence of 9.3% in 2019. 10 a population-based cohort study showed that type 2 diabetes increased the risk of death associated with pneumonia, and hyperglycemia on admission was associated with increased mortality for both diabetic and nondiabetic patients with communityacquired pneumonia. 11 yang et al. 12 reported that diabetes and ambient hyperglycemia are independent risk factors for death and morbidity in sars patients. diabetes also results in immune dysregulation and more severe and prolonged lung pathology in middle east respiratory syndrome. 13 the main mechanisms underlying the poorer clinical outcomes in cases of infections associated with diabetes mellitus are as follows: 1) decreased t lymphocyte response; 2) decreased neutrophil function; 3) disorders of humoral immunity; and 4) depression of the antioxidant system. 14 in a recent study, covid-19 patients without other comorbidities but with diabetes were shown to be at greater risk of severe disease as assessed by organ damage, inflammatory factors, and hypercoagulability. in addition, covid-19 patients with diabetes are at high risk for disease progression. 15 the results of the present study suggested that the progression of covid-19 is influenced by diabetes mellitus. physicians should pay close attention to whether diabetic patients with covid-19 show rapid clinical deterioration. body temperature is one of the variables included in the pneumonia severity index 16 and systemic inflammatory response syndrome (sirs), 17 which can predict clinical outcomes in pneumonia. the febrile response is thought to be mediated by endogenous factors, called endogenous pyrogens. pyrogenic cytokines, such as tumor necrosis factor (tnf), interleukin (il)-1, il-6, and interferons (ifns), are released in response to exogenous stimuli, such as bacterial or viral products and toxins. 18 in covid-19, the levels of the proinflammatory cytokines il-1β, il-4, il-6, il-10, ifn-γ, and tnf-α are significantly higher in severe cases than in mild cases. 19 the results of the present study suggested that critical covid-19 patients have elevated levels of inflammatory cytokines, which increase body temperature. low peripheral oxygen saturation was shown to be an independent prognostic factor for severe covid-19. 8 many covid-19 patients experience rapid respiratory failure and hypoxemia without any signs of dyspnea, which is referred to as silent hypoxemia. 20 this unique characteristic of covid-19 makes it difficult to predict clinical deterioration accurately using traditional scores, such as quick sequential organ failure assessment and sirs. as covid-19 is a highly contagious infectious disease, medical staff tend to have less contact with patients. therefore, the discovery of a worsening condition in patients may be delayed. from this viewpoint, peripheral oxygen saturation measured immediately upon hospitalization through pulse oximetry can be used as a convenient and accurate marker for the prediction of clinical deterioration in covid-19. cardiac injury is associated with death, and severity of covid-19 is associated with acute cardiac injury. in the systemic review of the 28 studies with 4,189 confirmed covid-19 patients, severe covid-19 infection was associated with high cardiac injury related markers, such as troponin, ck-mb, and myoglobin. and also cardiac injury in covid-19 were related with higher mortality (or, 3.85; 95% ci, 2.13-6.96; p < 0.001). 21 it has been known that, the sars-cov-2 invades human cells via the receptor angiotensin converting enzyme ii (ace2). ace2 is expressed in the lung, heart, esophagus, kidney, bladder, and ileum. thus, organs that express ace2 are vulnerable to sars-cov-2 infection. 22 therefore, the measurement of cardiac damage markers on admission is needed in patients with covid-19, which predict the prognosis of covid-19. there are several chinese studies demonstrating the risk factors for severity of covid-19. li et al. 5 reported that elder age, hypertension, high cytokine levels, and high ldh levels were associated with severe covid-19 inpatients in wuhan. a study in anhui, china revealed that low fingertip oxygen saturation, and decreased cd4 cell count were independent risk factors for severe covid-19 patients. 8 diabetes, and maximum body temperature admission were risk factors for progression of covid-19. 15, 23 the predictors of severe disease progression on korean patients and those in chinese patients were not much different. this study had several limitations. first, this was a retrospective study conducted in a single center in korea, which subjected only hospitalized patients. therefore, these results cannot be generalized to all covid-19 patients. second, antiviral agents and corticosteroid usage were not included as variables in this study. our research focused on the baseline clinical characteristics and laboratory findings related to worsening of the patients' condition due to severe disease and not on treatment. third, selection bias could not be avoided because population-based data were not used. the disease severity of patients may vary between hospitals in the same region. fourth, proinflammatory cytokines and early cd8+ t-cell response that can be associated with disease severity, were not measured in this study. in conclusion, we found that the presence of diabetes mellitus, body temperature ≥ 37.8°c, peripheral oxygen saturation < 92%, and ck-mb > 6.3 are independent predictors of severe disease in hospitalized covid-19 patients. the likelihood of progression to severe covid-19 increased with an increasing number of prognostic factors. appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of covid-19. clinical characteristics of coronavirus disease 2019 in china characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention clinical characteristics and outcomes of older patients with coronavirus disease 2019 (covid-19) in wuhan, china (2019): a single-centered, retrospective study early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (covid-19) risk factors for severity and mortality in adult covid-19 inpatients in wuhan host susceptibility to severe covid-19 and establishment of a host risk score: findings of 487 cases outside wuhan risk factors for disease severity, unimprovement, and mortality in covid-19 patients in wuhan, china risk factors for severe covid-19: evidence from 167 hospitalized patients in anhui acute respiratory distress syndrome: the berlin definition global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9 type 2 diabetes and pneumonia outcomes: a population-based cohort study comorbid diabetes results in immune dysregulation and enhanced disease severity following mers-cov infection infections in patients with diabetes mellitus: a review of pathogenesis diabetes is a risk factor for the progression and prognosis of covid-19 a prediction rule to identify low-risk patients with community-acquired pneumonia the accp-sccm consensus conference on sepsis and organ failure circulating cytokines as mediators of fever clinical features and outcomes of 98 patients hospitalized with sars-cov-2 infection in daegu, south korea: a brief descriptive study critical care crisis and some recommendations during the covid-19 epidemic in china the impact of 2019 novel coronavirus on heart injury: a systematic review and meta-analysis single-cell rna-seq data analysis on the receptor ace2 expression reveals the potential risk of different human organs vulnerable to 2019-ncov infection analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease key: cord-277144-106q6ae0 authors: lee, ji yeon; kim, hyun ah; huh, kyungmin; hyun, miri; rhee, ji-young; jang, sukbin; kim, ji-yeon; peck, kyong ran; chang, hyun-ha title: risk factors for mortality and respiratory support in elderly patients hospitalized with covid-19 in korea date: 2020-06-11 journal: j korean med sci doi: 10.3346/jkms.2020.35.e223 sha: doc_id: 277144 cord_uid: 106q6ae0 background: the mortality risk of coronavirus disease 2019 (covid-19) is higher in patients with older age, and many elderly patients are reported to require advanced respiratory support. methods: we reviewed medical records of 98 patients aged ≥ 65 years who were hospitalized with covid-19 during a regional outbreak in daegu/gyeongsangbuk-do province of korea. the outcome measures were in-hospital mortality and the treatment with mechanical ventilation (mv) or high-flow nasal cannula (hfnc). results: the median age of the patients was 72 years; 55.1% were female. most (74.5%) had at least one underlying condition. overall case fatality rate (cfr) was 20.4%, and median time to death after admission was 8 days. the cfr was 6.1% among patients aged 65–69 years, 22.7% among those aged 70–79 years, and 38.1% among those aged ≥ 80 years. the cfr among patients who required mv was 43.8%, and the proportion of patients received mv/hfnc was 28.6%. nosocomial acquisition, diabetes, chronic lung diseases, and chronic neurologic diseases were significant risk factors for both death and mv/hfnc. hypotension, hypoxia, and altered mental status on admission were also associated with poor outcome. crp > 8.0 mg/dl was strongly associated with mv/hfnc (odds ratio, 26.31; 95% confidence interval, 7.78–88.92; p < 0.001), and showed better diagnostic characteristics compared to commonly used clinical scores. conclusion: patients aged ≥ 80 years had a high risk of requiring mv/hfnc, and mortality among those severe patients was very high. severe initial presentation and laboratory abnormalities, especially high crp, were identified as risk factors for mortality and severe hospital course. coronavirus disease is an infectious disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (sars-cov-2). approximately 3 months after the first report in wuhan, china, the number of cases exceeded 400,000 by late march. 1 high viral shedding early in the disease course and slow progression make the effort for containment extremely difficult, and a large surge of cases has been observed in europe and north america. 2, 3 its clinical course ranges from asymptomatic infection to acute respiratory distress syndrome (ards) and death. 4 although most patients undergo mild febrile illness, a relatively large proportion of patients need hospitalization and respiratory support such as high-flow nasal cannula (hfnc) or mechanical ventilation (mv). 5 case fatality rates (cfrs) vary significantly by country, as the magnitude and velocity of surge greatly affect the care of patients. however, severe cases and mortality are consistently reported among the elderly, and patients aged ≥ 60 years comprise the majority of fatal cases in both china and italy. 6,7 despite the importance of old age with respect to outcome, there have been no reports specifically aimed at examining the clinical characteristics and treatment outcomes in elderly patients with covid-19 who require hospitalization. information on the outcomes in this population, especially the need for mv/hfnc that requires specialized machines and considerable resources, is necessary for the public health response and planning. since february 19, 2020, a regional outbreak of covid-19 occurred in the daegu/gyeongsangbukdo province of korea (fig. 1) . owing to an expanded testing capacity and rapid public health response, most patients are considered diagnosed and monitored. although the healthcare capacity has been overstretched during the outbreak, the cfr observed in the area is substantially lower than the cfrs reported in china and italy, suggesting that the healthcare system has been largely capable of providing adequate care for patients. 8, 9 the clinical data from daegu/ gyeongsangbuk-do province would provide useful information regarding the characteristics of covid-19 in a situation that is different from the other two gravely affected countries. thus, we conducted a retrospective study to elucidate the clinical characteristics and risk factors for mortality and the need for mv/hfnc in elderly patients hospitalized with covid-19. we obtained medical records of patients aged ≥ 65 years who were admitted with laboratoryconfirmed covid-19 in four hospitals between february 18 and march 4, 2020. the end date was set to ensure that all patients were observed for at least 14 days after admission, as the median time from onset to mv was 10.5 days in a previous report and 75th percentile of time to death after symptom onset was reported to be 14 days. 9,10 all patients were residents in the daegu/gyeongsangbuk-do province, and diagnosis of covid-19 was made using a real-time reverse-transcriptase polymerase chain reaction (rt-pcr) assay of a nasopharyngeal swab or sputum according to the national guidelines. electronic medical records were reviewed to extract demographic characteristics, comorbidities, clinical features and laboratory findings on the day of admission, clinical course, treatment, and outcome. patients were followed until death or discharge from hospital, whichever came first. the outcome measures were all-cause in-hospital death and mv/hfnc. we did not include care in intensive care units (icus) as an outcome measure as many mechanically ventilated patients were treated outside an icu due to a shortage of icu beds. the severity of the clinical course was evaluated through the highest respiratory support required during the hospital stay. they were categorized into none, supplementary oxygen (via nasal prong or facial mask), hfnc, mv, and extracorporeal membrane oxygenation. noninvasive positive pressure ventilation was not administered to any of our study patients. nosocomial acquisition was defined as a diagnosis of covid-19 during admission in an acute-care hospital or a long-term care facility for other unrelated illnesses. the modified early warning score (mews) and national early warning score 2 (news2) were calculated as previously described. 11,12 patient characteristics were summarized and compared among outcomes using student's t-test or mann-whitney u test for continuous variables and χ 2 or fisher's exact test for categorical variables, as appropriate. in-hospital mortality of the two groups was compared using the kaplan-meier curve. a receiver operating characteristic curve was used to evaluate the accuracy of the prognostic factors. all tests were two-tailed, and significance was assessed at p < 0.05. r version 3.6.1 (r foundation for statistical computing, vienna, austria) was used for the analyses. the study was approved by the institutional review board of the samsung medical center (smc 2020-03-116-001) with waived informed consent. we identified 98 patients hospitalized with covid-19 who were aged ≥ 65 years. fifty-four patients (55.1%) were female, and the median age was 72 (interquartile range [iqr], 68-79; range, 65-93) years. most patients (74.5%) had underlying conditions; hypertension (52.0%), diabetes (27.6%), cardiovascular diseases (16.3%), chronic neurologic disease (14.3%), and malignancy (11.2%) were common comorbidities. eight patients (8.2%) had chronic lung disease, and six patients (6.1%) had chronic kidney disease. none of the patients had endstage renal disease requiring dialysis before their covid-19 diagnosis. lopinavir/ritonavir or darunavir/ritonavir was administered to 75 patients (76.5%) and hydroxychloroquine to 59 patients (60.2%). systemic glucocorticoids were administered to 28 patients (28.6%). the median time of follow-up since admission was 18 (iqr, 13-22) days. twenty patients died during their hospital stay, and the overall cfr was 20.4% ( table 1 ). the median time to death after admission was 8 (iqr, 5-11) days. the cfr among male patients was significantly higher than that among female patients (31.8% vs. 11.1%, p = 0.023). age was a significant predictor of mortality ( fig. 2a) ; the cfr was 6.1% among patients aged 65-69 years, 22.7% among those aged 70-79 years, and 38.1% among those aged ≥ 80 years died. the substantial effect of age on outcome was observed consistently when cfr was examined according to severity. the cfr among patients ≥ 80 years of age who required hfnc or mv was 87.5%, substantially higher than that of lower age groups (fig. 2b ). in addition, the time to death was longer in patients aged ≥ 80 years (median, 11 days; iqr, 6-15 days) than in patients aged 70-79 years (median, 7 days; iqr, 4-8 days), although the difference was not statistically significant (p = 0.141). the overall cfr among patients who required mv was 43.8% (n = 7/16). all 12 patients whose highest respiratory support was hfnc, who declined to be intubated, died. nosocomial acquisition was also a significant risk factor for mortality ( the overall proportion of patients received mv/hfnc was 28.6%. older patients were more likely to need mv or hfnc; among patients aged 65-69 years, 12.1% received mv/hfnc, but 36.9% of patients aged ≥ 70 years needed mv/hfnc (fig. 2c) . similarly, the proportion of patients who required supplementary oxygen was also higher in the older age groups. diabetes (or, 2.75; 95% ci, 1.07-7.05; p = 0.058), chronic lung diseases (or, 4.86; 95% ci, 1.08-21.93; p = 0.041), and chronic neurologic diseases (or, 4.27; 95% ci, 1.32-13.77; p = 0.021) were associated with the need for mv/hfnc ( (continued to the next page) data are presented as mean ± standard deviation, median (interquartile range) or number (%). or = odds ratio, ci = confidence interval, dm = diabetes mellitus, n/a = not available, mews = modified early warning score, news2 = national early warning score 2. table 2 . (continued) characteristics of the patients according to the highest respiratory support required likely to require mv/hfnc during their subsequent hospital stay. all patients who required vasopressors also needed mv/hfnc (n = 8). mews and news2 were significantly higher in those who received mv/hfnc. among laboratory findings on admission, a high white blood cell count, lymphocyte < 900/mm 3 (or, 10.48; 95% ci, 3.73-29.43; p < 0.001), blood urea nitrogen > 20 mg/dl (or, 6.08; 95% ci, 2.34-15.76; p < 0.001), serum creatinine > 1.0 mg/dl (or, 6.71; 95% ci, 2.53-17.78; p < 0.001), and crp > 8.0 mg/dl (or, 26.31; 95% ci, 7.78-88.92; p < 0.001) were predictive factors for higher respiratory support. a high crp level (> 8.0 mg/dl) showed the highest risk for a severe clinical course in our patients, so its diagnostic characteristics was compared with those of two commonly used prognostication scores ( table 3) . high crp levels showed higher sensitivity, specificity, and positive predictive value in predicting the need for mv/hfnc. the negative predictive values were comparable. the area under the receiver operating characteristic curve was also larger for high crp level. in our study of patients aged ≥ 65 years with covid-19, a high mortality rate and severe clinical course frequently requiring advanced respiratory support were observed. the cfr (20.4%) in our patients was markedly higher than the overall mortality of covid-19 in korea (approximately 1.4%). 13 approximately 29% needed mv or hfnc, and the cfr among that subgroup was very high (67.9%). most patients had at least one underlying condition, which complicated the clinical course. age was the most important preexisting risk factor for mortality and mv/hfnc. in particular, patients aged ≥ 80 years had a 38.1% chance of receiving mv/hfnc. among them, only one patient survived but was still on a mechanical ventilator at the time of data entry. the effect of older age on mortality has also been reported in china and italy, which is consistent with our findings. 6,7 furthermore, our data demonstrated the resources required to manage elderly patients with covid-19. combined with the relative risk of infection by age group and population distribution, our results provide critical information needed by healthcare facilities and public health authorities to prepare ventilators and hfnc machines to meet the expected demand. however, it should also be noted that no patients who used hfnc without further planning for mv survived in our study. the interpretation of our results is limited by the small number, but the limited role of hfnc alone may be taken into consideration when resources are extremely overwhelmed. as previous studies from china reported a lower mortality rate of patients treated with hfnc, there exists the possibility that our observation is specific to elderly patients. 14,15 nosocomial acquisition and the presence of comorbidities were identified as important risk factors for mortality. our results suggest that outbreaks in hospitals and long-term care facilities would result in grave consequences, which has been observed in the united states. 16 one interesting finding in our study is the lack of association between hypertension and mortality. previous large-scale epidemiological data from the chinese center for disease control and prevention reported that patients with hypertension had a high risk of death, similar to those in patients with chronic lung disease. 6 other studies also showed that hypertension is associated with mortality or icu care, 5,15,17 but conflicting reports also exist. 10, 18 in our study, hypertension was not a statistically significant risk factor in elderly patients, of whom about a half had hypertension. isolated hypertension is generally not regarded as an important prognostic factor in infectious diseases; thus, the possibility of confounding should be examined in future studies. a severe initial presentation, namely hypotension, tachypnea, hypoxia, or altered mental status, was indeed associated with a poor outcome. two commonly used prognostication scores (mews and news2) also correlated well with mortality. among laboratory findings, leukocytosis, lymphopenia, and high crp levels were associated with mortality and the need for mv/hfnc. such an association has been reported in previous studies on the overall population and in critically ill patients. 10,14,15 furthermore, we observed a very high degree of association with crp; its or for mortality was 25.33, and the or for mv/hfnc was 25.08. when the cutoff was set at 8.0 mg/dl, elevated crp had better diagnostic characteristics than those of mews and news2. these two scores measure vital signs only, so a high crp could be a useful addition for initial triage. neutrophilia, lymphopenia, and elevated lactate dehydrogenase or d-dimer have been associated with severe course and mortality in previous reports, but a strong association of crp was also reported in one study that specifically examined the risk factors for ards and death. 5 however, it is unclear whether this association reflects the degree of cytokine storm that leads to ards or the severity of viral infection. 19 nonetheless, this study suggests that respiratory support might be prepared in advance for patients with high crp as well as with mews ≥ 3 or news ≥ 2. our study has several limitations. first, it was a retrospective study with a relatively small number of patients. the possibility of confounding cannot be excluded. multivariable analysis using logistic regression was attempted, but an adequate model could not be constructed because of the small number and high collinearity between variables. second, our study subjects consisted of hospitalized patients; thus, those deemed to be sufficiently fit for home isolation were not included. this explains the high mortality and severity observed in our cohort. therefore, our results are not generalizable to mild cases. finally, although we limited our study to patients with a follow-up duration of ≥ 14 days, a substantial proportion of patients were still hospitalized at the time of data entry. although the risk of death was low after 14 days of admission in patients ( fig. 2a) , further follow-up is necessary. despite these limitations, we believe that our results provide valuable information on the clinical outcomes and resource requirements of care for elderly patients with covid-19 who have been shown to be the most vulnerable. we thought that waiting for the negative conversion of rt-pcr and subsequent discharge of patients would add little value to our results and delay the delivery of these important data. in a retrospective study on elderly patients hospitalized with covid-19, a high need for mv/hfnc and poor outcomes were observed. patients aged ≥ 80 years had a high risk of requiring mv/hfnc, and mortality among those patients with severe disease was extremely high. a severe initial presentation and laboratory abnormalities were identified as risk factors for mortality and severe hospital course. in addition to high mews or news2 covid-19) situation report -65. geneva: world health organization viral load kinetics of sars-cov-2 infection in first two patients in korea sars-cov-2 viral load in upper respiratory specimens of infected patients characteristics of covid-19 infection in beijing risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention case-fatality rate and characteristics of patients dying in relation to covid-19 in italy korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from korean society of infectious diseases and korea centers for disease control and prevention clinical features of patients infected with 2019 novel coronavirus in wuhan, china validation of a modified early warning score in medical admissions national early warning score (news) 2: standardising the assessment of acute-illness severity in the nhs. updated report of a working party. london: royal college of physicians updates on covid-19 in republic of korea clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study characteristics and outcomes of 21 critically ill patients with covid-19 in washington state outcome of elderly covid-19 inpatients clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of 140 patients infected with sars-cov-2 in wuhan pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology scores, high crp level was strongly associated with severity, suggesting its role in triage and prognostication. key: cord-283512-qly8iclf authors: na, ki ryang; kim, hae ri; ham, youngrok; choi, dae eun; lee, kang wook; moon, jae young; kim, yeon-sook; cheon, shinhye; sohn, kyung mok; kim, jungok; kim, sungmin; jeong, hyeongseok; jeon, jae wan title: acute kidney injury and kidney damage in covid-19 patients date: 2020-07-07 journal: j korean med sci doi: 10.3346/jkms.2020.35.e257 sha: doc_id: 283512 cord_uid: qly8iclf background: coronavirus disease 2019 (covid-19) is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection. this disease, which is quickly spreading worldwide, has high potential for infection and causes rapid progression of lung lesions, resulting in a high mortality rate. this study aimed to investigate the effects of sars-cov-2 infection on renal function in patients with covid-19. methods: from february 21 to april 24, 2020, 66 patients diagnosed with covid-19 at chungnam national university hospital were analyzed; all patients underwent routine urinalysis and were tested for serum creatinine, urine protein to creatinine ratio (pcr), and urine albumin to creatinine ratio (acr). results: acute kidney injury (aki) occurred in 3 (4.5%) of the 66 patients, and 1 patient with aki stage 3 underwent hemodialysis. upon follow-up, all 3 patients recovered normal renal function. compared with patients with mild covid-19, aki (n = 3) occurred in patients with severe covid-19, of whom both urine pcr and acr were markedly increased. conclusion: the incidence of aki was not high in covid-19 patients. the lower mortality rate in sars-cov-2 infection compared with previous middle east respiratory syndrome and sars-cov infections is thought to be associated with a low incidence of dysfunction in organs other than the lungs. novel coronavirus disease is a newly discovered contagious disease caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), primarily manifesting as an acute respiratory illness accompanied by interstitial and alveolar pneumonia; however, it can also affect multiple organs, such as kidneys and heart, the digestive tract, the blood, and the nervous system. 1 this disease was reported in december 2019 in wuhan, hubei province, china. 2, 3 in the following weeks, the infection spread across china and other countries. 4 -6 in korea, as of april 25, 2020, 10,718 patients have been diagnosed with covid-19, and 240 patients have already died. 9 worldwide, about 2.82 million patients have been diagnosed with the disease, and about 199,455 patients have died. 10 these numbers are difficult to compare due to differences in the medical systems of each country. nevertheless, the mortality rate of covid-19 is high (2.2% in korea and 7.0% worldwide). in this study, the clinical data of 66 patients diagnosed with covid-19 were analyzed, and the effects of sars-cov-2 infection on renal function and its complications were explored. we enrolled 68 patients with covid-19 who were hospitalized at chungnam national university hospital (daejeon, korea) from february 1 to april 24, 2020. all patients were tested for serum creatinine (scr) and underwent routine urinalysis. the inclusion criteria were: 1) age of at least 18 years, 2) having undergone urine protein to creatinine ratio (pcr) and urine albumin to creatinine ratio (acr) testing, and 3) estimated glomerular filtration rate (egfr) > 60 ml/min/1.73 m 2 at the time of visit. of 68 patients, one was pediatric, one was excluded due to a scr level of 4.3 mg/dl (egfr, 14.8 ml/min/1.73 m 2 ), and 66 were retained for the study. the patients' medical records were reviewed. data were collected, including age, gender, initial and follow-up scr and egfr (chronic kidney disease [ckd]-epidemiology collaboration), routine urinalysis with microscopy, urine pcr, urine acr, underlying disease (diabetes mellitus [dm], hypertension, ckd, and cardiovascular disease), and whether mechanical ventilation, extracorporeal membrane oxygenation (ecmo), or renal replacement therapy was implemented. both nasopharyngeal (using a swab) and sputum (secretion) samples were collected from all patients and tested by real-time reverse transcription polymerase chain reaction (rt-pcr) using the powerchek 2019-ncov real-time polymerase chain reaction kit (kogenebiotech co., ltd., seoul, korea). when positive was found in real-time rt-pcr, covid-19 was diagnosed. acute kidney injury (aki) was identified according to the guidelines of kidney disease: improving global outcomes (kdigo). it is defined as any of the following: an increase in scr of ≥ 0.3 mg/dl within 48 hours; an increase in scr of ≥ 1.5 times the baseline, which is known or presumed to have occurred within the past 7 days; or urine volume < 0.5 ml/kg/hr for 6 hours. aki is staged for severity according to the criteria presented in table 1 . 11 continuous variables were analyzed using student's t-test and categorical covariates using pearson's χ 2 test and fisher's exact test (used with limited data). continuous variables are expressed as means and standard deviation and discrete variables as percentages (%). the differences in the duration of follow-up according to group were evaluated using the kruskal-wallis test. all analyses were conducted using spss statistics version 20.0 (ibm corp., armonk, ny, usa), and p values of less than 0.05 were considered statistically significant (spss version 20.0; spss inc., chicago, il, usa). the institutional review board (irb) of chungnam national university hospital (irb no.2020-04-030) approved this study. the informed consent was waived. we conducted this study in compliance with the principles of the declaration of helsinki. a total of 66 patients, 35 (53.0%) of whom were male, were analyzed, and the mean age was 45.6 years. the mean initial scr level was 0.65 ± 0.18 mg/dl, and the mean initial egfr was 113.1 ± 17.4 ml/min/1.73 m 2 . the prevalence of dm, hypertension, and cardiovascular disease was 15.2%, 18.2%, and 3.0%, respectively ( table 3) . during the observation period, three (4.5%) patients were found to have aki, according to the criteria defined in this study. three patients had aki stage 1, aki stage 2, and aki stage 3 each. hemodialysis was performed in the patient with aki stage 3 due to renal function deterioration. however, renal function improved, hemodialysis was discontinued, and renal function returned to normal. two patients with aki stages 1 and 2 each regained normal renal function. for the three aki patients, it was confirmed that nephrotoxic agents were more likely to have been the cause than other causes of aki. all three patients used vancomycin, and aki developed after using vancomycin. the first patient, a 62-year-old-man, had no other underlying disease than schizophrenia, and his scr was 0.81 mg/dl at the first examination after hospitalization. chest computed tomography (non-contrast) examination during the first visit showed multifocal consolidation with ground-glass opacity and reticular opacity in all 5 lobes of both lungs. the patient took lopinavir/ritonavir for 19 days starting from the day of hospitalization. mechanical ventilation was performed the next day, and ecmo was commenced 4 days later and maintained for 17 days. blood cultures were performed when fever was identified, and vancomycin was added on the 10th day of hospitalization. before using vancomycin, his scr level was 1.0 mg/dl, but his renal function worsened after using vancomycin. his scr gradually deteriorated to 1.19 mg/dl after 2days, 2.26 mg/dl after 3 days, and 3.35 mg/dl (peak) after 4 days of using vancomycin. the urine output decreased too (< 400 ml/day), so vancomycin was discontinued and continuous renal replacement therapy (crrt) was started on day 14 of hospitalization and maintained for 18 days. the patient's laboratory data were closely followed up after crrt was discontinued. the urine output was well maintained, but his scr was continuously elevated (peak scr: 5.14 mg/dl) and hemodialysis was performed twice. afterwards, the scr values improved and remained in the normal range without hemodialysis. the last recorded scr value for this patient was 1.09 mg/dl. the second patient, a 78-year-old-woman, had hypertension as underlying disease and was on medication. although she had no history of dm, her serum glucose was over 200 mg/dl at the time of visit. the hba1c level measured after admission was 6.2%. on the first day of hospitalization, she was intubated and mechanical ventilation was maintained. an inotropic agent (norepinephrine) was used as blood pressure decreased. ecmo was commenced 1 day after the admission. initial scr was 0.53 mg/dl upon hospitalization. piperacillin/ tazobactam and lopinavir/ritonavir were used from the first day of hospitalization. piperacillin/tazobactam was maintained for 4 weeks, and lopinavir/ritonavir was used for 9 days. trimethoprim/sulfamethoxazole was used after 17 days of admission, and vancomycin was used after 29 days of admission. the scr level before using vancomycin was 0.60 mg/ dl, scr 0.61 mg/dl 1 day after, scr 1.10 2 days after, and scr 1.13 mg/dl (peak) after 3 days of vancomycin use indicated aki (stage 1). since then, though vancomycin was used continuously, scr improved to baseline cr level. the last recorded scr value was 0.54 mg/dl. the third patient, a 64-year-old-woman, had surgery for thyroid cancer 8 years ago and had no other underlying disease. her scr was 0.41 mg/dl at the time of admission. immediately after admission, the patient was intubated, after which mechanical ventilation and ecmo were performed. mechanical ventilation was maintained for 12 days, and ecmo was maintained for 11 days. during hospitalization, the patient took lopinavir/ritonavir for 12 days. vancomycin was commenced 4 days after admission. scr level before vancomycin use was 0.56 mg/dl, scr a day after the commencement of vancomycin use was 1.11 mg/dl, and scr 2 days after the commencement of vancomycin was 1.20 mg/dl (peak); indicating aki (stage 2). after that, although vancomycin was maintained for one week, scr improved to baseline cr level. the last recorded scr level was 0.54 mg/dl. the three patients' laboratory data and clinical events are shown in fig. 1 in all 66 patients, routine urinalysis with a dipstick test was performed at the time of or during hospitalization. trace and + albumin on a dipstick test was found in nine (13.6%) patients (trace in one patient, 1+ in two patients, and 2+ in six patients). all patients were randomly tested for urine pcr and acr more than once. in 20 (30.3%) out of 66 patients, urine pcr was higher than the normal range, 11 (16.7%) had severely increased proteinuria, and 9 (13.6%) had moderately increased proteinuria. of the 11 patients with severely increased proteinuria, 10 had increased albuminuria, and one patient had no albuminuria. none of the nine patients with moderately increased proteinuria had albuminuria. ten of 66 patients showed hematuria with red blood cell (rbc) counts > 3/ hpf on urine microscopy. 13 eight of them were patients with severely increased proteinuria, and two were young women whose hematuria was not clinically meaningful due to the overlapping menstrual period. the recovery of 20 patients with elevated urine pcr was compared. for patients with moderately increased proteinuria, on follow-up, six out of nine had not improved, and three had recovered to a normal range. for patients with severely increased proteinuria, on followup, 1 out of 11 had not improved, 4 had improved (a reduction of over 50% compared with their highest urine pcr levels), and 6 had recovered to a normal range. among covid-19 patients, the clinical classification was done according to the national health commission of china guidelines (version 7) into mild, moderate, and severe cases. 14 there were 21 mild cases, 37 moderate cases, and 8 severe cases. a total of three patients with aki were included in the severe cases (p = 0.001). there was a high frequency of both the urine pcr and acr in the severe cases, and proteinuria and albuminuria were also more severe in the severe covid-19 group (p < 0.001) ( table 4) . no patients died of covid-19 during the study period. the initial step of sars-cov-2 infection is its entry into the human cells. sars-cov-2 and sars-cov share a common ancestor resembling the bat coronavirus hku9-1. coronaviruses have very similar spike protein 3d structures considered to have a strong binding affinity to the human cell receptor, angiotensin-converting enzyme 2 (ace2). therefore, cells expressing ace2 may be target cells and are thus susceptible to sars-cov-2 infection; such cells include alveolar type ii cells of the lungs. 16 thus, we believe that the pattern of ace2 expression in different organs and tissues could reveal the potential risk for sars-cov-2 infection because the target cells expressing ace2 may permit the entry, multiplication, spread, and pathogenesis of coronavirus. previously, the rna and protein expressions of ace2 were investigated using bulk samples from the heart, lungs, kidneys, and other organs. 17 therefore, sars-cov-2 can affect not only the lungs but also other organs, as well as cause organ failure in other organs, including the kidney. chu et al. 18 reported that of the 536 sars patients analyzed, 36 (6.7%) had aki, and in a study that analyzed 30 patients with middle east respiratory syndrome coronavirus (mers-cov) infection, aki occurred in eight (26.7%). 19 in our study, 3 (4.5%) out of 66 patients had aki, and they all recovered to normal scr levels. compared with previous human coronaviruses, such as mers-cov and sars-cov, sars-cov-2 infections were found to have a lower incidence of aki. this is similar to the results of the analysis of 119 patients who were recently reported to have covid-19 infection (aki occurred in 0 out of 116 patients). 20 in a meta-analysis of covid-19 patients reported by hu et al., 21 the results were similar to those of aki occurring in 2.1% of patients. in 20 patients, the urine pcr increased, and in 10 patients, the urine acr increased. when the urine acr is normal and the urine pcr is increased, renal tubular damage can be estimated in relation to infection rather than glomerular disease or glomerular damage. 22, 23 compared with a previous study on mers-cov infection, 19 sars-cov-2 infection exhibited less proteinuria (30.3%), suggesting that aki and renal tubular damage caused by sars-cov-2 is less severe compared with previous coronavirus (mers-cov) infections (proteinuria occurred in 60% of patients). our study revealed results similar to those reported recently on sars-cov-2 infection. in a study recently published by wang et al., 20 dipstick tests were conducted on 111 sars-cov-2-infected patients (except for those with ckd), and 8 (7.2%) patients had trace or + albumin. this result is similar to that of the 9 (13.6%) out of 66 patients, in our study, whose dipstick tests revealed trace or + albumin. this study had some limitations. the study population was selected from a single institution. all three patients with aki underwent mechanical ventilation and ecmo, and it was difficult to distinguish whether aki was caused by sars-cov-2 infection or was associated with treatments, such as ecmo and vancomycin. 24,25 therefore, it is possible that the incidence of aki related to covid-19 was overestimated. in fact, all three patients used both ecmo and vancomycin, and aki developed after vancomycin use. 26 therefore, it is thought that aki is more likely to be associated with the treatment than with sars-cov-2 infection, and the likelihood of aki being associated with sars-cov-2 infection may be lower. in addition, when tubular damage, namely, acute tubular necrosis, occurred, a follow-up of more than 2-4 weeks after improvement of infection was considered sufficient 27,28 ; however, due to insufficient follow-up, it was difficult to evaluate whether there was an improvement in proteinuria. finally, it was difficult to tell whether it was proteinuria caused by kidney damage or functional proteinuria caused by fever and infection. in this study, tests for hematuria such as rbc count and dysmorphic rbc were not performed. however, hematuria was also found in eight out of 11 patients with severely increased proteinuria. as such, it can be assumed that the possibility of the proteinuria being due to kidney damage is higher than that of its being functional proteinuria. 7/9 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e257 in conclusion, covid-19, which is caused by sars-cov-2 infection, is thought to have less effect on the kidneys than the lungs, where it leads to rapidly progressing lung lesions. in our study, there was a lower percentage of patients with aki (4.5%) and moderately to severely increased proteinuria (30.3%) than in previous human coronavirus infections. compared with the mortality rates of mers-cov and sars-cov infections, which are 34.4% and 9.6%, respectively, the mortality rate of sars-cov-2 infection is lower, which may be due to the less organ dysfunction it causes overall despite its effect on the lungs. moreover, the highly infectious nature of sars-cov-2 infection, compared with mers-cov and sars-cov infections, and the rapid progression of lung lesions it causes make future research on vaccines and therapeutics of utmost importance. the novel coronavirus 2019 epidemic and kidneys clinical features of patients infected with 2019 novel coronavirus in wuhan, china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia importation and human-to-human transmission of a novel coronavirus in vietnam first case of 2019 novel coronavirus in the united states the first two cases of 2019-ncov in italy: where they come from the-second-meeting-of-the-international-healthregulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov). update 2020 world health organization. who director-general's remarks at the media briefing on 2019-ncov on 11 ministry of health & welfare (kr) covid-19 dashboard kidney disease: improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury kidney disease: improving global outcomes (kdigo) ckd work group. kdigo 2012 clinical practice guideline for the evaluation and management of chronic kidney disease diagnosis, evaluation and follow-up of asymptomatic microhematuria (amh) in adults: aua guideline diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7) evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission aki in covid-19 patients a pneumonia outbreak associated with a new coronavirus of probable bat origin single-cell rna-seq data analysis on the receptor ace2 expression reveals the potential risk of different human organs vulnerable to 2019-ncov infection acute renal impairment in coronavirusassociated severe acute respiratory syndrome renal complications and their prognosis in korean patients with middle east respiratory syndrome-coronavirus from the central mers-cov designated hospital coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from wuhan, china prevalence and severity of corona virus disease 2019 (covid-19): a systematic review and meta-analysis renal albumin absorption in physiology and pathology factors associated with major adverse kidney events in patients who underwent veno-arterial extracorporeal membrane oxygenation acute kidney disease stage predicts outcome of patients on extracorporeal membrane oxygenation support vancomycin and the risk of aki: a systematic review and meta-analysis imaging-based monitoring of the renal graft renal diseases key: cord-274788-oyk8js16 authors: bae, sanghyuk; kim, hwami; jung, tae-young; lim, ji-ae; jo, da-hye; kang, gi-seok; jeong, seung-hee; choi, dong-kwon; kim, hye-jin; cheon, young hee; chun, min-kyo; kim, miyoung; choi, siwon; chun, chaemin; shin, seung hwan; kim, hee kyoung; park, young joon; park, ok; kwon, ho-jang title: epidemiological characteristics of covid-19 outbreak at fitness centers in cheonan, korea date: 2020-08-05 journal: j korean med sci doi: 10.3346/jkms.2020.35.e288 sha: doc_id: 274788 cord_uid: oyk8js16 background: in february 2020, a coronavirus disease 2019 (covid-19) outbreak was reported in fitness centers in cheonan, korea. methods: from february 24 to march 13, an epidemiological investigation was conducted on the fitness center outbreak. all those who were screened were tested for severe acute respiratory syndrome coronavirus-2 (sars cov-2) using real-time reverse transcriptase polymerase chain reaction. contacts were traced and self-isolated for 14 days. we determined the epidemiological characteristics of confirmed cases of sars-cov-2 infection, and estimated the time-dependent reproduction number to assess the transmission dynamics of the infection. results: a total of 116 cases were confirmed, and 1,687 contacts were traced. the source cases were 8 zumba instructors who led aerobics classes in 10 fitness centers, and had the largest average number of contacts. a total of 57 zumba class participants, 37 of their family members, and 14 other contacts were confirmed as cases. the attack rate was 7.3%. the contacts at zumba classes and homes had a higher attack rate than other contacts. the mean serial interval (± standard deviation) were estimated to be 5.2 (± 3.8) days. the time-dependent reproduction number was estimated to be 6.1 at the beginning of the outbreak, but it dropped to less than 1, 2 days after the epidemiological investigation was launched. conclusion: the results suggest that the covid-19 outbreak was effectively contained with rigorous contact tracing, isolating, and testing in combination with social distancing without a lock-down. coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), and often presents with cough, fever, and shortness of breath. the severity varies from mild discomfort to fatal, and according to the korea centers for disease control and prevention (kcdc), the crude case fatality rate in korea is reported to be 3.02% among males and 1.91% among females as of may 2020. 1 the first case in korea, identified on january 19, 2020, was a chinese woman traveling from wuhan, china. she had fever of 38.3°c when she arrived at incheon airport, korea. 2 the 29th case reported in korea was the first person who had not traveled to china, and the confirmation of this case was taken as a sign of imminent community spread. soon, an outbreak at a church in daegu which involved the 31st reported case, and another outbreak at a local hospital in cheongdo dramatically increased the number of cases diagnosed in korea. on february 23, within a week of the first outbreak, the korean government raised its infectious disease alert level from alert (orange) to serious (red), and more people with respiratory symptoms were tested for sars-cov-2. 3 on february 24, the first cases were confirmed in cheonan, chunchungnam-do (province), a city with population of 650,000. an official epidemiological investigation was launched jointly by the chungnam center for infectious disease control & prevention and the kcdc, in cooperation with local governments. the number of cases in cheonan increased rapidly, and on february 27, 35 new cases were confirmed as having covid-19. among the newly confirmed cases, three with similar date of onset had reported attending the same fitness center. this was the first clue, and an outbreak associated with zumba classes in fitness centers was identified in subsequent epidemiological investigations. as of march 11, a total of 116 cases of among instructors, students, their family members, and co-workers had been confirmed. 4 zumba is an exercise fitness program which combines aerobic exercise with music, and oriental and latin dance moves. 5 in the fitness centers where the zumba classes were held, a large number of students had taken classes in a relatively crowded space, although ventilation systems were working properly. zumba is one of the most popular high-impact physical activities, 6 and it provides benefits regarding cardiovascular, respiratory and proprioceptive functions. 7 -9 however, considering that covid-19 is transmitted by droplet and fomites, 10 high-impact group exercise in a confined indoor space, such as a zumba class, could provide an environment prone to easy transmission of sars-cov-2 infection, as the droplets produced by exhalation or cough of a patient during the exercise have higher chance of reaching the nose, mouth or eye of other class participants directly, as well as remaining on the surface of the exercise equipment and later transmitted by contact. the staff of a hospital where some of the cases were treated have reported on the clinical characteristics of 54 cases who were treated in their hospital. 11 we included these cases in our investigation. however, the previous report was not based on the results of the official epidemiological investigation conducted by the kcdc, and it did not cover the all aspects of the outbreak, but described only a portion of the cases and contacts. in this report, we describe the epidemiological characteristics of the covid-19 outbreak at fitness centers in cheonan, korea, based on the official epidemiological investigation, and document the effectiveness of contact tracing and isolation at containing the outbreaks. from february 24 to march 13, 2020, all specimens of contacts were collected at designated screening centers/stations, based on the residential address of the contact. a total of 16 screening centers in 5 metropolitan cities/provinces, cheonan and asan in chunchungnamdo, sejong, seoul, daegu, and gyeonggi-do, were visited by the contacts. in sejong, cheonan, and asan, where most of the cases related to zumba classes occurred, drivethrough screening sites were opened on february 26 and 28, and march 3, respectively, and most contacts used this method. nasopharyngeal and oropharyngeal swab samples were collected from the contacts and sent to testing facilities selected by the kcdc which had been certified for quality control. samples were tested for sars-cov-2 using real-time reverse transcriptase polymerase chain reaction (rt-pcr). during the outbreak, approximately 298 public health workers were involved in contact tracing and isolation: 13 epidemiological investigators, approximately 140 at screening centers/stations, and 145 in quick response teams. when a person was confirmed with covid-19, he or she was interviewed and asked the onset date of their symptoms. then they were asked about their movements during the 14-days before the onset of symptoms. closed-circuit television camera footage, tracking credit card usage, and retrieving gps signal records of their mobile phone were used to identify possible transmission paths. contact was defined as any person who had been within 2 m from a confirmed case from 1 day before symptom onset of the case, without appropriate personal protection. however, in practice, the technical definition may vary due to type of mask, symptom of confirmed case, duration of contact, exposure status and timing, and the designation of contact was made based on the final assessment by epidemiological investigators. the contacts were instructed within 24 hours of being identified as a contact to self-quarantine for 14 days, and their activities were monitored telephonically twice a day by a public health official. the contacts were tested for sars-cov-2 when they developed related symptoms. the screening policy for asymptomatic contacts differed from one local government to another, and not all asymptomatic contacts were tested. in order to identify undetected contacts, public announcements on the movement of the cases were made and those who had been to the same places as the cases were encouraged to seek testing if they developed any covid-19-related symptoms. we recorded the daily number of contacts tested. demographic characteristics including age and sex, symptom onset date, the earliest and latest contact date with case were gathered by interviewing the patients at the time of epidemiological investigation. the symptom onset date of four cases who were identified by contact tracing could not be determined, and their dates of onset had not been recorded. the contacts were divided into 3 groups: students, family, and others including co-workers according to the setting of contact. we calculated attack rate for each contact type, and the attack rates were averaged. we subtracted the earliest and the latest contact dates from onset date to estimate incubation period. we used the two dates at the beginning and end of the contact window to estimate the minimum and maximum possible incubation periods, and calculated the medians of the estimated minimum and maximum individual incubation periods. we estimated serial interval and time-dependent reproduction number (r t ) as an indicator to measure the transmission of sars-cov-2. we estimated r t based on the date of symptom onset, using package "r0" 12 of r version 3.6.3. 13 the serial interval was estimated based on the assumption of a gamma distribution. we also estimated the reproduction number of the present outbreak using the exponential growth method. the data were collected as part of an epidemiological investigation of kcdc, and ethical approval and individual consent were not applicable. the use of the data was approved by kcdc. the epidemiological investigation revealed that the 8 zumba instructors among the cases had attended a national zumba instructors workshop in cheonan, and contacted a unknown source case. 4 these instructors led zumba classes in 10 fitness centers. zumba class students were contacted. among the cases, 8 were zumba instructors and 57 were their students, and additional 37 of their family members and 14 other contacts were diagnosed with covid-19 during the outbreak. the instructors had highest average number of contacts ( table 1) . there were 1,687 contacts identified, and 108 were diagnosed (except the first cases from the national workshop, who were not contacts). the attack rate was 7.3%, but it was higher among the zumba students (23.2% in fitness centers) and family members (21.6% in homes) ( table 2) . among family members, spouses of the cases had the highest attack rate (28%). the median incubation period is estimated between 4 and 9 days, and the maximum of the estimates of shortest and longest were 20 and 22 days, respectively (fig. 1) . the mean serial interval (± standard deviation) was estimated to be 5.2 (± 3.8) days. the epidemic curve ( fig. 2a) shows the waves of transmission of sars-cov-2. the first wave was the students who were infected by the instructors, and the second wave included the exposed family members. the trend of the number of testing shows two peaks which are roughly coincide with the number of the diagnosed (fig. 2b) . the highest number of testing were recorded on february 29, and 160 were tested. a total of 1,132 (66.4%) tests were conducted during the outbreak among the contacts. there was a mean of 2.2 (± 5.0) days between the date of symptom onset and diagnosis. due to the pre-emptive diagnostic testing strategy, 30 cases of confirmed sars-cov-2 infection were asymptomatic at the time of diagnosis. they developed symptoms while under quarantine, and the longest interval between diagnosis and subsequent symptom onset was 13 days (fig. 3) . among the initial asymptomatic patients, 4 transmitted sars-cov-2 infection to others. at the beginning of the outbreak, the r t was estimated to be as high as 6.1, but it fell below 1 on february 26, 2 days after the initiation of the epidemiological investigation (fig. 2c) . the reproduction number of the present outbreak was 0.79 (95% ci, 0.66-0.93). in the present study, we described epidemiological characteristics of a covid-19 outbreak in fitness centers in cheonan, korea from february 24 to march 13, 2020. a total of 116 cases were diagnosed, and 1,687 contacts were isolated and traced. as the epidemiological curve ( fig. 2a) shows, the sars-cov-2 infection was transmitted in waves, affecting the students and their family members. the attack rates were higher among contacts in the fitness centers and homes compared to other places. sars-cov-2 is transmitted by droplets and fomites, 10 and the results of this investigation show that contacts in a confined indoor space, such as high intensity group exercises and homes, are more likely to become infected. also, fitness centers and homes are places where social distancing and mask-wearing are hard to maintain, and contacts in these places are probably more vulnerable to infection. the attack rate among home contacts was higher than that reported at an outbreak at a call center in seoul, korea (16.2%). 14 this may due to the different characteristics of the cases in the two outbreaks; the initial cases at homes in the present outbreak were mostly housewives (zumba class enrollees), who spend a large amount of time at home and the chance of contacting other family members was probably higher than that among workers at a call center. the mean period between diagnosis and symptom onset was 2.2 days, and this was achieved by contact tracing and isolating. many took pre-emptive tests, and those who did not were closely monitored and tested as soon as they reported symptoms. this active contact tracing probably reduced the spread of sars-cov-2 in korea, and the contact tracing eventually exceeded the transmission of the virus, ending the outbreak. for example, there were hospital staff and cheonan city hall officials among the cases whose routine daily activities bring them into contact with a large number of people and who thus probably have higher chance of transmitting the virus to the wider population, but this was successfully averted by early detection. the mean serial interval reported in early stage of outbreak was 7.5 days in wuhan, 15 and 6.6 days in korea. 16 these estimates are longer than our estimate of 5.2 days. other study analyzed pooled data extracted from published reports and estimated that the serial interval was 4.7 days, 17 which is comparable to our estimate. the estimates in the previous reports were based relatively small numbers of cases: 6, 7, and 28 pairs in wuhan, korea, and pooled data, respectively, compared to our 116 cases. another study from china of 291 cases showed that estimated median incubation period was 4 days. 18 the authors estimated the incubation period by calculating the interval between the earliest contact date and the date of symptom onset, which is comparable to our method of shortest estimation, which was 4 days. the r t declined gradually from the beginning of the outbreak. when the outbreak was first identified in cheonan on february 24, the r t was already as low as 1.19, and the decrease cannot be entirely explained by the measures taken after the identification of the outbreak. the decline before the initiation of the epidemiological investigation may be explained by two factors. first, transmission in the earlier stage occurred in the confined indoor spaces where vigorous physical activities were taking place, and this might have provided more suitable environment for the virus to spread than in the later stage of the outbreak. the other factor is increased public awareness for covid-19. february 18, the date of onset of the first case in our study, was the same day that the 31st patient in korea was notified, which had heightened public awareness. the korean government initiated official social distancing on 7/9 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e288 cases period between diagnosis and onset, day february 22 and raised its infectious disease alert level to the highest on february 23, one day before the identification of the outbreak. it is possible that the increased awareness and national intervention had led public to adopt effective measures against the transmission of the virus before the present outbreak was identified. in wuhan, china, r t was used to demonstrate the effect of public health interventions, such as city lockdown and home quarantine. 19 in 13 days, the r t decreased from 3.80 to 1.02 after the initiation of city lockdown. cheonan had not been locked down, but the effectiveness of the measures appears to have been similar. as of may 8, no cases have been reported in cheonan since the last case was reported march 17, except for imported cases from other cities in korea or from outside the country. the were no case fatalities reported in the present outbreak. among the 54 hospitalized cases that described previously and only 1 patient (1.9%) required treatment with supplementary oxygen. 11 an ecological study showed that case fatality rate was positively associated with the cumulative number of cases and negatively associated with the intensity of testing. 20 the favorable clinical outcome of the present outbreak is probably the result of early detection of contacts and rigorous testing forsars-cov-2. a previous epidemiological investigation of an outbreak in a single call center in seoul, korea reported that 99.8% of traced contacts had been tested. 14 the contacts in the present study were not as rigorously tested, since the national capacity for testing was still being mobilized as the time of the outbreak. however, the same principle of early tracing, isolating, and testing of the contacts was effectively applied to control the outbreak at multiple fitness centers in a city with population of 650,000. ?brdid=1&brdgubun=11&ncvcontseq=&contseq=&board_id=&gubun=. updated 2020. accessed the first case of 2019 novel coronavirus pneumonia imported into korea from wuhan, china: implication for infection prevention and control measures korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from covid-19 outbreak at fitness centers in cheonan, korea 4. chungnam center for infectious disease control and prevention; epidemiology & case management team covid-19 national emergency response center investigation of covid-19 outbreaks through zumba dance classes in korea the effectiveness of an 8-week zumba programme for weight reduction in a group of maltese overweight and obese women effects of zumba® and aquagym on bone mass in inactive middle-aged women the health-enhancing efficacy of zumba® fitness: an 8-week randomised controlled study effect of two choreographed fitness group-workouts on the body composition, cardiovascular and metabolic health of sedentary female workers ®): is the "fitness-party" a good workout? report of the who-china joint mission on coronavirus disease 2019 (covid-19). geneva: world health organization cluster of coronavirus disease associated with fitness dance classes r0: estimation of r0 and real-time reproduction number from epidemics. vienna: r foundation for statistical computing r: a language and environment for statistical computing. vienna: r foundation for statistical computing coronavirus disease outbreak in call center early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiologic characteristics of early cases with 2019 novel coronavirus (2019-ncov) disease in korea serial interval of novel coronavirus (covid-19) infections clinical characteristics of coronavirus disease 2019 in china association of public health interventions with the epidemiology of the covid-19 outbreak in wuhan, china flattening-the-curve associated with reduced covid-19 case fatality rates-an ecological analysis of 65 countries we would like to express appreciation to hyunok baek, younglim jeong, hyeongi lee, youngmi kim, jeongdong shin, wontae cho, kwanyong jeong (chungnam epidemiology and case management team), yeongju na, sohee lee, jinseon choi (cheonan seo-buk-gu public health center), asan public health center, and sejong special self-governing city public health center for their efforts to investigate and respond to this outbreak of covid-19. key: cord-323326-p7vrlmrf authors: min, jinsoo; kwon, soon kil; jeong, hye won; han, joung-ho; kim, yeonkook joseph; kang, minseok; kang, gilwon title: end-stage renal disease and risk of active tuberculosis: a nationwide population-based cohort study date: 2018-12-13 journal: j korean med sci doi: 10.3346/jkms.2018.33.e341 sha: doc_id: 323326 cord_uid: p7vrlmrf background: the converging epidemics of tuberculosis (tb) and end-stage renal disease (esrd) have generated a significant public health burden, however, previous studies have been limited to a small number of patients. this nationwide cohort study aimed to assess the rate of developing active tb among patients receiving dialysis for esrd. methods: the korean national health insurance database was used to identify patients receiving dialysis for new-onset esrd during 2004–2013, who were propensity score matched to an equivalent number of non-dialysis subjects from the general population. the incidences of active tb in the esrd and control cohorts were calculated for 2004–2013, and multivariable cox proportional hazards model was used to evaluate the esrd-related risk of active tb. results: during 2004–2013, 59,584 patients received dialysis for newly diagnosed esrd. in the dialysis and control cohorts, 457 (0.8%) and 125 (0.2%) cases of active tb were detected, respectively. patients with esrd were associated with a significantly higher risk of active tb compared to the controls (incidence rate ratio, 4.80). the esrd cohort had an independently elevated risk of active tb (adjusted hazard ratio, 4.39; 95% confidence interval, 3.60–5.37). conclusion: we found that patients receiving dialysis for esrd had an elevated risk of active tb. these results highlight the need for detailed and well-organised guidelines for active tb screening among patients with esrd. tuberculosis (tb) is a global public health threat and remains a major cause of death from infectious diseases. among the many risk factors for active tb, 1 end-stage renal disease (esrd) that requires dialysis has recently been highlighted because of the high global prevalence of this condition, which is related to the increased incidence of diabetes and aging populations in both developing and developed countries. 2, 3 korea is confronted with increasing populations of elderly individuals and patients with diabetes, which has led to a rapid increase in the number of patients with esrd. 4 thus, the convergence of the tb and esrd epidemics is generating a significant public health burden and making it difficult to control tb in korea, which has an intermediate tb-related burden. chronic kidney disease (ckd) is associated with altered cellular immunity that is caused by various factors, including advanced age, uraemia, hypoalbuminemia, malnutrition, and medical immunosuppression. during esrd, abnormal functioning of monocytes, neutrophils, and dendritic cells are directly linked to the risk of infection. 5 furthermore, ckd is linked to other conditions that increase the risk of developing active tb, such as diabetes, transplantation, and human immunodeficiency virus (hiv) infection. moreover, dialysis patients with esrd are frequently exposed to the healthcare setting and are very susceptible to nosocomial infections, which might be a source of tb outbreaks. 6 transmission of infectious diseases, such as tb, has attracted considerable public attention in korea since the middle east respiratory syndrome outbreak during 2015, which involved a large number of suspected hospital-acquired infections. 7 tb is a known significant threat to patients receiving dialysis, as they have a 2-fold higher tbrelated mortality rate than the general population and a 3-fold higher rate than patients receiving dialysis without tb. 8 the health threats of tb to patients with esrd have attracted researchers' attention for several decades, however, previous studies have been limited to a small number of patients. this retrospective propensity score-matched cohort study used korean national health insurance data to examine the incidence of active tb in a large population of patients receiving dialysis, as well as the esrd-related risk of developing active tb. the dialysis and control cohorts were created using the korean national health insurance service (knhis) database, which is maintained by a single national insurance provider that covers > 97% of the korean population. data regarding patients who received dialysis were obtained from the knhis database, which contains reimbursement data from all medical facilities (fig. 1) . we also collected control data from the knhis-national sample cohort (nsc), which includes approximately 1,000,000 individuals (2.2% of the total korean population) and was created using the knhis database for use by public health researchers and policy makers. 9 the knhis database contains data regarding patient gender, age, and income level, as well as data regarding medical care utilisation (e.g., date of treatment, diagnosed disease, prescribed drugs, and medical or surgical procedures). patients with newly diagnosed esrd between 2004 and 2013 were selected as the dialysis cohort. cases with dialysis were identified using claims for any procedures or materials related to haemodialysis or peritoneal dialysis, based on the korean electronic data interchange codes (o7020 for haemodialysis; o7061 for peritoneal dialysis). patients with a diagnosis of esrd who had used medical services in 2003 were excluded based on the assumption that they had chronic esrd. patients were considered eligible if they had received dialysis for > 90 days, as a small portion of patients might have received renal replacement therapy after acute kidney injury and recovered sufficient renal function to stop the dialysis. the criteria for identifying dialysis were used to exclude patients in the knhis-nsc who had received dialysis, which created the control cohort for the present study. the incidences of active tb in the dialysis and control cohorts during 2004-2013 were identified using international classification of disease, 10th revision (icd-10) codes (a15-19). the diagnosis of active tb was then confirmed based on prescriptions for ≥ 2 anti-tb drugs during a 30-day period. the anti-tb drugs included isoniazid, rifampicin, ethambutol, pyrazinamide, amikacin, kanamycin, streptomycin, quinolones, thioamide, cycloserine, and para-aminosalicylic acid. patients diagnosed with active tb in 2003 were excluded to ensure that only newly diagnosed patients with tb from 2004 were included. factors that might influence the incidence of active tb, such as gender, age, income level, and comorbidities, were used as independent variables. data regarding these covariates were available for the dialysis and control cohorts using the knhis database. comorbidities were identified based on icd-10 codes such as diabetes mellitus (e10-14), malignancy (b21, c00-97, d37-48, z08, z12, z51.0-51.2, z85, u99), chronic obstructive pulmonary disease (copd) (j44), hiv infection (b20-24), and silicosis (j60-64). income level was scored on a scale of 0 to 10, and was categorised into three groups: low, middle, and high. data between and (n = , ) tb before dialysis (n = , ) dialysis history between and (n = , ) tb before (n = , ) data between and (n = , ) incorrect or missing value (n = , ) loss of data after matching (n = , , ) loss of data after matching (n = ) we included patients who began dialysis before their diagnosis of active tb based on the visit date. we washed out data in 2003 to ensure that only newly diagnosed patients with esrd were included. data between 2014 and 2015 were excluded, because the knhis-nsc database contained only data up to 2013. finally, these eligible patients, who started dialysis during 2004-2013 (dialysis cohort), were identified after excluding potentially pre-existing cases of dialysis or active tb. we identified individuals without esrd from the knhis-nsc database (control cohort), who were propensity score matched to an equal number of esrd cases. propensity score matching using the nearest neighbour method was performed to identify similar individuals in the dialysis and control cohorts using the matchlt package version 3.0.1 in r software (version 3.4.3; r foundation for statistical computing, vienna, austria). logistic regression was used to create propensity scores for each patient based on their age, gender, income level, and comorbidities. individuals in both cohorts were randomly ordered and matched 1:1 using the nearest neighbour method. a matching algorithm identified a unique matched control for each individual in the dialysis cohort according to the propensity score. once a match was completed, the match was not considered again. if a match could not be found, the algorithm then proceeded sequentially to an individual with the closest propensity score to make the next-best match. to improve generalisability and reduce potential bias caused by incomplete matching, we used a random selection of samples from the set of all subjects. 10 proportional differences in independent variables between the esrd and control cohorts were analysed using the wald χ 2 test. the incidence of active tb was expressed as the number of newly diagnosed active tb cases per 100,000 person-years. the incidence rate ratio (irr) of esrd, relative to the controls, was calculated with its 95% confidence interval (ci) using the epir package version 0.9-96 in r software (version 3.5.0; r foundation for statistical computing). we applied a multivariate cox proportional hazards model to all independent variables after combining the two cohorts to determine the esrd-related risk of developing active tb, which was reported as hazard ratio (hr) and 95% ci. we evaluated the proportional hazard assumption by testing the significance of time-dependent interaction terms for all variables, which were found to be satisfactory. cumulative tb incidence curves were generated using the kaplan-meier method, and differences between two cohorts were analysed using the log-rank test. the follow-up period started on the first date of dialysis for the cases and on randomly selected visit dates for the controls, which corresponded to the calendar year that matched to the start of dialysis for the cases. the follow-up period ended at the first date of tb diagnosis or the last follow-up date. analyses were performed using sas software (version 9.4; sas institute, inc., cary, nc, usa) and r software (version 3.4.3; r foundation for statistical computing). a search of the knhis database identified 59,584 patients with newly diagnosed esrd during 2004-2013 (the dialysis cohort), and a corresponding number of individuals were selected for the control cohort. the individuals' characteristics are summarised in table 1 . individual matching resulted in comparable distributions of age, gender, household income, and comorbidities between the dialysis and control cohorts. the observation periods were 212,417 person-years in the dialysis cohort and 278,960 person-years in the control cohort. the mean durations of follow-up were 3.6 ± 2.7 years in the dialysis cohort and 4.7 ± 2.8 years in the control cohort. newly diagnosed active tb was detected for 457 patients in the dialysis cohort (0.8%) and 125 individuals in the control cohort (0.2%) ( table 2 ). the incidences were 215/100,000 personyears in the dialysis cohort and 45/100,000 person-years in the control cohort. compared to the controls, the patients with esrd had a significantly elevated risk of active tb (irr, 4.80; 95% ci, 3.95-5.87). the subgroup analyses revealed similarly elevated risks of active tb among patients with esrd for most subgroups, with the exception of the ≥ 80 years age group. the average interval from the initial enrolment to the diagnosis of active tb was 2.0 years (1.7 years for the dialysis cohort and 3.1 years for the control cohort). the cumulative active tb incidence was significantly higher in the dialysis cohort than in the control cohort (p < 0.001; log-rank test) (fig. 2) , and subgroup analyses revealed similar results for both haemodialysis and peritoneal dialysis (both p < 0.001; log-rank test). however, there was no significant difference in the risk of active tb between the haemodialysis and peritoneal dialysis subgroups (p = 0.67; log-rank test this nationwide cohort study revealed that dialysis was associated with a 4.39-fold higher risk of active tb than among the matched control group. to the best of our knowledge, this is the largest study to investigate the risk of developing active tb after starting dialysis for esrd. however, the results are consistent with previous reports describing a high risk of active tb among patients with esrd. for example, one nationwide cohort study from a country with a low incidence of tb 11 included 14,506 patients receiving dialysis for esrd, and revealed that the overall incidence of active tb was 66.8/100,000 person-years. a recent meta-analysis 12 also estimated that dialysis was associated with a pooled unadjusted rate ratio of 7.69 (95% ci, 5.94-9.95). although numerous studies have investigated the relationship between active tb and ckd, most of the previous studies were case reports, case-control studies, small hospital-based cohort studies, or regional registry studies. 3 a recent taiwanese study 13 included 4,131 patients with new-onset esrd and an age-and gender-matched control group, and revealed that esrd was associated with a 2.40-fold higher risk of developing active tb. the present study also examined a large population-based sample of individuals who were receiving dialysis, and comparison to the matched control group revealed that there was a relationship between active tb and esrd. in addition to mortality and morbidity, several issues and burdens related to tb should be highlighted among patients with esrd. for example, the clinical manifestation of active tb during dialysis is often insidious and atypical, 14 as patients with esrd and tb frequently present with systemic symptoms that are similar to uraemia, which can delay the diagnosis. patients may also present with extra-pulmonary or disseminated diseases. 15 among patients with ckd, the standard anti-tb treatment involves quadruple therapy, although this is problematic because ethambutol and pyrazinamide are both cleared through the kidney and require renal-adjusted dosing. in addition, rifampicin often interacts with anti-hypertensive, antidiabetic, and immunosuppressive medications, which can necessitate dose adjustments. 16 furthermore, anti-tb medication causes more severe and frequent toxicities among patients with esrd, including gastrointestinal troubles and decreased appetite, which limits the treatment regimen and duration. 17 screening for latent and active tb infections among patients with esrd is another important issue for controlling tb. although the world health organization recommends systemic testing for tb among patients who are receiving dialysis or transplantation, there is a paucity of evidence for guiding the screening recommendation, and optimal treatment for latent tb infection is unclear among patients with advanced ckd. thus, there is a need for clear and consistent guidance to develop suitable protocols for screening, diagnosis, and treatment of tb among patient with ckd. haemodialysis and peritoneal dialysis were both associated with increased risks of active tb in the present study, and both modalities share the same risks associated with acquired immunodeficiency due to uraemia. two previous studies have evaluated the risk of active tb among patients undergoing peritoneal dialysis, and both revealed higher prevalence of tb in this population than among the general population. 18, 19 although patients undergoing haemodialysis have markedly more frequent hospital visits than those undergoing peritoneal dialysis, the risks of tb between them were not different in the present study, which is consistent with the results from previous studies. 13,20 therefore, we speculate that the risk of nosocomial tb infection is not a great concern among patients undergoing dialysis. several well-known comorbidities are associated with the risk of active tb. 1 in our subanalyses, patients with diabetes, malignancy, and copd also had increased rate ratios of active tb, although the multivariate analysis revealed that the associations between these comorbidities and tb were insignificant. we hypothesise that the uraemia-related risk of infection is strong enough to outweigh the influences of these conditions. in addition, hiv infection is another important risk factor for active tb, although the prevalence of hiv infection is low in korea. 21 we only identified one case of active tb among patients with hiv infection and esrd, which indicates that hiv infection status did not likely confound the relationship between dialysis and tb. the present study has several limitations that should be considered. first, this study collected data that were based on diagnostic codes and insurance claims, which precluded analysis of information regarding other lifestyle and clinical variables that could influence risk of tb infection. we attempted to control for such confounding using other available data. for example, we included copd to adjust for the effects of smoking, as copd is mainly attributed to smoking. 22 we also included household income, which represents various factors associated with socio-economic status. those with a history of anti-tb treatment before study enrolment were excluded in order to minimise the effect of recent tb infection. although use of immunosuppressant drugs is an important risk factor for active tb development, dialysis patients rarely use immunosuppressants in clinical practice, as dialysis also suppresses the patient's immune function. 23 thus, based on its limited use, we elected to omit immunosuppressant use as a co-variable. second, dialysis patients might have more frequent visits to clinics and a higher likelihood of receiving appropriate screening (e.g., chest radiography), and would be more likely to seek medical attention if tb symptoms arose. thus, ascertainment and detection biases might contribute to a higher rate of active tb identification in the dialysis cohort than in the control cohort. nevertheless, korea has a single national health insurance service that ensures citizens have easy and inexpensive access to medical care, and the national health screening program provides regular chest radiography examinations for every healthy adult, 24 which frequently leads to an early diagnosis of active tb. thus, although there might be some delays in the control cohort's tb diagnosis, we suspect any underestimation of active tb identification in that cohort would be minimal. third, the diagnosis of active tb was based on the icd-10 codes and drug prescription history, which may be associated with limited sensitivity. diagnosing tb with a specific combination of anti-tb drugs might not be accurate, because these drugs may be prescribed for other infectious diseases, such as non-tuberculous mycobacteria disease. a recent study 25 showed that some patients with mycobacterium avium complex lung disease transiently received anti-tb treatment before its final diagnosis. however, this criterion has been used in various previous studies and meta-analyses. because korean law requires all active tb cases to be reported using the icd-10 codes, we assumed the use of these codes to be a valid and reliable approach. despite these limitations, the major strength of the present study is its large sample size, which increased the results' statistical power and accuracy and provides for better generalisability. furthermore, the dialysis cohort was created using patients with a nephrologist-confirmed diagnosis of esrd, and both cohorts were designed by an epidemiologist. finally, the prolonged follow-up was sufficient to examine the temporal relationship between the onset of esrd and subsequent active tb. in conclusion, the present study revealed epidemiological evidence that receiving dialysis for esrd was associated with an increased risk of developing active tb. although there is accumulating evidence regarding the effects of tb and esrd on public health, international societies have only recently recommended systematic tb testing for patients receiving dialysis, and current guidelines are still ambiguous. 3 therefore, there remains a need for detailed and well-organised guidelines for identification of active tb cases among patients with esrd. the contribution of chronic kidney disease to the global burden of major noncommunicable diseases tuberculosis and chronic kidney disease: an emerging global syndemic aspects of immune dysfunction in end-stage renal disease tuberculosis transmission in a renal dialysis center--nevada middle east respiratory syndrome coronavirus (mers-cov) outbreak in south korea, 2015: epidemiology, characteristics and public health implications tuberculosis in maintenance dialysis patients cohort profile: the national health insurance service-national sample cohort (nhis-nsc), south korea a comparison of 12 algorithms for matching on the propensity score risk of tuberculosis in dialysis patients: a nationwide cohort study risk of active tuberculosis in chronic kidney disease: a systematic review and meta-analysis increased risk of tuberculosis in patients with endstage renal disease: a population-based cohort study in taiwan, a country of high incidence of end-stage renal disease the diagnosis of tuberculosis in dialysis patients diagnosis of tuberculosis in dialysis patients: current strategy mycobacterium tuberculosis infection in recipients of solid organ transplants side-effects of antituberculosis drug treatment in patients with chronic renal failure tuberculosis infection in chinese patients undergoing continuous ambulatory peritoneal dialysis tuberculosis in peritoneal dialysis patients in an endemic region mycobacterium tuberculosis infection of end-stage renal disease patients in taiwan: a nationwide longitudinal study incidence and risk factors of tuberculosis in patients with human immunodeficiency virus infection key: cord-306092-5bi2q3jj authors: choi, hee joung; kim, yeo hyang title: relationship between the clinical characteristics and intervention scores of infants with apparent life-threatening events date: 2015-05-13 journal: j korean med sci doi: 10.3346/jkms.2015.30.6.763 sha: doc_id: 306092 cord_uid: 5bi2q3jj we investigated the clinical presentations, diagnostic and therapeutic modalities, and prognosis from follow-up of infants with apparent life-threatening events (alte). in addition, the relationship between the clinical characteristics of patients and significant intervention scores was analyzed. we enrolled patients younger than 12 months who were diagnosed with alte from january 2005 to december 2012. there were 29 alte infants with a peak incidence of age younger than 1 month (48.3%). the most common symptoms for alte diagnosis were apnea (69.0%) and color change (58.6%). eleven patients appeared normal upon arrival at hospital but 2 patients required cardiopulmonary resuscitation during the initial alte. the most common alte cause was respiratory disease, including respiratory infection and upper airway anomalies (44.8%). there were 20 cases of repeat alte and 2 cases of death during hospitalization. four patients (15.4%) experienced recurrence of alte after discharge and 4 patients (15.4%) showed developmental abnormalities during the follow-up period. the patients with alte during sleep had lower significant intervention scores (p=0.015) compared to patients with alte during wakefulness and patients with previous respiratory symptoms had higher significant intervention scores (p=0.013) than those without previous respiratory symptoms. although not statistically significant, there was a weak positive correlation between the patient's total alte criteria and total significant intervention score (fig. 2, r=0.330, p=0.080). we recommend that all alte infants undergo inpatient observation and evaluations with at least 24 hr of cardiorespiratory monitoring, and should follow up at least within a month after discharge. graphical abstract: [image: see text] since the 1970s, many investigators have focused on episodes occurring in infants characterized by an acute and unexpected change in behavior either with or without apnea. these episodes were referred to as "near-misses" for sudden infant death syndrome (sids) (1), and considered a possible cause of sids. in 1986, the national institutes of health consensus conference named these episodes apparent life-threatening events (alte) and defined them using the following criteria: some combination of central or obstructive apnea; color change; marked change in muscle tone; and choking or gagging (2) . it is a frightening event, occurring predominantly in infancy and accounting for 0.6%-1.7% of all emergency department (ed) visits for infants younger than 1 yr of age and 0.5%-6% of all infant visits (3) (4) (5) (6) . it is associated with a 0%-6% mortality rate (2) . in some studies, high-risk groups for alte were defined as 1) having events during sleep, 2) needing resuscitation, 3) having a subsequent similar episode, 4) being siblings of sids patients, and 5) developing a seizure disorder. in addition, studies reported that high-risk groups for alte had a high mortality rate of about 25% (7) . however, infants with alte are often asymptomatic on arrival at the hospital and the natural course of alte has recently been reported to be more benign (8) . to date, it has been difficult to find reports of alte infants in korea. in this study, we investigated the clinical presentations, diagnostic and therapeutic modalities, and prognosis from followup of infants with alte. in addition, the relationship between the clinical characteristics of patients and significant intervention scores was analyzed. we enrolled patients younger than 12 was diagnosed if the patient had least 1 of the following: apnea, color change, change in muscle tone, or choking or gagging. all patients were admitted for evaluation and medical intervention, and patients' medical records were retrospectively reviewed. the patients' characteristics, status upon hospital arrival, description of the event, diagnostic investigation, medical treatment, clinical outcome, and final diagnosis were investigated. in order to identify the underlying cause of alte, various diagnostic investigations were performed during hospitalization. on the day of admission, blood samples were analyzed for complete blood count (cbc) with bacterial culture, blood gas analysis with electrolytes, and c-reactive proteins. in addition, respiratory virus reverse transcription polymerase chain reaction (rv rt-pcr) using nasopharyngeal aspirate, rotavirus antigen test in stool, urinalysis with culture, cerebrospinal fluid (csf) analysis, and chest radiography were all utilized. rv rt-pcr included tests for metapneumovirus, adenovirus (a-f), coronavirus 229e/oc43, parainfluenza virus 1/2/3, influenza a/b virus, rhinovirus, respiratory syncytial virus a/b, and bocavirus. electrocardiograms (ecg), 2-dimensional echocardiograms, upper gastrointestinal studies, electroencephalograms (eeg), brain image studies, and tests for metabolic disease were ordered on an individual patient basis. a confirmed bacterial or viral infection, abnormal chest radiographic finding, ecg, 2-dimensional echocardiogram, upper gastrointestinal study, eeg, brain image study, and any test to characterize metabolic disease were classified as significant diagnostic interventions. supplemental oxygen, stimulation, endotracheal intubation, parenteral antibiotics, and cardiopulmonary resuscitation (cpr) were classified as significant medical interventions. recurrence of alte and death during hospitalization were also classified as significant interventions. each intervention was rated 1 point, and we totaled the significant interventions on a scale from 0-16. all statistical analyses were performed using spss version 21.0 (spss for windows, version 21.0, spss inc., chicago, il, usa), and all values were described as frequencies and median with range. the mann-whitney u-test was applied to compare significant intervention scores according to patients' clinical characteristics. spearman rank correlation coefficient (r) was applied to analyze correlation between patients' characteristics and significant intervention scores. a value of p < 0.05 was considered statistically significant. this study was approved by the institutional review board of the keimyung university dongsan medical center (irb no. 2014-09-054). informed consent was exempted by the board. there were 29 patients (16 boys and 13 girls) who met the criteria for alte ( table 1 ). the median patient age was 39.0 days (range, 3-220 days), with a peak incidence of age younger than 1 month (48.3%) and 69.0% of patients younger than 2 months (fig. 1 ). twelve patients (41.4%) were preterm infants, and 8 (27.6%) were low birth weight infants. among 12 preterm infants, the median gestational age was 35.5 weeks (range, 27.5-36.3 weeks), and 2 patients were diagnosed as bronchopulmonary dysplasia and 2 patients were diagnosed as apnea of prematurity. fifteen infants (51.7%) were firstborn. the median maternal age was 31.0 yr (range, 25-42 yr) and no mother presented with a history of smoking. there was no history of sids or alte in their siblings. there was a recent history of fever in 2 patients, respiratory symptoms in 16, and both in 1. ten patients did not have any specific history. twenty-seven patients had an event at home. after the event, 12 patients visited an ed, and 17 patients visited an outpatient department (opd). twenty patients arrived at the hospital during the day, while 9 arrived at night. eleven patients appeared normal upon their clinical examination at the time of arrival, whereas 2 patients required cpr during the initial alte and 4 were transferred from other hospitals while intubated. other 12 patients showed sick appearance such as cyanosis, grunting, chest retraction and atonic posture. the predominant symptoms for alte diagnosis were apnea and color change in 20 (69.0%) and 19 (58.6%) patients, respectively (table 2) . change in muscle tone occurred in 9 (31.0%), choking in 6 (20.7%), and gagging in 3 (10.3%). the events occurred while sleeping in 5 and while awake in 24. of the 24 patients, the events occurred during and after feeding in 4, and with crying in 3. in the other 17 patients, the specific situation associated with the event was not found in medical records. eight patients had confirmed bacterial infections such as enterobacter or escherichia coli in urine in 3 patients, staphylococcus or streptococcus in blood in 3 patients, and streptococcus in both blood and csf in 2 patients. although not statistically significant, the patients with confirmed bacterial infection showed higher incidence of fever than the other patients (25.0% vs. 4.8%, p = 0.176). also, in laboratory test, they showed higher level of white blood cell (wbc) count (11,156.3 ± 5,066.3/μl vs. 9,699.0 ± 3,543.7/μl, p = 0.388) and c-reactive protein (crp) (3.4 ± 5.1 mg/dl vs. 0.4 ± 0.5 mg/dl, p = 0.135) than the other patients. rv rt-pcr was performed for 11 patients, and several viruses were identified in 8 patients: respiratory syncytial virus in 3, human rhinovirus in 3, human parainfluenza virus in 3, and bocavirus in 1. rotavirus antigen test showed positive result in 1 patient. primary medical management for alte was supplemental oxygen and stimulation, each given to 18 patients (table 3) . eleven patients needed mechanical ventilator support with endotracheal intubation because of recurrent apnea in 9 patients, dyspnea in 1, and a cpr situation in 1. the median duration of ventilator care was 2.0 days (range, 1-25 days). seventeen patients were treated with parenteral antibiotics for a suspected bacterial infection, including culture-confirmed bacterial infection. infections were suspected to be pneumonia with respiratory symptoms in 11, sepsis with fever or shock in 4, and urinary tract infections with pyuria in 2. two patients required cpr because of bradycardia and hypotension during the initial alte, but recovered. after analyzing the relationship between the patients' clinical characteristics and significant intervention scores, we saw that patients with alte during sleep had significantly lower scores ( fig. 2 , p = 0.015) compared to patients with alte during wakefulness. we also saw that patients with previous respiratory symptoms had significantly higher scores (fig. 2 , p = 0.013) than those without previous respiratory symptoms. although not statistically significant, there was a weak positive correlation between the patient's total alte criteria and total significant intervention score (fig. 3 , r = 0.330, p = 0.080). table 4 summarizes the common causes of alte. the most common alte cause was respiratory disease, including respiratory infection in 10 patients and upper airway anomalies in 3. the next most common cause was neurologic disease such as a convulsive disorder, congenital hypoventilation syndrome, and haddad syndrome. three patients had confirmed bacterial meningitis and sepsis. gastroesophageal reflux (ger)-related alte was diagnosed in 3 patients, prematurity-related causes in 2, previously known congenital heart disease-related alte in 1, and sedative medication-related alte in 1. two cases of alte remained unexplained. the median duration of hospitalization was 8.0 days (range, 2-38 days), and 20 patients (69.0%) showed repeat alte in the hospital. there were 2 cases of death, resulting in an overall mortality rate of 6.9%. one death caused by group b streptococcal meningitis occurred at 25 days after admission. both csf and blood culture confirmed his streptococcal infection, and abnormal findings were also seen in his eeg and brain sonography. the other death with unexplained alte occurred at 18 days after admission. she had preterm birth and low birth weight history and diagnosed as bronchopulmonary dysplasia previously. except for 3 patients, 26 patients had a follow-up at an opd and the median duration of follow-up was 6.0 months (range, 1-52 months). there were no cases of mortality after discharge, although 4 cases (15.4%) experienced recurrence of alte after discharge, all of whom also showed recurrent alte in the hospital. the characteristics of recurrent alte are described in table 5 . four patients (15.4%) showed developmental abnormalities during the follow-up period. their final diagnoses were pneumonia with prematurity history in 2, haddad syndrome in 1, and narrowing of supraglottic larynx with ger grade iii in 1. in the present study, we identified the heterogeneity of altes; some patients often appeared healthy upon arrival in the ed or opd, while some patients required immediate cpr. this heterogeneity causes difficulties for clinicians deciding how to manage patients with alte. the admission rate for alte is usually 75%-100% (9-12), reflecting the recommendations of many centers that all patients with alte be admitted for a period of inpatient observation. some studies suggested that the major indicators of admission and further evaluation were prematurity, age younger than 30 days or older than 60 days, history of other illness, recurrent alte, and abnormal result in the initial examination (4, 9, 10) . in our study, the admission rate of alte infant was 100% and duration of hospital stay was 2-38 days. in previous studies, the causes of alte were grouped into gastrointestinal (50%), neurological (30%), respiratory (20%), cardiovascular (5%), metabolic and endocrine (2%-5%), and others such as child abuse (13, 14) . the most common diagnosis was gastrointestinal disease, including ger. al khushi et al. (15) reported that the most important diagnoses of alte included serious bacterial infections, seizures, child abuse, metabolic disorders, and severe apnea with hypoxemia. among the infectious causes of alte, reported prevalences were about 0%-1.6% for meningitis, 0%-2.5% for bacteremia, 0%-7.6% for urinary tract infection, 0%-10% for lower respiratory tract infection, and 9%-82% for bronchiolitis (5, (16) (17) (18) (19) . about 35%-50% of alte cases had no diagnosable cause, despite a medical history and complete evaluation (12, 13) . in contrast to previous studies, the present study showed that the most common discharge diagnosis was respiratory disease, including respiratory infection, followed by neurological disease. two patients' altes (6.9%) remained unexplained. in a review of several studies, tieder et al. (20) demonstrated that the most frequently evaluated diagnostic tests were for ger, neurologic abnormalities, anemia, infections, toxic ingestions, metabolic disorders, and cardiac dysrhythmias. there was no evidence to recommend routine nonspecific tests such as cbc, serum glucose, or electrolyte levels (20) . on the other hand, vandenplas et al. (21) suggested that, although ger was considered a major cause of alte, routine ger testing is unnecessary in children with alte. the incidence of ger is generally high in infancy regardless, and a positive result is not a confirmation of a relationship between ger and alte. in our study, 8 patients underwent an upper gastrointestinal study because 4 had been previously diagnosed with ger, 2 had feeding-related alte, 1 had a history of esophageal atresia with tracheoesophageal fistula, and 1 had recurrent pneumonia. seven patients showed positive signs of ger (grade i in 2, grade ii in 3, grade iii in 2), but ger was only confirmed as a cause of alte at discharge in 3 patients. in this regard, our results were similar to the previous study. many studies have investigated potential predictors of subsequent events in alte patients. some studies identified a history of prematurity and multiple altes as risk factors for a serious underlying condition or poor prognosis (10, 11) . davies et al. (4) found that more serious diagnosis was associated with a presentation age greater than 2 months, abnormal initial clinical examination, and recurrent alte. mittal et al. (12) reported that 12% of alte infants needed significant intervention during hospitalization, and that prematurity, abnormal results from the physical examination, color change to cyanosis, absence of symptoms of upper respiratory tract infection, and absence of choking were all predictors of significant intervention. in order to determine whether to discharge patients from the ed, the authors recommended a clinical decision rule based on components of patient history and examination findings that have been established as significant predictors. in this study, we analyzed the relationship between the patients' clinical characteristics and total significant intervention scores. we identified the following results: 1) alte occurring during sleep had a low incidence of significant interventions, 2) alte with a recent history of respiratory symptoms had a high incidence of significant intervention, and 3) patients with numerous signs of alte criteria had high scores of significant intervention (r = 0.330). risk factors, such as prematurity, which had been described as poor prognosis factors in previous studies, did not show statistical significance in relation to the significant intervention scores. this result was somewhat different from previous studies, and we thought that it was caused by the difference of underlying diagnosis of alte. in our study, the most common alte cause was respiratory disease (44.8%), and these patients may show the more symptoms while awake. in previous studies of alte prognosis after discharge, the mortality rate was 0%-0.5% during 12-60 months of follow-up (3, 9, 22, 23) . recently, kant et al. (24) reported a mortality after discharge of 1.1% (2 deaths/174 infants) during 34 months of follow-up, with 2 deaths occurring within 15 days of discharge. bonkowsky et al. (22) studied the recurrence of alte and found that 71% of the initial patients with alte returned to the hospital within 1 month with a second event. this study showed the importance of close follow-up after discharge. the authors also found that 5% of patients developed adverse neurological outcomes, including chronic epilepsy and developmental delays. nunes et al. (25) reported that among 56 patients with alte, 51.5% show ed normal outcome, 4 showed repeated alte, and none report ed deaths due to sids. the authors concluded that the outcome is generally related to the associated underlying disease. we found no cases of mortality after discharge, but there were 4 cases (15.4%) of recurrent alte after discharge occurring nearly within 2 weeks. during the median 6-month followup period, 4 patients (15.4%) showed developmental abnormalities, although we could not definitively identify the relationship between developmental delay and alte relapse. our study had several limitations. the present study was a small sized retrospective study, and patients' data were collected only from a retrospective chart review. accordingly, we could have missed some portion of alte patients. the number of deaths was too small to analyze any potentially significant difference of clinical course according to death. considering that alte encompasses a wide range of clinical presentations, we recommend that all alte infants undergo inpatient clinical observation and evaluations with at least 24 hr of cardiorespiratory monitoring. in addition, alte infants should be followed up at least within a month after discharge. long-term follow-up should be decided on an individual basis according to the underlying status of the patients. prolonged infantile apnea: 1985 national institutes of health consensus development conference on infantile apnea and home monitoring apparent life-threatening events presenting to a pediatric emergency department apparent life threatening events in infants presenting to an emergency department serious bacterial infections in infants who have experienced an apparent life-threatening event an update on the approach to apparent life-threatening events identification of a high-risk group for sudden infant death syndrome among infants who were resuscitated for sleep apnea apnea, sudden infant death syndrome, and home monitoring ed evaluation of infants after an apparent life-threatening event do all infants with apparent life-threatening events need to be admitted? risk factors for extreme events in infants hospitalized for apparent life-threatening events a clinical decision rule to identify infants with apparent life-threatening event who can be safely discharged from the emergency department european society for the study and prevention of infant death. recommended clinical evaluation of infants with an apparent life-threatening event. consensus document of the european society for the study and prevention of infant death apparent lifethreatening events and apnea of infancy apparent life-threatening events: assessment, risks, reality yield of diagnostic testing in infants who have had an apparent life-threatening event infections and apparent life-threatening events surveillance study of apparent life-threatening events (alte) in the netherlands respiratory syncytial virus infection in infants admitted to paediatric intensive care units in london, and in their families management of apparent life-threatening events in infants: a systematic review north american society for pediatric gastroenterology hepatology and nutrition, european society for pediatric gastroenterology hepatology and nutrition. pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the north american society for pediatric gastroenterology, hepatology, and nutrition (naspghan) and the european society for pediatric gastroenterology death, child abuse, and adverse neurological outcome of infants after an apparent life-threatening event mortality and child abuse in children presenting with apparent life-threatening events mortality after discharge in clinically stable infants admitted with a first-time apparent life-threatening event associated and prognosis in apparent life threatening events (alte) the authors have no conflicts of interest in this work. key: cord-304010-n4gxxl5i authors: sung, ho kyung; kim, jin yong; heo, jeonghun; seo, haesook; jang, young soo; kim, hyewon; koh, bo ram; jo, neungsun; oh, hong sang; baek, young mi; park, kyung-hwa; shon, jeung a; kim, min-chul; kim, joon ho; chang, hyun-ha; park, yukyung; kang, yu min; lee, dong hyun; oh, dong hyun; park, hyun jung; song, kyoung-ho; lee, eun kyoung; jeong, hyeongseok; lee, ji yeon; ko, ja-young; choi, jihee; ryu, eun hwa; chung, ki-hyun; oh, myoung-don title: clinical course and outcomes of 3,060 patients with coronavirus disease 2019 in korea, january–may 2020 date: 2020-07-28 journal: j korean med sci doi: 10.3346/jkms.2020.35.e280 sha: doc_id: 304010 cord_uid: n4gxxl5i background: the fatality rate of patients with coronavirus disease 2019 (covid-19) varies among countries owing to demographics, patient comorbidities, surge capacity of healthcare systems, and the quality of medical care. we assessed the clinical outcomes of patients with covid-19 during the first wave of the epidemic in korea. methods: using a modified world health organization clinical record form, we obtained clinical data for 3,060 patients with covid-19 treated at 55 hospitals in korea. disease severity scores were defined as: 1) no limitation of daily activities; 2) limitation of daily activities but no need for supplemental oxygen; 3) supplemental oxygen via nasal cannula; 4) supplemental oxygen via facial mask; 5) non-invasive mechanical ventilation; 6) invasive mechanical ventilation; 7) multi-organ failure or extracorporeal membrane oxygenation therapy; and 8) death. recovery was defined as a severity score of 1 or 2, or discharge and release from isolation. results: the median age of the patients was 43 years of age; 43.6% were male. the median time from illness onset to admission was 5 days. of the patients with a disease severity score of 3–4 on admission, 65 (71.5%) of the 91 patients recovered, and 7 (7.7%) died due to illness by day 28. of the patients with disease severity scores of 5–7, 7 (19.5%) of the 36 patients recovered, and 8 (22.2%) died due to illness by day 28. none of the 1,324 patients who were < 50 years of age died; in contrast, the fatality rate due to illness by day 28 was 0.5% (2/375), 0.9% (2/215), 5.8% (6/104), and 14.0% (7/50) for the patients aged 50–59, 60–69, 70–79, and ≥ 80 years of age, respectively. conclusion: in korea, almost all patients of < 50 years of age with covid-19 recovered without supplemental oxygen. in patients of ≥ 50 years of age, the fatality rate increased with age, reaching 14% in patients of ≥ 80 years of age. coronavirus disease 2019 , caused by severe acute respiratory syndrome virus 2 (sars-cov-2), was first reported in china on december 31, 2019. since then, it has spread throughout the world; consequently, the world health organization declared the covid-19 outbreak as a pandemic on march 12. as of june 13, the pandemic disease had spread to 215 countries, resulting in approximately 7.5 million cases and over 423,000 deaths. 1 in korea, the first case of covid-19 was confirmed on january 20. 2 as of june 15, there were 12,121 confirmed cases of covid-19, with 277 deaths. 3 the clinical spectrum of covid-19 encompasses asymptomatic infection, mild upper respiratory tract illness, pneumonia that may result in respiratory failure, multi-organ failure, and death. most infections are non-severe: of 44,500 laboratory-confirmed cases, 81% were mild (no or mild pneumonia) disease. 4 however, the clinical outcomes of patients with severe pneumonia vary widely. for example, in china, the case-fatality ratio (cfr) among critical cases was 49.0% (1,023/2,087). 4 in the lombardi region of italy, 26% (405/1,581) patients admitted to the intensive care unit died. 5 in new york city, 24.3% (665/2,741) patients were discharged to hospice care or died. 6 in contrast, the overall cfr in korea is 2.3%. the observed differences in clinical outcomes and cfrs in patients with covid-19 in various countries may be related to patient demographics, surge capacity of the healthcare system, and medical care quality, as well as the case definition of covid-19. towards a better response to the next wave of the pandemic, the clinical course and outcomes of covid-19 patients need to be defined. here, we have described the clinical characteristics, temporal progression, and fatality rate of covid-19 in a large cohort of patients hospitalized during the first wave of the epidemic in korea. on february 3, 2020, to cope with the public health crisis caused by the covid-19 pandemic, the korea national committee for clinical management of covid-19 (knccmc) was founded. the knccmc consisted of 59 infectious disease specialists and attending physicians of patients with covid-19 in korea. in collaboration with the korea centers for disease control and prevention (kcdc), the knccmc constructed a registry to collect clinical data of patients hospitalized with covid-19. the kcdc requested that all of the designated hospitals for covid-19 treatment were to submit clinical data to the registry. for the registry, we developed a standardized clinical record form (crf) that was modified from the world health organization global 2019-novel coronavirus clinical characterization crf. 7 clinical severity, based on an eight-category ordinal scale (described below), was also assessed every day. based on the standardized crf, the attending physicians of each participating hospital extracted data from medical records and entered them into a web-based, clinical research management system of the kcdc (http://icreat.nih.go.kr). if the core data were missing, requests for clarification were sent to the attending physicians. given the high workload of the physicians, the laboratory results were not included in the data extraction request. for this study, we extracted data from the registry for patients who had been confirmed to have covid-19 between january 21, 2020 and may 31, 2020; the data cutoff point was june 1, 2020. for national epidemiologic data, we used publicly available data from the kcdc. 8 according to the definition of the kcdc, 8 a confirmed case was defined as a patient with a positive result in the real-time reverse transcription polymerase chain reaction (rrt-pcr) assay based test for sars-cov-2 in upper respiratory specimens (nasopharyngeal and oropharyngeal swabs), with or without a lower respiratory specimen (sputum), regardless of symptoms. the criteria for discharge from hospital and ending isolation were: 1) symptomatic improvement and afebrile; and 2) rrt-pcr negative tests at 24 hours intervals. to measure the clinical progression and recovery of a patient with covid-19, we modified an ordinal scale and defined the severity scores as follows 9 : 1) no limitation of daily activities; 2) limitation of daily activities but no need for supplemental oxygen therapy; 3) need for supplemental oxygen therapy via nasal cannula; 4) need for supplemental oxygen therapy via facial mask; 5) need for high-flow supplemental oxygen therapy or noninvasive mechanical ventilation; 6) need for invasive mechanical ventilation; 7) multi-organ failure or the need for extracorporeal membrane oxygenation (ecmo) therapy; 8) death. recovery was defined as a score of 1 or 2, or discharge to home and release from isolation. baseline patient characteristics, treatments, and clinical course were presented as frequencies with percentages for categorical variables, and as the median with interquartile range (iqr; 25th, 75th percentiles) for continuous variables. as data collection is ongoing, we provided the number of patients for whom information was collected in each variable as denominator. categorical variables were compared using the χ 2 test, although fisher's exact test was used when the data were sparse. continuous variables were compared using the kruskal-wallis test. all tests were two-tailed, and results with p values of < 0.05 were considered statistically significant. all data preparation and statistical analyses were conducted by using sas 9.4 (sas institute, inc., cary, nc, usa). the present study protocol was reviewed and approved by the institutional review board of the seoul national university hospital (e-2006-006-1129); a waiver of informed consent was obtained for the use of the retrospective data. in total, 11,503 patients were confirmed to have covid-19 before may 31, 2020; of these, 3,060 (26.6%) patients were included in this study. of the 8,262 patients in daegu city and gyeongbuk province, where a large cluster of cases related to a religious group had occurred, only 1,042 (12.6%) patients were included (fig. 1a) . for each age group, approximately 20%-30% of the total number of patients in each age group was included (fig. 1b) . the median age of the patients was 43 years; 64 (2.1%), 1,515 (49.5%), 1,081 (35.4%), and 398 (13.0%) of the 3,058 patients were < 15 years of age, 15-44 years of age, 45-64 years age, and 65 years of age and older, respectively. in total, 1,334 (43.6%) patients were male ( table 1 ). the median time from illness onset to hospital admission was 5 days. the median time from illness onset to diagnosis was 4 days. on the day of admission, disease severity scores for patients were 1-2, 3-4, and 5-7 in 2,585 (93.0%), 141 (5.0%), and 55 (2.0%) patients, respectively (total 2,781 patients). the median ages of the patients with disease severity scores of 1-2, 3-4, and 5-7 were 40, 63, and 70 years, respectively. in patients of 45-64 years of age, 1.7% (16/967) presented with a disease severity score of 5-8, whereas in patients of 65 years of age or older, 10.9% (38/349) patients presented with a disease severity score of 5-8. the most common symptoms on admission were cough (40.8%), sputum (25.9%), and sore throat (20.3%). only 851 (28.8%) of the 2,954 patients had a history of fever; diarrhea was rather uncommon (7.1%). chest radiography showed no abnormality in 1,749 (68.4%) of the 2,557 patients. the most common comorbid conditions were hypertension (15.8%), diabetes (8.4%), and smoking (7.0%). antiviral agents were administered to 1,471 (48.1%) of the 3,060 patients: 1,108 (36.2%) received lopinavir/ritonavir, and 652 (21.3%) received hydroxychloroquine ( table 2) . sixty (2.0%) patients were treated with invasive mechanical ventilation. the median time from illness onset to the initiation of invasive mechanical ventilation was 8 days (iqr, 4-11 days). one-hundred and forty-eight (4.8%) patients were admitted to the intensive care unit. at the time of data cutoff (june 1, 2020), 2,421 (79.1%) of the 3,060 patients had been discharged, and 32 (1.1%) patients had died. the median time from illness onset to death was 5 days (iqr, 4-9 days). of the 1,905 patients with a disease severity score of 1-2 on admission, by illness day 28, the severity score had progressed to 3-7 in only 8 (0.4%) patients, and none died ( 2) data are presented as median (interquartile range) or number (%), unless otherwise indicated. bmi = body mass index, ecmo = extracorporeal membrane oxygenation. a 1, no limitation of daily activities; 2, limitation of daily activities but no need for supplemental oxygen therapy; 3, need for supplemental oxygen therapy via nasal cannula; 4, need for supplemental oxygen therapy via facial mask; 5, need for high-flow supplemental oxygen therapy or non-invasive mechanical ventilation; 6, need for invasive mechanical ventilation; 7, multi-organ failure or need for ecmo therapy; 8, death. patients with no disease severity score on admission day (279, 9.1%) were excluded from this analysis; b data regarding age were missing for 2 patients (0.1%); c data regarding illness onset were missing for 350 patients (11.4%); d fisher's exact test. may 2020, inclusive. the median age of the patients was 43 years of age. almost all patients of < 50 years of age with covid-19 recovered without supplemental oxygen, whereas by illness day 28, 0.5%, 0.9%, 5.8%, and 14% of patients of 50-59, 60-69, 70-79, and 80 years of age and older, respectively, died. of the patients who needed noninvasive or invasive mechanical ventilation, 24.5% died. percentages may not total 100 owing to rounding. patients with no disease severity score on admission day (279, 9.1%) or who died on admission day (2, 0.1%) were excluded from this analysis; b 1, no limitation of daily activities; 2, limitation of daily activities but no need for supplemental oxygen therapy; 3, need for supplemental oxygen therapy via nasal cannula; 4, need for supplemental oxygen therapy via facial mask; 5, need for high-flow supplemental oxygen therapy or non-invasive mechanical ventilation; 6, need for invasive mechanical ventilation; 7, multi-organ failure or need for ecmo therapy; c including the patients hospitalized for isolation purposes, even if their severity score had improved to 1 or 2; d fisher's exact test. percentages may not total 100 because of rounding. patients without a disease severity score on admission day (279, 9.1%) or died on admission day (2, 0.1%) were also excluded from this analysis; b 1, no limitation of daily activities; 2, limitation of daily activities but no need for supplemental oxygen therapy; 3, need for supplemental oxygen therapy via nasal cannula; 4, need for supplemental oxygen therapy via facial mask; 5, need for high-flow supplemental oxygen therapy or non-invasive mechanical ventilation; 6, need for invasive mechanical ventilation; 7, multi-organ failure or need for ecmo therapy. the most common symptoms on admission were cough (40.8%), sputum (25.9%), and sore throat (20.3%). only 28.8% of the enrolled patients had a history of subjective fever, and diarrhea was uncommon (7.1%). radiologic pneumonia was not evident on simple chest radiography in 68.4% of patients. our previous study also showed that patients with radiologic pneumonia did not feel unwell and were able to carry on their daily activities ("walking pneumonia"). 10 as the presenting symptoms were non-specific, the early detection and isolation of patients with covid-19 was challenging. 11 disease severity on hospital admission was mild in 91% of patients, and almost all of them recovered without supplemental oxygen. in china, the proportion of mild disease (i.e., no pneumonia and mild pneumonia) was 81% (in a study of 44,415 patients 4 ), and they recovered within approximately 2 weeks. 12 previous studies showed that the severity of covid-19 increased with age. 6,13 in our study, half of the patients were 15-44 years of age; and only 13% were 65 years of age or older. this age distribution may reflect aggressive contact tracing and the comprehensive testing of a cluster of members in the shincheonji religious group, of which the majority comprised young adults. 14 our study showed that disease severity on hospital admission increased with age. the fatality rate also increased with age. these results were in line with the estimated case fatality rates in china, which was 6.4% in patients of ≥ 60 years of age, and increased to 13.4% in patients of ≥ 80 years of age. 13 in contrast, in the new york city area, the fatality rate in patients of ≥ 65 years of age who did not receive mechanical ventilation was 26.6%. 15 in the lombardy region in italy, the fatality rate in patients of 64 years of age and older admitted to the intensive care unit was 36%. 5 the differences in mortalities among the countries may be explained by the differences in the prevalence of the comorbid conditions of the patients, as well as overwhelmed healthcare systems. percentages may not total 100 because of rounding. patients with no data on illness onset (350, 11.4%), disease severity score on admission day (279, 9.1%), or age (2, 0.1%) were excluded from this analysis; b 1, no limitation of daily activities; 2, limitation of daily activities but no need for supplemental oxygen therapy; 3, need for supplemental oxygen therapy via nasal cannula; 4, need for supplemental oxygen therapy via facial mask; 5, need for high-flow supplemental oxygen therapy or non-invasive mechanical ventilation; 6, need for invasive mechanical ventilation; 7, multi-organ failure or need for ecmo therapy. few natural history studies have reported the clinical progression of patients with covid-19. in our study, 98% of the patients who did not need supplemental oxygen on admission recovered by illness day 14, and no patients died. of the patients requiring supplemental oxygen via nasal cannula or facial mask, 71.5% recovered and 7.7% died. this recovery rate was congruent with that from the actt-1 remdesivir trial, 16 which reported that 70.2% of the patients in the placebo arm who required supplemental oxygen recovered. our data suggested that patients of < 50 years of age and those who did not need supplemental oxygen at presentation may safely be treated at outpatient clinics. indeed, during the height of the covid-19 epidemic in korea, the government decided to prioritize treatment of severe cases at hospitals, 17 and mild cases were successfully managed at the designated/repurposed facilities in the community. 18 there are several limitations in this study. first, we were not able to extract laboratory data for this study, as many clinicians from the participating hospitals were overburdened owing to the heavy burden of clinical activities. there were also many missing values for clinical progression data. however, before the sudden increase of the epidemic curve in korea, we compiled detailed laboratory, radiologic, and virus shedding data from the first 28 patients with covid-19 and reported these data. 10 second, in korea, a huge cluster of cases related to a religious group had occurred in daegu city and gyeongbuk province, and health system in the region was overwhelmed during late february to march. but, only 12.6% of the patients were included in this study, therefore our study might under-represent severe cases from the region. third, some of our patients were treated with hydroxychloroquine and lopinavir/ ritonavir; however, these were later proven to be of little benefit. 19,20 approximately half of the severe patients received steroid treatment, and this might affect the outcomes. lastly, most people wore face masks in korea, and this practice might reduce inoculum size of infecting viruses and therefore the severity of pneumonia. in conclusion, during the first wave of the covid-19 epidemic in korea, patients with covid-19 who were of < 50 years of age recovered without supplemental oxygen. among patients of ≥ 50 years of age, the fatality rate increased with age, reaching 14% in patients of ≥ 80 years of age. our results may help to better prepare health system and clinical management for the next waves of the covid-19 pandemic. world health organization. coronavirus disease (covid-2019) situation report-143 the first case of 2019 novel coronavirus pneumonia imported into korea from wuhan, china: implication for infection prevention and control measures coronavirus disease-19 main website characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region factors associated with hospital admission and critical illness among 5279 people with coronavirus disease global covid-19: clinical platform: novel coronavius (covid-19): rapid version. geneva: world health organization coronavirus disease-19 who working group on the clinical characterisation and management of covid-19 infection. a minimal common outcome measure set for covid-19 clinical research clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus 2 infection: a preliminary report of the first 28 patients from the korean cohort study on covid-19 a cluster of tertiary transmissions of 2019 novel coronavirus (sars-cov-2) in the community from infectors with common cold symptoms report of the who-china joint mission on coronavirus disease 2019 (covid-19). geneva: world health organization estimates of the severity of coronavirus disease 2019: a model-based analysis korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the clinical outcomes of covid-19 presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area remdesivir for the treatment of covid-19 -preliminary report operating protocols of a community treatment center for isolation of patients with coronavirus disease clinical course of asymptomatic and mildly symptomatic patients with coronavirus disease admitted to community treatment centers observational study of hydroxychloroquine in hospitalized patients with covid-19 a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 we thank all the members of the national committee for clinical management of covid-19 for their tireless efforts in data collection. we also thank the doctors and nurses of the following participating hospitals: chonnam supplementary table 1 demographic and clinical characteristics according to disease severity on admission and outcomes at 28 days (± 1 day) after admission a click here to view key: cord-000402-unr44dvp authors: yoo, hyun jung; yoon, sung soo; park, seon yang; lee, eun young; lee, eun bong; kim, ju han; song, yeong wook title: gene expression profile during chondrogenesis in human bone marrow derived mesenchymal stem cells using a cdna microarray date: 2011-06-20 journal: j korean med sci doi: 10.3346/jkms.2011.26.7.851 sha: doc_id: 402 cord_uid: unr44dvp mesenchymal stem cells (mscs) have the capacity to proliferate and differentiate into multiple connective tissue lineages, which include cartilage, bone, and fat. cartilage differentiation and chondrocyte maturation are required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. this study was designed to identify novel genes that might help clarify the molecular mechanisms of chondrogenesis. chondrogenesis was induced by culturing human bone marrow (bm) derived mscs in micromass pellets in the presence of defined medium for 3, 7, 14 or 21 days. several genes regulated during chondrogenesis were then identified by reverse transcriptase-polymerase chain reaction (rt-pcr). using an abi microarray system, we determined the differential gene expression profiles of differentiated chondrocytes and bm-mscs. normalization of this data resulted in the identification of 1,486 differentially expressed genes. to verify gene expression profiles determined by microarray analysis, the expression levels of 10 genes with high fold changes were confirmed by rt-pcr. gene expression patterns of 9 genes (hrad6b, annexina2, bmp-7, contactin-1, peroxiredoxin-1, heat shock transcription factor-2, synaptotagmin iv, serotonin receptor-7, axl) in rt-pcr were similar to the microarray gene expression patterns. these findings provide novel information concerning genes involved in the chondrogenesis of human bm-mscs. mesenchymal stem cells (mscs) are present in a variety of tissues during human development, and in particular, are prevalent in adult bone marrow (1) . mscs isolated from bone marrow (bm) and expanded in vitro in their undifferentiated phenotype, retain an extensive capacity for multi-lineage differentiation into chondrocytes, adipocytes, osteoblasts, and tenocytes under appropriate environmental cues (2) . the presence of specific, distinct antigens identified by the monoclonal antibodies sh2, sh3, and sh4, on the surfaces of marrow-derived mscs, that are not present on osteocytes and osteoblasts, suggests that these epitopes are developmentally regulated. the antigen which bound to sh2 antibody was identified as endoglin (cd105), a receptor for tgf-β3, which potentially plays a role in mediating the chondrogenic differentiation of mscs and in their interactions with hematopoietic cells (3) . chondrogenesis, the differentiation of mscs into chondrocytes, is crucial required for skeletal development and maturation, since the cartilage anlage is the model for bone formation. cartilage development thus includes the differentiation of mscs into chondrocytes, followed by their maturation, and eventual their hypertrophy and death (4) . differential gene expression profiling has been widely performed to identify and characterize candidate genes that play potentially important roles in particular biological process (5) . although the amount of information regarding the role of growth factors and cytokines as inducers and mediators of msc differentiation continues to increase, little is known about the gene expression profiling of msc chondrogenic differentiation. in this study, we employed abi genechips (representing > 30,000 genes) to identify genes differentially expressed during bm-msc chondrogenesis. abi is introduced technology based on nylonspotted 60 mer oligonucleotides, that uses on oligomers to detect each gene for most genes, chemiluminescence to measure gene expression levels, and fluorescence to grid to normalize and identify microarray features. the abi gene list was compiled from information in public and celera databases (6) . this study was designed to identify differential gene expression profiles and novel genes that might be involved in bm-msc chondrogenesis. mononuclear cells from bm aspirates were isolated by density ficoll-paque gradient separation. bm was placed in a 50 ml syringe containing 5,000 units of preservative-free heparin, diluted 1:1 with phosphate buffered saline (pbs), resuspended in pbs to a final volume of 10 ml, and layered over an equal volume of histopaque-1,077 (sigma chemical co., st. louis, mo, usa). after centrifugation at 2,000 rpm for 30 min, mononuclear cells were recovered from the gradient interface, rinsed twice in pbs, adjusted to a concentration of 1.5 × 10 7 cells/10 ml, and seeded onto 100-mm culture plates in dulbecco's modified eagle's medium-low glucose (dmem-lg; 1 g/l glucose, jbi, seoul, korea) containing 1% penicillin-streptomycin (p/s; 10,000 units/ml, gibco/brl, new york, ny, usa) and 10% (v/v) heat-inactivated fetal bovine serum (fbs; hyclone, logan, ut, usa). total numbers of nucleated and viable cells were determined using a hemocytometer and trypan blue (gibco/brl, gaithersburg, md, usa) staining. cells were incubated at 37°c in a humidified 5% co2 atmosphere and allowed to adhere for 72 hr. non-adherent cells were then removed. the medium was changed twice a week. when cells were 80%-90% confluent, adherent cells were trypsinized (0.05% trypsin, gibco/brl) at 37°c for 5 min and replated in 100-mm culture plates. after passage 3, a morphologically homogenous population of adherent cells was obtained. during this expansion, medium was changed every 4-5 days. mscs that adhered to spot slide bottoms were fixed with -20°c methanol (100%) for 5 min. cells were then rehydrated in pbs for 5 min at room temperature, washed three times with pbs, blocked with 3% bovine serum albumin in pbs, and incubated overnight at 4°c with sh2 (american type culture collection [atcc], rockville, va, usa) as a positive control. primary antibody (sh2) was removed by washing three times with pbs, and cells were then incubated with fluorescein isothiocyanate (fitc)labeled affinity-purified antibody to mouse igg + igm (h + l) (dinona inc., seoul, korea) for 1 hr at room temperature. secondary antibodies were removed by washing three times with pbs. coverslips were mounted onto slides with a solution containing 50% pbs and 50% glycerol. labeled cells were observed under an axiovert 200 (zeiss, thornwood, ny, usa). flow cytometry was performed to determine mscs positive for sh2. cells were permeabilized with ice cold 75% methanol in pbs for 30 min at 4°c, and washed three times. a fitc-conjugated sh2 antibody (dinona), diluted 1:500 in pbs, was then added, and cells were incubated for 1 hr at 4°c. cells were analyzed within 2 hr of staining using a flow cytometer (facscali-bur, becton dickinson, bedford, ma, usa). a total of 1 × 10 6 cells were collected for each measurement. negative control samples were stained with an isotype-matched irrelevant mab. to induce chondrogenic differentiation, 200,000 mscs were placed in a 15-ml polypropylene tube and centrifuged at 1,000 rpm for 5 min. pellets were then cultured at 37°c in 5% co2 and 300 μl of serum-free chondrogenic medium consisting of dulbecco's modified eagle medium-high glucose (dmem-hg, jbi) supplemented with 10 ng/ml of transforming growth factor-β3 (tgf-β3, r&d systems, minneapolis, mn, usa), 100 nm dexamethasone (sigma-aldrich, st. louis, mo, usa), 50 μg/ml ascorbate-2-phosphate, 100 μg/ml pyruvate, and 50 mg/ml its + premix (becton dickinson biosciences, bedford, ma, usa; 6.25 μg/ml insulin, 6.25 μg/ml transferrin, 6.25 ng/ml selenious acid, 1.25 mg/ml bovine serum albumin [bsa], and 5.35 mg/ ml linolenic acid); the medium was replaced every 2-3 days for 3, 7, 14, or 21 days. total rna was extracted from undifferentiated mscs and from pellets after 3, 7, 14, or 21 days of differentiation using rneasy kits (qiagen, valencia, ca, usa), according to the manufacturer's instructions. and 1,200 μl of rlt buffer supplemented with beta-mercaptoethanol (10 μl/ml) was added to the washed cells. rna integrity was assessed by gel electrophoresis and rt-pcr and concentrations were determined by measuring absorbance at 260 nm. total rna was processed using the genesys applied biosystem facility (genesys, munster, germany), according to manufacturer's recommendations. each rna pool (2 μg) was labeled with digoxigenin-utp using the abi chemiluminescent rt-ivt labeling kit v 1.0. double-stranded cdna was prepared from total rna. utp-digoxigenin-labeled complementary rna (crna) was synthesized by in vitro transcription. labeled crna (10 μg) was hybridized to abi human genome survey microarray v 2.0, which was then incubated with alkaline phosphatase-linked digoxigenin antibody. phosphatase activity was then initiated to produce the chemiluminescent signal. chemiluminescent (crna) and fluorescent (spot background) signals of the crna and standard control spots were then scanned. chemiluminescent detection and image acquisition was performed using an applied biosystems 1,700 (ab1,700) chemiluminescent microarrays analyzer, according to the manufacturer's instructions. using the software supplied with the ab1,700 apparatus, the spot chemiluminescent signal was normalized over the fluorescent signal of the same spot to obtain normalized signal value. for inter-array normalization, global median normalization was ap-plied across all microarrays (7). data analysis and data normalization were performed using the method described by quackenbush (8) . for background correction, the mean intensities of areas surrounding spots were subtracted from spot intensities (local area background). data sets were normalized by dividing the mean intensity value of every spot (in duplicate) by sum of all spot intensities within a sample to eliminate experimental or data acquisition variations. normalized data were used to calculate the gene expression level ratios of different culture stages. a two-fold expression cut-off was applied. for hierarchical gene cluster analysis, expression ratios were calculated for all genes as described by eisen et al. (9) . first strand cdna was synthesized using reverse transcriptase (rt) and 1 μg of total rna. reactions were conducted in 20 μl of buffer containing; 0.5 μl oligo (dt)12-18 primer (gibco/brl, grand island, ny, usa), 50 mm tris-hcl (ph 8.3), 75 mm kcl, 3 mm mgcl2, 40 mm dtt, 0.5 mm deoxynucleotide triphosphate (dntp) mixture (invitrogen, carlsbad, ca, usa), 10 unit rnase inhibitor (gibco/brl), and 200 units of mmlv reverse transcriptase (invitrogen). after incubation at 37°c for 60 min, reactions were stopped by heating at 70°c for 15 min. to remove remaining rna, 1 μl of e. coli rnase h (4 mg/ml) was added to reaction mixtures and incubated at 37°c for 30 min. cdnas obtained were used as a template for pcr amplification using gene-specific primers for target genes and for glyceraldehyde 3-phosphate dehydrogenase (gapdh). primer sequences are listed in table 1 . the in vitro growth pattern of msc is shown in fig. 1 . human bone marrow-derived mscs were cultured and expanded. durtable 1 . ing the log phase of growth, cells proliferated with a population doubling time of 30 hr, and this growth period was followed by a confluent growth-arrested phase. colonies were examined approximately 7 days after initial plating. a morphologically homogeneous population of 90% confluent fibroblast-like cells was obtained after 2 weeks. the cells were replated into culture dishes and cultured for 2 weeks. the replated cells were used for subsequent experiments. the cultured mscs were positive for sh2 by flow cytometry (fig. 2) . mscs were pelleted into micromasses and differentiated in serum-free medium in the presence of tgf-β3 and dexamethasone. immediately after centrifugation, the cells appeared as flattened pellets at the bottom of tubes. one day later, pellets had a thickened lip, and between days 2 and 3, pellet became spherical without any increase in size. pellets then grew in size and pellet diameters increased to about 2-fold on days 7 and 14 (fig. 3a) . using normalized microarray data, we identified 1,486 differen-tially expressed genes (fig. 4a) , which included 1,303, 121, 40, 20, and 2 genes exhibiting minimum 2 to < 5, 5 to < 10, 10 to < 20, 20 to < 70 and > 70-fold changes, respectively. to verify gene expression profiles determined by microarray analysis, the expression levels of 10 genes with high fold changes (2-48 fold changes, table 2 ) were confirmed by rt-pcr. the expression levels of the 10 genes selected (hrad 6b, annexin a2, bmp-7, contactin-1, peroxiredoxin-1, heat shock transcription factor-2, synaptotagmin iv, serotonin receptor-7, axl, and il-15) were analyzed by rt-pcr, by using total rnas obtained from 5 samples (fig. 4b) . the expression levels of 9 genes (hrad 6b, annexin a2, bmp-7, contactin-1, peroxiredoxin-1, heat shock transcription factor-2, synaptotagmin iv, serotonin receptor-7, axl) were low in undifferentiated cells and increased in differentiated cells by rt-pcr and microarray, but the expression pattern of il-15 was different. expression level of il-15 tended to be decreased in microarray, but increased in rt-pcr (fig. 5 ). in this study, we determined gene expression profiles in differentiated chondrocytes and bm-mscs. the microarray technology used did not allow quantitative comparisons between the expressional levels of different genes, but did allow us to compare fold changes with time and quantify differences in the expressions of multiple genes. our results show the sequences for gene expressional changes during bm-msc chondrogenesis. microarray data showed that axl, synaptotagmin iv, hrad6b, peroxiredoxin-1, bmp-7, heat shock transcription factor-2, annexin a2, contactin-1 and serotonin receptor-7 expressions were maintained in differentiating bm-mscs until day 14. axl is overexpressed in a number of tumors (10) , and il-15 is known to mediate the transactivation and upregulation of axl with subsequent activation of pi3k/akt and upregulations of bcl-2 and bcl-xl (11) . on the other hand, synaptotagmin iv is required for the maturation of secretory granules in pc12 cells (12) . human homologues of yeast rad 6 (hrad6b) encode ubiq-uitin-conjugating enzymes, and is highly expressed in lung cancer cell. it has been reported that dna repair and uv mutagenesis are defective in saccharomyces cerevisiae rad6 mutant (13) . peroxiredoxin-1 is the most ubiquitously expressed member of the peroxiredoxin family, and is found in the cytoplasm, nucleus, mitochondria, and peroxisomes of many cell types (14) . furthermore, recent studies have reported high levels of peroxiredoxin-1 expression in the bovine bladder, seminal vesicles, testes, adrenal gland (15) , and in the rat liver, skin, lungs and nervous system (14) . the role of peroxiredoxin-1 in cell differentiation and proliferation suggests that it has a possible role in growth and development. recent studies have confirmed that bmp-7 is a strong chemotactic component in cartilage cells produced by mesenchymal stem cells, and it can promote cartilage cells to secrete specific extracellular matrix (proteoglycans and collagen type ii). and bmp-7 can induce the differentiation of bm-mscs into cartilage cells, and that it offers a greater efficiency in repairing cartilage and subchondral bone defects (16) . heat shock transcription factor-2 (hsf-2) has been shown to be a transcriptional regulator of heat shock protein gene expression during the differentiation and development of eukaryotic cells in a tissue dependent manner (17) . hsf-2 plays an important role in fgf-2 stimulated osteoclast formation, and hsf-2 deficiency was found to modulate gene expression in stromal/ preosteoblast cells and affect osteoclastogenesis in the bone microenvironment (18) . annexins bind to negatively charged phospholipids in a ca 2+ -dependent manner and have a conserved structure. the human annexin, annexin a2 (alternative names: annexin ii, p36, and lipocortin ii) is expressed abundantly in various human organs, including the placenta, lungs, heart, and liver (19) . at the cellular level, annexin a2 is expressed on endothelial cell surfaces and acts as a co-receptor for plasminogen and tissue plasminogen activator (20) . furthermore, annexins are commonly dysregulated in cancer (21) and annexin a2 is upregulated in a variety of tumors and cancer cell lines (22, 23) . contactin-1 is a cell surface adhesion molecule, which is normally expressed by neurons, oligodendrocytes, and human astrocytic gliomas (24, 25) . previous studies have reported that mscs express il-15, essential hematopoietic growth factor (26, 27) and il-15 is also a potent apoptosis inhibitor and has many immunomodulatory activities (28) . the serotonin receptor 7 is the most recently identified member of the serotonin receptor family and is found in brain, mainly in the hypothalamus, thalamus, hippocampus, and cortex (29) . in the present study, we performed microarray analysis during bm-msc chondrogenesis in vitro. we found that over 1,486 genes were expressed by bm-mscs during chondrogenesis, and we identified genes that were differentially expressed. these data may provide novel information of the genes involved in chondrogenesis of human bm-mscs. multilineage potential of adult human mesenchymal stem cells transgene expression and differentiation of baculovirus-transduced human mesenchymal stem cells cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies gene expression profiling following bmp-2 induction of mesenchymal chondrogenesis in vitro. osteoarthritis suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cdna probes and libraries cross platform microarray analysis for robust identification of differentially expressed genes open software development for computational biology and bioinformatics microarray data normalization and transformation cluster analysis and display of genome-wide expression patterns gas6 induces growth, beta-catenin stabilization, and t-cell factor transcriptional activation in contact-inhibited c57 mammary cells a promiscuous liaison between il-15 receptor and axl receptor tyrosine kinase in cell death control synaptotagmin iv is necessary for the maturation of secretory granules in pc12 cells decreased hrad6b expression in lung cancer differential cellular and subcellular localization of heme-binding protein 23/peroxiredoxin i and heme oxygenase-1 in rat liver cloning of bovine peroxiredoxins-gene expression in bovine tissues and amino acid sequence comparison with rat, mouse and primate peroxiredoxins bmp7 induces the differentiation of bone marrow-derived mesenchymal cells into chondrocytes heat shock factor 2 is activated during mouse heart development rank ligand expression in heat shock factor-2 deficient mouse bone marrow stromal/preosteoblast cells differential expression of annexins i, ii and iv in human tissues: an immunohistochemical study specific interaction of tissue-type plasminogen activator (t-pa) with annexin ii on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro annexin a2 on lung epithelial cell surface is recognized by severe acute respiratory syndrome-associated coronavirus spike domain 2 antibodies tenascin c and annexin ii expression in the process of pancreatic carcinogenesis redox regulation of annexin 2 and its implication for oxidative stress-induced renal carcinogenesis and metastasis faivre-sarrailh c. f3/contactin, a neuronal cell adhesion molecule implicated in axogenesis and myelination contactin is expressed in human astrocytic gliomas and mediates repulsive effects phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (mscs) and stromal cells gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell death deflected: il-15 inhibits tnfalpha-mediated apoptosis in fibroblasts by traf2 recruitment to the il-15r alpha chain functional, molecular and pharmacological advances in 5-ht7 receptor research mesenchymal stem cells (mscs) have the capacity to proliferate and differentiate into multiple connective tissue lineages such as cartilage and bone. in this study, using an abi microarray system, the authors determined the differential gene expression profiles of differentiated chondrocytes and bone marrow (bm)-mscs. normalization of this data resulted in the identification of 1,486 differentially expressed genes. to verify gene expression profiles of microarray, rt-pcr was also performed. gene expression patterns of 9 genes in rt-pcr were similar to the microarray results. these findings provide novel information concerning genes involved in the chondrogenesis of human bm-mscs. key: cord-003258-yrbo0hdk authors: ha, seok gyun; oh, kyung jin; ko, kwang-pil; sun, yong han; ryoo, eell; tchah, hann; jeon, in sang; kim, hyo jeong; ahn, jung min; cho, hye-kyung title: therapeutic efficacy and safety of prolonged macrolide, corticosteroid, doxycycline, and levofloxacin against macrolide-unresponsive mycoplasma pneumoniae pneumonia in children date: 2018-09-18 journal: j korean med sci doi: 10.3346/jkms.2018.33.e268 sha: doc_id: 3258 cord_uid: yrbo0hdk background: we aimed to compare the therapeutic efficacy of prolonged macrolide (pmc), corticosteroids (cst), doxycycline (dxc), and levofloxacin (lfx) against macrolide-unresponsive mycoplasma pneumoniae (mp) pneumonia in children and to evaluate the safety of the secondary treatment agents. methods: we retrospectively analyzed the data of patients with mp pneumonia hospitalized between january 2015 and april 2017. macrolide-unresponsiveness was clinically defined with a persistent fever of ≥ 38.0°c at ≥ 72 hours after macrolide treatment. the cases were divided into four groups: pmc, cst, dxc, and lfx. we compared the time to defervescence (ttd) after secondary treatment and the ttd after initial macrolide treatment in each group with adjustment using propensity score-matching analysis. results: among 1,165 cases of mp pneumonia, 190 (16.3%) were unresponsive to macrolides. the proportion of patients who achieved defervescence within 48 hours in cst, dxc, and lfx groups were 96.9% (31/33), 85.7% (12/14), and 83.3% (5/6), respectively. the ttd after initial macrolide treatment did not differ between pmc and cst groups (5.1 vs. 4.2 days, p = 0.085), pmc and dxc groups (4.9 vs. 5.7 days, p = 0.453), and pmc and lfx groups (4.4 vs. 5.0 days, p = 0.283). no side effects were observed in the cst, dxc, and lfx groups. conclusion: the change to secondary treatment did not show better efficacy compared to pmc in children with macrolide-unresponsive mp pneumonia. further studies are needed to guide appropriate treatment in children with mp pneumonia. mycoplasma pneumoniae (mp) is one of the most common pathogens of community-acquired pneumonia in children and adolescents. it can cause a variety of clinical manifestations, from mild respiratory symptoms to severe fatal pneumonia with extrapulmonary given the increase of mrmp, some secondary treatment agents, such as corticosteroids, tetracyclines, and fluoroquinolones, have been considered for the treatment of mrmp pneumonia, although several studies have suggested that macrolides have clinical efficacy for the treatment of mrmp. [17] [18] [19] tetracyclines, including minocycline and doxycycline, have been reported as alternative agents for children with mrmp. 20,21 however, they are not recommended for use in patients younger than 8 years of age, because tetracyclines can cause tooth discoloration in children during the periods of osteogenesis and odontogenesis. 22 in addition, fluoroquinolones have been associated with a risk of musculoskeletal toxicities, including tendinitis, arthritis, and growth impairment in children. 23 although there is still lack of information on their safety in children, it was reported that there were no clinically detectable adverse events for up to 5 years after treatment with levofloxacin (lfx). 24 some studies have reported the clinical effectiveness of systemic corticosteroids (cst) in the treatment of refractory mp pneumonia, because hyper-reaction of the host immune system may contribute to its pathogenesis. 25, 26 however, cst can also cause several side effects, such as growth disorder, glucose intolerance, and the suppression of the immune system. 27 we aimed to compare the therapeutic efficacy of prolonged macrolides (pmcs), cst, doxycycline (dxc), and lfx against macrolide-unresponsive mp pneumonia in children, and to evaluate the safety of cst, dxc, and lfx. we retrospectively analyzed the medical records of patients with mp pneumonia aged ≤ 18 years old who were hospitalized at gil medical center between january 2015 and april 2017. the diagnosis of mp pneumonia was confirmed if all the following conditions were satisfied: 1) signs and symptoms (fever, cough, dyspnea, productive sputum, chest pain, or abnormal breath sounds) of pneumonia; 2) abnormal chest x-ray findings compatible with pneumonia; and 3) identification of mp igm antibody performed during the illness via enzyme-linked immunosorbent assay. among these patients, macrolide-unresponsive mp pneumonia cases were clinically defined as persistent fever ≥ 38.0°c at ≥ 72 hours after macrolide treatment in this study. the macrolide-unresponsive mp pneumonia cases were divided into four groups, pmc, cst, dxc, and lfx. the pmc group was defined as cases treated with pmc without a change of antibiotics. the cst, dxc, and lfx groups were defined as cases with treatment added on (cst) or changed to secondary treatment (dxc, lfx) because of persistent symptoms despite macrolide treatment. patients with any of the following were excluded: 1) patients for whom clinical symptoms and radiologic findings were not compatible with pneumonia, despite positive mp igm; 2) patients with a history of mp infection within the past year; 3) patients whose fever had subsided within 72 hours after macrolide treatment; 4) patients who were prescribed oseltamivir because of proven influenza during hospitalization period; or 5) patients for which a secondary treatment was started ≥ 12 hours after the last time with a fever of ≥ 38.0°c. the mean duration of administration in the cst, dxc, and lfx groups was 5.9 ± 3.1 days (oral prednisolone dosage of 1 mg/kg/day or intravenous methylprednisolone dosage of 1-2 mg/kg/day), 9.4 ± 3.4 days (at a dosage of 4 mg/kg/day), and 8.2 ± 2.4 days (at a dosage of 10 mg/kg/day). the collected data included age, sex, hospitalization period, duration of fever (febrile days before macrolide treatment, febrile days during macrolide single treatment, time to defervescence [ttd] after initial macrolide treatment, and ttd after secondary treatment), chest x-ray findings, prescribed antibiotics, extrapulmonary symptoms (hepatitis, skin rash, arthritis, hematologic, and neurological symptoms), oxygen use, intensive care unit (icu) hospitalization, percutaneous catheter drainage (pcd) insertion, re-hospitalization, and side effects associated with secondary treatments (cst, dxc, and lfx). the chest x-ray findings were from the records read by two radiologists and classified according to the presence of consolidation (lobar or patchy), reticular opacities, pneumonic infiltration, and parapneumonic effusion. in addition, information about mixed infections with other respiratory pathogens identified through multiplexed reverse transcription-polymerase chain reaction (rt-pcr) for respiratory viruses from a nasopharyngeal swab was included. we compared the ttd after secondary treatment, the use of combined antibiotics, other required treatments and outcomes among the cst, dxc and lfx groups. in addition, we compared the ttd after initial macrolide treatment and the length of hospital stay between pmc group vs. each cst, dxc, and lfx group. to adjust some variables which could affect the fever duration, we performed propensity score (ps) matching analysis. side effects such as cushing appearance and peptic ulcer for cst, tooth discoloration for dxc, and tendinopathy, arthritis for lfx were evaluated for one month after medication. all analyses except ps matching were performed using ibm spss statistics ver. 20.0 (ibm co., armonk, ny, usa). the kruskal-wallis test or mann-whitney test was used for continuous variables such as age, hospitalization period, and duration of fever. the χ 2 or fisher's exact tests were used for categorical variables such as sex, chest x-ray findings, antibiotics, extrapulmonary symptoms, oxygen use, icu hospitalization, pcd insertion, and re-hospitalization. if the variables were statistically significant when compared among more than two groups, they were further analyzed by mann-whitney test, χ 2 test or fisher's exact test for comparing two groups. we compared the ttd after initial macrolide treatment between pmc group and each secondary treatment group through ps matching to reduce selection bias and to control potential confounding factors. the estimated ps for being assigned to each group was calculated for each patient using multiple logistic regression models with the following covariates: age, sex, radiographic findings, mixed infection with other pathogens. patients were matched at a ratio of pmc:cst = 2:1, pmc:dxc = 1:1, and pmc:lfx = 2:1, based on a greedy 8-1 digits matching algorithm. this algorithm attempted to match the pmc subjects and the secondary treatment subjects on the first 8 digits of the ps. the pmc subjects that did not match were then matched to secondary treatment subjects on 7 digits of the ps. we processed through the algorithm sequentially to the 1-digit match on the ps. the patients with no corresponding match were excluded. ps matching was performed using sas 9.1.3 (sas institute inc., cary, nc, usa). p values of < 0.05 were considered to be statistically significant. this study was approved by the institutional review board (irb) of gachon university gil medical center (irb no. gbirb2017-361). the total number of subjects who met the inclusion criteria for mp diagnosis within the study period was 1,165. after exclusion by our study criteria, 190 cases (16.3%) of macrolideunresponsive mp pneumonia were enrolled. among those, 138 cases were continuously treated with macrolide approximately for 7-14 days, and 32 cases were treated with addon cst and continuous macrolide. fourteen and 6 cases were treated with secondary antimicrobial therapy with dxc and lfx, respectively. two patients were excluded: one patient had improved when administered a combination therapy of corticosteroid and lfx after treatment failure of the add-on of corticosteroid alone; the other patient was treated with corticosteroid and lfx simultaneously. the median age of patients in the pmc, cst, dxc, and lfx groups was 5.2 years old (range: 0.6-16.0), 4.9 years old (range: 1.2-14.8), 10.1 years old (range: 8.1-14.6), and 9.7 years old (range: 4.8-17.0), respectively (p < 0.001). patients in the dxc group were significantly older than in the pmc and cst groups (p < 0.001 for both). the number of boys in each group was 59 (42.8%), 19 (59.4%), 4 (28.6%), and 3 (50.0%), respectively (p = 0.850). the median duration of hospitalization was 9.5 days (range: 5.0-22.0), 9.5 days (range: 6.0-17.0), 9.0 days (range: 4.0-16.0), and 9.5 days (range: 8.0-23.0), respectively (p = 0.726) ( table 1) table 2 ). after the change to the secondary treatment, the ttd was the shortest in the cst group (8.4 ± 26.8 hours) , followed by the lfx (16.8 ± 18 .0 hours) and dxc (27.4 ± 33. 2 hours) groups (fig. 1) . the numbers of patients who achieved defervescence within 48 hours in cst, dxc, and lfx groups were 31 (96.9%), 12 (85.7%), and 5 (83.3%), respectively ( the ttds after initial macrolide treatment were compared in the matched analysis between the pmc group and each secondary treatment group. the ttds after initial macrolide treatment were not significantly different between pmc and cst groups ( table 3) . there was no difference in the length of hospital stay between the pmc group and each secondary treatment group. the number of patients who received combined treatment with third-generation cephalosporin was higher in the pmc than other groups. patients who received combined treatment with vancomycin or needed pcd insertion were identified only in the pmc group. there was no patient who required icu care and no difference in re-hospitalization rates was found among the groups ( table 4 ). there was no patient whose clinical symptoms were aggravated after secondary treatment. no side effects associated with cst, dxc, and lfx were observed. combined use of 3rd generation cephalosporin was significantly different between pmc with corticosteroid or dxc groups (p < 0.001 for both). the incidence of macrolide resistance of mp has recently increased and has been related to life-threatening or refractory mp pneumonia in children. 16 several studies on macrolide and alternative treatments for mrmp have been reported. however, data on their therapeutic efficacy and safety in children are still limited. we compared the therapeutic efficacy of pmc, cst, dxc, and lfx against macrolide-unresponsive mp pneumonia and collected data about their safety in children. most of the patient achieved defervescence within 48 hours after the secondary treatment and any side effect was not observed in the cst, dxc, and lfx groups. however, ttd after initial macrolide treatment did not differ significantly between the pmc, cst, dxc, and lfx groups. macrolide resistance of mp is genetically determined by the 23s rrna gene mutation. as there was no difference in the clinical manifestation between macrolide-susceptible m. pneumoniae (msmp) and mrmp, it is difficult to clinically distinguish mrmp from msmp. however, it has been reported that the duration of fever after the administration of macrolide was longer in mrmp than msmp in childhood pneumonia and that persistent fever might suggest the possibility of infection with mrmp. the patients with msmp achieved defervescence within 48-72 hours in more than 80% of cases after treatment with macrolide. 14,15,28 as mycoplasma takes a long time to isolate, antibiotic susceptibility testing is difficult to apply in practical clinical situations. molecular tests to confirm macrolide resistance are not currently available in korean hospitals, except in some cases for research purposes. japanese societies have recommended a change of antibiotics to second-line agents when fever does not subside in 48-72 hours from macrolides administration. 28 in this study, macrolide-unresponsive mp pneumonia was defined as persistent fever of ≥ 38.0°c at ≥ 72 hours after macrolide treatment. in this study, the prevalence of macrolide-unresponsive mp pneumonia was 16.3%, which was much lower than the prevalence of mrmp reported in korea (87.2% in 2015) . 14 this discrepancy between macrolide-resistance and macrolide-unresponsiveness indicated that most patients with mrmp pneumonia achieved defervescence within 72 hours after macrolide administration. matsubara et al. 19 demonstrated that 22.7% of mrmp cases showed clinical improvement within 3 days after macrolide treatment. in addition, suzuki et al. 17 reported that fever resolved with the initially prescribed macrolide, without changing antibiotics, for the treatment of mrmp infection, and there was no apparent treatment failure or cases of serious illness. it was suggested that macrolides have anti-inflammatory effects, as well as antimicrobial effects, through the inhibition of the production of cytokines such as il-6 and il-8 in human bronchial epithelial cells. 29, 30 in our data, there were no cases of treatment failure in the pmc group, except for two cases of re-hospitalization. in these two cases, defervescence occurred within 24 hours without a change in antibiotics after rehospitalization. in some previous reports, systemic cst induced clinical and radiological improvement in severe refractory mp pneumonia. 25, 26, 31 immune regulatory and anti-inflammatory effects of cst could result in the clinical improvement of severe refractory mp pneumonia. 32, 33 in this study, cst improved fever in the shortest time (8.4 ± 26.8 hours) compared with other medications, which was similar to those reported in other studies. lee et al. 34 reported that 93% of patients with severe mp pneumonia achieved defervescence within 24 hours. in another study, the ttd was approximately 8-48 hours in prednisolone-treated patients. 25 recently, several studies suggested that tetracycline and fluoroquinolone had a therapeutic effect on mrmp in children. most patients administered dxc or minocycline achieved defervescence within 24 hours, with a significantly shorter ttd than macrolide in the mrmp group (13.5 ± 4.1 vs. 123.3 ± 59 .0 hours). 21, 35 miyashita et al. 36 reported that 77% of patients with mrmp in the quinolone group achieved defervescence within 48 hours after the initiation of antibiotics and quinolone was more effective than macrolide for mrmp treatment (p = 0.036). in this study, ttd after dxc and lfx treatment was 27.4 ± 33.2 hours and 16.8 ± 18 .0 hours, respectively. in addition, 85.7% and 83.3% of patients achieved defervescence within 48 hours in the dxc and lfx groups, respectively ( table 2) . direct comparison of ttd between the pmc group and the secondary treatment groups was not possible, because all patients were initially treated with macrolide and added on or switched to cst, dxc, and lfx. therefore, we performed ps matching to adjust differences in baseline characteristics among the groups and compared ttd after initial macrolide treatment between groups. however, the ttds after initial macrolide treatment of the cst, dxc, lfx groups did not differ from that of each matched pmc group (p = 0.085, p = 0.453, and p = 0.283, respectively). there was no difference in length of hospital stay between the pmc group and the secondary treatment groups ( table 3) . we investigated the frequency of the use of broad-spectrum antibiotics in the treatment of community-acquired pneumonia in children. the number of patients treated with 3rd generation cephalosporin was higher in the pmc group than other groups. in addition, the use of vancomycin was observed only in the pmc group ( table 4 ). these results suggested that the choice of appropriate second-line agents in the treatment of macrolide-unresponsive mp pneumonia reduced the use of unnecessary broad-spectrum antibiotics. in the dxc and lfx groups, no side effects such as tooth discoloration or tendinopathy and arthritis were observed. it was reported that tooth staining or color change were not observed in children aged between 2 and 8 years old treated with dxc. 37 however, because dxc, approved by the u.s. food and drug administration for children aged ≥ 8 years old, is still contraindicated for children younger than 12 years of age in korea, the age indications for tetracycline-bound drugs, including dxc, should be reconsidered. in addition, the risk of cartilage injury with lfx was clinically undetectable in children over 5 years old, or was easily reversible. 24 of the 1,340 subjects treated with lfx, only one case (0.07%) was 'possibly related' to drug therapy assessed at 5 years, and this was not different from the comparator group (1/893, 0.1%). however, because concerns about the safety of tetracycline and fluoroquinolone in children still exist, it should be cautiously used with the consideration of both the risk and benefit in children with macrolide-unresponsive mp pneumonia. this study has some limitations. firstly, as this study was performed retrospectively, the clinical information might be uncertain, especially with regard to the use and duration of macrolide prescribed in other clinics. secondly, the numbers of patients in dxc and lfx groups were small. in the future, it is necessary to carry out prospective randomized studies or to conduct studies involving more subjects through multicenter studies. lastly, the igm antibody test was used to diagnose mp infection. although the patients with a history of mp infection within past year were excluded, some subjects with false positive could be included due to prolonged existence of igm for several months after past infection. in addition, false negatives could also exist due to a lack of igm antibodies in early stages. however, other alternative methods, such as isolation or the molecular detection of mp, cannot differentiate asymptomatic carriage of mp in the nasopharynx from infection or mp pneumonia. in this study, the macrolide resistance of mp determined by molecular analysis or susceptibility test was not identified. but, this study was based on an actual treatment course for mp pneumonia in a clinical setting. if fever persists despite the use of macrolide, it is necessary to consider a secondary treatment without the results of antimicrobial susceptibility. we compared the therapeutic efficacy of the secondary treatments on clinically assessed macrolide-unresponsive mp pneumonia. most of macrolide-unresponsive mp pneumonia patients achieved defervescence within 48 hours with cst add-on or treatment changes to dxc, and lfx, and any side effects were not observed in the secondary treatment groups. however, the secondary treatments did not shorten the duration of fever or hospitalization compared to pmc treatment. a large-scale prospective study is needed to guide appropriate treatment in children with mycoplasma pneumonia. pathogenesis of extrapulmonary manifestations of mycoplasma pneumoniae infection with special reference to pneumonia mycoplasma pneumoniae pneumonia in children epidemiology, clinical manifestations, pathogenesis and laboratory detection of mycoplasma pneumoniae infections mycoplasma pneumoniae in korean children: the epidemiology of pneumonia over an 18-year period epidemiological comparison of three mycoplasma pneumoniae pneumonia epidemics in a single hospital over 10 years mycoplasma pneumoniae and its role as a human pathogen nationwide surveillance of macrolideresistant mycoplasma pneumoniae infection in pediatric patients surveillance of macrolide-resistant mycoplasma pneumoniae in beijing macrolide-resistant mycoplasma pneumoniae, united states the increased incidence of mycoplasma pneumoniae in france in 2011 was polyclonal, mainly involving m. pneumoniae type 1 strains mycoplasma pneumoniae and chlamydia spp. infection in community-acquired pneumonia emergence of macrolideresistant strains during an outbreak of mycoplasma pneumoniae infections in children macrolide resistance of mycoplasma pneumoniae prevalence and clinical manifestations of macrolide resistant mycoplasma pneumoniae pneumonia in korean children differences in the frequency of 23s rrna gene mutations in mycoplasma pneumoniae between children and adults with community-acquired pneumonia: clinical impact of mutations conferring macrolide resistance life-threatening pneumonia caused by macrolide-resistant mycoplasma pneumoniae clinical evaluation of macrolideresistant mycoplasma pneumoniae characterization and molecular analysis of macrolide-resistant mycoplasma pneumoniae clinical isolates obtained in japan a comparative clinical study of macrolide-sensitive and macrolide-resistant mycoplasma pneumoniae infections in pediatric patients therapeutic efficacy of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolide-resistant and macrolide-sensitive mycoplasma pneumoniae pneumonia in pediatric patients rapid effectiveness of minocycline or doxycycline against macrolide-resistant mycoplasma pneumoniae infection in a 2011 outbreak among japanese children tetracycline and other tetracycline-derivative staining of the teeth and oral cavity systemic quinolone antibiotics in children: a review of the use and safety assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin effects of prednisolone on refractory mycoplasma pneumoniae pneumonia in children effects of methylprednisolone pulse therapy on refractory mycoplasma pneumoniae pneumonia in children side effects of corticosteroid therapy epidemiology of mycoplasma pneumoniae infections in japan and therapeutic strategies for macrolide-resistant m. pneumoniae interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells erythromycin suppresses interleukin 6 expression by human bronchial epithelial cells: a potential mechanism of its antiinflammatory action effects of methylprednisolone or immunoglobulin when added to standard treatment with intravenous azithromycin for refractory mycoplasma pneumoniae pneumonia in children steroids in severe pneumonia: a literature review antiinflammatory action of glucocorticoids--new mechanisms for old drugs role of prednisolone treatment in severe mycoplasma pneumoniae pneumonia in children rapid defervescence after doxycycline treatment of macrolideresistant mycoplasma pneumoniae-associated community-acquired pneumonia in children macrolide-resistant mycoplasma pneumoniae pneumonia in adolescents and adults: clinical findings, drug susceptibility, and therapeutic efficacy absence of tooth staining with doxycycline treatment in young children key: cord-344969-q1wqfeh7 authors: min, kyung-duk; kang, heewon; lee, ju-yeun; jeon, seonghee; cho, sung-il title: estimating the effectiveness of non-pharmaceutical interventions on covid-19 control in korea date: 2020-09-01 journal: j korean med sci doi: 10.3346/jkms.2020.35.e321 sha: doc_id: 344969 cord_uid: q1wqfeh7 background: the coronavirus disease 2019 (covid-19) pandemic has posed significant global public health challenges and created a substantial economic burden. korea has experienced an extensive outbreak, which was linked to a religion-related super-spreading event. however, the implementation of various non-pharmaceutical interventions (npis), including social distancing, spring semester postponing, and extensive testing and contact tracing controlled the epidemic. herein, we estimated the effectiveness of each npi using a simulation model. methods: a compartment model with a susceptible-exposed-infectious-quarantined-hospitalized structure was employed. using the monte-carlo-markov-chain algorithm with gibbs' sampling method, we estimated the time-varying effective contact rate to calibrate the model with the reported daily new confirmed cases from february 12th to march 31st (7 weeks). moreover, we conducted scenario analyses by adjusting the parameters to estimate the effectiveness of npi. results: relaxed social distancing among adults would have increased the number of cases 27.4-fold until the end of march. spring semester non-postponement would have increased the number of cases 1.7-fold among individuals aged 0–19, while lower quarantine and detection rates would have increased the number of cases 1.4-fold. conclusion: among the three npi measures, social distancing in adults showed the highest effectiveness. the substantial effect of social distancing should be considered when preparing for the 2nd wave of covid-19. the coronavirus disease 2019 (covid19) pandemic has posed severe global health challenges with substantial damage to the world economy. until april 17th, 2020, approximately 2 million confirmed cases and more than 139,000 deaths were reported worldwide, 1 while the global gross domestic product was estimated to have declined by imported cases. a schematic diagram of the meta-population compartment model with the seiqh structure is shown in fig. 1 , and incorporated equations are described in detail in supplementary material 1. four types of parameters were included in the model: the rate at which exposed individuals become infectious (θ), detection rate (γ), quarantine probability (υ), and effective contact rate (β). the rate at which exposed individuals become infectious was reciprocal with the latent period; thus, the time between exposure and onset of infectiousness reflected the probability of transition from the exposed (e) to infectious (i) state in a given time unit. the latent period was employed as 4.5 days, considering that the incubation period was reported as 5.5 days 8 and infectiousness could be developed one day before presenting symptoms. 9 the detection rate was reciprocal with the infectious period, reflecting the time between the onset of symptoms and isolation. the infectious period used was 5.8 days, as the reported time gap between symptom onset and isolation is 4.8 days 10 and the assumption that infected individuals start transmitting the virus one day before presenting symptoms. 9 quarantine probability was defined as the proportion of quarantined people detected by contact tracing before they became infectious. the probability was set to 4% as status quo, considering that 4% of confirmed cases were detected before symptom onset in gyeonggi-do. 10 effective contact rate is the product of contact rate and transmission probability per contact. as we used a discrete-time model for our analyses, the effective contact rate indicated the number of people who were infected by one infectious patient per time unit (day). due to the heterogeneity in the number of contacts between infectious individuals and between time periods, we employed time-dependent effective contact rates. different effective contact rates were used for each week for individuals aged 20+, and for each month for individuals aged 3/13 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e321 the population was categorized into five states: susceptible (s), exposed (e), infectious (i), quarantined (q), and hospitalized (h). the population was also stratified according to age: aged 0-19 (subscript "c") and aged 20+ (subscript "a"). four types of parameters were used to determine the transition rates between the different states: the rate at which exposed individuals become infective (parameter θ), the detection (or isolation) rates of infectious individuals (parameter γ), quarantine probability (parameter ν), and the force of infection (parameter λ), which was time-varying and dependent on the number of infectious individuals and their effective contact rates. 0-9. considering that the effective contact rate was not measurable, we estimated the timevarying effective contact rate by calibrating the model using daily reported confirmed cases. calibration was performed using a monte-carlo-markov-chain algorithm 11,12 with gibbs sampling. the parameters used in this study and their values are summarized in table 1 . in this study, we included data from february 12th, six days before the first case of the religion-related large cluster was reported, reflecting the time gap between the onset of infectiousness and isolation the study period was seven weeks (until march 31st). the early phase of the covid-19 epidemic (from january 20th to february 11th) was excluded because the local transmission was not significant at that time. in this study, we evaluated the effectiveness of various npis, including social distancing in adults, spring semester postponement, diagnostic testing, and contact tracing, using the developed mathematical model and scenario analysis. weekly effective contact rates among adults within the study period were estimated by model calibration. regarding the estimated rates as status quo, increased effective contact rates were applied to simulate an epidemic situation by reduced intensity of social distancing in adults. to assess the effectiveness of social distancing after the religious gathering-related event, which was expected to increase the effective contact rate between weeks 1 and 2, we performed scenario analysis by applying an increased contact rate between weeks 3 and 7. as a severe-case scenario, we assumed a two times higher effective contact rate than the maximum estimated effective contact rate between weeks 3 and 7. as a mild-case scenario, we assumed an effective contact rate equal to the maximum estimated effective contact rate between weeks 3 and 7. spring semester initiation at the usual time (march 2nd) in elementary, middle, and high schools would have increased the contact rates among children and adolescents. herein, by estimating the level of increase in the contact rates, we determined the effectiveness of the effective contact rate among individuals aged 20+ in week 1 calibrated d β 4 effective contact rate among individuals aged 20+ in week 2 calibrated d β 5 effective contact rate among individuals aged 20+ in week 3 calibrated d β 6 effective contact rate among individuals aged 20+ in week 4 calibrated d β 7 effective contact rate among individuals aged 20+ in week 5 calibrated d β 8 effective contact rate among individuals aged 20+ in week 6 calibrated d β 9 effective contact rate among individuals aged 20+ in week 7 calibrated d φ ca multiplier for effective contact rate from individuals aged 0-19 to individuals aged 20+ calibrated d φ ac multiplier for effective contact rate from individuals aged 20+ to individuals aged 0-19 calibrated d a latent period was assumed as 4.5 days, considering that the reported incubation period of the virus is 5.5 days and that infected individuals start transmitting the virus one day before presenting symptoms; b infectious period was assumed to be 5.8 days, considering that the reported time between the onset of symptoms and isolation is 4.8 days and that infected individuals start transmitting the virus one day before presenting symptoms; spring semester postponement. to this end, we used varicella incidence data from the korea centers for disease control and prevention (kcdc). although etiology and transmissibility differ between the two diseases, we assumed an equivalent contact rate ratio before and after the school semester. kcdc provided weekly reported varicella incidence in individuals younger than 20 years old. using simple susceptible-exposed-infectious-recovered (seir) compartment model with time-dependent effective contact rate, we estimated contact rate ratio (k 1 ) between before (january and february) and after school opening (march and april) in 2019 and contact rate ratio (k 2 ) between january and february in 2020. the ratio "k 1 " represented an increased contact rate after the opening semester in the previous year (without . the ratio "k 2 " was used as an estimate of contact rate decrease, by comparing the contact rate in january (when the outbreak was not severe) and february (when voluntary social distancing was rampant in korea). in the scenario analysis, we applied a k 1 *(1/k 2 ) times higher effective contact rate to child and adolescent groups from march 2nd to march 31st. the scenario analysis is described in detail in supplementary material 2. extensive contact tracing and diagnostic testing could reduce the risk of secondary transmission by quarantining exposed individuals before they become infectious and reducing the infectious period of covid-19 patients. non-extensive contact tracing and diagnostic testing were simulated by applying a decreased detection rate (increased infectious period) and quarantine probability. as an increased infectious period, we used 9.09 days because 8.09 days was the longest reported time between symptom onset and isolation, 13 and infected individuals can start transmitting the virus one day before presenting symptoms. 9 the decreased level of quarantine probability was set to 2% (half of the status quo). two sensitivity analyses were implemented considering uncertainty of parameters. the time gap between onset of infectiousness and symptoms was assumed as 2 days in the first sensitivity analysis. in the second sensitivity analysis the time gap between onset of symptoms to detect or isolation was assumed as 3 days following report from ki et al. 5 and the assumption for the first sensitivity analysis was also applied. no ethical approval is required. the calibration results of the developed model are illustrated in fig. 2 in this study, we estimated the expected epidemic size of covid-19 in korea, if social distancing among adults in march was more relaxed while maintaining the effective contact rate at a higher level than the status quo (fig. 3) . the effective contact rate in week 6 (beta 8) showed the higher estimate than those in other weeks (beta 3-9). in the severe-case scenario, where the effective contact rates in weeks 3-7 were assumed as two times higher than estimated beta 8 (0.498, 95% cri = 0.410-0.578), 252,011 cases (95% cri = 136,882-431,181) would have been confirmed by the end of march, which is approximately 27 times more than the status quo. in the mild-case scenario, where the effective contact rates in weeks 3-7 were assumed as same as estimated beta 8, 41,688 cases (95% cri = 30,302-56,224) would have been confirmed by the end of march, which is approximately 4.5 times more than the status quo. we also simulated the epidemic size in korea, in the case that the spring semester would begin on march 2nd, as usual (fig. 4) . using varicella incidence in 2019 and 2020 as a model, we found that non-postponement of the semester would have increased the contact rate 2.407fold (95% cri = 2.140-2.688) in the severe-case scenario and 1.752-fold (95% cri = 1.701-1.801) in the mild-case scenario (supplementary material 2) . using scenario analysis for the contact rate ratio of covid-19, we showed that the number of confirmed cases among individuals aged 0-19 would have been 1,090 (95% cri = 1,001-1,197) and 890 (95% cri = 877-903) assuming the severe-case scenario and mild-case scenario, respectively. these estimates are 1.71 times and 1.39 times higher than the status quo, respectively. note: the effectiveness of social distancing among adults was estimated by increasing the effective contact rate in individuals aged 20+. in the severe-case scenario, the effective contact rate in weeks 3-7 was assumed to be 0.497 (95% credible interval = 0.410-0.578), which was two times higher than the maximum estimated effective contact rate in weeks 3-7. in the mild-case scenario, the effective contact rate in weeks 3-7 was assumed to be 0.249 (95% credible interval = 0.205-0.289), which was equal to the maximum effective contact rate estimated for weeks 3-7. less strict quarantine measures and less extensive diagnostic testing would have resulted in 12,741 confirmed cases by the end of march, which is 1.39 times higher than the status quo (fig. 5) . if the detection time (time between the onset of symptoms and isolation) was reduced to 4 days and the quarantine probability was increased to 10%, more than 3,000 cases could have been averted by the end of march. however, if the isolation of infected individuals was delayed to 8 days, and the quarantine probability was reduced to 2%, more than 2,500 additional cases would have been reported by the end of march. the parameters used in the scenario analysis are detailed in table 2 , and the results are summarized in table 3 . in the first sensitivity analysis, where longer time gap between onset of infectiousness and symptoms was assumed, both effectiveness of social distancing and school opening postponement increased but that of contact tracing decreased. in the second sensitivity analysis, where longer time gap between onset of infectiousness and symptoms and shorter time gap between symptom onset and isolation were assumed, the effectiveness of social distancing decreased but the effectiveness of school opening postponement and contact tracing increased. the effectiveness of the spring semester postponement was estimated by increasing the effective contact rate among individuals aged 0-19. in the severe-case scenario, the highest effective contact rate between march 2nd and march 31st was 0.170 (95% credible interval = 0.151-0.190), which was 2.39 times higher than the effective contact rate estimated for february. in the mild-case scenario, the estimated effective contact rate from march 2nd to march 31st was 0.124 (95% credible interval = 0.120-0.127), which was 1.75 times higher than the effective contact rate estimated for february. 9/13 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e321 daily new cases cumulative cases the effectiveness of extensive diagnostic testing and contact tracing was estimated by decreasing the quarantine probability and detection rate. in the scenario analysis, the quarantine probability was reduced to 2%, which was half the status quo (4%). additionally, the detection rate was reduced to 1/9.09, reflecting a longer infectious period (9.09 days) than the status quo (5.8 days). (e) contour plot illustrating the variations in the additional cumulative cases by the end of march. scenario 1 employed a higher effective contact rate among individuals aged 20+ in weeks 3-7 (β 5 to β 9 ) to evaluate the effectiveness of social distancing. in mild case scenario, β 8 which is the highest effective contact rate among β 5-9 , was applied to β 5-9 . in severe case scenario, twice higher effective contact rates were assumed than mild case scenario; b scenario 2 employed a higher effective contact rate among individuals aged 0-19 in march (β 2 ) to evaluate the effectiveness of school opening postponement. the increase level of effective contact rate for the school opening scenario was obtained from increase level of effective contract rate by school opening in march 2019 using a mathematical model for varicella among adolescence; c scenario 3 employed a lower detection rate (γ) and quarantine probability (ν) to evaluate the effectiveness of extensive diagnostic testing and contact tracing; d effective contact rate-related parameters for status quo were estimated by calibration with reported data of confirmed covid-19 cases. a mathematical simulation model with a seiqh compartment structure was developed to evaluate the effectiveness of npi strategies for the covid-19 epidemic in korea, including social distancing, and extensive contact tracing and diagnostic testing. our findings highlighted the effectiveness of the npis employed and indicated that a steep rise in the epidemic curve would have been observed if they had not been implemented. notably, social distancing among adults was the most effective measure contributing to the control of the epidemic. although the estimated effectiveness varied as different parameters were assumed, the high effectiveness of social distancing in all sensitivity analysis showed robustness of the results. the reasonable fit of the calibrated model with reported daily new confirmed cases, from february 12th to march 31st, was shown by both visual examination and correlation analysis, although some extreme values such as 814 cases on february 29th, was not replicated by the model. drastic reduction in the effective contact rate was estimated in both age groups in march. the decreasing trend was attributed to a decrease in contact rate rather than a decrease in transmission probability per contact because the transmissibility is not believed to be affected by the temperature. 14 high contact rates among adults in weeks 1 and 2 reflected the religious super-spreading event that took place in korea. however, the high contact rates can be overestimated because the majority of confirmed cases from the religion-related event were detected by mass diagnostic testing which increased the number of confirmed cases in a short period of time. in weeks 3 and 4, the median estimate of the contact rate was close to zero, which is unlikely in the real-life situation; hence, it should be interpreted as an extremely low mean contact rate among infectious patients. in the reallife situation, in weeks 3 and 4, extensive and large-scale diagnostic testing and preemptive quarantine were implemented, especially among the attendees of the religious gathering. although some undetected infected individuals have spread the virus, the mean effective contact rate among all infectious individuals in that period was low. to simulate the drastic decline in new confirmed cases, a close-to-zero effective contact rate was used, which is 10/13 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e321 the time gap between onset of infectiousness and symptoms was assumed as 2 days in a sensitivity analysis. a scenario 1 employed a higher effective contact rate among individuals aged 20+ in weeks 3-7 (β 5 to β 9 ) to evaluate the effectiveness of social distancing; b scenario 2 employed a higher effective contact rate among individuals aged 0-19 in march (β 2 ) to evaluate the effectiveness of school opening postponement; c scenario 3 employed a lower detection rate (γ) and quarantine probability (ν) to evaluate the effectiveness of massive diagnostic testing and contact tracing. the time gap between onset of infectiousness and symptoms was assumed as 2 days and the time gap between symptom onset and isolation was assumed as 3 days in a sensitivity analysis. a scenario 1 employed a higher effective contact rate among individuals aged 20+ in weeks 3-7 (β 5 to β 9 ) to evaluate the effectiveness of social distancing; b scenario 2 employed a higher effective contact rate among individuals aged 0-19 in march (β 2 ) to evaluate the effectiveness of school opening postponement; c the maximum decrease rate that the compartment model can suggest (given the constant infectious period). although this is one of inherent limitations of compartment models, both model and real-life situation showed 'extremely-low level' of mean contact rate in weeks 3 and 4. in weeks 5 and 6, the effective contact rate increased; however, the rate was decreased in the subsequent week, when the korean government recommended social distancing. consistent with modeling studies in different countries, scenario analysis confirmed the effectiveness of npis. 15-17 notably, with relaxed social distancing, the number of cases could have been 4.5-27 folds higher. the estimated effectiveness reported in this study is considerably higher than a previous study that predicted a 2.6-fold higher number of infections in china in the absence of inter-city travel restrictions. 17 this difference could be attributed to the early implementation of social distancing in korea. for example, during the period of the religion-related superspreading event, strict social distancing was imposed on citizens in daegu where the superspreading events occurred. in addition, travel to and from daegu was reduced and voluntary social distancing had also been implemented before the government announcement of official social distancing. consistent with this, walker et al. 7 reported that implementation of suppression strategies in the early phases of an epidemic could be five times more effective than a late phase implementation. however, the differences in methods between studies could also contribute the different results. for example, the previous study used a seir structure for the model but we used a seiqh structure. in addition, the previous study estimated contact rate by population movement datasets, such as mobile phone data, which were not used in this study. kim et al. 18 predicted that spring semester postponement would prevent at least 200 cases in march, assuming that the transmission rate would increase 10-fold after the start of the semester. this estimate was similar to the estimate of our mild-case scenario analysis, which suggested 250 additional cases among individuals aged 0-19. additionally, both studies estimated a limited impact on adults. however, severe-case scenario analysis estimated an additional 451 cases and the new number of cases was maintained. the maintaining trend implied potential impact after beginning of the spring semester. if the number of new cases is low, then the maintaining trend would produce low-burden, but in the severe epidemic situation, the maintaining trend would give high burden. the level of increase in the third scenario analysis was not profound, with a 1.39-fold higher predicted number of cases. considering that a prolonged infectious period would increase the probability of super-spreading events, which was not considered in the model, the effectiveness of extensive contact tracing and diagnostic testing could have been underestimated in this study. lai et al. 17 found that early case detection and isolation could reduce the number of infections by 20%. there are several limitations to this study. first, we added q compartment in this study compared to seir model in order to evaluate the effectiveness of contact tracing. however, uncertainties for some parameters should be considered. for example, although a constant detection rate and quarantine probability were assumed, these parameters could be timevarying and can be affected by the number of daily confirmed cases. for example, high number of daily confirmed cases could exhaust capacity for epidemiological investigation which leads to a decrease in detection rate and quarantine probability. extracting the relevant data from epidemiological studies could improve the simulation model. second, to minimize the complexity of the model structure, we assumed a homogenous contact rate among individuals aged 20+; however, a varying contact rate among different age groups is expected. 19 third, individual characteristics, such as comorbidity, health behavior, or occupation, were not considered in our compartment models. future agent-based model studies are required to improve the predictions reported here by incorporating individual factors. fourth, transmissibility can be time-varying because viral load tends to change after the onset of symptoms. 20 finally, we simplified the model structure to minimize uncertainty of parameters. for example, we did not differentiate asymptomatic, pre-symptomatic and symptomatic cases in this study, and the compartment i represented all these cases for simplification. in addition, the compartments were not classified by geographical regions. considering that the transmission probability, infectious period could be different by each type of infectious status and effective contact rate could be different by geographical regions, future studies with complex structure or microsimulation design could improve accuracy of models. in this study, we simulated the covid-19 epidemic in korea from february 12th to march 31st, using a compartment model with a seiqh structure, and estimated the time-varying effective contact rate by calibrating the model with reported daily new cases. using the model, we estimated the effectiveness of npis by assuming less strict social distancing, spring semester non-postponement, or less extensive diagnostic testing and contact tracing. without each of these npis, the number of covid-19 cases would have been considerably higher, highlighting the importance of npis. in particular, social distancing among adults was the most effective npi. covid-19): situation report, 88. geneva: world health organization the potential impact of covid-19 on gdp and trade: a preliminary assessment estimating the asymptomatic proportion of coronavirus disease 2019 (covid-19) cases on board the diamond princess cruise ship covid-19: identifying and isolating asymptomatic people helped eliminate virus in italian village epidemiologic characteristics of early cases with 2019 novel coronavirus (2019-ncov) disease in korea korean society for antimicrobial therapy, korean society for healthcare-associated infection control and prevention the global impact of covid-19 and strategies for mitigation and suppression the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application viral load of sars-cov-2 in clinical samples covid-19) gyeonggi daily report, data as discrete time modelling of disease incidence time series by using markov chain monte carlo methods a tutorial introduction to bayesian inference for stochastic epidemic models using markov chain monte carlo methods feasibility of controlling covid-19 outbreaks by isolation of cases and contacts evaluation of heating and chemical protocols for inactivating sars-cov-2 impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand. london: imperial college covid-19 response team the effect of human mobility and control measures on the covid-19 epidemic in china effect of non-pharmaceutical interventions for containing the covid-19 outbreak in china school opening delay effect on transmission dynamics of coronavirus disease 2019 in korea: based on mathematical modeling and simulation study projecting social contact matrices in 152 countries using contact surveys and demographic data viral dynamics in mild and severe cases of covid-19 key: cord-000964-ysyz3grd authors: kim, soo jin; kim, chu hyun; shin, sang do; lee, seung chul; park, ju ok; sung, joohon title: incidence and mortality rates of disasters and mass casualty incidents in korea: a population-based cross-sectional study, 2000-2009 date: 2013-05-02 journal: j korean med sci doi: 10.3346/jkms.2013.28.5.658 sha: doc_id: 964 cord_uid: ysyz3grd the objective of study was to evaluate the incidence and mortality rates of disasters and mass casualty incidents (mcis) over the past 10 yr in the administrative system of korea administrative system and to examine their relationship with population characteristics. this was a population-based cross-sectional study. we calculated the nationwide incidence, as well as the crude mortality and injury incidence rates, of disasters and mcis. the data were collected from the administrative database of the national emergency management agency (nema) and from provincial fire departments from january 2000 to december 2009. a total of 47,169 events were collected from the nema administrative database. of these events, 115 and 3,079 cases were defined as disasters and mcis that occurred in korea, respectively. the incidence of technical disasters/mcis was approximately 12.7 times greater than that of natural disasters/mcis. over the past 10 yr, the crude mortality rates for disasters and mcis were 2.36 deaths per 100,000 persons and 6.78 deaths per 100,000 persons, respectively. the crude injury incidence rates for disasters and mcis were 25.47 injuries per 100,000 persons and 152 injuries per 100,000 persons, respectively. the incidence and mortality of disasters/mcis in korea seem to be low compared to that of trend around the world. disasters can be defined as rapid or emerging incidents that require excessive resources, or more resources than are available in a local area when natural or technical dangers are present (1) (2) (3) (4) . the term mass casualty incident (mci) refers to disasters that involve many people (5, 6) . mcis occur in many different contexts, including car crashes, chemical leaks, building collapses, fires, terrorism events, and mass gatherings (7, 8) . the frequency of disasters and mcis is increasing, and calamities always involve mass casualties because they are unpredictable. from 1994 to 2005, according to a un report, the world witnessed over 67,000 deaths and 260 million people wounded each year due to disasters (9) . an estimated loss of u$204 billion occurred due to natural disasters in the 1980s (10, 11) . disasters and mcis consume local resources in the short and long term, and therefore, appropriate preparation is required to avoid high death and failure rates in such cases (7, 8) . disaster and mci-related research in korea has mostly focused on the establishment of a national disaster management system (12) , the role of disaster management agencies (13) , database (db) building for disaster prevention (14) , and descriptive studies on post-disaster stress management (15) , post-traumatic stress disorder (ptsd) (16) , hospital disaster (17) , incidents at mass gatherings and sporting events and building collapses (18, 19) . according to statistics report over the 1990's (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) , natural disasters/mcis such as storms and floods have caused an annual average of 122 people dead or missing, 17,219 refugees and property losses of over 580 billion won (krw) (20) . in the same period technical disasters/mcis such as train derailments, plane crashes, bridge collapses, fires aboard liners, city gas explosions and building collapses cause tens to http://dx.doi.org/10.3346/jkms.2013. 28.5.658 hundreds of victims. in the 2000s, mcis such as the daegu subway fire and the 2007 mt hebei spirit oil spill raised issues of the physical health of local residents and volunteers (21) . however, it is difficult to compare and evaluate korean cases with those from other parts of world because there is no research that presents an epidemiologic indicator for annual disaster-and mci-related events; thus, we lack the basis for practical evaluation. the aim of this study was to calculate the incidence, mortality and overall rates of disasters and mcis and to examine their relationship with population characteristics, using health-related indicators to facilitate future comparison of disasters and mcis between domestic and foreign cases. south korea covers an area of approximately 99,720 km 2 and has a population of just over 48 million people. korea, based on act no. 7188 (march 11. 2004 ) the framework act on the management of disaster and safety, adopts mixed model between civil defence model and emergency medical treatment priority system as disaster policy, in which administration security department carries out a key role (22). disaster management system of korea consists of the central safety management committee, headed by the prime minister and subcommittees headed by the ministers of various government ministries. the central safety management committee supervises and coordinates overall policy related to disaster and safety, and also promotes negotiations and coordination among the relevant ministries. the subcommittees help ensure the seamless operation of the central committee, especially, the coordination committee under the minister of public administration and security, is in charge of the overall process of negotiations and coordination with regard to tasks delegated by the central committee. the national emergency management agency (nema) provides emergency medical service (ems) to korea and plays a key role in the response to disasters and mcis in most communities. a single-tiered fire-based ems handles disasters and mcis occurring throughout the entire korean region and includes 16 regional headquarters of the fire department with a total of 1,400 advanced ambulances and 5,400 ems providers. in addition, headed by the administrator of the nema, operates the central emergency rescue control team to supervise and control matters related to emergency rescue, command, and control at the disaster site. we aimed to calculate the incidence, mortality and overall rates of disasters and mcis and to examine their relationship with population characteristics, using health-related indicators based on disaster/mci database of nema to facilitate future compari-son of disasters and mcis between domestic and foreign cases. this study was a population-based cross-sectional study based on nema administrative data from 2000 to 2009. the centre for research on the epidemiology of disasters (cr-ed), which is an international epidemiological disaster research institution, has defined a disaster as a case in which more than 10 deaths are reported, more than 100 people are affected, a national emergency has been declared, or international assistance has been requested (10). the centers for disease control (cdc) in the united states (us) has defined an mci as a case in which more than 6 casualties have occurred (23) . thirty papers were reviewed by searching medline and the cochrane library prior to conducting expert interviews to create a definition for both disasters and mcis that would fit the situation of korea. a number of the aforementioned survey papers and classroom presentations on various definitions of disasters and mcis were introduced in further expert interviews with instructors who had finished the national disaster life support (ndls) course, a disaster emergency medical expert training program. the classic delphi method was used to conduct the first survey via e-mail with experts who are instructors of the ndls course, and the policy delphi survey (24) was undertaken as a secondary survey after presenting the results of the first survey to interview subjects so that they could collect ideas and suggestions. on the basis of these discussions, a disaster has been defined for korea as an incident that affects more than one municipal local governing district, involves the death of more than 10 people, or involves more than 50 casualties. an mci has been defined as an incident that involves more than 6 casualties, regardless of the affected area or number of deaths. with regard to the credibility of the representative data, the study employed data for 2000 to 2009 taken from the nema administrative database to analyze the major disaster and mci types in korea. this database includes all official records of disasters that have occurred in korea information from the statistics korea website (http://kosis.kr/feature/feature_0102list.jsp?me-nuid = all&mode = listall) was used to present other social statistics, such as population and size of korea. people who were killed or injured in korean disasters or mcis who were registered in the nema administrative database for the period from 2000 to 2009 were selected as study subjects. we collected study data in two steps: first, we collected the 'daily accidental management situation report' , which inhttp://dx.doi.org/10.3346/jkms.2013.28.5.658 cludes daily incidents, and is sorted by severity. the 'daily accidental management situation report' can be downloaded from the home page of nema (www.nema.go.kr) and is prepared by the nema disaster status control center. next, we collected and analyzed internal nema reports, referred to as 'accidental status reports' , which notify the relevant teams within nema (e.g., fire investigation, rescue and ems) about major incidents (appendix 1-4). these reports were made available for this study through the cooperation of nema. using the daily accidental management situation reports, all nema disaster reports from the 16 korean provinces were coded and entered into an electronic database. using the accidental status reports, more detailed information was coded and added to this database. finally, the cases that met the defined category of disasters and mcis for this study were extracted to establish the final dataset. the final dataset for this study is the result of the reconstructed database of reports from 16 regional fire department headquarters within nema from january 2000 to december 2009. the extracted variables were the dates of the disaster, the address, the disaster type, the number of casualties, the estimated financial loss, the mobilized manpower, the victims' gender, age and major symptoms, the location of the fire (if the event was a fire), the type of collision (if the event was a car crash), and the number of mobilized ambulances (table 1) . statistical analysis sas version 9.1 was used as the statistical analysis tool. the primary outcome was analyzed using a descriptive analysis to calculate the incidence, crude mortality rates and crude injury incidence rates of disasters and mcis for each year, using central populations from the ministry of statistics. the secondary outcome was the assessment of the incidence trends of disasters/ mcis by time-series and by type and calculation of the number of deaths and casualties by disaster/mci type, the number of deaths and crude death rates by province, and the number of injuries and crude injury incidence rates by province. we collected 43,169 events from the nema administrative database, covering the period from january 2000 to december 2009. of these, 115 and 3,079 were defined, respectively, as disasters and mcis that occurred in korea. there were 2,286 (72.3%) cases of disasters and mcis in rural areas, which is approximately 2.6 times greater than the 879 (27.7%) cases that occurred in urban areas. the incidence of technical disasters/mcis was approximately 12.7 times greater than that of natural disasters/ mcis (2,960 cases vs 233 cases). with regard to both disasters and mcis, transportation crashes were the most common cases. in an analysis of the seasonal factors, both disasters and mcis occurred more frequently in the summer (june-august) and the winter (november-february). with respect to the provincial factor, the gyeonggi province showed the highest frequency of disasters (27 cases, 23.5%) and mcis (606 cases, 19.7%), followed by seoul with 17 cases (14.8%) of disasters and 343 cases of mcis (11.1%) and gyeongnam with 5 cases (4.4%) of disasters and 269 cases of mcis (8.7%) ( table 2) . from 2000 to 2009, both disasters and mcis showed a tendency to increase in number over time, but there is no significant time trend, although the frequency of incidents and the number of casualties were directly proportional in mcis (fig. 1, 2) . as for natural factors, general floods were the most common type of disaster and mci with 125 cases (61.0%), followed by flash floods with 47 cases (20.2%) and tropical cyclones with 24 cases (10.3%). the number and the frequency of injuries and deaths were on the same order. for disasters only, general floods were the most common type (17 cases, 68.4%), followed by tropical cyclones (4 cases, 15.4%) and flash floods (3 cases, 11.5%). the number and frequency of injuries and deaths were on the same order. for mcis, the number and frequency of occurrence and the number of injuries and deaths were the same as those of the total ( table 3) . as for technical factors, road crashes were the most common type of disaster and mci with 2,326 cases (78.6%), followed by fire with 221 cases (7.5%) and others incidents such as isolations of closed space, escalator incident, rippling incident, leisure place incident with 166 cases (5.6%). the number and the frequency of affected and deaths were on the different order for disaster and mci. for affected victims of disaster only, road crashes were the most common type (2,369 persons, 48.3%), followed by mass gatherings (1,499 persons, 24.9%), fires (991 persons, 16.5%). for dead victims of disaster, fires were most common type (258 persons, 35.9%), followed by road crashes table 4) . the crude mortality rates for disasters and mcis nationwide were 2.36 per 100,000 people and 6.78 per 100,000 people, respectively. the crude injury incidence rates per 100,000 people for disasters and mcis nationwide were 25.47 and 152, respec-tively (table 5) . for disasters by province, ulsan showed the highest injury incidence rate (11.15 per 100,000), followed by jeonnam (7.67) and gangwon (7.09). for mcis, the rate for gangwon was 23.34 per 100,000 people, followed by jeju (18.5) and jeonnam (17.4) . most research undertaken in the early and mid-20th century focused on the definition of disaster, epidemiologic studies and research methodology. subsequent research by the world health organization (who) and cred was mostly focused on natural disasters, such as earthquakes, floods, high winds, tornados, and heat waves, comparing the causes of disasters between countries and continents and measuring the economic losses, mortality, injuries and suffering incurred by these events (3, 4, 8, 25, 26) . previous research carried out in the us, britain, and spain dealt only with natural disasters, mcis, and major incidents (7, 27, 28) . spain showed a linear increase in the incidence of disasters over a 55-yr period , 82% of which were natural and 18% technical (2) . most disasters showed a mixed pattern. for disaster types, flood was the most common (31.5%), followed by air crashes (30.2%). with regard to the effects of technical disasters, transit crashes showed the highest death rates (71.6%). for transit crashes, land-based events were the most common (43.6%), followed by air (32.1%) and sea (24.4%), results that were significantly different from those of korea. in britain, major incidents documented in research papers over a 28-yr period were analyzed to calculate the incidence rate; the results indicated a rate of 3 to 4 incidents per year with a total of 108 incidents (range 0-10) (2, 8) . there were 63 cases (59.2%) of public transportation crashes, 22 cases of civil disturbance (20.3%), and 16 cases of industrial incidents (14.8%). these results were similar to those for mcis in our study. in our study, disasters and mcis were analyzed to calculate the national and regional statistics for the incidence, crude mortality, crude injury, and characteristics of each disaster type using the nema database, which includes all major incidents and accidentals, to increase the credibility and sensitivity of the study and decrease the selection bias. we reconstructed our database from nema reports to verify the special characteristics of disasters and mcis in korea. furthermore, in our study, both disasters and mcis were analyzed to show the incidence frequency, the number of incidents for each incident type, and the number of injuries and deaths by time-series. in previous research, traffic crashes, residential fires and violence were reported as the leading causes of mci (7) . however, the leading causes for disasters in korea were road crashes, general floods, incidents at mass gatherings, and fires. the leading causes for mcis were road crashes, fires, and general floods. nema has two separate lines of work, fire-based tasks and mitigation-based tasks, and it focuses only on prevention, rapid response and mitigation to minimize disaster damage with a minimum expenditure of resources. thus, there is no efficient connection and cooperation with the ministry of health and welfare, which handles the public health sector. a disaster management plan for public health is warranted to properly analyze and present the characteristics of disasters/mcis, thus enabling preparations for each region, mitigating damages, and monitoring trends in disasters/mcis. nema and the ministry of health and welfare need to establish a system for cooperation on disaster management and epidemiologic investigation of the disasters/mcis using a predetermined standard. in this regard, this study may have significant value if it is used to compare domestic cases with those in foreign countries. furthermore, a set of standards needs to be established for epidemiologic research on disasters/mcis, along with a web-based registry system to maintain and update research results and a monitoring system for measuring the impact of disasters/mcis. there are certain limitations to this study due to the nature of the information available in the administrative database. first, the nema administrative data were not fully computerized, and they may not contain sufficiently meaningful variables for an epidemiologic survey. therefore, many of the variables that could have been used in the discussion of disasters and mcis were not included in the study, and only some of the extracted variables were used to calculate the indicators for epidemiologic assessment using a descriptive method. second, even though this study was a retrospective observational study, the environmental exposure at the time of each incident could not be found due to the characteristics of the administrative data. the cause-effect relationship between disasters/mcis and exposure of the disasters/mcis related environment to risks could not be determined, and thus, this result could not be analyzed. third, some of the administrative data were duplicated or may have been overlooked because when the incident occurred on the boundary of two provinces, such data were excluded from the study. fourth, the data source used in this study was the administrative data prepared for immediate incident reports, and these data may not be suitable for monitoring or for the establishment of a long-term database. finally, administrative data from all provinces were used in our analysis, but the number of incidents and casualties may have been underestimated. in addition, the data reported to nema for early and mid-2000 did not contain data on mcis and biological disasters such as severe acute respiratory syndrome (sars) and avian influenza, which may have contributed to an underestimation of the number of incidents. in conclusion, from january 2000 to december 2009, 115 disasters and 3,079 mcis occurred in korea. technical disasters/ mcis occurred more frequently than natural disasters/mcis. there was no significant trend in the time-series regarding the numbers of disasters and mcis. with regard to the type of disaster, the most common types were road crashes, general http://dx.doi.org/10.3346/jkms.2013.28.5.658 floods, and mass gathering incidents. for mcis, the most common types were road crashes, fires, and general floods. floods and transportation crashes were the main causes of natural and technical disasters/mcis, respectively. the crude death rates per 100,000 people for disasters and mcis were 2.36 and 6.78, respectively. the crude injury incidence rates per 100,000 people for disasters and mcis were 35.47 and 152, respectively. we established a nation-wide administrative ems-reported disaster and mci database that includes 10 yr of data. the incidence and mortality of disasters/mcis in korea seem to be lower compared to that of trend around the world. these data can be used to determine the optimal response plan for disaster and mcis in korea. further study will be needed for disaster and mci data base computerization to monitor incidents and to establish preparedness and early warning systems. three decades of disasters: a review of disaster-specific literature from 1977-2009 trends in disasters in spain and their impact on public health disaster epidemiology: prudent public health practice in the pacific islands methodological challenges and contributions in disaster epidemiology definition and classification of disasters: introduction of a disaster severity scale the definition and classification of disasters analysis of multiple casualty incidents -a prospective cohort study major incidents in britain over the past 28 years: the case for the centralised reporting of major incidents world disaster report: international federation of the red cross and the red crescent societies centre for research on the epidemiology of disasters. annual statistical review: numbers and trends 2010 cred: brussels order in chaos: modelling medical management in disasters an information fusion-based disaster information system framework building the governance system for the effective disaster management of local government: focusing buchon city a study of the extraction algorithm of the disaster sign data from web posttraumatic stress responses of taean residents: focused on a regional comparison at two and eight months after the disaster crisis intervention models: a comparison of six models for improving mental health of disaster victims analysis of hospital disaster in south korea from 1990 to 2008 a survey of human injury and crowd packing in mass gathering insjury type in sampung collapse an annual report of disaster biomarker responses in pelagic and benthic fish over 1 year following the hebei spirit oil spill emergency preparedness and response building consensus using the policy delphi method disaster epidemiology: or why most international disaster relief is ineffective task force on quality control of disaster management; world association for disaster and emergency medicine; nordic society for disaster medicine. health disaster management: guidelines for evaluation and research in the utstein style: volume i. conceptual framework of disasters overview of deaths associated with natural events mortality from flash floods: a review of national weather service reports appendix 1. incident report criteria of nema* (article 3 in fire basic act no.11690) fire which belongs to one of the following criteria a. fire with more than 5 deaths or 10 casualties b. fire with more than 100 people affected c. fire with financial loss of more than 2 billion won fire at government buildings, schools, rice-polishing mill, cultural assets, subways, or underground tunnel e. fire at tourist hotel, building with more than 11 stories, underground shopping street, market, department store, manufacturer/storage/station of dangerous materials which are more than 3,000 times of standard, accommodations with more than 5 stories or 30 guest rooms, hospital with more than 5 stories or 30 patient rooms, mental institution, oriental-medicine hospital, nursing home fire at train, ship heavier than 1,000 tons, aircraft, power plant, or power transforming station disaster which is otherwise selected by administrator of nema (amended on appendix 2. nema* directive for fire investigation and incident report emergency incident report) fire chief or fire commissioner shall report to the administrator of nema for the following incidents during investigation ) 2. major fire a. fire at public buildings and facilities such as government buildings, schools, rice-polishing mill, cultural assets, subways, or underground tunnel b. fire at tourist hotel, high-rise building, underground shopping street, market, department store, manufacturer/storage/station of dangerous materials, fire-vulnerable subjects, and fire in fire alert area fires a. fire at train, ship stationed at seaport, aircraft, power plant, or power transforming station b. special incident, fire with special cause (e.g. arson) c. fire at foreign embassy and residence d fires and incidents involving other important national establishments or special fire which may draw public attention and broadcasting by media is expected *2 seriously wounded people can be considered as 1 death and used to decide whether to report we are grateful to the national emergency management agency for their cooperation in providing the data. any opinions, findings, conclusions, and recommendations are those of the authors and do not represent the official views of nema in korea. the authors have no conflicts of interest to disclose. appendix 4 . incident report criteria of nema* dispatch center a. incident report criteria for the administrator of nema* a. human damage or damage is expected -incident with more than 3 deaths or 10 casualties -incident with 50 affected people and more # incident which requires rescue operation/ems service b. fires -vulnerable subjects: large-scale fire at bazaar market or other places -publicly used establishments: 2 deaths or more / 3 casualties or more â�¢ general fire -3 deaths or more (2 casualties = 1 death) -financial loss of more than 200 million won (krw) / when the second damage is expected c. security accidental: explosion, collapse, large-scale car crashes -damage at major establishments, theater, auditorium -when rapid rescue/ems are required # 3 deaths or more / 5 casualties or more d. earthquake (tsunami) -over 3.0 (inland)/over 3.5 (coast) -when warning or alert for tsunami is issued e. mountain fire, others -in case of mountain fire: when fire spread is expected / when residential or human damage are expected -opening of water gate at dam near border, mountain fires, etc. key: cord-319024-11cdzkrs authors: park, seon-cheol; park, yong chon title: secondary emotional reactions to the covid-19 outbreak should be identified and treated in korea date: 2020-04-23 journal: j korean med sci doi: 10.3346/jkms.2020.35.e161 sha: doc_id: 319024 cord_uid: 11cdzkrs nan the "primary emotional reaction" during the covid-19 outbreak in korea may be considered the fear or anxiety of the physical disease itself, or the "contagion" myth, directly related to infectious diseases. on the basis of our knowledge of pandemics throughout history, the presumption is that the primary emotional reaction may be shared worldwide during pandemic events. with respect to the primary emotional reaction, mental health care should focus on patients in isolation, individuals in quarantine, and healthcare workers who treat covid-19 cases. thus, care for the primary emotional reaction to covid-19 has been relatively well prepared and provided in korea. 4 first, national hospitals and mental health welfare centers across the country have prepared to provide mental healthcare services for individuals in isolation or quarantine because of the covid-19 outbreak. second, the leaflets promoting mental healthcare related to the distress due to the infectious disease outbreak have been distributed by the national center for disaster trauma. the "secondary emotional reaction", beyond the anxiety of the physical disease itself, or the contagion myth, may be considered the other psychological consequence of the covid-19 outbreak. the secondary emotional reaction may involve an indirect psychological response to the covid-19 outbreak, which © 2020 the korean academy of medical sciences. this is an open access article distributed under the terms of the creative commons attribution non-commercial license (https:// creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. the authors have no potential conflicts of interest to disclose. reveals the public psyche's repressed emotional problems and may be deeply influenced by specific sociocultural factors in korea. although mental health care for secondary emotional reactions to covid-19 is also urgently needed, it may be poorly prepared for and supported in korea compared to that for primary emotional reactions. 3 consequently, we introduce herein two groups who should urgently be considered for care in korea due to secondary emotional reactions prompted by the covid-19 outbreak. in addition, as requested, potential therapeutic approaches for the two groups are proposed below. the critical outbreak of covid-19 has been closely linked to the recent massive-scale rallies of the shincheonji religious group which occurred on february 9 and 16, 2020, in daegu, korea. based on epidemiological survey reports from the korea centers for disease control and prevention (kcdc), approximately two-thirds of the accumulated covid-19 cases may be directly related to the shincheonji church of jesus. the shincheonji is a newly coined korean word that designates a new heaven and a new earth in the book of revelation of john. as a result, this religious group believes from the viewpoint of eschatology that "the end of this world is at hand, and the new world is about to begin." because shincheonji congregants are convinced that only 144,000 individuals worldwide can go to heaven, they usually abandon all social relationships, including family and occupation, under the direction of charismatic totalitarian religious leaders. thus, before the covid-19 outbreak, the shincheonji church of jesus has been usually regarded as an unacceptable religious group in korean society. 5, 6 khan and huremovic 7 have explained the psychology of the pandemic as follows: "not only can contagion not be controlled or mastered, but the search for causality creates the unconscious narrative of the pandemic being a result of the community's own badness." it is likely that the secrecy and collectivism of the shincheonji religious group has contributed to the rapid spread of covid-19 and also to non-cooperation with the epidemiological survey for covid-19 in korea. therefore, apart from facing discrimination because of their religious activities, shincheonji congregants who are infected with covid-19 are likely to face anger and be blamed for the covid-19 outbreak in korea. moreover, they may develop serious emotional problems after they leave the cohesive large group. therefore, based on the previous psychosocial support for the unification church (moonie) dropouts, shincheonji congregants with covid-19 must be supported by "establishing social networks with a clear-cut cognitive framework at the level of individual mental health" and also with specific treatment for the psychological trauma of covid-19. 5,6,8 approximately 25% of workers in korea are self-employed, which is much higher than the average figure of 15% in the organization for economic cooperation and development countries. 9 because social distancing in response to the covid-19 outbreak is persistent and may be prolonged, most self-employed workers in korea are experiencing severe economic difficulties. in addition, the difficulties of the economically weak population in korea have worsened during the covid-19 outbreak. based on previous findings, korea has shown a tendency to experience an increase in suicide rates during crises, such as during the 1997 financial crisis. the psychological autopsy reports have shown that economic problem is the main cause of stress for more than 60% of suicide completers. 10 in addition, the unemployment rate and income inequality have been proportional to suicide rates. 11 according to a report by the korean suicide prevention center, over 60% of suicides were associated with economic problems that were a key source of stress at the time of suicide. economic problems had the largest effect on suicide among elderly adults. 12,13 thus, even after the end of the covid-19 outbreak in korea, it will be necessary to strengthen the social welfare support system and suicide prevention programs for the economically weak people. in terms of the medical policy for suicide prevention, strengthening early and effective intervention programs in the psychiatric area has been proposed as the effective reduction method for suicide rates. 14 mental health care related to the covid-19 outbreak in korea should cover not only primary emotional reactions, but also secondary emotional reactions. also, pro-active care for secondary emotional reactions in shincheonji congregants and the economically weak is of key importance. special care is required to treat followers of pseudo-religions and the groups at high-risk of suicide experiencing the covid-19 outbreak in korea. the first case of 2019 novel coronavirus pneumonia imported into korea from wuhan, china: implication for infection prevention and control measures covid-19) outbreak in republic of korea the emotional epidemiology of h1n1 influenza vaccination mental health care measures in response to the 2019 novel coronavirus outbreak in korea acculturation and new religions in korea psychiatry in korea for 21 century: quo vadis? psychiatry of pandemics: a mental health response to infection outbreak moonie") dropouts: psychological readjustment after leaving a charismatic religious group organization for economic cooperation and development. oecd data: self-employment rate psychological autopsy analysis result korea health statistics: cause of death key: cord-323656-bzefn894 authors: yoo, jin-hong title: convalescent plasma therapy for corona virus disease 2019: a long way to go but worth trying date: 2020-04-06 journal: j korean med sci doi: 10.3346/jkms.2020.35.e150 sha: doc_id: 323656 cord_uid: bzefn894 nan dosage and administration protocols have not been standardized yet. in both cases, plasma was administered when antiviral drugs and steroids were given. it is hard to tell that the successful treatment is not necessarily due to plasma, and it cannot be refuted even if it is interpreted as an effect of antiviral agent or steroid. or it is possible that these three elements were combined to create a synergistic effect. but i'm going to change the way of interpretation. given the mechanism of convalescent plasma therapy, i think this combination is rather worth being recommended. the targets of covid-19 treatment should be largely divided into two categories. first, it is aimed at the virus itself. the first thing you can think of is destroying the body of the virus. however, destroying the virus itself is a concept of disinfection and is too dangerous for humans to apply. as a therapeutic agent, there are drugs that inhibit rna-dependent rna polymerase by inhibiting the replication of viruses (e.g., remdesivir), or drugs that inhibit protease (e.g., lopinavir/ritonavir). 1,13 another target is angiotensin converting enzyme 2 (ace2), a gatekeeper and receptor for viruses to enter human cells. by raising the intracellular ph, glycosylation of ace2 can be prevented to block the entry of the virus (e.g., chloroquine), 13,14 or it can be prevented from binding to ace2 in advance by sticking to the spike protein of the virus. 15, 16 the latter, not the former, is the antibody. considering the above treatment mechanisms, it can be seen that it is difficult to succeed with only one mechanism to treat covid-19. blocking a virus with antibodies is not enough to win the battle. we must also suppress the replication of the virus, and prepare for a cytokine storm that occurs during treatment. 17 in conclusion, it makes no sense as to which of these treatment methods was a decisive factor in the successful treatment. rather, it is necessary to combine all of these to engage in treatment. we need to examine another important problem in plasma treatment. plasma therapy itself has important complications. examples are transfusion-related acute lung injury (trali), circulatory overload, or anaphylaxis. 18 fortunately, no adverse events have been reported. nevertheless, these complications should always be a concern. there is also the possibility of side effects that have been raised recently. it is the antibodydependent enhancement of entry (ade). neutralizing antibodies, once bound to the spike protein of the virus, cause a conformational change of the spike and, consequently, could trigger the paradoxical result of better entry into human cells through the igfc receptor. 19 -21 this side effect has not yet been realized, but should be kept in mind in the future of plasma treatment and vaccine development. convalescent plasma therapy gives us a lot of hope, but there are challenges to overcome. in the implementation, thorough ethical verification is required, and donor selection criteria should be strictly enforced. and it needs further extensive research to see if it really works. to this end, i think that institutional support is required to approve every attempt as quickly as possible. again, it is time to focus all of our capabilities on treatment. drug treatment options for the 2019-new coronavirus (2019-ncov) convalescent plasma: new evidence for an old therapeutic tool? convalescent plasma as a potential therapy for covid-19 use of convalescent plasma therapy in two covid-19 patients with ards in korea treatment of 5 critically ill patients with covid-19 with convalescent plasma the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis use of convalescent plasma therapy in sars patients in hong kong experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a taiwan hospital treatment with convalescent plasma for influenza a (h5n1) infection convalescent plasma treatment reduced mortality in patients with severe pandemic influenza a (h1n1) 2009 virus infection use of convalescent whole blood or plasma collected from patients recovered from ebola virus disease for transfusion, as an empirical treatment during outbreaks viral load kinetics of sars-cov-2 infection in first two patients in korea remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro chloroquine is a potent inhibitor of sars coronavirus infection and spread perspectives on monoclonal antibody therapy as potential therapeutic intervention for coronavirus disease-19 (covid-19) potent binding of 2019 novel coronavirus spike protein by a sars coronavirus-specific human monoclonal antibody pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology adverse effects of plasma transfusion molecular mechanism for antibody-dependent enhancement of coronavirus entry anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a ph-and cysteine proteaseindependent fcγr pathway antibody-dependent sars coronavirus infection is mediated by antibodies against spike proteins key: cord-338181-9sgygg8x authors: kim, sun-kyung; kim, eun ok; kim, sung-han; jung, jiwon title: universal screening of severe acute respiratory syndrome coronavirus 2 with polymerase chain reaction testing after rally of trainee doctors date: 2020-10-27 journal: j korean med sci doi: 10.3346/jkms.2020.35.e380 sha: doc_id: 338181 cord_uid: 9sgygg8x there were two rallies of medical students and trainee doctors, where 9,000 participants gathered. we performed polymerase chain reaction (pcr)-based universal screening for the participants using pooling at a tertiary care hospital. around 609 (94%) of 646 participants underwent pcr tests for severe acute respiratory syndrome coronavirus 2; all of them tested negative. our data suggested low transmission rates in open air mass gatherings when appropriate personal protective practices were followed. for the participants by pooling 5 specimens 3-4 days after the rally (considering the incubation period). 2, 3 the participants informed the infection control office if they developed covid-19 symptoms within 2 weeks of participating in the rally using an app-based system. subsequently, sars-cov-2 pcr tests were performed. a total of 646 trainee doctors and medical students participated in the rally at least once. among them 318 (49%) were men with a median age of 29 (interquartile range, 27-32) years. there were 95 interns, 378 residents, 131 clinical fellows, and 42 medical students. all 609 (94%) participants who underwent pcr screening tested negative. there were 387 participants (50 interns, 307 residents, and 30 medical students) in the first rally. among them, 360 (93%) participants underwent pcr tests on august 10 (3 days after the rally). the number of participants in the second rally was 555 (67 interns, 300 residents, 131 clinical fellows, and 27 medical students). among them, 525 (95%) participants underwent pcr tests on august 18 (4 days after the rally). from august 7 to august 28, 11 participants had covid-19 symptoms including fever, cough, myalgia, sore throat, and headache. however, pcr results were negative for all of them. historically, sports, religious, musical, and other mass gatherings have been the source of infectious diseases. 4 to mitigate the risk of sars-cov-2 transmission in the rally of korean trainee doctors, we developed an action plan and an app-based system for notification of covid-19 symptoms. additionally, after the participants returned from the rally, we performed universal screening for over 600 (94%) of them. no participant was infected because appropriate personal protective practices were followed in the open space. further, high-risk behaviors such as physical contact, singing, drinking, or chanting were avoided. to save resources, we used the pooling strategy, reported previously. 5 finally, because this was a single-center study and korea has a low prevalence of covid-19, further studies in other settings are warranted. in conclusion, our study provides important information regarding low transmission rates in mass gatherings at open space when appropriate personal protective practices are followed. trainee doctors strike over plan to raise number of medical students the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (covid-19): a review mass gathering events and reducing further global spread of covid-19: a political and public health dilemma universal screening with sample pooling in preoperative patients as long-term strategy in the covid-19 pandemic key: cord-301553-bq8h13np authors: lee, jaehyeon; kim, so yeon; sung, heungsup; choe, young june; hong, ki ho title: letter to the editor: the interpretation of covid-19 seroprevalence study should be cautious date: 2020-09-10 journal: j korean med sci doi: 10.3346/jkms.2020.35.e338 sha: doc_id: 301553 cord_uid: bq8h13np nan conceptualization: lee third, although the authors have acknowledged selection bias, they should recognize that the patient group had more of health-related issues compared with general population, resulting limited generalizability of the study. the generalization of the prevalence obtained from patient group should be cautious. a recent systematic review found that 89% of antibody test evaluation results had selection bias. 4 in addition, the pcr-negative specimens collected during covid-19 pandemic period are inadequate for the evaluation of specificity, as the convalescent patients may show positive results in antibody assay, but negative results in pcr. 7 if the authors claimed the high seroprevalence in the population, then authors should not use the pcr-negative samples from the population as negative control group. moreover, given only small specimens have been included (60 positive and 30 negative), providing the confidence intervals for distribution would be more informative. the confidence interval of the specificity seems to be 88.4%-100.0%, based on clopper-pearson interval. https://jkms.org https://doi.org/10.3346/jkms.2020.35.e339 dr. lee and colleagues 1 raised several issues related to our study, 2 which can be summarized into two categories: 1) the possibility of low specificity of rapid test kit and 2) selection bias of study subjects. first, we appreciate the authors because this letter allowed us to identify a critical typographical error in the published article. they stated that 92% specificity of the assay was a study limitation. however, the truth is that the specificity was 100% but sensitivity was 92%. it was a simple typo which occurred during manuscript revision. the authors criticized that the seroprevalence of 7.6% of our study can be totally attributed to false-positive cases due to 92% specificity. however, it is more accurate to state that even the value of 7.6% was an underestimation of the true figure because the sensitivity was 92%. in addition, recent findings, which demonstrated the disappearance of antibodies among coronavirus disease 2019 (covid19) patients in months, 3 suggested an additional reason to justify our speculation; the epidemic peak of daegu was late february, while the collection of blood was performed from late may to early june. in particular, a rapid decline in antibodies was observed in mild cases 4 ; the majority of covid19 patients in daegu only had mild symptoms or were asymptomatic. in fact, many details raised by the authors relate to the accuracy of rapid test kit, especially the possible low specificity. although 92% specificity is not relevant anymore as explained above, the authors' perspective on accuracy of antibody testing requires further discussion because the importance of this issue differs substantially depending on the purpose of the test. 5 if the results of antibody test are applied to individuals, such as immunity passports, the accuracy of the test is crucial to avoid risks due to false-positive and false-negative cases. however, when an antibody test is performed to estimate seroprevalence at the population level, even a serological test with moderate sensitivity and specificity is acceptable 5 because of the tradeoff between false-positive and false-negative cases. a recent nationwide population-based study in spain, reporting 5.0% seroprevalence, clearly demonstrated that the performance of the rapid test was satisfactory compared with that of immunoassay. 6 4/4 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e339 between patients and guardians, and given that all of the positive cases belonged to different households, the selection bias may not be as serious as the authors have suspected. moreover, despite the possibility of selection bias, we believe that the size of missing undiagnosed cases in daegu should be estimated because it is one of most important reasons underlying any seroprevalence study during the epidemic. this estimation is more important for infectious diseases with a high proportion of asymptomatic or mild cases, such as covid 19, to determine the optimal public health strategy. sometimes, information with limitation would be better than at least no information. the estimated size of missing undiagnosed cases during any epidemics may be a case in point. of course, it would be best if a seroprevalence survey of representative samples in daegu could have been performed in march or april. currently, however, even a population-based seroprevalence survey with a perfect serological assay may not validly estimate the size of missing undiagnosed cases in daegu because of antibody loss in many previously infected cases. 3,4 igg seroprevalence of covid-19 among individuals without a history of the coronavirus disease infection in daegu covid-19: understanding the science of antibody testing and lessons from the hiv epidemic sars-cov-2-specific antibody detection for sero-epidemiology: a multiplex analysis approach accounting for accurate seroprevalence antibody tests for identification of current and past infection with sars-cov-2 the interpretation of covid-19 seroprevalence study should be cautious igg seroprevalence of covid-19 among individuals without a history of the coronavirus disease infection in daegu longitudinal evaluation and decline of antibody responses in sars-cov-2 infection rapid decay of anti-sars-cov-2 antibodies in persons with mild covid-19 serology for sars-cov-2: apprehensions, opportunities, and the path forward prevalence of sars-cov-2 in spain (ene-covid): a nationwide, population-based seroepidemiological study the authors have no potential conflicts of interest to disclose.the authors have estimated the "actual number" of sars-cov-2 infection in daegu to be greater than 180,000 persons, which may be misled from the intrinsic limitation of the study. they also have stated several interesting opinions such as the limited value of containment and the limited role of antibody assay in selecting donor for plasma therapy. however, the points that we have mentioned above should be clarified before drawing the conclusion of the study.the authors were also skeptical about applying the seroprevalence results of our study to the general population due to selection bias, which was already discussed as a study limitation in our paper. our study subjects consisted of patients and guardians who visited outpatient clinics, not only a patient group as the authors have described. due to the similar seroprevalence key: cord-334811-l5fxswfz authors: nan title: analysis on 54 mortality cases of coronavirus disease 2019 in the republic of korea from january 19 to march 10, 2020 date: 2020-03-26 journal: j korean med sci doi: 10.3346/jkms.2020.35.e132 sha: doc_id: 334811 cord_uid: l5fxswfz since the identification of the first case of coronavirus disease 2019 (covid-19), the global number of confirmed cases as of march 15, 2020, is 156,400, with total death in 5,833 (3.7%) worldwide. here, we summarize the morality data from february 19 when the first mortality occurred to 0 am, march 10, 2020, in korea with comparison to other countries. the overall case fatality rate of covid-19 in korea was 0.7% as of 0 am, march 10, 2020. there is a battle of life and death during this coronavirus disease 2019 (covid-19) outbreak in korea like any other parts of the world. this is what is happening in korea now in march 2020. mr. k, a 73-year-old man, was diagnosed with covid-19 in gyeonsangbukdo on february 28 and had been cared at the hospital a in pohang, 88 km from daegu. he developed massive hematochezia and was referred to hospital b for intensive care in seoul, 320 km from pohang. he received 10,000 ml of blood transfusion at hospital b on march 1. the medical team in hospital b found that he had massive bleeding from huge duodenal ulcer by endoscopy. bleeding control was strengthened, and he was placed on a mechanical ventilator. he needed an emergency operation at a negatively pressured operation suite, which was not available at hospital b at that time, with already tight operation schedules being carried out. rapid communications were held among top hospitals in seoul, and a special transport team from hospital c moved the patient in a very critical condition to the hospital d across the han river from south to north of seoul, where he received a successful bowel resection operation. mr. k has been off the ventilator for a while and appeared to recover, but unfortunately, he succumbed to covid-19 later. korean doctors at the frontline of covid-19 battle work tirelessly to save lives, and this was just one example of their dedication. the numbers shown here are not just the numbers of deceased patients. these are numbers for struggles of those who were infected to survive and for efforts of those who were at the frontline of the field to save lives. we summarized the mortality data of 54 deceased patients when the total number of covid-19 patients in korea reached 7,513 as of march 10, 2020. data were achieved from the daily press release from kcdc and briefing contents from national/local government authority press conferences were analyzed. since the last report on the epidemiology of the korean outbreak 1 on march 2, 2020, when the number of fatal cases was 22 patients, the mortality number has increased to 54 cases as of march 10, 2020. fig. 1 shows the timeline for the occurrence of fatal cases in korea. the first fatal case (national patient number 104) occurred on february 19 and was officially reported on february 20 by korea centers for disease control and prevention (kcdc). 2 national patient number 443 (mortality patient number 3) was the first patient who died suddenly without an epidemiological link and was diagnosed with covid-19 after death on february 21. 3 since the patient (national patient number 31) was identified and related to the religious group was reported on february 18, there was a surge of the confirmed cases with hundreds of new cases per day, mainly in daegu and gyeongsangbuk-do area. 1 with a significant surge of new cases, there was the first fatal case (national patient number 1,443; mortality patient number 13) that the patient died during home isolation after having been confirmed with covid-19 on february 27, 2020. 4 since march 1, referrals from daegu area to hospitals in seoul (the capital city of the nation with more tertiary hospitals) and other parts of the area in korea were started for serious patients who needed intensive care. on march 2, patients in mild conditions were relocated to "life treatment centers" that were temporarily transformed for housing the mild confirmed patients in individual rooms ( supplementary fig. 1 ). 5 these facilities were initially been used as accommodation facilities for human resource training centers of the local government, universities, or corporations. 6 on march 4, there was the first case of mortality in a patient (mortality patient number 32, the national patient number was not available) without significant underlying illness. as of 0 am, march 10, 2020, there were 54 out of 7,513 confirmed patients with covid-19 died in korea. 7 it is of importance to expect what would happen during the outbreak as the epidemic evolves with increasing numbers. fig. 2 shows the mortality related milestones, the cumulative number of confirmed cases, number of daily new cases, and cumulative number of cases that have been released from isolation in korea, by march 10, 2020. 1,8,9 therefore, reviewing these data is important to assess the impact on the patient-care capacities of the healthcare facilities, especially during a surge of an outbreak. the first death due to covid-19 occurred on february 19 and was reported on february 20. this patient was the national patient number 104. 2 the first sudden-death case with postmortem diagnosis of covid-19 was observed when the total number of patients reached 204 on february 21. 3 the first death on home isolation due to covid-19 occurred when the number of daily new patients reached 505 with a total number of over 1,766 on february 27. 4 first death without underlying illness occurred when the total number of patients reached 5,328 on march 4. 10 of note, although without significant illness, this was a 72-year-old woman who developed symptoms on february 23 and was diagnosed with it is of note that even when the total confirmed cases reached 7,513, only 247 patients were released from isolation after treatment on march 10, 2020 (fig. 2) . cumulative deaths/number of total patients on each day). 8 during the first week after the first morality case, the daily cfr was 1.22%. however, it soon decreased to 0.04% on march 10, 2020. the cumulative cfr of covid-19 in korea was 0.7% (54 deaths of total 7,513 confirmed cases) as of 0 am, march 10, 2020. we tried to analyze survival duration from symptom onset to death in 31 patients (57.4%) of whom the symptom onset dates were available (table 1 and fig. 4a) . among the 31 patients in whom the dates of symptom onset were available, the median days from symptom onset to death was 10 days (iqr, 5-12 days; range, 35-93) duration from symptom onset to death was not different between men and women (data not shown, p = 0.677) or the two age groups (< 70 years old [n = 9] vs. ≥ 70 years old [n = 22]; p = 0.086) (fig. 4b) . it also did not differ between the patients with underlying illness (n = 28) and without underlying illness (n = 3) (p = 0.499, log-rank test) (fig. 4c) . however, it is of note that all three patients without underlying illness were alive until day 10 from the symptom onset. 5 shows the distribution of cfr in some selected countries, including korea. 11 cfrs of the three countries (italy, iran, and korea) with the highest numbers of confirmed cases next to china, were 5.0%, 3.0%, and 0.7%, respectively. in addition, cfrs in the us and italy were similar (5.2% and 5.0%), although the numbers of confirmed cases were different. fig. 5 shows the age distribution of the general population in the background, the proportion of age groups among confirmed cases, and cfrs in each group in korea (as of march 10), china (as of february 21), and italy (as of march 9) . age distribution of the korean outbreak shows m shape with peak ages in the 20s and 50s (fig. 6a) 7, 12 while chinese data shows bell shape with a peak age in the 50s (fig. 6b) . 13, 14 in italy, it appears that more individuals in older ages were infected compared to korea or china (fig. 6c) . 15 we summarized the data of 54 fatal cases with covid-19 in korea as of march 10, 2020. clearly, older patients above 70 are more likely to die from covid-19 infection than younger individuals, and men had higher cfr compared to women. mortality is the most important issue when dealing with the unexpected or expected outbreak and setting up priorities to control the epidemics. under outbreak circumstances, maintaining the healthcare system is the key issue, especially when there is a rapid surge in the number of confirmed cases in the community as happened in wuhan, china, daegu, korea, and lombardy, italy. it is premature to mention any factors responsible for the differences in cfr in different regions and countries. however, when there was a sudden rise in numbers, the cfr also rose. the most important strategy is to keep the hospitals' capacity to treat severe patients from the early phase through careful and proper triage and maintain the healthcare system. further studies in larger number of mortality case analyses should be performed to understand covid-19 related mortality. in conclusion, covid-19 poses a significant global health threat in 2020. although difficult without effective antivirals or vaccines, countermeasures should be continuously applied in many aspects of outbreak situations to decrease the mortality. korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from korea centers for disease control and prevention. the update of covid-19 in korea as of korea centers for disease control and prevention. the update of covid-19 in korea as of press release of covid-19 in daegu as of govt to open more treatment centers for covid-19 patients with mild symptoms korea centers for disease control and prevention. the update of covid-19 in korea as of march 2. http:// ncov.mohw.go.kr/tcmboardview.do?brdid=&brdgubun=&datagubun=&ncvcontseq=353274&contse-q=353274&board_id=&gubun=all korea centers for disease control and prevention. the update of covid-19 in korea as of press release of covid-19 in daegu as of press release of covid-19 in daegu as of world health organization population census updated by the kosis the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china, 2020 population census della salute m. covid-19 situazione in italia resident population by age, sex and marital status on 1st we express our sincere consolation for the patients and their families who had covid-19 in korea. we greatly appreciate the efforts of all the hospital employees and their families who are working tirelessly during this outbreak. we thank all the members of the korean society of infectious diseases and korea centers for disease control and prevention. we also appreciate the collaborative partnership at all levels of individuals in the public and private sectors of the nation. we appreciate the contribution of drs key: cord-349680-rz2ep5jf authors: lee, jacob title: better understanding on mers corona virus outbreak in korea date: 2015-06-10 journal: j korean med sci doi: 10.3346/jkms.2015.30.7.835 sha: doc_id: 349680 cord_uid: rz2ep5jf nan in june 2012, the first human with middle east respiratory syndrome coronavirus (mers-cov) infection was found in saudi arabia. the one was a 60-year old man. he visited a hospital due to pneumonia; it was later found out that renal failure developed (1) . he eventually died due to his illnesses. from 1 june 2015, 1,154 patients were infected with the virus; 431 patients died (who http://www.who.int/csr/don/archive/disease/coro-navirus_infections/en/). mers is suspected to spread from animals to humans like severe acute respiratory syndrome coronavirus (sars-cov). it was from a similar coronavirus with respiratory infection syndromes and it is highly transmitted. additionally, since the virus is related to a high rate of fatality, it has become a big issue for public health doctors and officials over the world. the latency period of mers-cov is known to be between 2 to 14 days (median 5.4 days). from the development of the disease to the patient`s admission, it takes 4 days and the period that people die from the disease takes 11.5 days (2) . in the first stage, flu like symptoms such as fever, coughing, chilling, myalgia, and arthralgia are observed. after this, respiratory difficulty is added. this quickly progresses to pneumonia (3). a part (30%) of the patients complain of bowel symptoms like vomiting and diarrhea (1). cases of mers-cov can be found in countries like america, uk, france, tunisia, italy, malaysia, the philippines, greece, egypt, the netherlands, algeria, austria, turkey, etc. whose citizens have travelled to the middle east. on may 20 2015, a man at the age of 68 was the first to be diagnosed with mers-cov in korea. he travelled to bahrain, saudi arabia, and qatar for 16 days. on may 4 2015, this patient entered in korea, and febrile sense and respiratory symptoms appeared on may 11. he visited clinic a on the day and was admitted to hospital b from may 15 to 17. since the symptoms got worsened, he visited clinic c on may 18, and finally he was transferred to a university hospital in seoul on may 18. on may 20, it was confirmed that he was suffering from mers-cov. after finding out about the disease, his family members and medical staffs who had been exposed to the virus were isolated. by june 9, 2015, 2 medical staffs in the clinic a and c, one medical staff in the hospital b, one patient and her wife who was together with the index case in the same room and 35 of admitted patients in the same ward and their family members visiting same ward with the index case in the hospital b were confirmed to have been infected with mers-cov. after then, several tertiary cases were identified in the hospital b or other hospitals that secondary patients were transferred from the hospital b. a total of 108 people were infected, and 9 (8.3%) of them died by june 10, 2015. one person among the 36 patients exposed in the hospital b left for china through hong kong, because the korea center for disease control and prevention (cdc) could not confirm the exposure to the index case. china cdc is performing isolated treatments. hong kong and china cdc started to manage people who are suspected to be exposed. at present, the outbreak pattern in korea has been progressing similarly to the hospital outbreak occurred in the middle east. the secondary infection developed in people who had a close contact with the person who was initially infected. medical staffs who were involved in treating some of the patients with mers-cov were also infected (2) . the secondary ones to be infected like the patients and medical staffs were not as severe as the first infected patients and mortality was lower than the index case (1). if korea also follows the outbreak pattern of the middle east, i expect more tertiary infection will be developed. the secondary infection occurred from the index case before the correct diagnosis, which was inevitable. at present, the korea cdc should focus on close monitoring of medical staffs and patients or visitors who have been exposed to the index, secondary, and tertiary cases in hospitals. it is very important to make nationwide effort to cope with this outbreak more actively and aggressively by organizing an emergency team with medical experts. also correct and timely well-designed briefing to mass media is necessary in order to prevent further spread, to calm down public panic, and to lessen its untoward impacts in the society. further imported cases of other variable noble infectious diseases may occur within the foreseeable future. health officials and infectious disease researchers have to be prepared about further challenges of these new infectious diseases. severe acute respiratory syndrome vs. the middle east respiratory syndrome ksa mers-cov investigation team. hospital outbreak of middle east respiratory syndrome coronavirus middle east respiratory syndrome coronavirus in dromedary camels: an outbreak investigation key: cord-341933-dwki1hwu authors: jeong, han-gil; lee, yunghee; song, kyoung-ho; hwang, in-chang; kim, eu suk; cho, young-jae title: therapeutic temperature modulation for a critically ill patient with covid-19 date: 2020-06-03 journal: j korean med sci doi: 10.3346/jkms.2020.35.e210 sha: doc_id: 341933 cord_uid: dwki1hwu we report a rapidly deteriorating coronavirus disease 2019 (covid-19) patient, a-58-year-old woman, with severe acute respiratory distress syndrome and shock with hyperpyrexia up to 41.8°c, probably due to the cytokine storm syndrome. considering extracorporeal membrane oxygenation (ecmo) as the last resort, we applied therapeutic temperature modulation for management of hyperpyrexia. the patient demonstrated rapid improvement in oxygenation and shock after achieving normothermia, and fully recovered from covid-19 three weeks later. therapeutic temperature modulation may have successfully offloaded the failing cardiorespiratory system from metabolic cost and hyperinflammation induced by hyperpyrexia. the therapeutic temperature modulation can safely be applied in a specific group of patients with cytokine storm syndrome and hyperpyrexia, which may reduce the number of patients requiring ecmo in the global medical resource shortage. the cytokine storm syndrome, which rapidly progress to acute respiratory distress syndrome (ards), shock, and multiorgan dysfunction, has been observed in a subgroup of patients with severe coronavirus disease 2019 (covid-19). 1,2 several therapeutic measures, including steroids and cytokine blockade, have been suggested. 3 we present the case of a covid-19 patient whose condition rapidly deteriorated with hyperpyrexia but was successfully managed with therapeutic temperature modulation (ttm). spread. seven days before icu admission, the patient was diagnosed with pneumonia and started lopinavir/ritonavir 400 mg/100 mg tablets twice a day and supplemental oxygen was started 3 days ago. vital signs on presentation to the icu were: blood pressure 145/90 mmhg, pulse rate 90/min, respiratory rate 32/min, and body temperature 36.9°c. arterial blood gas analysis showed ph 7.383, partial pressure of carbon dioxide (pco 2 ) 33.5 mmhg, partial pressure of arterial oxygen (pao 2 ) 83.9 mmhg, and bicarbonate (hco 3 -) 19.5 mmol/l on high-flow nasal cannula (fraction of inspired oxygen [fio 2 ], 0.95; flow rate, 50 l/min). the patient was intubated and placed on mechanical ventilation with elaborate lungprotective strategies. 4 the pao 2 improved to 229.1 mmhg on fio 2 0.9, and we initiated intravenous methylprednisolone 60 mg. a chest radiograph showed bilateral, multifocal, patchy consolidations in the lungs (fig. 1) . the c-reactive protein level was 22.9 mg/dl. nasopharyngeal and oropharyngeal swabs as well as sputum specimens were obtained for retesting at our hospital and reported positive for infection with the novel severe acute respiratory syndrome coronavirus 2 (sars-cov-2) by real-time reverse-transcriptasepolymerase-chain-reaction (rt-pcr) assay. from the evening on day 1 of hospitalization, the patient's body temperature began to increase, reached approximately 40°c on day 2, and was followed by tachycardia and desaturation (fig. 2) . the fever was refractory to repeated administration of antipyretics. the body temperature increased up to 41.6°c, heart rate to 156 per min, and oxygen saturation decreased to 88% on fio 2 of 1.0. nitric oxide (no) inhalation was initiated and raised to 40 ppm, and injection of methylprednisolone 60 mg was repeated. however, arterial blood gas analysis showed pao 2 of 77.6 mmhg, and the troponin i level increased to 6.22 ng/ml. considering extracorporeal membrane oxygenation (ecmo) as the last resort for treatment, we applied a surface cooling device (arctic sun ® ) with a target temperature of 37°c. from an initial core temperature of 41.8°c, the target temperature was rapidly attained within 4.5 hours. pao 2 was markedly improved to 318.2 mmhg, and tachycardia resolved after a few hours. the norepinephrine requirement that had increased up to 16 µg/min during the shock phase was tapered off. echocardiography on day 4 showed mid-to-apical-segment akinesia and depressed left ventricular systolic function with an ejection fraction of 26%. the patient was extubated on day 6 and ttm was stopped on day 9. other treatment details including antibiotics and steroid use are summarized in table 1 . on day 12, sars-cov-2 rt pcr results converted negatively in all nasopharyngeal, oropharyngeal, and sputum specimens. supplemental oxygen was discontinued on day 16, and the patient's cardiac function was confirmed to have recovered on day 19 with an ejection fraction of 54%. a coronary computed tomographic angiography was also normal. a chest radiograph on day 22 showed considerable improvement compared to the previous ones (fig. 1) . the patient presented with mild ards but rapidly progressed to severe ards and shock with hyperpyrexia, probably due to a hyperinflammatory syndrome. however, the patient demonstrated rapid improvement in oxygenation and shock after the initiation of ttm. pyrexia confers a metabolic cost, which increases oxygen consumption by 10% per degree celsius rise in temperature. 5 therefore, rapid reduction in core temperature by 5°c successfully offloaded the patient's failing cardiorespiratory system. the hyperinflammatory response and hyperpyrexia may have a reciprocal synergism, wherein uncontrolled inflammation promotes thermogenesis and vice versa, and this vicious cycle may have been forcibly terminated by ttm. 6 the pandemic caused by sars-cov-2 infection has necessitated several management strategies, although many have not been concretely established as conferring a patient benefit. ecmo can serve as a life-saving rescue therapy, although concerns exist about potential adverse effects of ecmo therapy for patients with covid-19. 7 the therapeutic temperature modulation may safely be applied in a specific group of patients with cytokine storm syndrome and hyperpyrexia. if efficacy and safety can be demonstrated through further studies, targeted therapeutic modulation will reduce the number of patients requiring ecmo in the global medical resource shortage. despite the potential contribution of pyrexia to host defense, the dramatic response to ttm in this patient suggests that the severe metabolic stress induced by hyperpyrexia may be considerably more harmful than beneficial in the hyperinflammatory stage of sars-cov-2 infection. the institutional review board of seoul national university bundang hospital approved the publication of this report, and written informed consent was waived (b-2005-611-701). covid-19: consider cytokine storm syndromes and immunosuppression epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal clinical practice guideline of acute respiratory distress syndrome should we treat pyrexia? and how do we do it? fever and the thermal regulation of immunity: the immune system feels the heat key: cord-344235-rd6cylsl authors: kim, kyung mi; han, su ha; yoo, so yeon; yoo, jin-hong title: potential hazards of concern in the walk-through screening system for the corona virus disease 2019 from the perspective of infection preventionists date: 2020-04-14 journal: j korean med sci doi: 10.3346/jkms.2020.35.e156 sha: doc_id: 344235 cord_uid: rd6cylsl nan since 70% alcohol is used in relatively small areas such as stethoscopes, instrument surfaces, carts, counters, and laboratory benches, 4 it is inappropriate to disinfect the relatively large areas such as the inside of walk-through booths with alcohol. if sodium hypochlorite is used, it needs to be maintained for at least 10 minutes after wiping. in addition, the floor or surface must be repeatedly wiped thoroughly with a disposable cloth moistened with disinfectant to prevent recontamination of the surface. 4 in the case of surface disinfection, a method of spraying is also being used, but it is not recommended by korea centers for disease control and prevention guidelines as it has uncertain coverage and may promote aerosol production. in addition, after cleaning and disinfection, it is necessary to ventilate sufficiently. moreover, since personnel performing disinfection work can inadvertently inhale the aerosolized disinfectant in a small space, it is inevitably a little bit dangerous environment for employee's safety. therefore, healthcare workers must wear adequate ppe for their safety during the disinfection work. ultraviolet light irradiation is difficult to expect good effect if the applied area and sufficient irradiation time are not secured. when designing an isolation room, it should be set to minimize the exposure of all persons entering the room to the source of infection. negative pressure isolation room (npir) uses a ventilation system to keep the air pressure inside the room at negative value, allowing outside air to enter the room, but not indoor air. the diluting effect in npir has been reported to be influenced by the airflow pattern along with the air changing rate. 5 npir requires air exchange at least 6 times per hour (hospital room) or 12 times (new or renovated building). 6,7 an examinee in the booth will be asked to sampling procedure while he or she temporarily put off his or her mask, and the procedure could inevitably cause them to cough or sneeze. therefore, the safety of the next examinee should be particularly ensured because there is a risk that aerosols containing viruses may remain in the booth. to remove 99% of airborne contaminants from npir, a minimum of 23 minutes is required for 12 cycles of air circulation per hour, and 35 minutes is required to remove 99.9%. 7,8 therefore, it is dangerous to think that it will be safe to conduct screening at short intervals without considering air changing per hour. npir doors should be always closed, but in the case of walk-through system, examinees frequently enter and exit, so there is a possibility that proper negative pressure may not be maintained due to the inflow of external air. even if the air conditioning system is stopped due to a power or mechanical failure, a system such as a backflow prevention damper should be equipped to prevent the spread of infection and cross contamination due to backflow of air. the principle of using gloves is as follows: disposable gloves are recommended when there is a possibility of contact with contaminated objects. gloves should be replaced for each patient, never reused, and should not be washed and reused. 4 in the walk-through system where the gloves are fixed to the booth, this principle may not be strictly observed, and crossinfection due to contaminated gloves could occur. to prevent this, gloves should be replaced at every screening test. both drive-through and walk-through systems have advantages in terms of efficiency. both methods can be quickly performed. since the medical personnel and the examinees are separated from each other, consumption of ppe can be reduced, and contamination of medical staff that may occur when removing the ppe can be prevented. however, as for walk-through, consideration should be given to minimizing cross-infection that a non-infected person may be contaminated during the screening test, and minimizing cross-contamination that a non-infected person may be erroneously diagnosed as an infected person. safety issues of examiners and medical personnel that may occur due to exposure to disinfectants should be also considered. we think developing innovative methods is a very desirable trend, but we should not forget the basics. drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents review of disinfection and sterilization -back to the basics korea centers for disease control and prevention. the standard guideline for the prevention of health care associated infection virus diffusion in isolation rooms guidelines for environmental infection in health-care facilities guidelines for preventing the transmission of mycobacterium tuberculosis in health-care settings stability of middle east respiratory syndrome coronavirus (mers-cov) under different environmental conditions key: cord-334284-rut6mheb authors: kim, harin; park, kee jeong; shin, yong-wook; lee, jung sun; chung, seockhoon; lee, taeyeop; kim, min-jae; jung, jiwon; lee, jina; yum, mi-sun; lee, beom hee; koh, kyung-nam; ko, tae-sung; lim, eunyoung; lee, jung soo; lee, jee yeon; choi, ji yeon; han, hyo myung; shin, woo ah; lee, nam-ju; kim, sung-han; kim, hyo-won title: psychological impact of quarantine on caregivers at a children's hospital for contact with case of covid-19 date: 2020-07-08 journal: j korean med sci doi: 10.3346/jkms.2020.35.e255 sha: doc_id: 334284 cord_uid: rut6mheb quarantine often provokes negative psychological consequences. thus, we aimed to identify the psychological and behavioral responses and stressors of caregivers quarantined with young patients after a close contact to a coronavirus disease 2019 case at a children's hospital. more than 90% of the caregivers reported feelings of worry and nervousness, while some of them reported suicidal ideations (4.2%), and/or homicidal ideations (1.4%). fear of infection of the patient (91.7%) and/or oneself (86.1%) were most frequently reported stressors. a multidisciplinary team including infection control team, pediatrician, psychiatrist, nursing staff and legal department provided supplies and services to reduce caregiver's psychological distress. psychotropic medication was needed in five (6.9%), one of whom was admitted to the psychiatry department due to suicidality. quarantine at a children's hospital makes notable psychological impacts on the caregivers and a multidisciplinary approach is required. on march 26, 2020, a 9-year-old girl was referred to our pediatric emergency room from another hospital for intracerebral hemorrhage. on arrival, she developed a fever of 38.1°c, and was tested for sars-cov-2 pcr (allplex 2019-ncov kit; seegene, seoul, korea), whose results were negative. on march 31, however, an outbreak was reported at the previous hospital where she had visited, and her second test for sars-cov-2 pcr was positive. the epidemiologic investigator of the city of seoul decided to implement cohort isolation for all patients and their caregivers who stayed at the same ward and the other wards on the same floor as well as those who had close contacts with the index patient. on april 4, a mother of a pediatric patient who shared the six-patient room with the index patient was also confirmed to be positive for sars-cov-2. the infection control team at our hospital identified the close contacts with the second patient. as a result, 62 patients and 72 caregivers were quarantined at four covid-19 isolation units of our children's hospital for 2 weeks according to the incubation period of sars-cov-2. 17 as of the second day of the quarantine, both the caregivers and the patients developed psychological distress; as such, we established a psychiatric consultation team on the third day of the quarantine, and every caregiver underwent at least one psychiatry evaluation. a total number of 6 board-certified psychiatrists interviewed the caregivers and the nursing staffs and identified psychological and behavioral responses as well as stressors of caregivers. the demographic and clinical characteristics of the patients and the caregivers were collected. the psychological and behavioral responses and stressors of the caregivers were classified according to brooks et al.'s review, 6 which extensively revealed numerous emotional outcomes as well as specific stressors of quarantined people and of health care providers. it was thoroughly reviewed by the consultation team and considered to be adequate to apply to those under quarantine as suggested by a perspective article. 18 interventions provided to each patient and/or every caregiver were also recorded. categorical data are presented as numbers and percentages and continuous variables are presented as means and standard deviations. all statistical analyses were performed using spss ver. 24 (ibm spss statistics, ibm corporation, armonk, ny, usa). seventy-two caregivers of 62 patients who were quarantined at the children's hospital were analyzed. the mean age of the patients was 5.2 ± 5.5 years (range, 15 days-22 years) and 33 (53.2%) were male. the most common diagnosis of the patients was gastrointestinal diseases (n = 17 [ the psychological and behavioral responses and stressors of the caregivers are listed in table 1 . worrying (94.4%) and nervousness (90.3%) were observed in more than 90% of the caregivers. three caregivers manifested suicidal ideation (4.2%), and one reported homicidal ideation (1.4%). as for stressors of caregivers, fear of infection of the patient (91.7%) and fear of infection of oneself (86.1%) were highly prevalent among the caregivers. to reduce the stressors such as inadequate supplies and inadequate information, the following provisions were available to the caregivers and the patients. the patients received regular rounding by the patient's attending physician, the infection control team, unit director (pediatrician), legal department, and the psychiatric consultation team. any inadequacies in basic supplies were fully addressed by providing daily necessities such as food, drinking water, clothes, underwear, sanitary napkins, and toys. moreover, online shopping packages and personal belongings were brought to the isolation units upon caregivers' requests. the basic supplies and other belongings were delivered by nursing staffs. if caregivers reported lack of information which occurred due to quarantine, they were allowed to ask attending physicians and/or a member of infection control team during regular rounding. potential legal conflicts (e.g., financial loss due to mandatory quarantine) were consulted by legal department. all medical expenses and the supplies were covered by the hospital. the specific interventions needed by individual caregivers are shown in table 2 . thirteen (18.1%) caregivers asked for environmental rearrangements such as temperature adjustment and provision of adequate spaces and nursing staffs of the isolation units managed the requirement accordingly if possible. two (2.8%) caregivers had difficulties in taking care of the newborn babies and required babysitting by the nursing staffs. five (6.9%) caregivers were prescribed medications such as painkillers for joint pain, topical agents for skin rash, and antihistamine for allergic rhinitis by their attending physicians or infection control team. a single session of supportive psychotherapy was needed in 5 (6.9%) caregivers and multiple sessions were needed in 20 (27.8%) caregivers. psychiatrists prescribed psychotropic medication to 5 (6.9%) patients (antidepressant, n = 3; benzodiazepine, n = 2). one ( caregiver was admitted to the department of psychiatry because of suicidal ideation. every intervention was adjusted and harmonized by infection control team and the unit director. in this study, the caregivers had a higher prevalence of worrying, nervousness, and fear of infection compared with the subjects in the preceding studies. 12,15,19 -24 while most previous studies focused on the psychological reactions of hospital staff or those under voluntary selfisolation at home, we focused on the psychological and behavioral responses of caregivers of young patients with underlying illnesses under compulsory isolation in hospital units. moreover, we evaluated the caregivers during a 2-week quarantine period, thus reflecting more severe and acute psychological reactions. our results suggest that significant clinical attention is required in caregivers of young patients under mandatory quarantine. the psychological adverse effects of quarantine could be dramatic and severe in some cases. in our study, 3 caregivers reported suicidal ideations and 1 reported homicidal ideations. one female caregiver was eventually admitted to the department of psychiatry because of suicidality. a study on previous epidemics showed that cases of completed or attempted suicides were reported during the first weeks of the imposition of quarantine. 11, 25 these results collectively suggest that the mental health of children 26 as well as caregivers should be closely monitored during quarantine. a multidisciplinary team approach was essential for fully comprehending and addressing the caregivers' unmet demands. 27,28 in line with previous research, 23,29 -32 caregivers reported that inadequacies in supplies, medication, and information as well as difficulty in childcare were major stressors. we sought to follow the suggestions from brooks et al.'s review 6 by providing as much information and supplies as possible, reducing the boredom, and improving the communication. to achieve these goals, we fully encouraged open communication between multidisciplinary teams consisting of the infection control team, unit director (pediatrician), legal team, psychiatrists, and nursing staff. several limitations should be taken into consideration. psychological distress or stressor was not evaluated based on a semi-structured interview or clinical rating scale. therefore, the 4/7 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e255 psychological impact of quarantine on caregivers for children with covid-19 degree of the psychological impacts of quarantine, which could vary among subjects, was not estimated. in addition, this study did not consider several other clinical characteristics that could be associated with the distress of isolated caregivers (i.e., personality, coping strategy, previous experience of isolation, or past psychiatric history 33,34 ). in conclusion, mandatory quarantine at a children's hospital due to contact with a patient with covid-19 had notable psychological impacts on the caregivers. the decision to impose a large-scale quarantine in healthcare facilities should be made carefully by considering the possible psychological ramifications on the caregivers as well as the patients. potential benefits of mandatory mass quarantine need to be weighed carefully against the possible psychological costs. when such quarantine must be pursued, thorough psychiatric evaluation and intervention through a multidisciplinary approach may be helpful in reducing the caregivers' stressors. covid-19 epidemic in switzerland: on the importance of testing, contact tracing and isolation world health organization. considerations for quarantine of individuals in the context of containment for coronavirus disease (covid-19): interim guidance ethical and legal challenges posed by severe acute respiratory syndrome: implications for the control of severe infectious disease threats ethics and public health emergencies: restrictions on liberty the psychological impact of quarantine and how to reduce it: rapid review of the evidence an exploration of the psychologic impact of contact isolation on patients in singapore the relevance of psychosocial variables and working conditions in predicting nurses' coping strategies during the sars crisis: an online questionnaire survey the experience of sars-related stigma at amoy gardens the psychological impact of the sars epidemic on hospital employees in china: exposure, risk perception, and altruistic acceptance of risk posttraumatic stress disorder in parents and youth after health-related disasters mitigate the effects of home confinement on children during the covid-19 outbreak the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application mental health and the covid-19 pandemic mental health status of people isolated due to middle east respiratory syndrome the factors affecting household transmission dynamics and community compliance with ebola control measures: a mixed-methods study in a rural village in sierra leone accepted monitoring or endured quarantine? ebola contacts' perceptions in senegal factors influencing compliance with quarantine in toronto during the 2003 sars outbreak the psychosocial effects of being quarantined following exposure to sars: a qualitative study of toronto health care workers the emotional impact of coronavirus 2019-ncov (new coronavirus disease) the impact of epidemic outbreak: the case of severe acute respiratory syndrome (sars) and suicide among older adults in hong kong mental health considerations for children quarantined because of covid-19 timely mental health care for the 2019 novel coronavirus outbreak is urgently needed the experience of quarantine for individuals affected by sars in toronto risk and resilience in canine search and rescue handlers after 9/11 prevalence and predictors of posttraumatic stress symptoms in utility workers deployed to the world trade center following the attacks of key: cord-262681-2voe4r7f authors: kim, moon-young; cheong, harin; kim, hyung-seok title: proposal of the autopsy guideline for infectious diseases: preparation for the post-covid-19 era (abridged translation) date: 2020-08-14 journal: j korean med sci doi: 10.3346/jkms.2020.35.e310 sha: doc_id: 262681 cord_uid: 2voe4r7f with the rapidly spreading coronavirus disease 2019 (covid-19) pandemic over the past few months, the world is facing an unprecedented crisis. innumerable lives have been lost to this novel infectious disease, the nature of which supersedes conventional medical understanding. the covid-19 pandemic is not just a global health crisis, several aspects of life in the post-covid-19 era are also being contemplated. experts in unison are warning that the upcoming changes in all areas of life could potentially be far more drastic than ever experienced in the entire human civilization. the medical community is no exception, and therefore, personnel involved in forensic medicine also need to be adequately prepared for the future. forensic medicine is a branch of medicine dedicated to one of the most important stages of the human lifecycle and has always been at the forefront in times of unprecedented social change. the autopsy, one of the most important tools of forensic medicine, is also useful to infectious diseases because it identifies the causal relationship between death and infection, reveals medical and epidemiological knowledge, and provides objective evidence for legal disputes. we present new autopsy guidelines in forensic medicine, formulated based on the various infectious diseases that we presently live with and may encounter in the future. in formulation of these guidelines several considerations have been taken into account, namely, the role forensic pathologists should play in the post-covid-19 era and the necessary preparations as well as the support needed from society to fulfill that role. the present covid-19 outbreak should be a starting point for formulating improvements in current practices in forensic science, including autopsy biosafety practices and the medicolegal death investigation system. despite the development of medical science, as the complexity of our society increases, various microorganisms that have the potential to be infectious agents constantly threaten humanity. through accumulated mutation, even well-known microorganisms are becoming new species, resulting in stronger transmission or higher number of fatalities. korea is also in a situation where management is required of both the interior spread and the foreign inflow of various infectious diseases. for examples of the former in korea, there are respiratorymediated infectious diseases, such as tuberculosis, which is known to be endemic, and bloodmediated infectious diseases, such as hepatitis b, hepatitis c, and acquired immune deficiency syndrome (aids), which need continuous monitoring. 1,2 numerous foreign infectious diseases are newly emerging as a result of changes in climate and biological distribution due to environmental degradation, and the collapse of interspecies barriers. as international exchange increases, they can flow into other countries at any time. 3 recently, several respiratory diseases caused by novel viruses, such as severe acute respiratory syndrome ( in a situation where enormous social and economic losses are caused by the periodic outbreak of novel infectious diseases, the national quarantine system requires improvement to cope with the public health crisis. we believe that autopsy can provide the basic data for establishing appropriate quarantine and preventive measures. the autopsy is the most direct approach to a disease or other medical abnormalities. historically, a wide range of information on pathogenesis, epidemiology, and the natural course of numerous diseases has been collected through autopsy, leading to the development of medicine. also, the autopsy identifies legal problems related to death and prevents potential disputes, the necessity for which has been recognized across many sectors of society. it should be considered more important in a death related to an infectious disease. while the clinical environment is ready for infectious diseases under administrative and financial support, the death investigation system in korea does not seem to be comparable. although many infectious diseases are diagnosed only postmortem through autopsy, the personnel related to the autopsy are exposed to the risk of infection, due to insufficient clinical information, lack of facilities or equipment for protection, and injury accidents. therefore, a guideline for the standard autopsy for infectious diseases is stated here, which aims to: 1) provide scientific grounds to establish appropriate plans for the prevention and treatment of infectious diseases, 2) contribute to improving national health by controlling the spread of pathogens within the community, and 3) protect human resources engaged in autopsy-related work from the risk of infection. several autopsy guidelines, including more recent ones focusing on covid-19, have been adopted here. [5] [6] [7] [8] [9] most of them suggest that the principles of handling covid-19 during autopsy are not different from that of the handling of other infectious diseases. this guideline does not present the current modus operandi, but indicates the way in which we need to operate from now on, and which needs our continuous effort dedicated to forensics, as well as support from the related social systems. the pathogen of infectious diseases includes various microorganisms, such as bacteria, viruses, fungi, parasites, and even prions. among various routes of transmission, direct contact of blood or body fluids, and aerosol transfer via droplet or its nuclei are considered as important during the autopsy. patients with active infection could have symptoms of acute, subacute, or chronic status, which is called clinical disease, or have no apparent symptoms, which is called subclinical or occult disease. infection by some agents could be inactive for a certain period, which is called latent infection. the diagnosis of an infectious disease could be considered based on 1) medical history, from the statements of his or her acquaintances or formal medical records; 2) postmortem tests for the detection of microorganisms, such as serologic, genetic, or culture tests using blood, secretion, fluid, or tissue; 3) pathologic findings, using conventional and special stains; and 4) epidemiologic information about the deceased or his or her close contacts, such as the location of residence and workplace, occupation, travel history, and recent whereabouts. the infectious disease control and prevention act of korea designated some infectious diseases with epidemiologic importance as 'legal infectious diseases.' these diseases were classified into four classes according to their severity, infectiousness, and isolation level (appendix 1). an emerging infectious disease with the possibility of severe symptoms or rapid transmission is considered an 'emerging infectious disease syndrome' in class 1. covid-19, caused by sars-cov-2, is an example of this temporary classification, which should be classified properly after the pathogenesis and clinical features are further revealed. according to the act, a doctor who identified an infectious disease from a living patient or a dead body should report to the regional public health center. the director of the korea centers for disease control and prevention (kcdc) may order an autopsy of the deceased who is suspected of having died from an infectious disease, to confirm the final diagnosis. the autopsy process should be conducted by a specialist in infectious disease, human anatomy, pathology, or forensic medicine, in a facility with an adequate level of biosafety. the kcdc has suggested a revised classification of the risk groups of infectious agents (appendix 2) in 2016, which is based on the classification for the biology laboratory published by the who in 2004. 10 according to this classification, risk group 2 includes the pathogens that are unlikely to be a serious hazard, such as hbv and hcv, while risk group 3 includes the pathogens that usually cause serious diseases, such as mycobacterium tuberculosis, sars-cov, and hiv. for both groups, effective treatment and preventative measures are available in general. the infectious disease control and prevention act of korea classifies the safety control measures of the facilities handling high-risk pathogens into four grades (appendix 3), which correspond to the biosafety levels (bsls or bls) suggested by the who. they could be applied to all the pathogens identified so far. registration with the kcdc is required for handling high-risk pathogens of grade 1 and 2, while permission from the kcdc is required for those of grade 3 or 4. the classification is as follows: • grade 1: facilities that handle high-risk pathogens that are unlikely to cause diseases to healthy adults. • grade 2: facilities that handle high-risk pathogens that can cause human diseases unlikely to be a serious hazard and for which effective treatment and preventive measures are available. • grade 3: facilities that handle high-risk pathogens that usually cause serious human diseases and for which effective treatment and preventive measures are available. • grade 4: facilities that handle high-risk pathogens that usually cause serious human diseases and for which effective treatment and preventive measures are not usually available. in addition, the same act designates some infectious agents as 'high-risk pathogens' that require special attention from the nation and society, because of the potential of serious risk to public health if used for biological terrorism, or spread to the outside by accident (appendix 4). some agents in risk group 2, 3, and 4 recommended by the who and some causative agents of a recent outbreak, such as sars-cov and mers-cov, are included in this list. it is anticipated sars-cov-2 will be added here in the near future by revision of the act. autopsy plays a critical role in 1) determining the situation and specific causes of death, 2) excluding other causes of death when a patient dies during treatment or isolation for a confirmed infection, and 3) evaluating the medical relationships between infection and death if the infection is not a direct cause of death. autopsy is able to provide crucial information for 1) the establishment of an appropriate treatment plan based on the pathological mechanisms by confirming the clinical course, symptoms, histology, and prognosis, and 2) scientific evidence to control and prevent the spread of pathogens within the community, by identifying the path of transmission, and the prevalence of the target population. since immediately after a particular death, the possibility of legal disputes related to the death are often unclear, and the bereaved family are often confused, the conducting of an autopsy should be decided under careful consideration of the circumstances surrounding the death. potential legal disputes may be related to the validity and relevance of medical treatment or administrative actions, compensation claims against industrial accident insurance or commercial medical insurance, or professional negligence of a business owner. most of the situations are already covered by the criteria for the decision of unnatural deaths suggested by the kslm (appendix 5), or the instructions for handling unnatural deaths declared by the korean national police agency (appendix 6). most of the medical history provided before the autopsy by the police is limited to the statements of bereaved families or acquaintances, or concise data from the national health insurance corporation. obtaining the medical records of the deceased needs an additional effort of the police or the bereaved families. however, the medical information is mandatory in identifying the health status of the deceased, and preparing against the potential risk of infection. the incidence of tuberculosis among autopsy workers is known to be 100-200 times that of the general population, 11 while it has never been investigated in korea. a smallgroup survey in korea indicated that the prevalence of tuberculosis and hepatitis b among medical workers was suspected to be very high. 12 because hepatitis c and aids are difficult to cure and have a poor prognosis, serologic tests are performed on all surgical patients to protect medical personnel. but currently in korea, no particular tests are required to be conducted in the routine for a dead body before the autopsy. the purpose of the medico-legal autopsy may be divided into a judicial one, to confirm criminal relevance, and an administrative one, to manage public issues related to infectious diseases, accidents, or disasters, while that of the clinical autopsy is usually focused on medical evaluation. in korea, the legal basis for all forms of autopsy is prepared. for example, in the cases of infectious diseases that are not expected to be related to crime, the autopsy may be conducted by the minister of health and welfare, the mayor, the governor, the director of the kcdc, or the head of the quarantine office. but in practice, the autopsy is always requested by the police, which inevitably limits its purpose. although autopsy rooms are installed at the national forensic service (nfs) and its local branches, and some medical schools having forensic or pathology departments, their bsls are in different situations. for example, the headquarters of the nfs has a special autopsy room of bsl3, while some medical schools have only bsl1 rooms. in principle, if the deceased is known to be a tuberculosis patient, the autopsy should be conducted in the bsl3 autopsy room, because mycobacterium tuberculosis belongs to risk group 3 with sars-cov and hiv. 10 but this principle is hard to follow, due to the high prevalence of tuberculosis in korea, and a lack of medical history, as mentioned above. each institution is in charge of the management of personal protective equipment (ppe) required for the autopsy, without sharing a standardized protocol. to assess the risk of infection caused by autopsy, the medical conditions of autopsy personnel should be checked periodically, especially after the autopsy of a high-risk person. 5 throughout the branches of the nfs and the universities, there are no principles for the list of target pathogens, the method and frequency of surveillance test, and the criteria for subjects who need such monitoring. to conduct an autopsy, the sequence of procedures should be involved, of 1) transfer from the funeral home, 2) receive the body at the autopsy room, 3) check the identity of the body with the police or bereaved family, 4) perform the autopsy, 5) return the body to the funeral home, and 6) transfer the samples for postmortem test to other departments. the workers who will be involved before and after the autopsy should be guided and trained in the use of ppe and hygiene control, because during the wrapping and transporting processes, there is a possibility of contagion from the deceased. laboratory personnel dealing with samples taken from the body during the autopsy should be aware of the potential risk of infection in all autopsy samples, and receive the same level of health support as the autopsy personnel. in particular, all laboratories dealing with the initial sample that has not been chemically treated or biologically inactivated, must have bsl2 or higher level of facilities and appropriate ppe. 10 throughout the autopsy-related facilities in korea, there is only a low level of safety considerations for these types of personnel who are not directly involved in the autopsy, and the level is insufficient to deal with a body or samples infected by a highrisk pathogen. all bodies should be considered to be infected by unspecified microorganisms, until they are diagnosed as negative by a medically verified examination, using appropriate samples. the autopsy personnel have the right to be protected from infection by the body, for which the affiliated agencies should make appropriate efforts. even if an infectious disease is newly diagnosed after the autopsy, the risk of infection to the autopsy personnel should be low level. a 'standard autopsy' for infectious diseases is defined as an autopsy conducted by an agreed procedure for this purpose, which should always be observed, regardless of the prevalence of the infectious disease. for confirmed cases, some conditions could be added for the optimal protection of the autopsy personnel. in contrast, if any of the facilities, personnel, equipment, or procedure did not meet the standard, an autopsy shall be considered as an 'ordinary autopsy'. the risk of transmission during an autopsy could be assessed according to the infection status of the body ( table 1) . to conduct an autopsy for a confirmed case, the biosafety levels of the facilities for autopsy and laboratory tests should be equivalent to or higher than that of the pathogen. during the prevalence of a certain infectious disease, all the unknown cases should be regarded at least as suspected cases. however, considering the realistic restrictions, if there were reasonable compensations, such as preliminary tests before the autopsy, adequate ventilation and disinfection of the facilities, or additional use of ppes, the autopsy could be conducted by substandard protocols. even for the negative cases that are allowed for the ordinary autopsy, a higher level of protection is recommended, because there is always the possibility of a false-negative. considering the prevalence and biological risks, a list of infectious pathogens should be selected, and periodically evaluated for surveillance. preliminary tests for these pathogens are recommended. during the prevalence of high-risk pathogens (appendix 4) or their equivalents, preliminary tests are mandatory for clinically suspected cases to determine the conduct and the coverage of the autopsy. 4 the autopsy can be postponed until the results of the preliminary tests are available. even for the cases in which the preliminary test was negative, if suspicious findings were found during the autopsy, it is recommended to repeat the test with the autopsy samples. the possibility of false-negatives should always be considered, because the results could be affected by the infection period, sampling methods, status of the samples or bodies, or the characteristics of the test itself. place the body in a leak-proof transparent plastic bag with a thickness of 150 μm, and seal it. do not use pins or clips that can damage the sealing conditions. 13 put the plastic bag into another opaque body bag, and wipe its outer surface with sodium hypochlorite diluted 1:4 (e.g., 5% sodium hypochlorite 100 ml + water 400 ml mix), and dry. attach an identification tag to both the body and its bag, respectively, and make sure that they are not lost. refrigerate the body at 4°c. at the beginning of the autopsy, disinfect the outer and inner surface of the body bag and the skin of the body with 70% alcohol or sodium hypochlorite diluted 1:99 (e.g., 5% sodium hypochlorite 5 ml + water 495 ml mix). the biosafety standard of the autopsy-related facilities may correspond to the bsl in general, although a little modification is required to reflect the procedure and equipment of the autopsy. the concept of bsl is also adopted in the 'standards for the installation and operation of facilities handling high-risk pathogens (ministry of health and welfare notice no. 2019-59)' (appendix 3) , which the korean institutes should follow for handling microorganisms with potential biologic risk. a bsl2 autopsy room is required for the ordinary autopsy, while a bsl3 or higher level is required for the standard autopsy, according to the risk group of the confirmed or suspected pathogen. 10 in an autopsy room that does not meet the above criteria, at least 1) the air inside the autopsy room should not escape to other spaces in the building, 2) the route of exhaust should avoid other intake vent or public spaces, and 3) additional devices or ppes should be utilized to compensate insufficiently met requirements. considering the environment of the autopsy room and the prevalence status of the time, the preliminary test of all the requested bodies should be considered for certain pathogens, and be referred to the decision of the conduct and coverage of the autopsy. waste generated in all processes related to the body correspond to medical waste. they should be immediately disposed of in a dedicated envelope or containerboard box. in particular, sharp tools, such as injection needles, suture needles, or scalpels, should be discarded in a dedicated plastic container. waste are sealed, disinfected, and then refrigerated in a dedicated warehouse. they should be transported to a medical waste incinerator within 7 days, and disposed of within 2 days. if a surface is contaminated, wipe it with sodium hypochlorite diluted 1:49 (e.g., 5% sodium hypochlorite 10 ml + water 490 ml mix), and leave it for 15-30 minutes, before wiping it again with water. if a metal surface is to be disinfected, wipe it with 70% alcohol (e.g. 100% alcohol 70 ml + water 30 ml mix). if a surface is visibly contaminated by blood and body fluids, wipe it with sodium hypochlorite diluted 1:4 (e.g., 5% sodium hypochlorite 100 ml + water 400 ml mix), and leave it for 10 minutes, before wiping it again with water. the sodium hypochlorite solution should be newly mixed each time. after disinfection is finished, thorough ventilation is required. reusable surgical garments (e.g., gown, mask) made of cotton could be included in the alternative list of ppes. the cotton contaminated with blood or body fluids should be washed with hot water at 70°c or higher. if unavailable, soak them in sodium hypochlorite diluted 1:49 (e.g., 5% sodium hypochlorite 100 ml + water 4,900 ml mix), and leave them for 30 minutes before washing. handle as gently as possible, to avoid aerosols. aiming to protect the whole body of the autopsy personnel, including respiratory tract, eyes, and hands, from the infection, ppe should be selected in consideration of the nature and the infection route of the pathogen, and the expected situation of possible exposure. ppe should in principle be disposable or single-use, but some items (e.g., powered air-purifying respirators (papr), goggles, face shields, surgical garments made of cotton, and boots or shoes) may be designed for reuse, which should be disinfected or sterilized according to the manufacturer's instructions. keep hair from flowing down, and remove personal accessories, like watches, in advance. to prevent unnecessary contamination, each manual of the ppes, including dressing and undressing orders, should be understood in advance, and properly applied. once the ppes are used, they shall be discarded or disinfected, being regarded as contaminated. hand hygiene shall be carried out before and after dressing or undressing. damaged or contaminated ppes should be discarded, without being reused or stored again. cross-check between the autopsy personnel is recommended of whether the ppes are worn properly, or not. the dressing order of ppe should be as follows: the undressing order of ppe should be as follows: it is recommended to disinfect inner gloves at each step, as during the undressing they may become contaminated. if ppes are found to be damaged, these cases should be considered as exposure to the pathogen, followed by proper management for the personnel. all the processes should be supervised by an experienced forensic pathologist. the number of people who participate in the autopsy should be minimized. however, it is recommended that at least two people be present in the autopsy room, in case of an emergency. 8 to prevent cutting injuries, the dissection of each body part should be conducted by only one person at a time. a person who is not directly participating in the autopsy, such as the bereaved family member or police, is restricted from entering the autopsy room. during the prevalence of certain infectious diseases or the autopsy for confirmed cases, the access of trainees, such as medical students or residents, is also restricted. if necessary, observation through a window or a monitor is recommended, in a completely separate space from the autopsy room. all the autopsy personnel should be cautious with sharp objects, such as scalpels, knives, needles, or bone sections, which can cause cutting injuries. damaged or contaminated ppes should be immediately discarded, and replaced with new ones. in the case of exposure to infection source, disinfect the exposed area immediately in a proper way; and if there is medical evidence, start prophylactic treatment. if the body is suspected to have an airborne disease, the following should be operated with special caution, to prevent aerosols: 1) cutting bone with electronic saws, for which replacement if a full-body suit is not available, surgical cap and long boots can be used to minimize exposed parts. also, if the suit or gown is not made of waterproof material, the waterproof function of the ppes can be supplemented with a plastic apron or arm covers; b although they are not truly cut-proof, work gloves made of cotton may interrupt the movement of blades. by manual saws or additional use of vacuum inhalers is recommended, 2) opening the containers or centrifugation of samples, 3) body movement during transportation or postural adjustment during autopsy, which may cause spout of oral and nasal contents, 4) incision of the bronchus or lung parenchyma, which may expose the secretion inside, and 5) washing the body with a showerhead, which may spray its body fluids or adhesives together. for the suspected cases or the unknown/negative cases with suspicious findings in the autopsy, a medically verified test at the time for each pathogen or disease should be requested, with appropriate samples. in these cases, the autopsy personnel and facilities should be managed as if they participated in the autopsy for confirmed cases, until the test result is assured to be negative. the initial sample, which is not chemically treated nor biologically inactivated, should be handled within the biosafety cabinet installed in the bsl2 laboratory by experienced personnel wearing the ppes equivalent to that used in the autopsy room. meanwhile, after chemical treatment or biologic inactivation, the samples can be handled on an ordinary bench. purified dna or protein can be handled in the bsl1 laboratory, but the use of a biosafety cabinet or its equivalent is recommended. to transport the autopsy samples, they should be prepared in the following order: 1) put the samples into the primary container, and seal it, 2) disinfect the outer surface of the primary container with 70% alcohol, and label it with an identification tag, 3) wrap the primary container with an absorbent (e.g., paper towel), 4) put the primary container into the secondary container, and seal it, 5) put the secondary container into the tertiary container and seal it, and then label it with a tag. the personnel who pack or open the containers should wear the ppes equivalent to that used in the autopsy room or laboratory. any work that requires contact with the containers, for example, simple transportation in sealed status, requires at least the wearing of gloves. the affiliated agency should recognize the major infection history of all personnel who participate in autopsy or handle postmortem samples, and take necessary measures to prevent infections. if the standard autopsy was conducted without any damage of ppes, the risk of infection is generally low. however, if the biologic nature of the pathogen or the epidemiology and pathophysiology of the disease are not fully identified, all the participants should be alert during the expected incubation period, even though they are not obviously exposed, with self-monitoring of the symptoms and the minimizing of face-to-face contacts. all the personnel who have accessed the autopsy room should be recorded: not only the direct participants in the autopsy, but also assistants for the maintenance of the facilities. considering the prevalence and biological risk, a list of infectious pathogens should be selected, and periodically evaluated for surveillance. if there is clinical evidence, prophylaxis, like vaccination, is recommended. in particular, each participant in the autopsy of confirmed cases should check whether he or she is already infected with the pathogen or not, so that if he or she is infected during the autopsy, the infection source could be traced. in the case of personnel who participated in the autopsy of a body confirmed to be infected but the standard protocol was followed, there is no possibility of exposure, so only selfmonitoring of the symptoms and the minimizing of face-to-face contacts during the expected incubation period are required. however, if the autopsy procedures failed to meet the standard protocol, or the ppes were damaged, infection should be suspected. in this case, self-isolation during the expected incubation period, and if available, prophylaxis, is required. the relevant personnel should be tested for the pathogen at the time point when related symptoms are shown, or the isolation period is nearly ended. if a test was requested after the autopsy, but the results are pending, the same actions are required in the interim. if the autopsy procedures failed to meet the standard protocol, or the ppes were damaged, the forensic pathologist in charge of the autopsy may consider adjusting the participant members, or discontinuing and delaying the autopsy schedule, to protect the autopsy personnel. if a test for certain infection was requested after the autopsy, the process and the result should be shared with all the personnel who had, or would have, contact with the body, including the police, the bereaved family, the person who has discovered, reported, inspected, or transported the body, and the funeral staff. they are required to minimize faceto-face contacts, until the test result is confirmed. covid-19 is a respiratory syndrome caused by the infection of sars-cov-2, which belongs to the coronavirus family. currently, in korea, covid-19 is regarded as an 'emerging infectious disease syndrome,' which is included in class 1 legal infectious disease (appendix 1), and sars-cov-2 is considered a high-risk pathogen, which needs 'urgent management' (appendix 4) . it is known to be transmitted through aerosols, droplets, or direct contact, while the viruses have also been found in tears and feces. 14, 15 the incubation period is up to 14 days, and symptoms were expressed within 12.5 days after exposure in 95% of the infected. according to the studies published so far, the survival period of sars-cov-2 is 3 hours in aerosols, 4 hours on copper surfaces, 24 hours on cardboard surfaces, and 2-3 days on plastic or iron surfaces, which indicate that sars-cov-2 can survive for a considerable period outside of the host. 16 2) clinical and pathologic findings sars-cov-2 patients show diverse symptoms, ranging from asymptomatic to severe respiratory failure. major symptoms are fever, fatigue, dry cough, muscle ache, and shortness of breath; and a few cases included sputum, headache, hemoptysis, and diarrhea. recently, the cdc of the united states and the kcdc added ageusia and anosmia as major symptoms of covid-19. the patients are frequently diagnosed with viral pneumonia, regardless of the actual severity of their symptoms. as of yet, there is no specific therapeutic agent or vaccine. severe patients suffer from respiratory failure, septic shock, and multiple organ failure. the median time to respiratory failure was 8.0 days from symptom onset, while that to mechanical ventilation was 10.5 days. according to a few reports of autopsy or histopathology test, microscopic findings included diffuse alveolar damage, fibromucinous exudates, inflammatory infiltration in the interstitium or intra-alveolar area, viral cytopathic-like change, and thrombogenic vasculopathy. 17-21 a diagnostic test for sars-cov-2 could be considered based on 1) medical history or symptoms, which are mainly fever or respiratory symptoms, and also include headache, abdominal pain, and fatigue, 2) epidemiologic connection, such as temporal, spatial, or geographical relationships with an epidemic region or confirmed patient, and 3) gross pathologic findings of the lungs, such as consolidation, thick exudates, excessive mucus, or other findings suggestive of acute or severe pneumonia, regardless of the clinical symptoms. the autopsy of confirmed and suspected cases should be conducted at bsl3 or equivalent facilities. for unknown cases, the autopsy could be conducted under bsl3 facilities, but there should be reasonable compensations, such as preliminary tests before the autopsy, adequate ventilation and disinfection of the facilities, or additional use of ppes. the management of autopsy related facilities follows the standard autopsy protocol as mentioned above. even though the generation of droplets or aerosols from bodies is unlikely, it is recommended to minimize direct contact with the bodies or postmortem samples, and prevent damage of ppes. 22 for pathologic study, the respiratory system, including proximal and distal trachea, pulmonary hilum, main and segmental bronchi, pulmonary parenchyma, and other organs, such as the heart, the liver, kidney, spleen, and intestines, could be sampled, according to the purpose of the study. fix them with 10% formalin for 2-3 days. 25 (1) the autopsy for confirmed cases the management of facilities, environment, and human resources follows the standard autopsy protocol suggested above. the initial samples should be sent to the bsl3 laboratory. if there is a risk of infection due to damage of ppes, skin exposure, aerosol-prone manipulation, or cutting injuries, the relevant autopsy personnel and his or her contacts should be provided with proper medical treatment, including disinfection and virus test. also, for 2 weeks from the exposed time point, which is the expected incubation period of covid-19, they should be isolated and excluded from the work, even though the initial test result is negative. the affiliated agency should monitor his or her symptoms. (2) the autopsy for suspected or unknown cases if a virus test for the body is carried out during the autopsy, the participated autopsy personnel should minimize face-to-face contact, until the results are notified. if the result of the virus test is positive, a postmortem test, such as toxicology (except for alcohol), biochemical, or genetic test should be requested, after the disinfection of the samples by mixing with 100% alcohol for 3 (sample):7 (alcohol) ratios. 24 then the samples should be transported according to the standard protocol above. the management of the facilities, environments, and human resources generally follows the standard protocol above, while the disinfection process of the autopsy room and related facilities should refer to the kcdc guideline. if an infection is suspected, for example, due to a substandard autopsy procedure or damaged ppes, the autopsy personnel and their contacts should be provided with proper medical treatment, including disinfection and virus test, with isolation and monitoring for 2 weeks, as mentioned above in section 6)(1) . when the body is confirmed to be negative for the virus test, the isolation and monitoring could be discontinued. since the autopsy personnel are under constant risk of infection, there should be consistent effort for the implementation of the standard autopsy guidelines. first of all, expecting the periodic spread of infectious diseases in the future, the preparation of adequate level of ppes 13/25 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e310 and bsl of the autopsy related facilities, and the establishment of a health monitoring and surveillance system are required. to compensate for the problems of the current death investigation system, which is focused on the judicial purpose, in the short term, the range of unnatural death considered as the subject of judicial autopsy should be expanded as wide as possible, in consultation with the police and the prosecution. in the long term, the autopsy request ordered by the directors of the ministry of health and welfare or the kcdc should be encouraged with systemic supports. also, the ministry of health and welfare or the kcdc should be in charge of the management of biosafety requirements in the autopsy facilities and the arrangement of the qualified human resources and financial support, so that this guideline could be satisfactorily implemented. forensic medicine has developed and gradually improved over a long period, despite all the difficulties such as unfavorable environment and systemic constraints. however, in the upcoming post-covid-19 era, there should be more integrated and organized provision, especially against the risk of infectious diseases. health authorities and forensic pathologists should work together to improve the autopsy environment and the death investigation system, so that a better national health system can be established in the near future. trends in infectious disease mortality the korean society of infectious diseases. guidelines for potential emerging infectious diseases in korea. seoul: the korean society of infectious diseases republic of korea biosafety considerations for autopsy interim guidance for collection and submission of postmortem specimens from deceased persons under investigation (pui) for covid-19 briefing on covid-19: autopsy practice relating to possible cases of covid-19 guide to forensic pathology practice for death cases related to coronavirus disease 2019 (covid-19) (trial draft) central disaster management headquarters and central disease control headquarters. corona virus infection-19 response guideline. 7-4th ed. cheongju: central disaster management headquarters and central disease control headquarters mycobacterium tuberculosis at autopsy--exposure and protection: an old adversary revisited occupational infections of health care personnel in korea review article: gastrointestinal features in covid-19 and the possibility of faecal transmission evaluation of coronavirus in tears and conjunctival secretions of patients with sars-cov-2 infection aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 pathological findings of covid-19 associated with acute respiratory distress syndrome covid-19 autopsies withdrawn: mortality of a pregnant patient diagnosed with covid-19: a case report with clinical, radiological, and histopathological findings complement associated microvascular injury and thrombosis in the pathogenesis of severe covid-19 infection: a report of five cases death in the course of judicial execution, such as arrest, interrogation, detention, etc death at the accommodation for health, welfare, and nursing, etc 1. the term "unnatural death" means a death falling under any of the following whose cause is unclear:a. death suspicious, or confirmed to be related to a crime b. accidental death due to natural disaster, traffic accident, safety accident, industrial accident, fire, drowning, etc. c. suicide, or death suspected as suicide d. death in the course of judicial execution, such as arrest, interrogation, detention, etc. e. death at the accommodation for health, welfare, and nursing f. death suspected as acute poisoning by drug, pesticide, alcohol, gas, etc. g. other death with unknown cause 2. the term "unnatural death case" means a case in which one or more bodies that correspond to, or are suspected of unnatural death, are found. 1. the director of an unnatural death case shall apply for a warrant for an autopsy in any of the following cases (referred to as a "priority control case"), unless there are special circumstances: a. death suspected to be by murder b. unidentified body, despite the investigation of belongings, fingerprints, etc. at the scene c. death that is expected to draw social attention, such as collective death, child abuse, etc. d. severely decomposed body, so hard to identify injuries or cause of death 2. the director of an unnatural death case shall consider a warrant for an autopsy in any of the following cases (referred to as a "autopsy-considered case"), to confirm the relation to a crime: a. unexpected death of infant or child b. death in the course of judicial execution, such as arrest, interrogation, detention, etc. c. death suspected as acute poisoning by drug, pesticide, alcohol, gas, etc. d. death suspected to be drowning or falling, for which eyewitness or cctv footage is unavailable e. body that is carbonized or skeletonized f. death for which the bereaved family harbors suspicions about the cause g. death by traffic accident suspicious for the relationship to other crime h. death of a person with excessive death benefit, compared to his or her property i. death with disagreement about the cause between the inspection doctor, the investigators, or the director of the case j. other death for which autopsy is required to confirm its cause or circumstance key: cord-336225-ijodhrwf authors: chang, mee soo; woo, jun hee title: severe fever with thrombocytopenia syndrome: tick-mediated viral disease date: 2013-06-03 journal: j korean med sci doi: 10.3346/jkms.2013.28.6.795 sha: doc_id: 336225 cord_uid: ijodhrwf nan a small tick haemaphysalis longicornis called 'sochamjindeugi' in korean has bitten a week before, and an onset is characterized by fever, lymph node swelling, diarrhea, thrombocytopenia, leucocytopenia, multiorgan dysfunction, altered consciousness, and occasionally to death in extreme cases (1, 2) . this emerging febrile disease, severe fever with thrombocytopenia syndrome (sfts), was reported in 2007 by the new england journal of medicine (3) and clinical infectious diseases (4) (5) (6) . the etiology of sfts turned out to be the sfts virus. yet most physicians are not familiar with this disease, and initially it is difficult to differentiate from other febrile illnesses (7-9). ding et al. (4) reported 2,047 cases of sfts in china, the majority of patients were in late 50's, and their occupation was farmer in agriculture or forestry. sfts virus was transferred by the tick, h. longicornis. the incidence is high from may to august because of a lot of outdoor activities at that time, when ticks and mites usually absorb animal's body fluids in order to grow and proliferate. the case fatality of 6% has been reported. yu et al. (3) observed the infected tissue by electron microscopy and revealed virions in golgi apparatus with the morphologic characteristics of a bunyavirus, cytopathic effects (virus induced cellular changes), and granular particles in the cytoplasm. additionally the possibilities of person-to-person spread were raised (5, 6) . the same patients with sfts began to occur in japan and some of them died. on may 21, 2013, the first patient of sfts in korea was diagnosed at seoul national university hospital (1, 2) . only a few days later, another sfts patient was confirmed in the jeju island. the 2 cases confirmed that sfts has been endemically transmitted in korea. why the virus is the target of fear is quite simple. viruses are the lowest living substance on earth, and they can most quickly transform. higher animals including human had more genetic materials. no matter how seemingly some damage on dna, biologic characters do not change. in addition, when mutations occur in the dna, self-repair capacity inside the cell is triggered. however, the virus and its component materials are so small that it takes on a different look with just a slight change. the catastrophe by virus recorded in human history, is the the reason why influenza virus intermittently attacks human is to keep constantly transforming their dnas or rnas. human immunologic surveillance system operates not well efficiently against the continuously transformed influenza virus. since the name is long and hard to pronounce, the disease may feel scared even more for the public. "the terror of the unknown is seldom better displayed than by the response of a population to the appearance of an epidemic, particularly when the epidemic strikes without apparent cause. " infectious disease physician, dr. edward h. kass in boston city hospital, harvard medical school, made this statement in 1977 in reference to the newly discovered legionnaire's disease. it could be applied equally to severe acute respiratory syndrome (sars) (11), pandemic h1n1 influenza, mad cow disease, or any other new and mysterious disease (12) . however, advanced medical technology including genetic engineering, molecular biology, found out the causative virus. in blood of the patient in our country who died in 2012, sfts virus was identified (1). some people simply grumble that diagnosis only is of no use and there should be a treatment. that is true but we need to keep in mind, "more haste, less speed. " the korean centers for disease control and prevention released health tips already to the public which is helpful for the people not to be infected (1, 2) . this is important because there is not yet a cure remedy. therefore, to prevent the spread of the infectious disease avoiding the direct contact with ticks is critical during outdoor activities, for example, to put on a long-sleeved coat and long pants, to use tick and mite repellant, to launder the clothes immediately after coming home from outdoor activities (7) (8) (9) . in terms of virulence of a virus, 1999 outbreak of ebola virus in congo killed more than 200 at one instance. the ebola virus was the most virulent one, but ironically, it has failed to flourish http://dx.doi.org/10.3346/jkms.2013.28.6.795 because it was too virulent. the ebola virus killed itself within 10 days because it had killed the host very soon. that was a very fortunate case for human. on the contrary, other human viruses can coexist without serious fighting. herpes virus would be a representative, which is probably able to survive the last. experts say the risk of emergence of new viruses, like sars virus, which humans have never experienced, is increasing. the clearing of forests for urbanization revealed the virus originally hidden in the jungle to be exposed to humans. aids that did not cause harm to african green monkeys is a fatal immune deficiency disease brought to the human is an example. another thing that we need to be aware of is 'the era of globalization of the virus' due to the crowded population, development of massive transportation including airplanes, and global environmental change. sars in 2003 was first reported in north america just after one and a half month from the hong kong outbreak. when a few thousand people were sick in the 2009 pandemic influenza outbreak, mass media alarmed it and reported a few patients' mortality sensationally, and then people had a great fuss about it. more accurate knowledge and correct deal will not terrorize us anymore. the vaccine development to combat the sfts virus is not easy due to its characteristics. the virus has very few points to attack because it has only essential dna and proteins required for just living. also any treatment by killing the virus is able to give human damage. people say commonly 'to develop an antivirus vaccine becomes useless because there are numerous variants of the virus made. ' it says half-right, half-wrong. while it is true that virus mutation happened ceaselessly ever, but a few virus vaccines have been properly produced. therefore we should do our best to develop the vaccine. however, the human is not at the end of his rope against the virus. hiv was discovered as the causative agent in 3 yr after aids described. doctors and scientists investigated how to transmit and spread, and diagnose hiv virus. while there is no silver bullet against aids, the life of patients can be extended longer than 5 yr after disease developed. we were able to eradicate human smallpox virus on earth, and poliovirus is also close to it. the human is at war with virus, but in fact viruses do not chan ge to wipe out the human. they were born into existence to transform well and a number of strains of some species harmonized with the environment to survive and cause disease. the human attacks virus to wake up from their position rather quietly buried in the jungle, and lays blame for the disease on virus. learning from history, we may encounter a new disease but are not afraid, and embarrass but cope with life in the world. human develop new antimicrobials, new vaccines, and new therapeutic modalities, but we should aware pathogenic microbes provide new strategy to invade human and give us their own challenging tactics. korean center for disease control. severe fever with thrombocytopenia syndrome confirmed cases and follow-up measure korean center for disease control. document for physicians about severe fever with thrombocytopenia syndrome (sfts) fever with thrombocytopenia associated with a novel bunyavirus in china epidemiologic features of severe fever with thrombocytopenia syndrome in china a family cluster of infections by a newly recognized bunyavirus in eastern china, 2007: further evidence of person-to-person transmission person-to-person transmission of severe fever with thrombocytopenia syndrome bunyavirus through blood contact hemorrhagic fever with renal syndrome clinical features and diagnosis of scrub typhus clinical relevance of pulmonary involvement in leptospirosis clinical use of oseltamivir understanding of severe acute respiratory syndrome harrison's principle of internal medicine key: cord-338057-ycmr9prw authors: lee, jae hoon; lee, chang-seop; lee, heung-bum title: an appropriate lower respiratory tract specimen is essential for diagnosis of middle east respiratory syndrome (mers) date: 2015-07-15 journal: j korean med sci doi: 10.3346/jkms.2015.30.8.1207 sha: doc_id: 338057 cord_uid: ycmr9prw nan the editorial, "better understanding on mers coronavirus (mers-cov) outbreak in korea, " was previously published by lee (1) . he briefly summarized the ongoing status of the middle east respiratory syndrome (mers) outbreak and emphasized close monitoring of medical staffs, patients, and visitors, and timely well-designed briefings to mass media. he pointed out critical aspects to control the mers-cov outbreak in korea. the present opinion proposes a topic on mers by focusing on early diagnosis of patients via appropriate specimen collection. as on july 2, 2015, there have been 183 confirmed cases of mers and 33 fatalities reported in the republic of korea (2). this national outbreak of mers has not been controlled yet but there is a rapid decrease in the number of current infections and fatalities. all patients in korea acquired their disease in hospital settings where they came in direct or indirect contact with mers patients. the ministry of health and welfare and the korea centers for disease control and prevention have carried out strong enforcement measures including quarantine care for up to 14 days (the maximum incubation period of the disease) in cases of symptomatic travelers from the arabian peninsula who arrived in korea within the past 2 weeks and individuals who came in close contact with confirmed cases of mers (2) . suspicious cases are transferred to an assigned hospital if symptoms occur during the observation period. real-time reversetranscription polymerase chain reaction (rt-pcr) assay conducted in 48-hour-intervals using respiratory samples is the standard diagnostic tool for mers. a 63-year-old man developed fever, chills, and myalgia on june 10, 2015. on may 27, he visited the emergency department of a hospital that had previously reported several cases of mers. during this time, he stayed in close contact with a laboratoryconfirmed mers patient. he was quarantined on may 27, 2015 at his home and he developed fever and chills, nausea, anorexia, and myalgia after the quarantine isolation. he was then moved to an institutional isolation care unit where real-time rt-pcr was conducted twice on sputum samples in 48-hour-intervals and resulted in negative findings. he was afebrile but his gastrointestinal discomfort and myalgia continued, and the isola-tion location was changed to his home on june 2, 2015 because he was improving. on june 8, he became febrile with symptoms of cough, dyspnea, and myalgia, which gradually deteriorated. he was tested again and the results returned positive for mers-cov on june 10. radiographic findings revealed far-progressed bilateral peripheral radio-opacities. some reasons that could be considered for the delayed diagnosis of mers include: 1) low initial viral load and shedding, and 2) poor sample collection in patients with "no cough" or dry cough. rapid and correct diagnosis of infection and control measures are critical in preventing the possible spread of mers-cov. however, the early symptoms of mers are non-specific and are the same as those of common pneumonia. in this context, it is very important to conduct thorough and careful patient interviews with a high interest of mers in mind and to obtain optimal samples for diagnosis. in the clinical findings of patients infected with mers-cov, patients with dry cough are more common than patients with productive sputum (3, 4) . therefore, optimal sample collection is frequently limited, particularly in patients with no cough or dry cough. dipeptidyl peptidase 4 (dpp4) has been identified as the receptor for mers-cov (5). dpp4 is expressed in type i and ii alveolar cells, ciliated or non-ciliated bronchial epithelium, and bronchial submucosal glands (5, 6) . this corresponds with viral tropism in ex vivo human lung cultures (5) (6) (7) . in studies with rhesus macaques, intra-tracheally inoculated virus was present in the lungs but neither in the upper respiratory tracts, trachea, nor other organs (8, 9) . all of marmosets infected with a high dose of mers-cov via various routes showed multifocal to coalescing, moderate to marked acute broncho-interstitial pneumonia centered on small calibre and terminal bronchioles which further extended into the adjacent pulmonary parenchyma. in summary, in vitro and in vivo studies concluded that mers-cov had adherence to the lower respiratory tract and high viral loads were mainly detected in distal respiratory tissues. therefore, lower respiratory tract specimens such as bronchoalveolar lavage fluid, deep tracheal aspirates, and induced sputum contain the highest viral loads which are optimal for increasing diagnostic accuracy (10) (11) (12) (13) . in re-evaluating the patient's diagnostic history, his viral load could have been low due to the early phase of disease and/or could have been falsely negative due to inadequate dry coughlinked respiratory samples. in any occasion, his diagnosis was quite delayed. delayed diagnosis of patients is inevitably linked to delayed quarantine care of persons with contact history. to obtain an accurate diagnosis, the circumstances in the early phase of mers-cov infection should be considered and at least two repeated diagnostic tests during the late incubation period should be considered for patients with less severity but persistent symptoms. the nationwide pneumonia census has been conducted to identify hidden mers-cov infections. however, inadequate sputum specimens must have resulted in false negatives. for accurate surveying, appropriate specimens should have been obtained by collecting sputum from the lungs or bronchi and not saliva. in suspicious patients who are unable to produce sputum for examination, aerosol administration of a hypertonic saline solution may be used to increase the flow of secretions and stimulate coughing. however, during the procedure of induced specimen collection, clinicians must consider the high risk of contamination of the surroundings because the procedure would create a large amount of aerosols and increase the risk of transmitting the virus to other individuals. the optimum time for collection of a sputum specimen is in the early morning before eating or drinking. at this time secretions accumulated in the bronchi through the night are more readily available. in conclusion, to control the mers-cov infection completely, delicate history taking related with mers is very important, and appropriate specimen collection is essential as well. moreover, even two real-time rt-pcr tests in negative results during the early stage of the disease process cannot rule out silent mers-cov infections. clinicians should consider the possibility of false negative real-time rt-pcr findings resulting from inappropriate sample collection. finally, a sufficient period and strict quarantine of suspected cases are critical for control of the mers outbreak in korea. better understanding on mers corona virus outbreak in korea middle east respiratory syndome information middle east respiratory syndrome epidemiological, demographic, and clinical characteristics of 47 cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-emc emerging human middle east respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs pathogenesis of middle east respiratory syndrome coronavirus an animal model of mers produced by infection of rhesus macaques with mers coronavirus middle east respiratory syndrome coronavirus (mers-cov) causes transient lower respiratory tract infection in rhesus macaques clinical features and viral diagnosis of two cases of infection with middle east respiratory syndrome coronavirus: a report of nosocomial transmission respiratory tract samples, viral load, and genome fraction yield in patients with middle east respiratory syndrome kinetics and pattern of viral excretion in biological specimens of two mers-cov cases first confirmed cases of middle east respiratory syndrome coronavirus (mers-cov) infection in the united states, updated information on the epidemiology of mers-cov infection, and guidance for the public, clinicians, and public health authorities key: cord-323449-r1gyjxei authors: kim, uh jin; lee, seung yeob; lee, ji yeon; lee, ahrang; kim, seung eun; choi, ok-ja; lee, ji suk; kee, seung-jung; jang, hee-chang title: air and environmental contamination caused by covid-19 patients: a multi-center study date: 2020-09-08 journal: j korean med sci doi: 10.3346/jkms.2020.35.e332 sha: doc_id: 323449 cord_uid: r1gyjxei background: the purpose of this study was to determine the extent of air and surface contamination of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) in four health care facilities with hospitalized coronavirus disease 2019 (covid-19) patients. methods: we investigated air and environmental contamination in the rooms of eight covid-19 patients in four hospitals. some patients were in negative-pressure rooms, and others were not. none had undergone aerosol-generating procedures. on days 0, 3, 5, and 7 of hospitalization, the surfaces in the rooms and anterooms were swabbed, and air samples were collected 2 m from the patient and from the anterooms. results: all 52 air samples were negative for sars-cov-2 rna. widespread surface contamination of sars-cov-2 rna was observed. in total, 89 of 320 (27%) environmental surface samples were positive for sars-cov-2 rna. surface contamination of sars-cov-2 rna was common in rooms without surface disinfection and in rooms sprayed with disinfectant twice a day. however, sars-cov-2 rna was not detected in a room cleaned with disinfectant wipes on a regular basis. conclusion: our data suggest that remote (> 2 m) airborne transmission of sars-cov-2 from hospitalized covid-19 patients is uncommon when aerosol-generating procedures have not been performed. surface contamination was widespread, except in a room routinely cleaned with disinfectant wipes. coronavirus disease 2019 (covid-19) is a respiratory disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2 (sars-cov-2). it was first detected in wuhan, china in december 2019. despite efforts to eliminate the disease, it remains a global health threat and has caused more than six million confirmed infections and 370,000 deaths as of june 1, 2020. 1 the basic reproductive number of sars-cov-2 is estimated to be between 1.95 and 6.49, necessitating aggressive control measures (e.g., active early surveillance and quarantine). 2 it is necessary to understand the modes of transmission of covid-19 to develop effective control measures. epidemiological studies have led the centers for disease control and prevention (cdc) to posit that person-to-person transmission of sars-cov-2 is mediated primarily by respiratory droplets or contact with contaminated surfaces. 3 however, remote (> 2 m) airborne transmission has been suggested with increasing frequency. 4 -9 in high-risk transmission settings, such as healthcare facilities, knowledge of the modes of transmission and adoption of the appropriate respiratory precautions are key factors in infection control. studies of the environmental contamination associated with covid-19 patients are needed to improve our understanding of the modes of transmission of sars-cov-2. however, few case reports are available. 10, 11 the objectives of the present study were 1) to investigate air and environmental contamination caused by covid-19 patients in a variety of hospital settings; 2) to evaluate the effectiveness of environmental cleaning; and 3) to examine the potential for remote airborne transmission in the absence of aerosol-generating procedures. eight covid-19 patients who were not subjected to aerosol-generating procedures were enrolled from march 25 to april 8, 2020, at four facilities: chonnam national university (cnu) hospital (hospital a; gwangju, korea), cnu hwasun hospital (hospital b; hwasun, korea), cnu bitgoeul hospital (hospital c; gwangju, korea), and keimyung university daegu dongsan hospital (hospital d; daegu, korea). room conditions differed by hospital. hospitals a and b had seven and five designated airborne infection isolation rooms (aiirs), respectively, with a minimum of 15 air changes per hour. hospital c has 180 beds and is a designated covid-19 hospital. patients in hospital c were admitted to isolation rooms without negative air pressure. hospital d, which is located in an outbreak region, has 465 beds and is also designated for covid-19 patients. patients are cohorted in common rooms without negative air pressure. the three patients in hospital d shared a room containing five beds. in all hospitals, the surfaces were disinfected before admission and after discharge. in addition, wipes for daily surface disinfection were used in hospital b, and spray disinfectants were used twice a day in hospital d. the wipes used for surface cleaning in hospital b were ed wipes (mh healthcare, gimpo, korea) containing benzalkonium chloride 0.4% and four enzymes (protease, alpha-amylase, lipase, and cellulase). aerosol-generating procedures were defined as open suctioning of airways, sputum induction, cardiopulmonary resuscitation, endotracheal intubation and extubation, noninvasive ventilation, bronchoscopy, manual ventilation, nebulizer administration, and high flow o2 delivery, following the recommendations of the cdc. all patients were admitted to the hospital within 7 days of the onset of respiratory symptoms. air and surface samples were obtained four times per patient: before admission and on hospital days 3, 5, and 7. to exclude the possibility of droplet and droplet nucleus acquisition in shortdistance during air collection, air flow was taken into account, and room air was sampled 2 m from the patient in the direction of air escape. the md8 airport portable air sampler (sartorius stedim biotech; göttingen, germany) with a gelatin membrane filter was used to collect 1,000 l air over 20 minutes at a rate of 50 l/minute. to obtain a positive control sample, a patient 2/7 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e332 deposited saliva droplets directly onto the gelatin membrane filter. this produced a sample that was positive for sars-cov-2 rna. surfaces at 10-18 sites in the patients' rooms were sampled using wet cotton swabs immediately before the next scheduled daily surface cleaning. each swab was used to sample an area of 0.25 m 2 . the entire surface of toilet door handles, patients' laptops, and patients' mobile phones were swabbed. the swabs were then submerged in 2 ml viral transport medium. each sample was then individually wrapped and transported to the laboratory of cnu hospital within 3 hours of sampling by a contracted car racer. real-time reverse-transcription polymerase chain reaction (rrt-pcr) was performed in the laboratory of cnu hospital, a diagnostic facility for covid-19 authorized by the korea cdc. first, 200 μl was taken from each sample, and rna was extracted using an automated nucleic acid extraction system (advansure™ e3 system; lg chem, seoul, korea due to the nature of this study, the institutional review board of chonnam national university hwasun hospital reviewed and approved the research protocol and waived the requirement for informed consent (cnuhh-2020-163). we enrolled two patients from hospital a (one with an upper respiratory infection and one with pneumonia), one patient with pneumonia from hospital b, two patients from hospital c (one with an upper respiratory infection and one with pneumonia), and three patients with pneumonia from hospital d. the patient characteristics are described in table 1 . in the rooms in hospital a (aiir without routine disinfection), sars-cov-2 rna was detected in 52 of 108 (48%) surface samples. the surfaces sampled after patient admission included bed rails, medical carts, the floor, door handles, the bathroom sink, the toilet, and other fomites (e.g., cell phones, intercoms, and tv remote controllers) (fig. 1a) . despite extensive surface sampling, sars-cov-2 rna was not detected in the room in hospital b (aiir with routine surface cleansing using disinfectant wipes the patient's respiratory samples (ct value 22.4-28.9) (fig. 1b) . detailed ct values are shown in table 2 . sars-cov-2 rna was detected in 14 of 84 surface samples (17%) from hospital c (isolation room without routine surface cleaning). surfaces sampled included bathroom door handles, the floor, and other fomites (fig. 1c) . sars-cov-2 rna was detected in 23 of 90 surface samples (26%) from the five-bed common room in hospital d. surfaces sampled included bed rails, the floor, the bathroom sink, the toilet, and other fomites (fig. 1d) . appropriate respiratory precautions for covid-19 are still being established, and airborne precautions have been recommended by some. 8, 9 however, shortages in personal protective equipment, medical staff, and hospitals equipped with aiir are of major concern during a pandemic. implementing airborne precautions for all patients may not be an option in some regions. this study of environmental contamination in four different hospital settings may aid the implementation of control measures for patients with mild covid-19 infection in whom aerosol-generating procedures have not been performed. the possibility of airborne transmission of sars-cov-2 has been demonstrated in vitro. 6 in addition, there have been several reports of air samples testing positive for sars-cov-2 rna. however, those findings are difficult to incorporate into clinical practice because those studies had small sample sizes, lacked information on patient characteristics, and were conducted in wuhan, where covid-19 has a higher reproductive number than in other countries. previous studies have reported air samples negative for sars-cov-2 rna. 10,11 a recent publication from hong kong also suggested that aerosol transmission is not a route of transmission from patients in whom aerosol-generating procedures have not been performed. 12 our data are consistent with that study in that remote airborne transmission (≥ 2 m) was found to be uncommon in patients with mild covid-19. although viral rna does not necessarily indicate an infectious virus, widespread surface contamination of sars-cov-2 rna was observed in the patients' rooms. this is consistent with previous case studies. 4,10,11 frequently touched surfaces tended to have higher percentage of positive sars-cov-2 rna pcr, and extensive environmental contamination was observed for 7 days after admission. this was true even in the rooms of patients with only upper respiratory symptoms (patients 1 and 4). the extent of environmental contamination in our study could be attributable to contamination via direct touching of patients and/or healthcare workers after contact with infected respiratory fluids. however, in this study, sars-cov-2 rna was not detected in a room routinely cleaned by disinfectant wipes. this demonstrates the importance of environmental cleaning in reducing exposure to sars-cov-2. however, sars-cov-2 rna was detected in a room sprayed with disinfectant, suggesting that disinfectant sprays may not be effective in reducing exposure to sars-cov-2. this study has several limitations. first, the number of patients was small, rendering it difficult to establish statistical significance. studies with larger samples and more extensive statistical analyses are needed. our study also excluded patients who had undergone aerosolgenerating procedures, which have the potential to increase airborne transmission. further studies are needed to evaluate the role of aerosols in these cases. in conclusion, our data suggest that remote airborne transmission (> 2 m) from covid-19 patients is uncommon when aerosol-generating procedures have not been performed. widespread surface contamination was observed in all rooms except one that was routinely cleaned with disinfectant wipes. the reproductive number of covid-19 is higher compared to sars coronavirus interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (covid-19) in healthcare settings detection of air and surface contamination by sars-cov-2 in hospital rooms of infected patients aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 aerodynamic analysis of sars-cov-2 in two wuhan hospitals airborne or droplet precautions for health workers treating covid-19? airborne transmission route of covid-19: why 2 meters/6 feet of inter-personal distance could not be enough air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) from a symptomatic patient environment and personal protective equipment tests for sars-cov-2 in the isolation room of an infant with infection air and environmental sampling for sars-cov-2 around hospitalized patients with coronavirus disease 2019 (covid-19) we express our gratitude to the car racer soo woong hwang (h-motorsports, gwangju) who transported the specimens and instruments necessary for specimen collection between daegu and gwangju.the english in this document has been checked by at least two professional editors, both native speakers of english. for a certificate, please see: http://www.textcheck.com/certificate/ixnwjt. key: cord-321748-9a54ekac authors: kim, sang il; lee, ji yong title: walk-through screening center for covid-19: an accessible and efficient screening system in a pandemic situation date: 2020-04-14 journal: j korean med sci doi: 10.3346/jkms.2020.35.e154 sha: doc_id: 321748 cord_uid: 9a54ekac with the ongoing novel coronavirus disease 2019 (covid-19) pandemic, the number of individuals that need to be tested for covid-19 has been rapidly increasing. a walk-through (wt) screening center using negative pressure booths that is inspired by the biosafety cabinet has been designed and implemented in korea for easy screening of covid-19 and for safe and efficient consultation for patients with fever or respiratory symptoms. here, we present the overall concept, advantages, and limitations of the covid-19 wt screening center. the wt center increases patient access to the screening clinics and adequately protects healthcare personnel while reducing the consumption of personal protective equipment. it can also increase the number of people tested by 9–10 fold. however, there is a risk of cross-infection at each stage of screening treatment, including the booths, and adverse reactions with disinfection of the booths. these limitations can be overcome using mobile technology and increasing the number of booths to reduce congestion inside the center, reducing booth volume for sufficient and rapid ventilation, and using an effective, harmless, and certified environmental disinfectant. a wt center can be implemented in other institutions and countries and modified depending on local needs to cope with the covid-19 pandemic. the novel coronavirus disease (covid-19) has been spreading globally since its outbreak was announced in december 2019. it is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2). on march 12, 2020, the world health organization (who) declared a pandemic of covid-19, and as of march 16, 2020, more than 160,000 confirmed cases have been reported in 151 countries. 1 in such a pandemic situation, it is important to protect medical staffs and use resources such as personal protective equipment (ppe) safely and efficiently. for this purpose, a drivethrough (dt) screening center was developed and implemented in korea and introduced in other countries as well. 2 however, there are many medical institutions that find it difficult to install or operate a dt screening center and there are many patients who find it difficult to visit it in their own cars. herein, we introduce a walk-through (wt) screening center for covid-19 and share our experience with healthcare authorities and providers globally. based on the safe assessment and fast evaluation technical booth of the h plus yangji hospital (safety), a wt screening center was designed and implemented at h plus yangji hospital, seoul. this general hospital with 350 beds is located in gwanak-gu, one of the busiest places in seoul. as of 2018, the total population of gwanak-gu was approximately 500,000. from 2015 to the date of writing, this hospital has been the only regional emergency center in gwanak-gu. 3 when this hospital started a screening clinic, there was only one other screening clinic in gwanak-gu. around 50-80 people visited the screening clinic during the operating hours. the hospital space, including the parking space, was not large enough to install a dt screening center or a well-ventilated outdoor screening center. in addition, because of the regional nature of gwanak-gu, there was a large proportion of patients who need to visit the screening clinic on foot. as a standard method, the following procedure should be performed before examining the next patient. first, the healthcare personnel (hcp) should properly doff the ppes and don new ppes. second, the test site should be ventilated so that the sars-cov-2 remains less than 1% in the air. third, the environment of the test site should be disinfected properly. finally, it should be sufficiently ventilated until the disinfectant dries and the residual effect of the disinfectant disappears. it took more than 30 minutes to complete all of these steps. although the only hcp trained to properly use ppe participated in screening process, only 9-10 people could be tested per day. moreover, in this covid-19 outbreak, there were not enough ppe resources. in this situation, it was difficult to follow the standard process accurately. as a result, the infection risk among patients as well as hcp had increased. for these reasons, safety and the safety-based wt center were designed. safety is a negative pressure booth for one person, inspired by the biosafety cabinet used in the bio lab. a schematic drawing of the safety is given in fig. 1 . safety has an area of 0.49 m 2 and a height of 2.05 m; each side of safety is made of a polycarbonate plate on a stainless steel frame. the wt center has 4 safetys. for each safety, the internal negative pressure was maintained using a mobile negative pressure device with a maximum air volume of 1,000 m 3 /hour and a high-efficiency particulate air filter. the estimated ventilation rate was 100 air change/hour. around 3 and 5 minutes were required to remove 99% and 99.9% of the particles from the air, respectively. 4 in the direction of the medical staff, a glove wall was installed with the glove facing towards the inside of the safety. the height of the glove entrance was different for each safety, thereby allowing examination according to the patient's height (fig. 2) . a stethoscope was installed on the glove wall. the interphone was installed inside the safety so that the patient could communicate smoothly with the medical staff outside the booth. sample collection kit, disposable tongue depressor, and medical pen light were provided. the patient's entrance was opposite the glove wall. the total cost to build a booth was approximately 2,400 dollars. the brief flow of the wt center was as follows: entrance -registration -wait -questionnaire -examination and specimen collection -medication and instructions -exit (fig. 3) . from the entrance to the exit, all patients were asked to wear a mask and move under the guidance of the hcp. at the entrance of the waiting zone, there was a tablet personal computer (pc) for registration and chairs were placed inside the waiting zone to allow waiting patients to sit > 2 m apart. when a patient entered his/her mobile phone number on the tablet pc and registers, a waiting number and entry request message was sent by a text or sns to enter the waiting zone without waiting in line. while the patient was waiting for the waiting zone entry sequence, a mobile questionnaire was prepared in advance using a qr code. if the patient was unable to complete the mobile questionnaire, he/she entered the pre-exam zone and filled out an electronic questionnaire using a computer. the pre-exam zone had 2 laptop computers, which were disinfected after each patient's use and alternately used while the disinfectant dried. upon completion of the electronic questionnaire or mobile questionnaire, this form was delivered to the medical staff through the hospital information system (his). the doctor checked the questionnaire and allowed the patient to enter the assigned booth if a medical examination or sample collection was necessary. after the patient entered the booth, the medical staff on the other side conducted an interview through the interphone and conducted examination and sample collection through the glove wall. upon completion of the sample collection, the patient wore a mask, exited the booth, stored it, received medicine and instructions, and returned home. after the patient left the booth, ventilation was performed for an appropriate period of time, environmental disinfection was performed using an appropriate environmental disinfectant, ventilation was again performed after disinfection completed before the next patient entered the room. the ventilation time for each safety was checked using a timer and the booth under disinfection and the booth after disinfection were marked with a sign. the outer gloves were applied to the gloves inside the booth to be replaced for each patient. after the introduction of the wt screening center, the average number of patients that could be tested in 8 hours increased from 10 to > 70. the most important process in the wt center is environmental cleaning. environmental cleaning is performed in the following order: ventilation after the patient has left, disinfection of the surface of the booth including gloves and ventilation after disinfection. an important part of surface disinfection is disinfecting gloves, maintaining sufficient contact time according to the disinfectant manufacturer's instructions and ventilation after disinfection according to the residual toxicity of the disinfectant. the booth door was closed after the patient left and ventilated for 5 minutes. after ventilation is complete, the outer gloves were removed and the inside surface of the booth, including the inner gloves, were disinfected. the outer gloves were replaced for each patient, and the inner gloves were also replaced if abnormalities were found. the ventilation time after disinfection depended on the type of the disinfectant. the centers for disease control and prevention (cdc), 5 world health organization (who), 6 when the wt center of the h plus yangji hospital started operating, the booth surface was sterilized by spraying with a disinfectant containing quaternary ammonium compounds. however, this method of spraying the disinfectant was discontinued because it was not recommended in the guidelines. instead, the surface was wiped with mops. even though the disinfectant was ventilated until it was completely dry after disinfection, it caused eye irritation in the hospital staff who entered the booth for work. therefore, the disinfectant was changed to 1,000 ppm sodium hypochlorite. sodium hypochlorite also caused skin irritation. in addition to the above two components, the components of surface disinfectants recommended by the cdc, who, or kcdc are alcohol (ethyl or isopropyl) and enhanced hydrogen peroxide. of these two components, alcohol is not recommended to disinfect large environmental surfaces. hence, we had to find a disinfectant containing enhanced hydrogen peroxide. the cdc guidelines recommend applying a united states environmental protection agency (epa)registered disinfectant against sars-cov-2 for environmental cleaning and disinfection in healthcare settings, including those patient-care areas where aerosol-generating procedures were performed. 5 oxivir ® tb solution, an enhanced hydrogen peroxide disinfectant, is one of the epa-registered disinfectants. 9 also, the kcdc guidelines recommend the use of oxivir ® tb solution, too. 7,8 this disinfectant was made with 0.5% enhanced action formulation of hydrogen peroxide. this disinfectant can kill enveloped viruses such as sars-cov-1, nonenveloped viruses and bacteria with a contact time of 1 minute. in addition, after disinfecting, the disinfectant decomposes into water and oxygen and is harmless to the environment and the human body. 10 theoretically, it is sufficient to ventilate for 5 minutes after disinfecting the surface to maintain a contact time of 1 minute or longer with this disinfectant. however, there were 4 booths in the wt center, and it took about 30 minutes for the next patient to enter the same booth after disinfecting one booth. for evaluating environmental cleaning after daily screening clinic work, environmental samples were collected and tested using the polymerase chain reaction (pcr) method in the area where the patient's face was located in the booth. as of march 31, 2020, two covid-19 confirmed patients were screened at our screening clinic, but the results of the daily environmental pcr tests were all confirmed negative. in the current pandemic situation, a wt screening center using safety has increased accessibility and efficiency. it can effectively reduce the consumption of limited ppe resources and reduce the fatigue and risk of infection associated with frequent ppe replacement. also, as compared to a dt screening center, it is easy to apply in situations where patients visit on foot in a relatively small space. 2 by reducing the volume of one booth, the ventilation rate is increased and the time required for ventilation and surface disinfection is reduced. several booths can be installed in a limited space. even if four booths are installed, it is possible to examine 9-10 times more patients in the same time than that using the conventional method. if more booths are installed and the diagnostic capacity of the laboratory is increased, more patients can be tested in the same time. it also helps lower the congestion of patients in the wt center by increasing the speed of the test. the safe and efficient use of these resources allows continued and appropriate screening care. the most important issue with the wt screening center is the disinfection of booths. the goal is to disinfect the surface with an appropriate disinfectant with sufficient time of ventilation after the patient has left and allow the next patient to safely enter the room after the disinfectant has sufficiently dried and the booth is ventilated. surface disinfection should be done with minimal consumption of ppe. selecting an appropriate and safe disinfectant is the most important issue. reducing patient congregation and the number of staffs in direct contact with the patient during all processes at the wt center is also important. to achieve this, we applied a mobile waiting system with sns or text messages, electronic questionnaires which were connected to the his and unmanned payment machines. patients can fill out and send the electronic questionnaires to his by their own mobile phones from anywhere outside the wt center. covid-19 can cause severe pneumonia. it is important to understand patient's severity of illness. safety allows the doctor to directly see and examine the patient in the booth with a stethoscope. safely assessing oxygen saturation, blood pressure, and chest radiography will further help assess the severity. a screening system using a well-ventilated open space may be considered. in this case, the cost for initial installation and maintenance may be less than that of h plus yangji hospital's wt system. however, because natural ventilation is influenced by wind speed, direction, temperature and humidity, natural ventilation may not be performed properly. in addition, natural ventilation precludes the use of particulate filters. 11 for this reason, installation requires a large space with little human traffic and good wind. also, the number of patients that can be tested in the same space is limited. it is difficult to apply this system when it is difficult to secure an open space for screening, such as h plus yangji hospital. in the case of dt center, it is possible to consider using a single n95 respirator for less than 4 hours because respiratory droplets may be blocked by the window of the car during sample collection. 2 however, when the wt center is installed outdoors and samples are collected by conventional methods, it is necessary to properly replace the ppe for each patient in principle because hcp are more directly exposed to the patient's respiratory droplets. and in this case, ppe consumption may increase. if ppe resources are limited, the risk of hcp exposure to infection may increase. another option is to take the booth glove-wall outwards so that the medical staff can enter the booth and take a patient's sample. in this case, as with the wt center of h plus yangji hospital, proper environmental disinfection needs to be considered after sampling. the cdc guideline recommends that specimens such as nasopharyngeal swabs are closed in the examination room. 5 if an ideal booth with all the functions of the wt center is built and well connected to the public healthcare system, these booths might be installed in public places such as airports and train stations as well as hospitals like public telephone boxes. for example, a telemedicine system might be used to allow a patient to receive a doctor's treatment, including sample collection or chest x-ray examination, in a booth. the electronic payment system is used to make payments, and electronic prescriptions can be issued to receive medicines through an appropriate delivery system. the inside of the booth is automatically cleaned with a suitable disinfectant. if the patient receiving medical treatment at the booth needs to be transported to the hospital, an ambulance and emergency transport team come to the booth to transport the patient. in addition to covid-19, such system might be used to cope with infectious fever and respiratory diseases that may occur in the future. in the covid-19 pandemic era, a wt screening center enables safe and efficient treatment while maintaining accessibility to the healthcare system even in resource-limited situations. we hope to be the cornerstone in developing a wt system with the least patient contact through appropriate infection control and modification using current and future technologies. world health organization drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak guidelines for preventing the transmission of mycobacterium tuberculosis in health-care settings interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (covid-19) in healthcare settings walk-through screening center for covid-19 infection prevention and control during health care when novel coronavirus (ncov) infection is suspected. interim guidance list n: disinfectants for use against sars-cov-2 natural ventilation for infection control in health-care settings. geneva: world health organization key: cord-297965-3bdv6ady authors: lee, sun young; song, kyoung jun; lim, chun soo; kim, byeong gwan; chai, young jun; lee, jung-kyu; kim, su hwan; lim, hyouk jae title: operation and management of seoul metropolitan city community treatment center for mild condition covid-19 patients date: 2020-10-12 journal: j korean med sci doi: 10.3346/jkms.2020.35.e367 sha: doc_id: 297965 cord_uid: 3bdv6ady background: in response to the disaster of coronavirus disease 2019 (covid-19) pandemic, seoul metropolitan government (smg) established a patient facility for mild condition patients other than hospital. this study was conducted to investigate the operation and necessary resources of a community treatment center (ctc) operated in seoul, a metropolitan city with a population of 10 million. methods: to respond covid-19 epidemic, the smg designated 5 municipal hospitals as dedicated covid-19 hospitals and implemented one ctc cooperated with the boramae municipal hospital for covid-19 patients in seoul. as a retrospective cross-sectional observational study, retrospective medical records review was conducted for patients admitted to the seoul ctc. the admission and discharge route of ctc patients were investigated. the patient characteristics were compared according to route of discharge whether the patient was discharged to home or transferred to hospital. to report the operation of ctc, the daily mean number of tests (reverse transcription polymerase chain reaction and chest x-ray) and consultations by medical staffs were calculated per week. the list of frequent used medications and who used medication most frequently were investigated. results: until may 27 when the seoul ctc was closed, 26.5% (n = 213) of total 803 covid-19 patients in seoul were admitted to the ctc. it was 35.7% (n = 213) of 597 newly diagnosed patients in seoul during the 11 weeks of operation. the median length of stay was 21 days (interquartile range, 12–29 days). a total of 191 patients (89.7%) were discharged to home after virologic remission and 22 (10.3%) were transferred to hospital for further treatment. fifty percent of transferred patients were within a week since ctc admission. daily 2.5–3.6 consultations by doctors or nurses and 0.4–0.9 tests were provided to one patient. the most frequently prescribed medication was symptomatic medication for covid-19 (cough/sputum and rhinorrhea). the next ranking was psychiatric medication for sleep problem and depression/anxiety, which was prescribed more than digestive drug. conclusion: in the time of an infectious disease disaster, a metropolitan city can operate a temporary patient facility such as ctc to make a surge capacity and appropriately allocate scarce medical resource. a disaster is a major public health problem. 1 a medical disaster is a situation where needs of health care overwhelm the ability of a community to meet the demand for that. 2 in addition to disaster such as typhoons and floods that traditionally caused a lot of casualties, emerging infectious disease is becoming an major global disaster with increasing population mobility around the world. 3 severe acute respiratory syndrome (sars) in 2002 and influenza a (h1n1) in 2009 caused many patients worldwide, and in 2015, middle east respiratory syndrome (mers) spread in middle east asia and korea. 4, 5 with the pandemic of coronavirus disease 2019 in 2020, infectious disease patients have exploded worldwide. 6 the rapid increase of the patients led to a shortage of medical resources such as negative-pressure isolation unit and ventilators. 7 not only covid-19 patients, but also patients with other disease did not receive adequate treatment due to lack of medical resources and deaths increased. 8, 9 although in all kinds of disasters the rapid increase of patients can lead to a shortage of medical resources, this problem is more serious in an infectious disease disaster. 8, 10 because it not only prevents patients receiving adequate treatment, but also spreads infection and increase the patients due to the failure of isolation of infected patients. 11 to properly respond to pandemic, surge capacity must be prepared in advance. 12 previous studies on disaster response have been mainly conducted on first aid and emergency response for suddenly occurring emergency patients. 13, 14 in the case of infectious disease disaster, most of the studies were about changes in healthcare use or relocation of resources in hospital. 15, 16 as with covid-19 in 2020, it is uncommon that large number of patients exceeding the capacity of hospitals require continuous medical treatment. despite the importance of building surge capacity for the treatment and isolation of infectious patients, there is insufficient research on how to prepare and operate surge capacity in a community. to respond the shortage of medical resource due to covid-19 outbreak, the korean government introduced a temporary patient facility called community treatment centers (ctcs). ctc is an intermediate model between home and hospital that isolate and monitor patients in a facility previously used as accommodation. 17 several studies were published on the model of ctc and the characteristics of mild condition patients admitted to ctc. 17-19 however, as a disaster response facility in the community, it was unknown that what proportions of patients were admitted to the ctc in the community and how many tests were performed and how many medications were prescribed for mild patients. the seoul metropolitan government (smg) operated seoul tae neung ctc (seoul ctc) in cooperation with the one municipal hospital for mild condition covid-19 patients in seoul. the purpose of this study was to investigate patient care and facility operation at a temporary patient facility for infectious disease pandemic in a metropolitan city. this is a cross-sectional observational study using a retrospective medical records review data. in korea, the outbreak spread at a religious facility in february. as the patient suddenly surged in daegu city and its surrounding north gyeongsang province, there was a shortage of hospital. nearly 2,300 people were left waiting for admission and at least two patients died before admission. 20 with the growing need for expanding patient facilities, in march 2020, the korean government decided to run ctc. by converting existing accommodation facility, the patient was quarantined in a room equipped with a toilet and medical staff were dispatched from the hospital. 17 chest x-ray (cxr) and reverse transcription polymerase chain reaction (rt-pcr) test were performed with portable x-ray equipment to determine patient deterioration and virologic remission. to minimize the risk of infection transmission, telemedicine was used to provide patient consultation using smartphone video-call. 17 admission targets of ctc are mild condition patients with minimal or no symptoms according to the criteria of the korea centers for disease control and prevention (kcdc). when the patients were diagnosed, critically ill patients were admitted to the hospital and mild condition patients were admitted to the ctc through triage. patients in ctc were transferred to the hospital when symptoms worsened, and patients in hospital were transferred to ctc when symptoms improved to reserve hospital resources. according to the guideline of the korea cdc, if the rt-pcr test was negative twice every 24 hours, the patients were released from quarantine and discharged to home. 17 seoul is the capital city of korea, with a population of 10 million at 605 km 2 . there are 279 hospital including 7 public hospitals. during the covid-19 epidemic, as a metropolitan city with a high population density, not only patient influx from abroad but also small infection spread continued in the community. 21, 22 to respond covid-19 outbreak, smg operated 82 testing centers and designated 5 public hospitals as dedicated covid-19 hospitals. in march 16, after large call center outbreak, smg implemented its own ctc for mild condition patients in seoul. 22 the residence facility for sports players outside the city (taeneung national athelete village) was converted to ctc (seoul ctc). the seoul ctc has a total of 208 rooms and was able to hospitalize 208 patients. smg was in charge of overall operation of the ctc and the seoul metropolitan government boramae medical center, a municipal hospital, was in charge of the medical operation and dispatched medical staffs to ctc. every day, 5 doctors worked during the day and one worked at night. all of the doctors were specialists. since the specialty of the doctors was not specifically restricted, all specialists in all departments of boramae medical center were dispatched with a set duty. nurses worked in 3 shifts, with 4 nurses in the daytime and 2 nurses in the evening and at night-time. routinely, 3 times of consultation (1 by doctor and 2 by nurse) was provided a day using a smartphone video-call function. if vital signs or symptom worsening were observed during the consultation, the doctor in charge of the patient at that time comprehensively judged the findings and decided to transfer to the hospital. when medical staff determined that a psychiatric consultation was necessary during the routine consultation, psychiatric consultation was provided by psychiatric specialist in the hospital by video-call. the ctc did not provide an anti-viral agent for covid-19 but provided 21 symptomatic medications (supplementary table 1 ). antipyretic drugs were provided to all patients at the time of admission, and other drugs were provided in necessary daily base. cxr was performed at the time of admission and repeated as needed. rt-pcr test was conducted regularly (24 hours after negative result and 3 days after positive result). the seoul ctc was closed on may 27 according to the decrease of covid-19 patients in seoul. according to the criteria by kcdc, mild and asymptomatic patients were admitted to ctc. the criteria for asymptomatic are as follows; alert, < 50 years old no underlying disease, nonsmoker, and < 37.5°c without antipyretic drugs. the criteria for mild are alert and meeting one or more of the follows; < 50 years old, one or more underlying diseases, and < 38°c with antipyretic drugs. 17 the following patients were classified as high-risk groups and were not admitted to ctc; > 65 years old, oxygen saturation < 90% in room air, severe underlying disease such as cancer, pregnancy, on dialysis, very obese, and transplanted patients. all 213 patients who were admitted to seoul ctc during the operation period of seoul ctc (from march 16 to may 27) were included in the study. the following information was collected through a retrospective medical records review.; 1) patient demographics (age and sex), 2) ctc information (admission date, discharge date [if transferred, transfer date], duration from diagnosis to admission, route of admission [hospital, home, and other ctc], and route of discharge [hospital and home]), 3) covid-19 related information (symptom at admission [cough, fever, sputum, rhinorrhea, sore throat, chest pain, dyspnea, and other symptom], result of rt-pcr test [negative and positive], and result of initial cxr). the result of cxr was classified into 3 categories.; normal, pneumonia suspicion, and nonspecific lesion. nonspecific lesion included things like old tuberculosis sequelae. patient demographics of death and ctc admission among all patients in seoul until the end of ctc was given in percentage. the patient characteristics according to the route of discharge were compared. the length of stay and period from diagnosis to admission were shown by median and interquartile range (iqr). consultations provided by doctor, nurse, and psychiatric specialist were combined to calculate the average daily number of consultations each week. number of cxr and rt-pcr test were combined to calculate the average daily number of tests each week. the medication used were presented in the order of frequency of prescription. the negative rate of all rt-pcr test and characteristics of patients who were prescribed medication more than 30 times were investigated. the study was approved by the institutional review boards (irb) of seoul metropolitan government-seoul national university boramae medical center (irb no. 30-2020-093 ) and the requirement for informed consent was waived. total 35.2% (n = 75) of patients were admitted from home directly after diagnosis and 64.3% (n = 137) who recovered after hospital treatment were transferred from the hospital. patients of 89.7% (n = 191) were discharged to home and 8.5% (n = 18) were transferred to hospital due to worsening conditions. four patients (1.9%) did not recover until the end of ctc operation and were transferred to hospital (fig. 1) . the maximum of 14 patients were admitted to ctc a day, and a total of 127 patients stayed when ctc had the largest number of patients (fig. 2) the median length of stay in ctc was 21 days (iqr, 12-29 days). half (50.0%) of 22 patients transferred to the hospital were within a week of admission. the patients who discharged to home after recovering were most likely to stay at ctc for 3-4 weeks (24.6%), and 6.8% (n = 13) were stayed for more than 6 weeks. among the patients transferred to the hospital, 45.5% (n = 10) had normal cxr in first, and 13.6% (n = 3) showed pneumonia suspicion. among the patients discharged to the home, 82.2% (n = 157) had normal cxr in first, and 8.4% (n = 16) showed pneumonia suspicion in first ( table 2) . a weekly average of at least 13.7 patients and a maximum of 121.9 patients stayed at ctc. depending on the number of patients, 2.5 to 3.6 consultation per patient were provided daily. the psychiatric consultation was conducted 0.9 to 2.9 times a day. the number of tests also differed from week to week depending on the number of patients, and average of 0.7 to 9.3 cxr and 1.9 to 46.6 rt-pcr test per day were performed. for one patient, 0.4 to 0.8 tests were performed daily ( table 3) . except antipyretic medication (acetaminophen) which was given to all patients routinely, the most frequently prescribed medications were symptomatic drug for cough/sputum and rhinorrhea, the typical symptoms of covid-19. psychiatric medication for sleep problem and anxiety/depressive symptoms was prescribed more frequently than digestive drug ( table 4 ). the patients who received the most medications were received drug 128 times for 27 days, average of 4.7 drugs per day. the most frequently received medication was digestive drug. the second and third patients were received 3.2 and 2.0 drugs per day, respectively. the most frequently received medications were psychiatric medication for both (supplementary a quarter of total covid-19 patients in seoul were admitted to the ctc. total 13.6% of ctc patients were admitted to the ctc directly. the median length of stay was 21 days and 7% were stayed for more than 6 weeks. during the operation period, 10% were transferred to the hospital and 90% were recovered and discharged to home. one patient had average of 3 consultation and 0.5 tests (cxr or rt-pcr) per day. the most frequently used medications were symptomatic drug for common symptoms of covid-19 (cough/sputum and rhinorrhea). psychiatric medication for sleep problem and anxiety/depression were used more than digestive drug. excess of available resources for resources in need is a key factor in defining disaster. 2 in many types of disasters with mass casualties, medical supply shortage can occurred. 8, 23 since lack of medical resources during the pandemic can leads to an increase in fatality, preparing surge capacity in advance is crucial to cope with disaster. 9,24 previous studies on disaster response focused on emergency room or redistributing of hospital resources for suddenly increasing emergent patients. 25, 26 in case of infectious disease, however, treatment of patients does not end with first aid and need continued care till virologic remission. 27 in addition, the patients with infectious disease needs to be treated and isolated at the same time. 28 however, few studies were conducted on the preparation and operation of surge capacity in actual pandemic situation. 27 during the global covid-19 pandemic, different countries responded in different ways. china urgently built new hospitals and other countries quarantined patients in their home without hospitalization. 27, 29 the korea government chosen to create a new concept of patient facility for mild condition patient rather than hospitals to allocate medical resource appropriately according to severity. the existing accommodations were used to isolate patients and medical staff monitored patients via telemedicine. 17 korea expanded medical resources in this way and distributed valuable hospital resources to critically ill patients. through this securing surge capacity and proper triage, korea showed low fatality rate of 2% until august 2020 despite the early surge of 31 seoul ctc is a community model of surge capacity for mild cases in covid-19 pandemic. previous studies reported that mild condition patients can be safely managed at the ctc. 18, 19 however, it is unknown how the ctc actually operated in test, medication prescription, and consultation and what role it played in the community during the pandemic. to prepare and respond second wave of covid-19 epidemic and future emerging infectious disease disaster, analysis of operation of actual ctc and information of patient triage in the community is needed. seoul metropolitan city prepared surge capacity on two levels, operating 5 hospitals as covid-19 dedicated hospital and one ctc for 10 million citizens. one-quarter of patients of seoul metropolitan city managed at the ctc. in patients aged 20-40s, 40% were hospitalized at ctc. by operating ctc for mild cases, seoul was able to prioritize scarce hospital resources to severe cases. through this triage and resource allocation according to severity, seoul has a low fatality rate in korea where the overall covid-19 fatality rate is low. 31,32 since ctc is a facility for mild cases, the seoul ctc was operated with minimal manpower, medical equipment and medications. when video-consultation was provided to quarantined patients 3 times a day, few additional consultations were needed except for psychiatric consultation. the seoul ctc did not perform blood tests and provided only the minimum tests (rt-pcr and cxr) to manage patients with respiratory viral infections. although rt-pcr test was performed up to 23 times in one patient, usually patients got the rt-pcr or cxr once every 2 days on average (supplementary table 3 ). of the 21 medications stored in seoul ctc, the most frequently prescribed drugs were for the symptoms of covid-19 itself. the next most frequently used medication was a psychiatric drug, not a general drug like a digestive drug. although only one patient had a psychiatric medical history (adjustment disorder), but isolated patients frequently complained of sleep problem and anxiety/depression. isolated patients may need psychiatric support in addition to treatment for infectious disease. 33 most patients (90%) were safely managed and discharged from the ctc, which was operated with minimal equipment and medications. one tenth (10%) of patients classified as mild condition at first and admitted to the ctc were exacerbated and transferred to hospital. this is higher than other studies reported that 2%-3% of patients were transferred to the 9/13 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e367 hospital. [17] [18] [19] one patient complained of a suicidal idea was transferred to a hospital with a psychiatric specialist. the rest of patients were exacerbated by covid-19 symptoms such as fever and chest pain and transferred to a covid-19 designated hospital. as reported in other studies, no patient died until the end of ctc operation. patients transferred to the hospital were older, had more suspicion of pneumonia on initial x-rays, and had more daily average medication use than those who were discharged to home. adequate patient triage and resource allocation are critical factor to respond disaster. 1,34 in a metropolitan city with a population of 10 million, through operating the two-stage surge capacity consisting of dedicated covid-19 hospitals and ctcs, allocating scarce hospital resources to critically ill patients was possible. because the ctc is a remodeling facility of existing accommodation, it has the advantage of being able to adjust the open and close according to the covid-19 spread trend. most of ctcs, which had operated more than 20 during the covid-19 surge, closed due to the decrease in patients. however, there are also disadvantages to be considered in the ctc operation. the first is the possibility of an emergency. in hospital, medical staff frequently visit patient room and closed circuit televisions (cctvs) are installed in isolation units. however, since ctc is also a living space for patients, we were not installed cctv in the room. while this did not happen during the operation period, it can be difficult to detect and respond to an emergency. the second is that since it is not a facility with negative pressure applied, it cannot completely prevent the spread of infection. there have been no reports of transmission of infection in the ctc. the third is a security issue related to the telemedicine. as telemedicine was first used for infectious disease disaster, a commercial video-call program was used instead of using a secured program. in the future, it is necessary to develop and use a security program to protect patient privacy. some experts warn of the second wave of covid-19 in winter season and there is always a risk of emerging infectious disease with rapidly increasing patients. 35 despite several limitation, ctc has a role as a facility that enables appropriate medical resource allocation by rapidly increasing patient capacity in disaster. by monitoring mild condition patients in ctc, it is possible to reduce mortality by focusing valuable medical resources on critically ill patients. to respond pandemic disaster with large number of patients, multi-level surge planning and flexible patient facility plan such as ctc should be prepared in advance. this study has several limitations. first, this study was conducted at one ctc in one region. depending on the rate of disease transmission and patient severity, the operation of ctc may be varied. further, the seoul ctc is a facility for respiratory viral infection with many mild condition patients. 36 the need of consultation, tests and medications may vary according to the type of disaster. seconds, this study investigated only process and patients of ctc. to comprehensively understanding the need of surge capacity of the community, it is necessary to analyze the hospital and ctc together. since many studies conducted on hospital treatment of covid-19, this study focused on the newly implemented patient facility called ctc. in conclusion, in the covid-19 pandemic, a metropolitan city can operate a temporary patient facility such as ctc with minimal staff, equipment, and medications. preparing a two-stage surge capacity consisting of hospital and ctc can assist proper triage and allocating medical resources to the patients who need it most. the historical development of public health responses to disaster disaster medical services reasons for the increase in emerging and re-emerging viral infectious diseases clinical aspects of pandemic 2009 influenza a (h1n1) virus infection a major outbreak of severe acute respiratory syndrome in hong kong at the epicenter of the covid-19 pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation. nejm catal innov care deliv the toughest triage -allocating ventilators in a pandemic critical supply shortages-the need for ventilators and personal protective equipment during the covid-19 pandemic preliminary estimate of excess mortality during the covid-19 outbreak fair allocation of scarce medical resources in the time of covid-19 feasibility of controlling covid-19 outbreaks by isolation of cases and contacts developments in surge research priorities: a systematic review of the literature following the academic emergency medicine consensus conference a rapid medical screening process improves emergency department patient flow during surge associated with novel h1n1 influenza virus the boston marathon bombings mass casualty incident: one emergency department's information systems challenges and opportunities an analysis of changes in emergency department visits after a state declaration during the time of covid-19 hospital preparedness for mass critical care during sars-cov-2 pandemic operating protocols of a community treatment center for isolation of patients with coronavirus disease clinical course of asymptomatic and mildly symptomatic patients with coronavirus disease admitted to community treatment centers community treatment centers for isolation of asymptomatic and mildly symptomatic patients with coronavirus disease covid-19: how doctors and healthcare systems are tackling coronavirus worldwide coronavirus disease exposure and spread from nightclubs coronavirus disease outbreak in call center too many patients… a framework to guide statewide allocation of scarce mechanical ventilation during disasters potential association between covid-19 mortality and health-care resource availability surge capacity principles: care of the critically ill and injured during pandemics and disasters: chest consensus statement inpatient disposition classification for the creation of hospital surge capacity: a multiphase study can we contain the covid-19 outbreak with the same measures as for sars? the effectiveness of quarantine and isolation determine the trend of the covid-19 epidemics in the final phase of the current outbreak in china emerging success against covid-19 pandemic: hospital surge capacity in taiwan korea disease control and prevention agency. coronavirus disease-19 main website clinical course and outcomes of 3,060 patients with coronavirus disease 2019 in korea seoul covid-19 information website mental health and the covid-19 pandemic allocating scarce resources in disasters: emergency department principles beware of the second wave of covid-19 clinical characteristics of coronavirus disease 2019 in china key: cord-285984-hjyqg8n5 authors: kim, ahreum; choi, minhyeok title: factors influencing the diagnosis and treatment of latent tuberculosis among contacts in congregated settings in korea date: 2019-05-07 journal: j korean med sci doi: 10.3346/jkms.2019.34.e138 sha: doc_id: 285984 cord_uid: hjyqg8n5 background: this study aimed to compare the indicators (the rates of diagnosis, need for treatment, treatment initiation, and treatment completion) of management of latent tuberculosis infection (ltbi) in contacts and to identify the impact of active tuberculosis (tb) index case characteristics on the exposed population in congregated settings, such as schools, workplaces, and medical institutes. methods: the data of 8,648 clusters in the tb epidemiological investigation database between 2013 and 2016 were extracted and analyzed to evaluate the indicators and perform multilevel logistic regression (mlr) analyses to identify the factors affecting each indicator. results: the rates of total ltbi diagnosis, need for treatment, treatment initiation, and treatment completion were 15.2%, 10.2%, 69.4%, and 76.6%, respectively. after adjusting for other factors on mlr, the probability of diagnosis and need for treatment of latent tb in contacts was higher in most types of facilities than in schools. conversely, treatment completion rates in these facilities were lower. notably, the correctional institutions showed the highest odds ratio (or) relative to school for ltbi diagnosis (or, 6.37) and need for treatment (or, 4.49) and the lowest or for treatment completion (or, 0.10). conclusion: this study provided evidence for the implementation of latent tb control policies in congregated settings. tuberculosis (tb) is an infectious disease, most commonly of the respiratory system, caused by mycobacterium tuberculosis. the symptoms on presentation include chronic cough, fever, and production of sputum, among others. according to the global tuberculosis report, 2017, approximately 1.6 million new cases of tb were reported worldwide in 2016, with approximately 1.67 million deaths. 1 asymptomatic individuals who do not transmit the infection despite being infected with m. tuberculosis are considered to have latent tuberculosis infection (ltbi). 1 it is estimated that 1 out of 3 adults are infected with latent tb in korea. 2 about 10% of people infected with latent and include data on epidemic clusters, tb patients, their contacts (i.e., those who had been in contact with a patient for more than 1 day during the period of communicability), and information on patients with ltbi. based on the four most recent years (2013-2016) of epidemiological investigations, data for 8,648 tb clusters (occurring in congregated settings) were available for the present study. the number of clusters and contacts analyzed by process are shown in fig. 1 . in this study, the general characteristic variables included were: gender of the first index case diagnosed with active tb in the cluster and age (0-12, 13-18, 19-29, 30-39, 40-49 , 50-59, 60-69, and 70 years or older). tb-related variables including sputum test results (negative and nontuberculous mycobacterium [ntm] , unknown, culture positive, and smear positive), chest radiography findings (normal, unknown, cavity-negative tb, cavity-positive tb), presence or absence of symptoms, and duration of symptoms (no symptom, 1-3 weeks, 4-5 weeks, 6-7 weeks, and 8 weeks and over). to examine the effect of facility type, congregated settings were categorized as: school, workplace, medical institution, social welfare facility, military and police units, correctional institution, and other facilities. to find the effect of the year when an epidemiological investigation was performed, the year cluster was divided into two groups (2013) (2014) (2015) (2016) . since the database did not include information on the sub-type of schools, categorization according to school type was not possible. for examining the variables related to the diagnosis and treatment of latent tb contacts, latent tb diagnosis, need for treatment, treatment initiation, and treatment completion were treated as outcome variables; rates for each indicator were then calculated. the diagnosis rate of latent tb was defined as the number of persons diagnosed with ltbi (n = 46,535 in 8,648 clusters) among the contacts who completed the test (n = 488,735). the rate of the need for treatment, was the percentage of people diagnosed with latent tb and deemed necessary to treat (individuals aged 35 years or younger, susceptible to isoniazid and rifampin, not immunosuppressed, no history of tb infection or treatment, and non-diabetic) (n = 32,938). 2 the rate of treatment initiation was defined as the percentage of people who needed and were started on treatment (n = 25,002); the rate of completion of treatment was defined as the percentage of people who completed the treatment schedule (n = 19,562). the general characteristics of the first index case in the tb outbreak groups were described using univariate analysis according to the types of facilities. mean values and 95% confidence intervals (cis) were also evaluated to determine the rates of diagnosis, need for treatment, treatment initiation, and treatment completion of ltbi in each tb outbreak group. in addition, t-tests and variance analysis were performed to identify differences between clusters depending on the characteristics of the first index case. to identify factors affecting the diagnosis and treatment of latent tb, multilevel logistic regression analysis was performed. multilevel analysis is known as an analytic method that considers upper level contextual effects, such as the 'area belonged to at the local level' or 'time for example, year cluster'. 29 in the multilevel logistic regression model used for this study, dependent variables included diagnosis and need for treatment of latent tb, as well as the initiation and completion of latent tb treatment in tb outbreak groups. independent variables corresponding to level 1 (individual level) were biological characteristics (gender and age), tb characteristics (sputum test results, chest radiography results, and presence or absence of symptoms and its duration) of the index case, as well as the facility type. independent variables for level 2 (year level) were year clusters (2013-2014 and 2015-2016). in addition, the median odds ratio (mor) was calculated to examine variations by year. mor is calculated as follows: here, ö refers to the cumulative distribution function in the normal distribution with a mean of 0 and a variance of 1, where ö −1 (0.75) is the 75th percentile. 30,31 mor refers to an indicator that quantifies the variation between levels, by comparison between two individuals between different levels (year cluster in the present study); this is the median value of the odds ratios (ors) in one group with a higher tendency and another with a lower tendency. mor is a the present study was performed after approval from the institutional review board (irb) of the pusan national university hospital (irb no. 1708-030-058). informed consent was waived by the irb. data pertaining to the characteristics for each epidemiological cluster is presented in table 1 . among the 8,648 tb clusters investigated from 2013 to 2016, schools (2,925 clusters, 33.8%), accounted for the highest proportion of outbreaks according to facility type, followed by medical institutions (2,100 clusters, 18.8%), and social welfare facilities (1,624 clusters, 13.2%). in terms of the gender and age of the first index case, the total cluster had a higher proportion of men (4,870 clusters, 56.3%) than women; and the age group of 19-34 years accounted for the highest proportion (2,483 clusters, 28.7%). regarding the sputum test of the index case, the highest rate of smear positivity was found to be 59.2% (5,188 clusters), while culture positivity was 31.7% (2,740 clusters). on chest radiography, the proportion of cases with cavity-negative tb was the highest at 61.5% (5,320 clusters), followed by cavitypositive cases, at 26.7% (2,306 clusters). the highest duration of symptoms for the index case was 1-3 weeks (3,371 clusters, 39.0%), followed by those with no symptoms (2,551 clusters, 29.5%), and those with symptoms for 4-5 weeks (1,275 clusters, 14.7%). for epidemiological investigation by year, the rate for the year 2015-2016 was 69.0% (2,678 clusters), which was 2.23-fold higher than that of the year 2013-2014. the treatment completion rate of contacts who started treatment was 76.6% (95% ci, 75.5%-77.7%). among facility type, schools showed the highest treatment completion rate at 81.1%, compared with the workplace, at 69.6%. the treatment completion rate of contacts progressively decreased in the recent years. as shown in table 3 , multilevel logistic regression analysis was performed using the diagnosis of latent tb in contacts, need for treatment, treatment initiation, and treatment completion as dependent variables, and the characteristics of the index case and cluster as independent variables; years were considered as a random effect. all indicators showed significant differences depending on year (mor, 1. that the index case belonged to, such as the workplace, showed a significantly higher rate of latent tb diagnosis in contacts (p < 0.001). correctional institutions had a high risk for latent tb diagnosis (or, 6.37; 95% ci, 5.92-6.86). by year cluster, ltbi became significantly lower with the progression of years (or, 0.75; 95% ci, 0.61-0.91). among contacts, men index cases had a 1.16-fold higher ltbi diagnosis rate than women index cases. compared to the 70 years or older age group, all other age groups showed a significantly higher ltbi diagnosis rate in contacts; however, there was no apparent pattern (p < 0.001). when the need for treatment of latent tb was used as a response variable, most variables showed significance similar to that of latent tb diagnosis. when compared by type of facility that index cases belonged to, other facilities showed significantly high ors for rates of need for treatment of latent tb compared to schools (p < 0.001). in particular, the risk for the need for treatment was the highest in correctional facilities (or, 4.49; 95% ci, 4.13-4.89; p < 0.001). when or was examined by year, the rate of need for treatment of contacts with latent tb was significantly lower in the most recent year (or, 0.82; 95% ci, 0.67-0.99; p < 0.05). men index cases had a 1.11-fold higher rate of need for treatment of contacts with latent tb compared to women cases; this was significantly higher in all ages of index cases (p < 0.001). when treatment initiation of latent tb was used as a response variable, most variables were statistically significant. other facilities except the workplace had significantly higher ors of treatment initiation rate in contacts (p < 0.01), while the or of the workplace was significantly lower, at 0.72 (95% ci, 0.654-0.793). by year cluster, the treatment initiation rate in latent tb became significantly lower in the most recent year (or, 0.65; 95% ci, 0.49-0.87; p < 0.01). compared to women cases, men index cases had a 1.19-fold higher rate of treatment initiation among contacts with latent tb. by age group, the 13-18 years and 40-49 years groups showed significantly higher rates than the group aged 70 years and above (p < 0.001); the rates in the other age clusters were not significant. multilevel logistic regression analysis using treatment completion in latent tb as the response variable, found that all variables except the gender of the index case and sputum test results were significant. when examined by facility type of index cases, all facilities except other facilities demonstrated significantly lower treatment completion rates among contacts (p < 0.01). unlike other indicators, when or was examined by year, it showed no significant results. the present study is the first to calculate the indicators related to latent tb and to investigate the influencing factors among congregated settings in korea. depending on the type of facility, each indicator was found to have significant differences along the process, from diagnosis of latent tb to treatment completion; differences were also noted depending on year cluster. according to the results of this study, the most extensive epidemiological investigation was conducted at schools, compared to other facilities. this may be explained by the fact that a longer time is spent in communal living in schools, with longer contact times. in addition, schools have a better reporting system and accessibility to medical systems than other facilities. epidemiological investigations for tb among congregated facilities in korea were started in schools from 2013. remarkably, the number of epidemiological investigations rapidly increased with age, beginning from when the first index case was aged > 13 years; this was probably due to the fact that this is a rapid period of growth in youths, and they spend longer times in high school. 6 as reported by fox et al. 26 in 2013, contact investigation is known to be important for children, because unlike older age clusters, in congregated settings with many children, the risk of developing active tb is higher, and the response to the latent tb test is often unreliable; more controls are therefore required. compared to schools, other facilities had significantly higher rates of diagnosis of ltbi and need for treatment and the rate was still high even after adjusting for other factors. in this study, correctional institutions showed the highest diagnosis rate and or. in comparison to international studies, the ltbi rate of contacts in correctional institutions was higher in korea than that reported in the united states (17%) 17 ; however, it was lower than that of spain (45.5%) 18 and brazil (49%-73%). 20 it may be speculated that the ltbi risk in correctional institutions was higher than of other facilities owing to the overpopulated setting and small rooms, in addition to medical accessibility issues. correctional institutions in korea accommodate 1,098.8 inmates on average in each institution, corresponding to the highest level in the organisation for economic co-operation and development (oecd) member countries. furthermore, the accommodation rate is 121.8%, corresponding to the second largest in the oecd member countries. 33 in this study, medical institutions had higher rates of latent tb diagnosis, need for treatment, and treatment initiation than schools. however, the treatment completion rate was lower. this finding may be explained by the fact that medical institutions perform more tests and monitor treatment more strictly. the hospital-ward characteristics in korea possibly had some impact. in 2017, there were a total of 154,753 wards, of which 99,523 (64.3%) were general wards accommodating at least four inpatients, indicating that a high proportion are dormitory-type wards, and 85.9% of the total 534,157 beds were in non-isolated wards. 35 the setting with the most bed supplies were the non-isolated wards; this was identified as the major cause of nosocomial infections during the middle east respiratory syndrome (mers) outbreak in 2015. 36 although treatment of latent tb was initiated, considering the short hospitalization period of within 1 month, a relatively low treatment completion rate of latent tb indicated a poor post-discharge control. to date, there is no clear regulation for post-discharge control of latent tb patients. a system has been established to share the information about tb-infected soldiers after discharge with the corresponding community health center. in contrast, for patients with ltbi, there is no system that registers these patients after discharge in the corresponding community health center or the tb control information system. thus, there is need to establish a system that provides continuous treatment for patients with ltbi after discharge, and the same is applicable to social welfare facilities, as well as the medical and other institutions that have admission and discharge processes. although the rates of initiation and completion of treatment for latent tb have reduced, patients with ltbi aged ≥ 35 years have been included as treatment targets since 2015. after 2015, in view of the lower ors for treatment initiation and completion, the general workplace has been particularly considered for active tb control interventions in congregated settings. in a similar study in japan, workers with latent tb had a lower treatment completion rate than patients in other occupation groups such as school students, healthcare professionals, and homemakers. 22 workplaces had lower treatment and completion rates of latent tb; this could be attributed to the large numbers of individuals aged ≥ 35 years who were recently included as treatment subjects. it could also be explained by the fact that unlike schools or correctional institutions, the guidelines for the management of infected cases in the workplace congregated settings were unclear leading greater difficulties in the management of infected individuals. overall, these results show that unlike the case of active tb patients a system of management from initiation to completion of treatment has not been fully established for ltbi, despite the expansion in numbers of treatment subjects with latent tb. an additional system, which can monitor and manage the treatment process in patients with ltbi aged 35 years or older is also necessary. despite the significant findings of this study, there are a few limitations. first, the database contained only the information of korean individuals; non-korean individuals were not included in the analysis. the number of new tb patients among foreigners has increased in recent years, while that of koreans has tended to decrease, showing an opposite trend. 37 follow-up studies should be performed among foreigners with tb, whose numbers seemed to be on an increase. secondly, the characteristics (gender and age, among others) of contacts of tb patients were not considered. however, the present study primarily intended to investigate the characteristics of clusters including type of facility and effect of timing after considering the characteristics of the index case; therefore, characteristics of contacts were not a major issue. since the age of the contacts was a characteristic of the cluster they belonged to, the range was relatively similar and its influence was considered minor. future studies should be performed with individual units considering the characteristics of contacts. thirdly, the characteristics of the sub-categories in the congregated settings were not considered in this study. schools maybe classified into kindergarten, elementary school, middle school, high school, and college; other facilities also have sub-types. in previous studies, the highest number of contact cases in korean schools was found in high schools. kindergartens and daycare centers also showed high ltbi rates. 6 as for correctional institutions in the united states, prisons where they serve their terms, had a higher treatment completion rate than detention centers that held inmates temporarily. 17 since the details supplied by the facilities were incomplete, the data in the present study did not completely reflect all sub-types of facilities. however, this study had a different goal and those variables were not considered. further studies are necessary to evaluate individual facilities according to sub-types. lastly, the jobs among the first index cases in congregated settings were not classified. school populations could be sub-categorized as students and teachers, and medical institutions could be sub-divided into patients and healthcare professionals (doctor and nurse). these characteristics are likely to vary. for instance, the index cases in a study had different types of occupations depending on school type 6 ; in another study, healthcare professionals had a higher risk of ltbi due to contact with patients. 13 however, the analysis in the present study was based on various types of facilities. therefore, they were not sub-divided to ensure consistency in the analysis. in future studies, analysis should be performed by facility type as well as by occupation in individual facilities. despite these limitations, this study identified the impact of characteristics of the first index case, type of facility, and timing in each cluster on latent tb; the findings of this study are therefore significant. these results have considerable implications. first, the overall incidence level in the school population needs to be reduced. since this population has more contact with the family than that of other collective facilities, it is also necessary to manage the family contacts. second, a strategy is needed to increase the tb-treatment completion rate among contacts in other facilities. in korea, the management of tb in collective facilities has been focused on finding additional tb patients and identifying ltbi cases through epidemiological investigations in case of epidemics. 37, 38 conversely, efforts to monitor treatment in cases with ltbi were relatively less enthusiastic. 37,38 in korea, patients with active tb are managed by the tb public-private mix model (ppm) recommended by the world health organization. 1, 38 the ppm is regarded as an effective policy for tb control in korea and other countries. 1,37,38 however, till date, people with ltbi have not been included in the target population of the ppm. for improving levels of completion of ltbi treatment, the active management of ltbi is essential. this may be achieved by sharing information about patients to medical institutions participating in the ppm; also, public health centers need to monitor and manage the completion of treatment via telephone and text communication. the directly observed treatment (dot) service needs to be extended to include patients with ltbi. in korea, the dot service has been implemented since 2013 for patients with tb. 38 however, till date, patients with ltbi are not included in the target population for dot. since dot is known to be effective in improving the compliance of tb patients, 1 it should be implemented to increase the treatment completion rate in these patients. third, a cohort of contact and latent tb cases should be established to monitor the status of management and the occurrence of active tb in the long-term. it is known that individuals with ltbi have a 10% of risk of latent tb for the rest of their lives. 38 in contact control programs, epidemiological investigations can take up to 9 months. 2 however, a period of 9 months is insufficient for obtaining information about the occurrence of active tb in contacts. fourth, tests should be performed for latent tb before including individuals in congregated settings and also during the period of stay. fifth, accessibility to medical institutions should be improved to facilitate timely access to medical services in case of suspected tb symptoms. lastly, it is necessary to establish a system that transfers information about latent tb patients to the corresponding community health centers after discharge from the congregated settings; this will serve to raise treatment completion rates in patients with latent tb. the present study investigated the states and influential factors along the process, extending from the diagnosis of latent tb to the completion of treatment in korea. the findings showed that compared to schools, other facilities carried high risks of ltbi. therefore, efforts should be made to enhance the early detection of the first patients with tb. in addition, efforts should be made to establish policies to determine the rates of treatment completion among latent tb cases in correctional institutions, medical institutions, and social welfare facilities, and to improve the treatment initiation rate in workplaces, particularly among those aged 35 years or older. there is a growing understanding of the need to manage ltbi, but the evidence for this is lacking. further research is needed to facilitate the implementation of evidence-based policies for the control of ltbi. geneva: world health organization 2017 national tuberculosis control guideline treatment of latent tuberculosis infection and its clinical efficacy diagnosis and treatment of latent tuberculosis infection guidelines for management of tuberculosis epidemiological investigation contact investigation for tuberculosis among children and adolescents in korea latent infection treatment to prevent tb transmission in school settings prevalence of latent tuberculosis infection among medical students in south korea assessment of latent tuberculosis infection in psychiatric inpatients: a survey after tuberculosis outbreaks infection control and the burden of tuberculosis infection and disease in health care workers in china: a cross-sectional study prevalence of latent tuberculosis infection among health care workers in south korea: a multicenter study a case study of pulmonary tuberculosis outbreak in a facility for the physically or mentally disabled prevalence of and risk factors for latent tuberculosis infection among employees at a workers' compensation hospital the role of tst in the diagnosis of latent tuberculosis infection among military personnel in south korea clinical characteristics of tuberculosis in combat and auxiliary police in korea management of tuberculosis outbreak in a small military unit following the korean national guideline treatment for latent tb in correctional facilities: a challenge for tb elimination multi-centre study of the prevalence of latent tuberculosis infection amongst inmates in spanish prisons tuberculosis control in prisons: current situation and research gaps active and latent tuberculosis in brazilian correctional facilities: a cross-sectional study a tuberculosis outbreak at a workplace in central taiwan trend and treatment status of latent tuberculosis infection patients in japan -analysis of japan tb surveillance data predictors of latent tuberculosis treatment initiation and completion at a u.s. public health clinic: a prospective cohort study treatment of latent tuberculosis infection: a network meta-analysis completing treatment for latent tuberculosis: patient background matters contact investigation for tuberculosis: a systematic review and meta-analysis contact investigation for active tuberculosis among child contacts in uganda prevalence and risk factors for mycobacterium tuberculosis infection among contacts of pulmonary tuberculosis patients neighborhoods and health appropriate assessment of neighborhood effects on individual health: integrating random and fixed effects in multilevel logistic regression hospital-level associations with 30-day patient mortality after cardiac surgery: a tutorial on the application and interpretation of marginal and multilevel logistic regression neighbourhood environments and obesity among adults: a multilevel analysis of an urban brazilian context prison doctors treat 216 people a day. herald corporation world health organization. who statement on the ninth meeting of the ihr emergency committee regarding mers-cov tuberculosis control in the republic of korea key: cord-346842-ip4i3bdk authors: jeon, juyeun; kim, hyeikyoung; yu, kyung-sang title: the impact of covid-19 on the conduct of clinical trials for medical products in korea date: 2020-09-07 journal: j korean med sci doi: 10.3346/jkms.2020.35.e329 sha: doc_id: 346842 cord_uid: ip4i3bdk background: the number of clinical trials conducted in korea continues to increase and an increasing proportion focus on severe and rare incurable diseases. after the start of the severe acute respiratory syndrome, coronavirus disease 2019 (covid-19), korea centers for disease control and prevention (kcdc) developed guidelines to prevent the spread of infection. this study evaluated the impact of covid-19 and the kcdc guideline on the conduct of clinical research in korea. the purpose was to develop recommendations on how to minimize the risk of infection while enabling subjects to take part in the trials if no better alternative treatment options were available. methods: the impact on subject's scheduled visits and major milestones of clinical trials in korea were measured by conducting a survey among clinical project manager (cpms) working at global clinical research organization. the policy on monitor's access to hospital and site initiation meetings was investigated through correspondence with clinical trial center of 39 hospitals. the top 25 pharmaceutical companies' official press and public clinical trial registry database were used to analyze companies' trial strategy during the pandemic and covid-19 clinical research status, respectively. results: of 85 cpms, 12% reported that trial subjects' scheduled visits had been affected in their project. monitors' access to hospital for source data verification was restricted at all sites in february 2020. accordingly, 43% of 105 cpms reported that the covid-19 epidemic had an effect on study major milestones and data cleaning and database lock accounted for > 60% of milestones affected. in addition, 87% sites advised not to have site initiation meetings and 52% pharmaceutical companies suspended recruitment or new study start-up due to the pandemic. on the other hands, the number of covid-19 related clinical trials increased rapidly in korea and worldwide, with investigator-initiated trials accounting for 47% and 63% of all trials locally and globally, respectively. most trials were phase 2 and were in the recruitment stage. conclusion: the covid-19 and the kcdc guideline influenced all parties involved in clinical trials in korea. in order to ensure the safety and well-being of trial subjects during the pandemic, new approaches are required for clinical trials to respond to the impact actively. method of non-contact is developed to replace and supplement the face-to-face contact and alternatives to reduce the travel is introduced to decrease the risk of infection for all trial participants in whole trial process. the relevant regulations should be developed and the guidelines for foreign countries need to be adopted in accordance with the situation in korea. covid-19 trial is rapidly increasing worldwide and continuous support of health authorities, regulation, and facilities is required for developing the treatments with protecting all trial participants. in terms of the clinical trial share, korea ranks eighth globally and is in third place in a single country clinical trial basis. 1 the number of approved clinical trials for medical product conducted in korea increased from 143 cases in 2003 to 679 in 2018. 2 the ministry of food and drug safety (mfds) has reported an increasing trend of trials for severe and rare incurable diseases. 2 anti-cancer clinical trials account for 36.4% of all clinical trials, and have been the most common indication of clinical trial for 3 consecutive years. 2 the conduct of clinical trials consists of a series of processes and multiple parties are involved in the overall trial process. 3 accordingly, face to face contact, meetings and travel to designated places are required (fig. 1) . coronavirus disease 2019 (covid-19) has spread globally since the first outbreak in december 2019 from wuhan in hubei province, china. 4 the first case in korea was confirmed on january 20, 2020, in an individual who entered korea from wuhan. 4 compared to previous respiratory syndrome, middle east respiratory syndrome (mers) epidemic that occurred in 2012-2015, covid-19 had greater community spread. 5 the first case not linked with epidemiologic evidence, identified on february 16, 2020, accelerated increase in the number of confirmed cases due to community transmission. 4 the korea centers for disease control and prevention (kcdc) raised the disease alert to the highest level on february 23, 2020 to heighten the response (fig. 2) . 4 as there was no available treatment approved for covid -19 in korea yet, the government emphasized prevention, to avoid the spread of infection. this strategy influenced not only personal lifestyles but also the conduct of clinical trials of medical products. there were no exceptions made to compliance with kcdc guideline when conducting clinical trials, because of the concern about infection during the operation of trial. the guideline called on all citizens to maintain social distancing, refrain from visiting crowded places and reduce gatherings as well as outdoor activities. 6 conducting clinical trials results in an increased number of subject visits to hospitals, face to face contact and meetings. there was thus a conflict between being compliant with the kcdc guideline firmly and clinical trials activities, including encouraging subjects' continuous participation. new approaches were necessary in clinical trials to eliminate the risk of infection by complying with the guideline and enable subjects to continue to participate in trials if no better alternative treatment options were available, for protecting the subjects' safety and well-being. the impact of the covid-19 pandemic has not been addressed on clinical trials in korea. the study evaluated the impact of the covid-19 epidemic and the kcdc disease control guideline on the conduct of clinical research in korea, on subjects, investigators, monitor, pharmaceutical companies, institutional review boards (irbs) and regulatory authorities (ras), in order to suggest recommendations for conducting clinical trials during the pandemic. to measure the impact of covid-19, the study selected individual indicators for each involved party in clinical trials. to evaluate the impact on subjects' study visits and study major milestones, a questionnaire was administered. the survey was distributed to total 140 clinical project manager (cpms) who were working at global clinical research organization and responsible for trials performed in korea, according to method of simple random sampling from february 24, 2020 to march 7, 2020. the questionnaire included questions on whether covid-19 had an effect on trial subjects' scheduled study visits and whether there was any major milestone influenced or expected to be delayed by covid-19. the milestones could be described by the cpms and in the process of data analysis, they were classified as site initiation, close out, first patients in/last patient in/last patient out, data cleaning and database lock. if a cpm reported that there was an impact on the milestone however did not provide details, they were contacted to try to obtain further information. if response was not received, the impact was classified as not specified. the impact of the policy by trial sites on monitor's access to monitoring room and site initiation was investigated by contacting clinical trial center in 39 hospitals. majority of hospitals (95%) were selected in seoul and gyeonggi-do where clinical trials were actively performed in korea and gyeongsangbuk-do and daegu where high infection rate was shown. they were contacted for the week of february 24, 2020 to march 1, 2020, when the confirmed cases increased dramatically and the week of april 23 to 29, 2020, when the daily confirmed cases decreased less than 10 in korea. the response on the access of monitor was classified as total closure, partially available and available, depending on the degree of access that monitors were permitted. the official press statement of the top 25 pharmaceutical companies on the conduct of their clinical trials during covid-19 pandemic were reviewed in april 2020 and their decision were classified. 7 10,000 4,000 of health were analyzed, during the week of june 22 to 28, 2020, according to the used investigational products, study status, phase and initiating parties, using the pivot table function. 8, 9 for investigational products-based analysis, drug intervention studies for covid-19 from both database were included. the used drugs in each arm of individual trial were classified and if 2 or more products were being administered in the same arm as a combination, each product was counted separately. of 140 cpms, survey was retrieved from total 105 (75%). of 105 respondents, 84 cpms provided valid answer on the question about the impact of covid-19 on subject study visits in korea and others left it blank. of 84 cpms, 12% reported that they had an impact of covid-19 in their project, 55% reported there was no impact on the subject visits, 29% reported that they had no planned subject's visit during the survey period so the impact could not be estimated, and 4% reported that they didn't have active subjects in korea at the time of survey, because recruitment was not initiated, or all subject visits were already completed (fig. 3) . the confirmed reason was that hospitals started restricting patient's physical visit from 2 local cluster, daegu and gyeongsangbuk-do, with the highest infection rates, 89.7% in korea, while seoul had a 1.8% infection rate at the time of the survey. 10 the number of outpatients visiting hospitals was lower during the covid-19 epidemic that in the corresponding period in 2019 and there were some trial subjects who requested to postpone hospitals visits because of concern about covid-19. 11 of total 39 sites contacted, during the week of february 24, 2020 to march 1, 2020, all sites (100%) restricted external visitor's access to the hospital, including that of monitors. four of the sites (10%) allowed only urgent monitoring to comply with the kcdc guideline. for the week of april 24 to 30, 2020, as the number of daily confirmed cases decreased, sites started opening the monitoring rooms again. of 39 sites, 20 (51%) partially opened the room with only limited seats available to maintain social distancing, 9 (23%) made the room available, and 10 (26%) remained closed the room but planned to reopen on may 1, 2020 (fig. 4) . even the sites that had reopened the room, applied the guidance for preventing spread of infection. monitors who had visited countries with a high incidence of covid-19 or lived with someone who had visited a high incidence country within 14 days were still restricted from visiting the monitoring room. some sites requested non-contact communication with site staff. of 140 cpms, a total 105 cpms (75%) answered the question of survey about impact on study milestone by covid-19 in korea. of 105 cpms, 43% reported that they expected the impact in their project. 53% reported that study milestone was not affected, and 4% reported that the study had been completed so the question was not applicable. data cleaning and database lock were the most common milestone affected (> 60%), as a result of restriction of monitor's access to the sites which resulted in delayed source data verification (fig. 5) . the site initiation meeting is an important milestone that marks the trial start at the site. some trial sites prohibited visits from subjects living in area with high infection rates, and subjects who were exposed to infectious agents were required to be quarantined according to the kcdc guideline, so some subjects were unable to attend scheduled study visits. 6 although clinical trial drugs could be delivered in accordance with exceptional regulation permit, appropriate examination should be conducted for subject's safety by investigators. 12 through temporally allowed remote assessment by mfds for trial subjects, it is required for investigator to evaluate the subjects' condition even during their isolation whether it is suitable to prescribe same investigational products repeatedly and whether laboratory tests could be omitted. 12 as a final decision-making authority on continuation and suspension of their clinical trials, the limitation and reluctance of subject to visit hospitals and medical profession's burden for covid-19 control are the factors to consider when deciding whether to proceed with trials, based on risk and benefit assessments. 3,11 ra of united kingdom, medicines and healthcare products regulatory agency, advised for the early phase healthy volunteer trials, where there is no therapeutic benefit to the volunteer but taking part in the trial dose pose a risk of infection. 14 to avoid adding to demands on healthcare system during this unprecedented crisis with covid-19 epidemic and to reduce the possibility of infection of trial participants, 13 (52%) of the 25 top pharmaceutical companies declared to hold recruitment or activation of the new trials at least partially. 7 five (20%) companies continued ongoing trials in close discussion with the trial investigators in all the participating countries. seven (28%) pharmaceutical companies did not mention a change in their conduct of trials on their official website or in press release ( fig. 6) . multiple countries are turning to pharmaceutical companies to develop coronavirus treatments, so accordingly, the number of covid-19 related clinical trials is growing very rapidly worldwide. 15 a notable feature of the global covid-19 treatment clinical study is that the existing licensed treatment or new drug candidate material is being evaluated to determine whether they can be repurposed for treating in korea, the mfds approved a total of 15 covid-19 clinical trials, 6 in march 2020 and 3 in each of the following 3 months. 8 two trials (13%) were for vaccine development and 13 (87%) were for treatment development. a total 10 covid-19 studies (66%) were recruiting patients or preparing for enrollment. of the 15 trials, investigator-initiated trials and sponsor-initiated trials accounted for almost the same percentage, 7 trial (47%) and 8 trials (53%) each. among the sponsor-initiated trials, phase 2 occupied highest portion (27%) (fig. 7) . remdesivir was the most commonly used investigational drug (3 trials), followed by hydroxychloroquine and nafamostat mesylate with 2 trials. kyungpook national university hospital, located in daegu, and seoul medical center in seoul, which operated a professional negative-pressure isolation ward took part in the largest number of covid-19 clinical trials in korea, with 4 trials each. globally, a total 963 drug or biological agent intervention clinical trials were registered for covid-19. 9 in terms of study status, almost half (49%) were recruitment phase. regarding initiating parties, 591 trials (63%) were investigator-initiated, 297 (31%) were sponsor initiated and 17 (2%) were sponsored by the us national institutes of health or us federal reserve, as of june 22, 2020. 15 the majority of studies were phase 2 trials (45%) and treatment development trials (96%) (fig. 8) . hydroxychloroquine was the most commonly used investigational drug ( table 1) . multiple sites, they recommended that a joint review committee be established to review each study protocol and make a joint decision. 12 to prevent the spread of covid-19 during review meetings, it was suggested that the review process be modified by having non-contact review meetings, and that this be documented. 12 in order to support covid-19 drug development, the mfds applied for expedited review of covid-19 trial protocols. a trial of remdesivir for treatment of covid-19, sponsored by gilead sciences, inc was submitted to the mfds for ra approval on february 27, 2020 and approved on march 2, 2020. the us food and drug administration suggested that sponsors and clinical investigators document the reason for any contingency measures implemented, how restrictions related to covid-19 led to changes in the study conduct, which trial participants were affected and how these participants were affected in the clinical study report. 17 the european medicine agency guided for regularities to put priority on any clinical trial application for the treatment or prevention of covid-19 infection, and the approval of applications for substantial amendments to existing clinical trials if necessary as a result of the covid-19 pandemic. the covid-19 pandemic is having a global impact. clinical trials are one of the areas that have been affected. clinical trials are meaningful in that they provide patients with novel treatment options during the process, and if they lead to marketing of new treatments, they may be of benefit to many future patients. moreover, considering that clinical trials are required for developing covid-19 treatments, conditions should be established in which necessary clinical trials can be carried out smoothly even during the pandemic, while protecting all trial participants' safety. in korea, all parties involved in the conduct of trials have been affected by covid-19 pandemic. various guidelines for conducting trials during the covid-19 pandemic have been released both locally and globally for supporting the operation of trials. guidelines developed by foreign countries should be considered and adopted in accordance with the situation in korea if they are judged to be appropriate. twelve percent cpms responded that subject study visits were not performed as planned according to the protocol. although the proportion of trials not affected (55%) was higher, given that the provision of treatment is contingent on assuring the safety of subject, 12% is a sizeable proportion that cannot be overlooked. if the treatment that subjects receive through clinical trial participation cannot be replaced by the standard of care, action should be taken to maintain the treatment while complying with the kcdc guideline. under the current article 50 (1) of the pharmaceutical affairs act, the sale of medicines outside pharmacies is prohibited in korea, which makes it impossible to deliver medicines by courier. 19 however, mfds released a guideline that allows investigational products to be delivered to subjects directly on a temporary basis, to enable them to receive the products while reducing the risk of sars-cov-2 infection that they could face on their way to hospital. 12 the guideline stipulates that the products be stored according to protocol requirements during the delivery process by a certified carrier. 12 the us fda guidance advises investigators to confirm that subjects voluntarily consent to receive investigational products via courier. the italy ra, decrees of the italian president of the council of ministers allow healthcare providers to provide an increased amount of investigational product, to cover an extended period of treatment if it is beneficial and safe for the subjects. for the products that are administered in a health care setting, the us fda permits utilize home nursing services or healthcare professionals to serve as alternative sites, in order to keep access to medical products from being cut off even if the products needs to be administered by professionals with specialized skills. 17 the guidance of the european medicines agency (ema) states that it is acceptable for laboratory, imaging or other diagnostic tests to be conducted at a local laboratory or relevant clinical facility certified to perform such tests routinely. 18 for the introduction of these foreign guidelines in korea, policies on the supply and demand of necessary personnel or the designation criteria of alternative institutions must first be in place. comparing monitoring room availability for source data verification in february and april 2020, it is evident that it is affected by the number of covid-19 confirmed cases per day. given the possibility of worsening of the pandemic situation, monitoring rooms may be forced to close again and considering the limited seats available and the high demand on monitor to verify cumulative clinical trial data, measures should be introduced to verify clinical data efficiently with fewer site visits or the methods of obtaining clinical data that require less verification should be considered. risk-based monitoring can be recommended. it enables earlier detection of issues through focused centralized and remote monitoring activities, and targeted on-site visit only for key risk indicators. this can reduce the total number of on-site monitoring visits required. association of clinical research organizations has suggested that even after routine monitoring is resumed, it is not necessary to perform 100% source data verification if remote monitoring was closely performed during the closure of monitoring room. 20 regulations in italy have allowed remote source data verification exceptionally, limited to covid-19 pandemic once these methods are described in a specific guideline by the sponsor and clinical research organization and approved by the personal data protection officer of the trial site. 21 once the research is equipped with a mechanism for collecting data remotely and directly from the patient or vendor, by using methods such as electronic questionnaires, centralized laboratories or electronic image data, remote verification can supplement on-site monitoring. the increasing number of investigator-initiated trials and trials conducted under the auspices of us federal reserve and the us national institutes of health indicates that all parties are making concerted efforts to develop covid-19 treatments and vaccines. 9 considering that the number of clinical trials of covid-19 related products is rapidly increasing and that most patients are being recruited, measures are needed to ensure an ongoing supply of clinical trial drugs. it is necessary to diversify supply and demand channels for raw materials and to establish regular import and export channels between countries. given that the studies target patients with sars-cov-2 infection, relevant regulations should be implemented and facilities should be supported to use non-contact methods in order to protect investigators and trial staff. as one of non-contact approaches, telephone consent process is allowed for patients during isolation. 12 guidance on the management of clinical trials during the covid-19 pandemic by ema advises the presence of an impartial witness, if written consent by the trial participant is not possible. 18 to enable trial facilities to maintain the non-contact between investigators and trial subjects, they should be well equipped for covid-19 trials with capabilities such as electronic informed consent or device to electronically scan and save the signed informed consent without bringing the form out of the subjects' ward. this study has some limitations. although a single indicator was used to identify the impact of the covid-19 pandemic on each party, the effects of more diverse areas needs to be assessed using a greater diversity of indicators. the analysis of covid-19 related trials was based on a search of clinicaltrials.gov, so the trials not registered in this database were not included in the analysis. we only consider the guidance from ras in the us, korea, european union and the united kingdom, so referring to the guidance of other ra could help to suggest more various measures. all ra guidelines put patient safety first, and mfds is making continuous efforts to conduct clinical trials that are beneficial to participants. health authorities and policymaker should refer to various guidelines and consider alternative measures to conduct trials during this pandemic situation, taking the scope of the application into consideration while prioritizing subject safety, so that the most appropriate method can be implemented and adopted in korea, in a timely manner. at this time, the impact of the covid-19 pandemic on clinical trials in korea has not been as marked as in some other countries. however, restrictions on subject study visits to hospital can directly impact on subject safety and monitor's restricted access to site caused a delayed safety review for subjects. therefore all the lessons learned and policies implemented internally and externally should be evaluated, in order to be prepared for persistence of the covid-19 pandemic or future pandemics. development of the required regulations, strategies, facilities, and platform could help korea not only adapt to the rapidly changed environments and protection of trial participants, but also emerge as a contributing country in the field of trials. in order to increase in the number of clinical trials for treatment of serious diseases, consideration should be given to developing regulations that will enable patients who have difficulty with visiting hospital physically even after pandemic is controlled, so that varying methods can be applied to patients with different clinical conditions. presentation of the results of approval of clinical trials for medicines in korea ich harmonized guideline integrated addendum to ich e6(r1): guideline for good clinical practice ich e6(r2) ich consensus guideline report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from daily status of middle east respiratory syndrome covid-19 response guideline 9th edition by central disaster management headquarters â· central disease control headquarters korea pharmaceutical and bio-pharma manufacturers' association integrated drug information system ministry health and welfare. daily status of covid-19 considerations for clinical trials in a situation of covid-19 notice of training considerations for clinical trial workers according to corona 19 situation united kingdom medicines and healthcare products regulatory agency. synopsis of mhra advice on management of clinical trials in relation to coronavirus analysis of domestic and international clinical trials guidance on conduct of clinical trials of medical products during covid-19 public health emergency guidance on the management of clinical trials during the covid-19 pandemic acro's considerations on monitoring during covid-19 clinical trials' management in italy during the covid-19 (coronavirus disease 19 we express our sincere appreciation for all clinical project managers who conducted the survey and all clinical trial participants who contributed new drug developments. key: cord-315181-emf4i6ir authors: ryoo, nayoung; pyun, jung-min; baek, min jae; suh, jeewon; kang, min ju; wang, min jeong; youn, young chul; yang, dong won; kim, seong yoon; park, young ho; kim, sangyun title: coping with dementia in the middle of the covid-19 pandemic date: 2020-10-27 journal: j korean med sci doi: 10.3346/jkms.2020.35.e383 sha: doc_id: 315181 cord_uid: emf4i6ir multiple neurological complications have been associated with the coronavirus disease-19 (covid-19), which is caused by severe acute respiratory syndrome coronavirus 2. this is a narrative review to gather information on all aspects of covid-19 in elderly patients with cognitive impairment. first, the following three mechanisms have been proposed to underlie the neurological complications associated with covid-19: 1) direct invasion, 2) immune and inflammatory reaction, and 3) hypoxic brain damage by covid-19. next, because the elderly dementia patient population is particularly vulnerable to covid-19, we discussed risk factors and difficulties associated with cognitive disorders in this vulnerable population. we also reviewed the effects of the patient living environment in covid-19 cases that required intensive care unit (icu) care. furthermore, we analyzed the impact of stringent social restrictions and covid-19 pandemic-mediated policies on dementia patients and care providers. finally, we provided the following strategies for working with elderly dementia patients: general preventive methods; dementia care at home and nursing facilities according to the activities of daily living and dementia characteristics; icu care after covid-19 infection; and public health care system and government response. we propose that longitudinal follow-up studies are needed to fully examine covid-19 associated neurological complications, such as dementia, and the efficacy of telemedicine/telehealth care programs. world pandemics have occurred throughout the history of mankind. despite the brilliant advances of modern medicine, we suffered from outbreaks of spanish flu, h5n1 bird flu, severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome (mers) coronavirus, and now, severe acute respiratory syndrome coronavirus 2 (sars-cov-2). so far, cases with viral encephalitis confirmed with sars-cov-2 in the cerebrospinal fluid claim that covid-19 can attack the cns. 7, 15 there are two possible ways that sars-cov-2 can directly invade the brain. first, sars-cov-2 can enter through the blood stream. high levels of cytokines including interleukin (il)-1, il-16, and tumor necrosis factor alpha (tnf-α) in the cerebral vessels can damage the blood-brain barrier (bbb). the meninges are rich in blood vessels and contain high levels of ace2, 16 and bbb breakdown permits the pathogen into brain meninges and parenchyma resulting in seizures and meningo-encephalitis. 13 the second suggested mechanism is via neuronal routes from the peripheral to cns. 17 anosmia and ageusia are common among patients with covid-19, yet the possibility for a central etiology remains unclear because the symptoms generally improve within weeks. 18 -20 however, current research report anosmia alone or in combination of parageusia among covid-19 patients while they showed no significant nasal congestion or rhinorrhea as influenza or rhinovirus. 18,19,21 -23 also, the murine model studies demonstrate that coronavirus enters the olfactory bulb after exposure by the nasal route and then it can invade the cns, supporting olfactory transmission of sars-cov-2. 24,25 by binding respiratory epithelial cells, sars-cov-2 activates the cytokines and hypercoagulation pathways in the blood, increasing levels of inflammatory markers such as c-reactive protein, ferritin, il-1, il-6, tnf-α, and d-dimer. 26 elderly individuals have increased existing baseline of inflammation 27 and may suffer more severe complication and higher mortality as a result of inflammatory reaction. this cytokine storm also triggers embolic cerebrovascular accidents, 14 and li et al. 28 claims that hypercoagulable status of covid-19 patients can lead to blood clots in both cerebral arteries and cerebral veins causing stroke and cerebral venous thrombosis. although further research is needed to clarify the exact mechanism of binding of sars-cov-2 to ace2 resulting cytokine storm and the secondary hypercoagulation, there are abundant cases reporting acute stroke in covid-19 patients. 14,28 31 li et al. 28 in the study suggests that early treatment to inhibit anti-inflammatory pathway can reduce the risk of acute cerebrovascular disease. 31 severe cases of covid-19 may involve acute respiratory failure, sepsis, and multi-organ failure necessitating mechanical ventilation in intensive care unit (icu). hypoxia occurs when oxygen supply to the brain is interrupted, and it can lead to confusion, disorientation, delirium and loss of consciousness. 32 solomon and colleagues report the neuropathological findings from autopsies of 18 covid-19 patients who died in a single teaching hospital between april 14 and april 29, 2020. they examined histopathological examination of brain specimens obtained from 18 patients who died 0 to 32 days after the onset of symptoms of covid-19. all cases were confirmed covid-19 by nasopharyngeal swab samples for sars-cov-2 on qualitative reverse transcription polymerase chain reaction assays, and histopathological examination of brain specimens and immunohistochemical viral analysis were done. intriguingly, all patients in the study showed only hypoxic changes and did not show other specific brain changes including encephalitis or viral invasion. 33 this valuable research on the neuropathological findings of covid-19 decedents demonstrates no evidence of direct invasion of sars-cov-2 and supports hypoxic brain damage by covid-19. however, lack of examination including brain magnetic resonance imaging (mri) and cerebrospinal fluid, and ambiguity of statements that all patients had a confusional state or decreased arousal from sedation for ventilation make it hard to conclude whether the patients had neurologic signs of cns involvement. another interesting research investigated by coolen et al. 34 was about postmortem brain mri of 62 patients who died from covid-19. only decedents with sars-cov-2 positive on nasopharyngeal swab specimen and with typical covid-19 chest computed tomography scan findings were selected and then brain mri was performed within 24 hours after death to investigate structural brain abnormalities associated with covid-19. 34 as a result, subcortical hemorrhages in 2 decedents and edematous changes evocative of posterior reversible encephalopathy syndrome in one decedent were detected supporting bbb breakdown via sars-cov-2. asymmetric olfactory bulbs were found in 4 decedents (21%) without olfactory tract nor brainstem abnormalities. although more data will be needed due to small number of patients excluding those without lung-related evidence, this survey is meaningful in that it shows the opposite results of the neuro-invasion hypothesis through olfactory pathways. both papers demonstrate acute stage of cns complication, and the abnormal misfolding and aggregation of proteins in patients who recovered from acute sars-cov-2 infection may lead to long-term brain degeneration. 35 helms and colleagues reported that a third of the covid-19 patients discharged from icu were observed to have a dysexecutive syndrome. 36 fotuhi claims that recovered patients from an acute sars-cov-2 infection may experience poor memory, attention, or slow processing speed so that it would be helpful to undergo inspection by a neurologist or neurocognitive testing 6-8 months after their hospital discharge if they feel any cognitive problem. as such, patients with low scores in certain cognitive areas should be treated with brain rehabilitation early, which may reduce their risk for future age-related cognitive decline. 13 ogier also suggests follow-up screening with cognitive evaluation, brain imaging (mri, positron emission tomography), and auditory brainstem responses would help to detect brain dysfunction of covid-19 patients. 12 overall, long-term follow-up study for those survivors may reveal new neurologic consequences of covid-19 such as cognitive decline, accelerated aging, and dementia in the future. dementia patients are especially vulnerable to covid-19 infection due to their disease state, age, 37 and comorbid diseases. 38 furthermore, covid-19 positive dementia patients may manifest their neurological complications as behavioral and neuropsychological problems. here, we review the underlying issues that make dementia patients especially vulnerable amid the covid-19 pandemic. dementia is typically diagnosed in older people, a population that is particularly vulnerable during the covid-19 pandemic. wu et al. 7 reported that covid-19 patients over 59 years of age suffered 5 times worse outcomes than younger patients. moreover, increases in morbidity range from 14.8% in china to as high as 58.9% in italy among those 80 years or older. 39 -41 in older individuals, comorbidities, such as hypertension, diabetes, obesity, and heart disease, are more likely to promote a cytokine storm resulting in life-threatening respiratory failure and multi-organ damage. 38,42 -44 also, respiratory distress is common among most late-stage alzheimer's disease (ad) patients. 45 bauer claims that individuals with dementia are more likely to have cardiovascular disease, diabetes, and pneumonia compared to individuals of the same age without dementia. 46 neuroinflammation is a pronounced feature of neurodegeneration and a critical role in the ad pathology. 27 david melzer and colleagues suggests that risks of severe covid-19 infection are related with the ad susceptibility gene, apolipoprotein e (apoe). the apoe e4 genotype not only increases risk of dementia and ad, but also exacerbates microgliamediated neuroinflammation by inducing immune responses to amyloid pathogenesis and neurodegeneration. 47,48 according to the data of participants (n = 451,367, 90% of sample) collected in the united kingdom biobank, apoe e4e4 homozygotes were 2.3 to 4.0-fold more prone to covid-19 test positives (odds ratio [or], 2.31; 95% confidence interval [ci], 1.65-3.24). 49 although the exact mechanisms still need to be studied, this may relate to co-expression of apoe e4 and ace2 within type ii alveolar epithelial cells in the lung. thus, dementia patients can be more vulnerable to covid-19 infection. dementia is a neurodegenerative disorder marked by memory or cognitive issues, behavioral disorders, and difficulty performing daily activities. ad is the most common form of dementia in the world, corresponding to about 60%-70% of cases. 50 the second most common cause of dementia is vascular dementia (vd), which accounts for about 20% of cases worldwide, followed by dementia with lewy bodies (15%), 51 and frontotemporal dementia (ftd, 5%). 52 patients with ad, or other types of dementia, initially present with mild cognitive decline, termed mild cognitive impairment (mci), as their daily life and activities are not significantly affected. as dementia progresses, cognitive impairment increases, and patients need more help to complete daily tasks and activities. since each cognitive disorder presents with overlapping, but often varying, characteristic symptoms, patients with concomitant dementia and covid-19 may suffer from a diverse array of difficulties. herein, we discuss the impact of the covid-19 outbreak on cognitive disorders in an attempt to gain insight for more detailed patient support. most individuals with mci can manage their daily activities independently; however, they may show impaired adaptation and response to changes in society relative to the general population. as mci patients stay at home during the covid-19 pandemic, lack of exercise and social connection, which are paramount to non-pharmacological treatment in mci patients, may accelerate their cognitive and psychological decline. moreover, stress, which can be caused by changes in exterior circumstances, i.e. a pandemic, can have detrimental effects on people with mci. 53 rogers's systemic review identified 72 independent studies that provided data on both the acute and post-illness neuropsychiatric features of covid-19 infection including depression, anxiety, fatigue, and stress 54 ; however, a more comprehensive study is needed to focus on people with mci or dementia. as ad progresses, patients progressively display long term memory loss and gradually show a deterioration of language abilities and reduced awareness of time and place, ultimately inhibiting their abilities to carry out daily activities without help. consequently, ad patients may have difficulty understanding and complying with new policies that are implemented in response to covid-19, such as wearing masks and keeping physical distance due to their memory impairment. as such, more advanced ad patients will not be able to understand and adjust to the current pandemic situation. clair et al. investigated the effects of confinement during the covid-19 crisis on neuropsychiatric symptoms in patients with ad using the neuropsychiatric inventory-questionnaire. neuropsychiatric symptoms in ad include depression, anxiety, apathy, verbal and physical agitation, and hallucinations. the patients with severe ad show higher tendencies toward confusion and disorientation, and, consequently, these patients were correlated with a higher incidence of neuropsychiatric symptoms. however, reduced social contact and physical activity during isolation may have also induced these changes. 55 also, ad patients are more vulnerable to infection because it is difficult to restrict physical contact with others in situations that require physical care. cognitive decline associated with vd, which occurs after a vascular brain injury, can vary depending on the brain region affected. vd patients often present with memory loss, similar to ad 56 ; vd patients with frontal lobe cerebrovascular damage can present symptoms similar to ftd. various brain dysfunctions including memory, behavioral, and neuropsychiatric symptoms make the vd patients more susceptible to covid-19 infection. in addition, patients with vd tend to have motor or sensory neurological deficits, as well as cognitive problems, that arise from previous cerebrovascular diseases. importantly, consistent, regular exercise and occupational therapy are important for vd patients; however, these therapy programs have been dramatically reduced or even terminated during the covid-19 pandemic. thus, the loss of these programs can have dire consequences for vd patients. diffuse lewy body (dlb) dementia is a disease characterized by the deposition and aggregation of alpha-synuclein, termed lewy bodies in the brain, that shares symptoms with both ad and parkinsonism. dlb patients often present with delirium-like fluctuating symptoms that include visual hallucination. 57,58 furthermore, they often show hypersensitivity to antipsychotics, which may inhibit effective treatment. specifically, dlb patients initially show signs of delirium or neuropsychiatric symptoms and are subsequently prescribed antipsychotic medications; moreover, the prevalence of hypersensitivity to antipsychotics in dlb patients is relatively high, from 30 to 50%, and leads to increased cognitive decline, drowsiness, agitation, delirium, or worsening of parkinsonism. 59 for dlb patients who show signs of parkinsonism, gait difficulty and postural instability increase the risk of falling, thereby restricting daily activities. as such, these require extensive help from other people, which may not be feasible in circumstances where there is a lack of community health services and caregivers, such as during the covid-19 pandemic. ftd is caused by progressive nerve cell loss in the frontotemporal lobes of the brain. ftd patients are diagnosed around 45 to 65 years of age, which is relatively young compared to ad. there are two types of ftd, which are known as behavior variant ftd and primary progressive aphasia. early ftd patients more prominently display behavioral and language problems rather than memory issues; however, memory loss becomes prominent in advanced stages. 60 due to cognitive decline, ftd patients may have difficulties in understanding the necessity for self-quarantining due to a lack of awareness of the criticality of the covid-19 pandemic. more importantly, they may not accept unfamiliar social guidelines, such as wearing face masks and social distancing. also, being relatively younger than those with other forms of dementia, ftd patients are more likely to be physically fit, thereby increasing risks associated with violent behavior, impulsivity, disinhibition, and dysexecutive impairment. furthermore, ftd patients may be resistant to altering daily activities they can no longer perform due to their compulsive and obsessive behaviors. consequently, these situations may make ftd patients more susceptible to exposure and transmission of covid-19. the living environments of patients with dementia can have a tremendous impact on their susceptibility to massive infection. as the disease progresses, they require a considerable amount of support for daily living. as such, dementia patients may either live with their families or reside in communal care homes; these congregated living situations may expose them at high risk of infection. 61 ergo, up to 80% of the covid-19 deaths are long-term care residents or workers, and over one-third of covid-19-related mortalities in the united states are those afflicted with ad. 62 additionally, over 600 nursing home residents from a total capacity of 6400 beds died between march 7 and 27, 2020 in bergamo, italy, 63 and approximately 5,000 older people died in nursing homes in madrid, spain. as quarantine measures, nursing home residents have remained in isolation and visitors are temporarily prohibited. 64 however, employee-mediated transmission at nursing homes remains inevitable, as they are required to commute to and from the facilities. 61 as these effects are seen worldwide, urgent health care policy changes are needed to avoid repeating these failures. nursing homes should not be hopeless places where elderly people wait to die but should be a supportive place and vibrant atmosphere for them to live out their remaining years. once infected by covid-19, elderly dementia patients will most likely experience neuropsychological problems such as delirium. 65 infected patients are subsequently transferred to an icu, or any isolated facility, and surrounded by unfamiliar medical workers with face shields and strange equipment. a study by helms reported the presence of agitation in 69% (40/58) of covid-19 patients with acute respiratory distress syndrome (n = 58, median age 63 years) admitted to an icu. 36 moreover, two-thirds of these agitated patients (26/40) showed confused mentality. many of these patients develop restlessness, anxiety, and agitation, and their attempts to get out of bed can result in the need for physical restraint and/or pharmacological sedation. finally, the medical community must consider the impact of covid-19-related social restrictions and containment policies on dementia patients. to prevent the covid-19 transmission, many countries adopted drastic measures such as strict quarantines, prohibiting social gatherings, and even lock-down. as a result, reduced physical activities, lack of social engagements with families and friends, and cancelled day care center programs may worsen the cognitive, physical, and neuropsychological condition of the patients with dementia. 66 being confined at home may increase levels of stress, anxiety, and a feeling of loneliness and depression. this is critical for dementia patients, as stress is known to be detrimental to patients with cognitive impairments. 53 in addition to the patients, we must also focus on the well-being of families and caregivers who may be suffering from reduced public health care support or home care services during the covid-19 outbreak. as covid-19 continues to evolve in many countries, contagious virus and social quarantine measures cause deleterious impact on elderly dementia people and their families or healthcare workers. thus, we propose multiple strategies to promote healthy living for people suffering from dementia and their caregivers. below, we discuss the following four strategies aimed at improving dementia patient care during the covid-19 pandemic: 1) general preventive measures of covid-19 infection, 2) strategies for dementia care at home and nursing facilities according to activities of daily living (adl) and dementia subtypes, 3) strategies for icu care after covid-19 diagnosis, and 4) measures and suggestions for public health care system and governmental response to covid-19. covid-19 is transmitted person to person through direct contact, respiratory droplets and aerosolized viral particles. 5 -7 there are still debates whether the virus transmits via droplet or aerosol, beyond the matter, wearing face mask is highly recommended considering the potential for asymptomatic or pre-symptomatic transmission. also, we unconsciously touch our eyes, nose, and mouth frequent times a day, and furthermore, the spread of coronavirus can occur through unexpected paths, such as elevator buttons or air conditioner. hand washing, alcohol gel sanitizer, masks, and even goggles can effectively prevent infections caused by touching. various measures, from reducing outdoor activity to social distancing, have been implemented to curb the viral spread. additional strategies for decreasing coronavirus transmission include regular house cleaning, frequent air ventilation through open windows, and disinfecting tableware or other items of frequent use via ultraviolet light. also, regular exercise, healthy eating, stress reduction, and regular sleep are other effective ways to stay healthy during the covid-19 pandemic. 67 general preventive strategies of covid-19 infection are summarized in table 1 moderate to severe symptoms of dementia as the disease progresses, dementia patients experience a decline in overall cognitive function and the majority of them enter nursing homes. in this case, keeping physical distance is extremely difficult because they are dependent on others even for basic living care. thus, caution and stringent measures against covid-19 are required for those in nursing homes or retirement facilities where massive infection and mortality can occur. 62 medical workers and caregivers at nursing facilities should pay more attention to using hand sanitizers that contain ethanol, hydrogen peroxide, or sodium hypochlorite before caring for the next patient, changing commonable supplies to individual use, disinfecting public places regularly, ventilating rooms frequently, and arranging separate mealtimes in small groups to promote physical distancing are recommended. also, nursing homes need to ensure adequate stores of ppe for caregivers, and, additionally, caregivers should be checked for body temperature and any symptoms related to covid-19 before entering the facilities. 76 testing for suspected covid-19 exposure should be carried out promptly. "at high risk" workers, e.g., workers who have relatives with covid-19 symptoms or who have had close contact history with confirmed covid-19 patients, must be excluded from front line care. also, regular testing for covid-19 among the staff is necessary to identify asymptomatic infections. next, we need to consider the characteristics of dementia patients since they may have unique difficulties amid the covid-19 pandemic. as mentioned above, ad patients have memory impairment, which will require a frequent explanation of current covid-19-related policies and hygiene measures. since stress accelerates cognitive decline in ad patients, 74 it is critical to balance exposure to stress-reducing environments, such as planned outdoor activities, while following basic hygiene guidelines. due to the effects of memory loss in dementia patients, their families and caregivers can be annoyed by their repeated questions and forgetfulness, and easily recognizable visual reminders on personal hygiene can be particularly helpful. sometimes behavioral and psychological symptoms of dementia (bpsd), which are common in ad and vary in characteristics and severity among patients, can cause greater stress to families and caregivers than the patients themselves. 77 tele-counselling hotlines can aid in relieving suffering related to bpsd symptoms. in addition, family members often feel tired and stressed due to long-term care of dementia patients 55,66 ; thus, it is important to share the burden of care with other family members or caregivers. this can be accomplished by making "care and rest" schedules. for vd patients, the continuation of their daily neurological training, such as speech, occupational, and gait therapy, is critically important. as such, web-based rehabilitation programs and renting portable therapy tools can be helpful for vd patients. extensive attention should be given to the prevention of delirium in dlb patients. neuropsychiatric symptom occurrences can often increase upon hospitalization due to 10/21 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e383 covid-19 infection; in these cases, physicians must realize that dlb patients require greater attention and, if prescribed antipsychotics (e.g. quetiapine and risperidone), their hypersensitivity to antipsychotics must be considered. previous studies suggest that both motor and cognitive training can be helpful in the management of psychiatric symptoms, including agitation and psychosis in dlb patients. 57 telecommunication, including phone or video, with physical, speech, and occupational therapists can be a helpful source of guidance for performing at-home therapeutic activities. 78 lastly, people with ftd often have trouble adapting their behavior to new circumstances and following covid-19-related social policies, such as social distancing. home-based exercise and planned outdoor activities with caregivers are encouraged, with the caveat of avoiding densely populated areas. confined ftd patients may experience boredom, causing an increase in compulsive and obsessive behaviors (e.g. overeating); therefore, these patients require more organized daily plans that include enjoyable therapeutics. creating a new routine that aligns with the current circumstances can be also a useful strategy for ftd patients. in addition, prevention of overuse or addiction to tv/video is critically important and can be accomplished by scheduling and limiting daily watching. counseling for behavioral management of ftd via telephone hotlines 27 and providing self-help guidance for reducing stress, such as exercise, relaxation, and meditation, through electronic media can also provide beneficial effects. 64 strategies for dementia care at home and nursing facilities are abridged in table 2 • provide guidelines to "at high risk" workers that exclude from the front line care workers • regularly testing for covid-19 among staff is necessary to identify asymptomatic infections 3. strategies with characteristics of dementia 1) alzheimer's disease • need to remind repeatedly about current policies and hygiene measures • use easily recognizable visual reminder on personal hygiene • plan outdoor activities that follow hygiene rules • tele-counselling hotline for bpsd symptoms can help families or caregivers deal with and relieve their suffering • share the burden of care by making "care and rest" schedules with other caregivers 2) vd • maintain everyday training according to the patient's neurological deficits, including speech, occupational, gait therapy • web-based rehabilitation programs and renting portable therapy tools can be helpful • depending on areas of dysfunction, vd patients can apply the strategies of ad or ftd patients 3) dementia with lewy bodies • care should be taken to prevent the occurrence of delirium • in cases of hospitalization in the icu or isolated wards due to covid-19 infection, dlb patients require greater attention; prescriptions of low dose antipsychotics (e.g. quetiapine and risperidone) is preferred in consideration due to hypersensitivity to antipsychotics • at-home therapeutic activities via telecommunication for both motor and cognitive training can be helpful 4) ftd • home based exercise and planned outdoor activities, avoiding densely populated areas, with caregivers are encouraged • have more organized daily plans that include enjoyable therapeutic activities • create a new routine which fits within the context of the current circumstances • prevent overuse or addiction to tv/video by scheduling and restricting daily use • counselling for behavioural management of ftd via telephone hotlines is helpful • providing self-help guidance for reducing stress through electronic media can result in beneficial effects for ftd patients adl = activities of daily living, ppe = personal protective equipment, covid-19 = coronavirus disease 2019, bpsd = behavioral and psychological symptoms of dementia, vd = vascular dementia, ad = alzheimer's disease, ftd = frontotemporal dementia, icu = intensive care unit, dlb = diffuse lewy body. family members of dementia patients must be prepared for a possible covid-19 diagnosis. once the patients are confirmed with covid-19 and sent to the hospital, it may be too late to discuss the issue with them. family members are recommended to explain the realities of a covid-19 diagnosis, including hospitalized treatment if covid-19 is confirmed, and to reassure patients that these actions are for the patient's benefit. preparations, such as making necessary item lists for admission or packing patient attachment items in advance, can help family members respond appropriately when hospitalization is needed. also, a care emergency may occur if the primary caregiver becomes ill with covid-19. in this case, family members should discuss contingency plans. 50,80 the prevention and management of delirium require detailed training for icu physicians and nurses who may care for elderly dementia patients with covid-19. once delirium and other neuropsychologic symptoms occur, infection control procedures become extremely difficult. the act of taking off the mask or the attached lines and trying to get out of bed by shouting can make the surrounding patients feel agitated. medical professionals can reduce icu-related delirium risks using standard guidelines to assess and manage pain, as well as by avoiding urinary retention and constipation and supplying adequate oxygenation. 81 common adjustable causes for delirium, such as electrolytes disturbance, hypoxemia, and dehydration, can be easily monitored and promptly managed. regular pain assessment through behavioral pain scales, numerical rating scale, or critical care pain observation tool are recommended. 82 regular delirium screening via the confusion assessment method for the icu and intensive care delirium screening checklist can take advantages to manage delirium early. also, physicians should review past medical history and previous medications of elderly patients. dlb patients can present hypersensitivity to antipsychotics so that antipsychotics (e.g. quetiapine and risperidone) at low dose are recommended. 59, 83 abrupt cessation of previous medications should be avoided in order to prevent withdrawal symptoms. during management, it is recommended to withdrawal unnecessary psychoactive medications and to prohibit prolonged use of sedatives or stay in icu. 81 non-pharmacological interventions are also emphasized by promoting psychological stability with warm attitudes and repeated reminding of current location and date. 81 using visual picture cards also can help identify and care for their needs. allowing a small desk clock, calendar, radio, and attachment items of patients can be helpful. in icu/isolation ward, face-to-face video call can be better promoted to enable frequent communication between patients and their families to mitigate delirium and patients' distress. 84 as discussed earlier, sars-cov-2 infection can provoke neurologic complications including acute stroke or encephalopathy. therefore, timely referral and engagement of neurologists are necessary if the elderly patients present any suspicious signs of neurological abnormality during covid-19 management. strategies for icu care after covid-19 diagnosis are briefly described in table 3 . in some countries, overwhelming numbers of covid-19 patients have caused shortages of hospital beds and ventilators, and, consequently, elderly patients with dementia have been relegated to the post-care ranking of critical care. 41,43 this disaster could be repeated if early prevention or control of an outbreak fails. conversely, we propose that vulnerable parties should be given priority of care to prevent these failures in the future. dementia patients and health care workers at group facility should be considered a public health priority and provided with enough preventive measures and supplies. 85,86 pre-emptive preventions for elderly dementia patients who are more vulnerable to infection and transmission is necessary for effective infection control, prevention of medical supplies shortages, and reduction of medical costs. during the covid-19 outbreak, treatment facilities and daycare centers were closed, and telecommunication became more important as elderly people were isolated due to termination or reduced social health services. to combat this issue, many dementia safety centers in korea have distributed "memory aid-packages" to quarantined elderly dementia patients. while these packages slightly vary between regions, they contain a variety of helpful items such as guidelines to prevent covid-19, face masks, exercise tools (e.g. stretching bands), plant raising kits, and learning materials or tools for cognitive activities. telecommunication and virtual communication with their families and friends are encouraged to maintain social connections. 79 web-based home programs for cognition, exercise, and counseling can help to improve dementia patient health. at the same time, dedicated employees have been conducting regular telephone consultations to monitor patient health and provide consultation about covid-19. advanced information and communications technologies (icts) have driven korea's successful pre-emptive response that help "flatten the curve" of daily infection (fig. 1) . icts played a pivotal role in preventing covid-19 transmission by promptly tracing contacts and providing the latest information on covid-19. 87 moreover, the availability of high-speed internet connections will become very important for rapid responses to pandemics in the future. however, some experts have outlined some issues with telemedicine, which must be solved before it is universally utilized. neurological patient exams are typically not feasible without direct contact and many countries do not have the wireless infrastructure to fully adopt telemedicine. 59 • assuming the patient is infected, it should be helpful to explain and reassure him/her about the physical symptoms prior to inpatient treatment and, further, to explain that these measures are intended for treatment, not for harm • preparations such as making a list of necessary items for admission or packing attachment items in advance can help family members respond quickly and appropriately when a new situation occurs • in case the patient's primary caregiver gets infected, family members need to have contingency plans • for prevention and management of delirium, reduce icu delirium risks using standard guidelines to assess and manage pain, avoiding urinary retention and constipation, and supplying adequate oxygenation • regular pain assessment and delirium screening is required • physicians must review past medical history of elderly patients as dlb patients can present hypersensitivity to antipsychotics, and previous medications in order to avoid withdrawal symptoms • during management, it is beneficial to withdrawal unnecessary psychoactive medications and to prohibit prolonged use of sedatives or stay in icu • the medical staff can promote psychological stability by presenting positive and compassionate attitudes and providing repeated reminders of the current location and date • use visual picture cards to identify and care for their needs • allowing a small desk clock, calendar, radio, and attachment items of patients can be helpful • face-to-face video calls that allow frequent communication between patients and their family members, which may mitigate delirium and patients' distress • contact a neurologist for further examination in the event a patient shows any symptoms of acute stroke or encephalopathy icu = intensive care unit, covid-19 = coronavirus disease 2019, dlb = diffuse lewy body. therapies should still be encouraged. for example, korea's dementia safety center provides guidelines for home visits that provide information to health care workers about following strict personal hygiene measures. also, the previous study by lee supports that homevisiting cognitive intervention for the elderly dementia patients can bring positive benefits to improve cognition, emotion, and functional abilities. 88 moreover, for dementia patients who stay at home for fear of infection, or who are under quarantine, health care services can be continued via telephone services in the event a "memory aid-package" has been delivered. due to the lockdown of facilities, there have been gaps in care, resulting in the need for government aid for a lot of families. 89 specifically, many people have had an increased burden of not only homeschooling their children but also watching over elderly parents as well. in addition to neuropsychiatric symptom severity in dementia patients, longer confinement durations have also been correlated with caregiver distress. 55 family caregivers of patients with ad are sometimes referred to as "invisible second patients," 90 and as a medical community, we need to be aware of their stress as well. moreover, financial problems, such as sudden job loss due to the economic shutdown, may compound stress among caregivers. governmental support for families, caregivers, and patients is important. in addition, care networks should be operated at the government level for elderly dementia patients without families. governmental policies that govern dementia patients are another key factor in controlling the spread of the virus. 91 for example, a guidebook or message with an on-line link that provides sufficient information in case of covid-19 infection may help patients and families prepare for these circumstances, thereby reducing anxiety. for patients with cognitive disorders, a guidebook covering the procedures of hospitalization and treatment with easy language and visual pictures could be helpful. moreover, contact information for urgent medical counseling should be available within any guidebook. delivery of aid-kits for cognitive and exercise training can also ensure consistency of at-home therapy during the covid-19 pandemic. government-level tele-healthcare 92 and counseling efforts for elderly dementia patients may greatly aid in overcoming the ever-changing landscape of the covid-19 pandemic. recommendations for public health care system and government are encapsulated in table 4 . the neurological complications of sars-cov-2 are similar to those attributed to earlier coronavirus epidemics, such as sars in 2003, and mers in 2012. however, the covid-19 pandemic has already exceeded the overall totals of people infected with previous coronaviruses and is still not under control in many countries. therefore, covid-19-related neurological complications for dementia patients must be examined. long term follow-up studies will be needed to understand the effects of covid-19 on the incidence or prevalence of dementia. also, well-designed large cohort studies to examine the effectiveness of therapeutic strategies on people with cognitive impairment are necessary in the near future. this is a narrative review study to present detailed strategies on caring for dementia patients during a pandemic. moreover, these strategies are based on cognitive impairment severity and features of each dementia type. measures are discussed from the viewpoint of three groups, dementia patients, their families and guardians, and medical or health care staff. our study provided information on infection prevention and mitigation of the hardships table 4 . measures and suggestions for public health care system and government measures and suggestions for public health care system and government • dementia patients and medical staff at group facility should be considered a public health priority and should be provided with enough preventive measures and supplies • supply "memory aid-packages," which are beneficial to home confined elderly dementia patients • monitor the health of dementia patients and caregivers during the covid-19 pandemic via regular telephone consultations • telecommunication and virtual communication with patient families and friends are encouraged to maintain social connection • web-based home programs for cognition, exercise, and counselling can help improve patient health • establishment of high-speed internet connections remains an important factor for the rapid response and control of a pandemic • medical experts can offer medical consultation via recorded logs from patients and caregivers outlining the patient's current cognitive, behavioural, and mental state • physical contact remains necessary for elderly dementia patients who have difficulties adapting to new technologies • human contact via at home-visiting services and small group therapies should be encouraged • provide guidelines to health care workers for home visits since they are required to follow strict personal hygiene measures when visiting patient homes • health care services should be continued by telephone after the delivery of "memory aid-packages" in cases of dementia patients who stay at home for fear of infection or who are under quarantine • governmental support for financial and mental problems among families and caregivers is necessary • care networks should be operated at the government level for elderly dementia patients without families • a guidebook or message with an on-line link that provide sufficient information about covid-19 infection data can help patients and families to prepare and, thereby, reduce anxiety • for dementia patients, a guidebook introducing the procedure of hospitalization and treatment with concise and easy language, expressed with visual pictures, and contact information for urgent medical counseling or help is needed • delivery of aid-kits to promote cognitive and exercise training can ensure therapy consistency at home • government-level efforts including tele-healthcare and counseling for elderly dementia patients can greatly help with overcoming the obstacles associated with the covid-19 pandemic covid-19 = coronavirus disease 2019. world health organization. coronavirus disease (covid-19) situation reports the first case of 2019 novel coronavirus pneumonia imported into korea from wuhan, china: implication for infection prevention and control measures billboard of covid-19 drive-through screening center for covid-19: a safe and efficient screening system against massive community outbreak how is covid-19 affecting south korea? what is our current strategy the effect of human mobility and control measures on the covid-19 epidemic in china nervous system involvement after infection with covid-19 and other coronaviruses epidemiology, genetic recombination, and pathogenesis of coronaviruses genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding origin and evolution of pathogenic coronaviruses the spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus 2 pandemic infection how to detect and track chronic neurologic sequelae of covid-19? use of auditory brainstem responses and neuroimaging for long-term patient follow-up neurobiology of covid-19 neurologic manifestations of hospitalized patients with coronavirus disease 2019 in wuhan, china a first case of meningitis/ encephalitis associated with sars-coronavirus-2 expression of the sars-cov-2 cell receptor gene ace2 in a wide variety of human tissues venous and arterial thromboembolic complications in covid-19 patients admitted to an academic hospital in large-vessel stroke as a presenting feature of covid-19 in the young a case of coronavirus disease 2019 with concomitant acute cerebral infarction and deep vein thrombosis intermittent hypoxia and cognitive function: implications from chronic animal models neuropathological features of covid-19 early postmortem brain mri findings in covid-19 non-survivors sars-cov-2: at the crossroad between aging and neurodegeneration apoe e4 genotype predicts severe covid-19 in the uk biobank community cohort world health organization. risk communication and community engagement readiness and response to coronavirus disease (covid-19): interim guidance. geneva: world health organization dementia with lewy bodies update on frontotemporal dementia psychological distress and risk for dementia psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the covid-19 pandemic the effects of confinement on neuropsychiatric symptoms in alzheimer's disease during the covid-19 crisis is mild cognitive impairment prodromal for vascular dementia like alzheimer's disease? diagnosis and management of dementia with lewy bodies: fourth consensus report of the dlb consortium delirium and dementia with lewy bodies: distinct diagnoses or part of the same spectrum? treatment of dementia with lewy bodies frontotemporal dementia covid-19: the precarious position of spain's nursing homes one-third of all u.s. coronavirus deaths are nursing home residents or workers nursing homes or besieged castles: covid-19 in northern italy dementia care during covid-19 delirium superimposed on dementia: a quantitative and qualitative evaluation of patient experience anticipating and mitigating the impact of covid-19 pandemic on alzheimer's disease and related dementias -19)-tips-for-dementia-care uk alzheimer's society. 5 great ways to keep moving at home -tips for people with dementia adi offers advice and support during covid-19 at home activities: meaningful activities for pwd, families and carers coronavirus: guidance for people with dementia and carers how to stay well during the covid-19 pandemic: 5 key messages for people living with dementia tips for vulnerable people living alone/self-isolating dementia in the covid-19 period mental health and psychological intervention amid covid-19 outbreak: perspectives from south korea consensus for prevention and management of coronavirus disease 2019 (covid-19) for neurologists best practice in the management of behavioural and psychological symptoms of dementia the coronavirus disease 2019 crisis as catalyst for telemedicine for chronic neurological disorders managing behavioral and psychological symptoms of dementia cdc's recommendations for the next 30 days of mitigation strategies for seattle-king, pierce, and snohomish counties based on current situation with widespread covid-19 transmission and affected health care facilities covid-19: icu delirium management during sars-cov-2 pandemicpharmacological considerations does the combination use of two pain assessment tools have a synergistic effect? hypersensitivity to atypical antipsychotics in dementia with lewy bodies: is it common or rare? telemedicine/virtual icu: where are we and where are we going? supporting the health care workforce during the covid-19 global epidemic infection prevention and control guidance for long-term care facilities in the context of covid-19: interim guidance ?seq=761548&srchfr=& srchto=&srchword=&srchtp=&multi_itm_seq=0&amp home-visiting cognitive intervention for the community-dwelling elderly living alone informal home care providers: the forgotten health-care workers during the covid-19 pandemic family caregivers of people with dementia suggestions to prepare for the second epidemic of covid-19 in korea dementia care in times of covid-19: experience at fundació ace in barcelona, spain from the management and care of dementia patients during the covid-19 outbreak. we hope this study can guide health care leaders to formulate new standard guidelines for dementia patient care during the current pandemic, as well as any future pandemics. key: cord-344087-4f40zj13 authors: jo, min-woo; go, dun-sol; kim, rhieun; lee, seung won; ock, minsu; kim, young-eun; oh, in-hwan; yoon, seok-jun; park, hyesook title: the burden of disease due to covid-19 in korea using disability-adjusted life years date: 2020-05-26 journal: j korean med sci doi: 10.3346/jkms.2020.35.e199 sha: doc_id: 344087 cord_uid: 4f40zj13 background: the world is currently experiencing a pandemic of coronavirus disease 2019 (covid-19). in korea, as in other countries, the number of confirmed cases and deaths due to covid-19 have been rising. this study aimed to calculate the burden of disease due to covid-19 in korea. methods: we used data on confirmed cases and deaths due to covid-19 between january 20 and april 24, 2020 provided by the korea centers for disease control and prevention, the local governments and the public media to determine disability-adjusted life years (dalys) by sex and age. morbidity was estimated directly among the confirmed, cured, and fatal cases. disability weights were adopted from previous similar causes on the severity of covid-19 for the years of life lived with disability (ylds). the years of life lost (ylls) were calculated using the standard life expectancy from the 2018 life tables for each sex and age. results: the ylds were higher in females (155.2) than in males (105.1), but the ylls were higher in males (1,274.3) than in females (996.4). the total disease burden attributable to covid-19 in korea during the study period, was estimated to be 2,531.0 dalys, and 4.930 dalys per 100,000 population. the ylds and the ylls constituted 10.3% and 89.7% of the total dalys, respectively. the dalys per 100,000 population were highest in people aged ≥ 80 years, followed by those aged 70–79, 60–69, and 50–59 years, but the incidence was the highest in individuals aged 20–29 years. conclusion: this study provided the estimates of dalys due to covid-19 in korea. most of the disease burden from covid-19 was derived from yll; this indicates that decision-makers should focus and make an effort on reducing fatality for preparing the second wave of covid-19. the world health organization declared a pandemic of coronavirus disease 2019 (covid19) , caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), on march 11, 2020 . between december 2019, when the virus was identified, and end-april 2020, there were more than 2.6 million cases of covid-19 globally. while it was initially reported that about 80% of confirmed covid-19 cases are mild with an estimated case fatality of 2.3%, 1 the exceptional infection rates of covid-19 have created multiple cases everywhere at the same time, resulting in increased burden of disease and increased case fatality which has now risen above 7.1%. 2 after the first case in korea was reported from a passenger who had entered via incheon international airport outside seoul on a plane from wuhan in china, korea had 10,708 reported covid-19 cases and 240 reported covid-19 deaths on april 24, 2020. 2, 3 although there are still new imported cases and cases due to community-spread, the number of new cases has slowed; therefore, korea might be at an end phase of the first wave of the covid-19 epidemic. however, the whole society is still maintaining the highest level of alert and practicing measures such as social distancing, extensive testing and tracing, and wearing facemasks in public because it is possible that a second wave of covid-19 will occur. despite being a respiratory illness caused by a virus, covid-19 shows different characteristics to those of other respiratory viruses such as severe acute respiratory syndrome (sars) and influenza. knowledge of the natural history of coronavirus is limited, but the burden of disease to our society appears to be substantial. therefore, this study aimed to calculate the burden of disease due to covid-19 between january 20 and april 24 in korea. the disability-adjusted life years (dalys) in korea due to covid-19 were measured using an incidence-based approach. 4-6 the dalys were calculated by the sum of the years of life lived with disability (ylds) and the years of life lost (ylls). for the calculation of the ylds, we used the numbers of confirmed cases by sex and age group, the duration of disease, and disability weights (dws). the numbers of confirmed cases of covid-19 by sex or age group were obtained from korea centers for disease control and prevention (kcdc). 3 the data covered all cases confirmed in korea, including foreign nationals. to estimate the duration of disease directly, we used the person-days of the confirmed case and days of symptoms before the confirmation of case. the person-days were directly calculated from the numbers of confirmed, cured, and dead cases. in order to determine the dw of covid-19, we considered the severity of the disease and its mental health effects even though the classical incidence-based approach does not consider the severity of disease. as the severity of covid-19 varies from asymptomatic sars-cov-2 infection to a severe, and sometimes fatal, disease, we categorized the severity of covid-19 into 4 categories (asymptomatic, mild, moderate and severe). 2,7 in addition, covid-19associated anxiety due to the lack of a known effective treatment or cure was also considered. however, as there were no published dw for covid-19 according to its severity, we adopted dws of similar conditions. a multiplicative approach was used to combine two dws. 8 table 1 shows the parameters used for calculation of ylds and range of sensitivity analyses. we considered the number of confirmed cases and deaths, range of severity distribution, disability weight, and morbid duration as variables with uncertainties. to calculate ylls, we used the number of deaths and the standard life expectancy for each sex and age. in order to obtain information of death case such as sex and age, we reviewed the press releases from the kcdc. we also checked the official homepage of the local government where the death occurred and the public media to identify the exact sex and age, because the kcdc only reported the number of deaths by sex and age group. the standard life expectancy was obtained from 2018 life tables according to sex and age, published by the statistics korea. 9 a time discount rate of 3% was applied to the years of standard life expectancy in the future to estimate the net present value of ylls. 5 to compare the results with previous studies, we estimated the ylls, ylds, and dalys per 100,000 population for the mid-year population of 2019 by sex and age, using data from the statistics korea demographic survey. 10 this study was approved by the institutional review board (irb) of korea university (ku-irb-18-ex-51-a-1). the requirement for informed consent was waived because no individuallevel data were used. between january 20, 2020, when the first case of covid-19 was reported, and april 24, 2020 a total of 10,708 confirmed cases of covid-19 (20. burden of covid-19 in korea females (fig. 1a) . the ylds rate per 100,000 population was highest in those aged 20-29 years (1.051) followed by those aged ≥ 80 years (0.666), 50-59 years (0.557), and 60-69 years (0.541) (fig. 1b ). shows the results of the sensitivity analyses investigating the effect of changes of the parameter estimates on the estimated ylds. dw was the most sensitive: decreasing the dws to the lower limit decreased the ylds to 174.7 (−32.9%), whereas increasing the dws to the upper limit increased the ylds to 364.3 (+39.9%). when the duration of covid-19 was one week longer than the baseline (28.4 days), the ylds increased to 324.5 (+24.6%). we also considered the scenario of two weeks isolation after discharge. the additional burden from the stress of prolonged isolation increased the ylds to 338.2, increasing the baseline for ylds and dalys by 29.9% and 3.1%, respectively. in addition, we also investigated the effect of a change in the distribution of severity. when the proportion of severe cases was increased to 9%, the ylds increased to 274.2 (+5.3%). if the classification was based on three stages, reclassification of the asymptomatic cases to the mild category, the ylds increased to 266.3 (+2.3%). 70-79 years age group (29.8%) in males, and the ≥ 80 years age group (40.4%) in females (fig. 3a) . the ylls per 100,000 population increased with age in both sexes (fig. 3b) . years age group, and 1.8% and 98.2%, respectively, in the ≥ 80 years age group. the total dalys were highest in the 70-79 years age group (744.7), followed by the ≥ 80 years (662.5), 60-69 years (573.1), and 50-59 years (335.3) age groups (fig. 4a) . the dalys per 100,000 population were highest in ≥ 80 years age group (37.444), followed by 70-79 years (21.243), 60-69 years (9.481), and the 50-59 years (3.936) age groups (fig. 4b ). we measured the burden of covid-19 from the first wave of covid-19 outbreak from january 20 to april 24 in korea using incidence-based dalys. respiratory infections, giardiasis and pneumococcal pneumonia. out of 243 diseases, covid-19 ranked 85th in ylls and 172nd in ylds. the burden of covid-19 had a higher percentage of ylls (89.7%) and a lower percentage of ylds (10.3%). the proportion of ylls is higher than the average of communicable diseases (72.0%), indicating that covid-19 has a greater impact on premature death. 11, 12 the portion of yll will be increasing because the case fatality is increasing for a while in this first wave. in terms of sex and age group, the dalys were higher in females than in males and increased with age. we found that the absolute numbers of dalys were the highest in 70-79 years age group, however, the population adjusted value, representing the dalys per 100,000 population, showed the highest in ≥ 80 years stage of development group. this implies that the higher the age group, the higher the risk of developing covid-19 disease and death due to covid-19, which is consistent with the findings of previous studies reporting age-specific mortality in other countries. [13] [14] [15] [16] in the last few days of korea, the burden of premature death was greater than the burden from the new cases. the care for those at high-risk, who are older adults or have serious underlying medical conditions is now a higher priority. compared to other communicable diseases from the knbd 2016 study, the covid-19 burden from january 20 to april 24 was 1.39-fold greater than influenza, and 1.16 and 5.18-fold less than pneumococcal pneumonia and upper respiratory infections, respectively. however, the ylds of covid-19 were lower than upper respiratory infections and influenza, and greater than pneumococcal pneumonia and haemophilus influenzae type b pneumonia. in addition, the ylls were lower than those attributable to pneumococcal pneumonia, and greater than those attributable to the other three diseases. although comparison with the diseases having similar symptoms, rather than similar epidemiological characteristics has limitations, the number of cases and the incidence rate of covid-19 was relatively low, on the other hand, the contribution in terms of dalys was relatively high, because of the higher case fatality rate. total burdens of covid-19 in korea are expected to be greater than these estimates, and the percentage of total dalys or rankings could be higher than those reported in this results because it is an ongoing outbreak. there could be undetected cases and there might be more death cases even in the first wave. especially, if the second wave of covid will occur, the covid-19 dalys will be larger. according to the sensitivity analysis, the number of confirmed cases increased by 10%, 20%, and 30%, the total dalys increased by 1.0%, 2.1%, and 3.1%, respectively. alternatively, if only the number of mild cases increased by 10%, 20%, and 30%, the total dalys increased by 0.6%, 1.2%, and 1.9%, respectively. in addition, the fatality of covid-19 on april 24 was 2.24% (240/10,708) but increased to 2.35% (256/10,909) on may 11. 3 the fatality is likely to increase for a while. according to the sensitivity analysis, as the number of the deaths increased by 10%, 20%, and 30%, the total dalys increased by 9.0%, 17.9%, and 26.9%, respectively, and the proportion of the ylls attributable to dalys increased to 90.6%, 91.3%, and 91.9%, respectively. considering these perspectives of covid-19 burden, we can reduce the burden of covid-19 even if the second wave will occur. the most important strategy to reduce dalys of covid-19 in the second wave will be to focus on reducing case fatality because the portion of yll was very high. for example, we can set very low case fatality as a target (0.3% of the case fatality of covid-19 in seoul). it might be achieved through a well-allocation of healthcare resources like healthcare professionals and beds on severity (i.e., while it could provide a care for mild cases in community treatment centers, severe cases were cared for in hospitals.) it was a lesson from the experiences of the first wave of covid-19 outbreak. in addition, it is also important to do primary preventions to reduce the incidence through various preventive approaches such a social distancing in a daily life. if the occurrence will overflow than the healthcare resource capacity, it will be very hard to control, and the covid-19 will increase rapidly. lastly, as early detections of cases also could reduce their reproductive number, it might reduce incidence of the daly metric, as a summary measure of disease burden, is useful in identifying the impact of a disease on public health, especially the impact of infectious diseases in epidemic situations. this study adopted the incident approach for estimation of dalys rather than the prevalent approach which was adopted more recently by the institute for health metrics and evaluation for the global burden of disease study. 18, 19 the reason why the institute for health metrics and evaluation adopted the prevalent approach was that it might be easy to obtain the prevalence than the incidence generally. 20 however, for covid-19 in korea, the confirmed cases were reported in real time by the government. in addition, because the kcdc has been conducting widespread screening for sars-cov-2 infection using realtime polymerase chain reaction, the real incidence could be identified. 20,21 moreover, in most cases, information on the outcome (cure or death) and the severity of the disease also were reported by the kcdc, therefore we were able to obtain most of the epidemiologic parameters required to estimate the dalys based on the covid-19 notification data. as most governments have reported this information, the methods used in this study could be used to estimate dalys due to covid-19 in other countries. to apply the dws by severity, we used dws of diseases having similar symptoms to covid-19. in addition, we considered the effect of covid-19 on mental health. one study reported that about 10% of cases were asymptomatic. 7 although there were no respiratory or infectious symptoms, asymptomatic infection can have negative mental health effects because covid-19 is an emerging disease without a vaccine or any specific treatment. some studies have reported that covid-19 patients experience mental health symptoms such as anxiety. 22,23 although many previous burdens of disease studies using an incidencebased approach did not consider disease severity, we considered the disease severity when calculating the dws because sars-cov-2 infection has a wide range of severity from no symptoms to death. 7, 24 the uncertainty regarding the new disease and anxiety that it could harm other people cause more burden than other diseases. in addition, there is no vaccine or other known effective treatment yet, and the government's actions such as tracking the route of the confirmed patients and informing it to the public, cause not only the disease burden but also the mental burden. therefore, we tried to calculate the covid-19 considering its severity and mental impacts. to combine two dws, multiplicative method was applied because the global burden of disease group also used this approach to combine two or more dws when they mapped health states into sequalae. 20 there are some limitations to this study. first, dws for covid-19 were adopted from those of similar respiratory infections diseases because covid-19 is an emerging disease and covid-19-specific dws have not yet been determined. therefore, the results were interpreted with carefully. in addition, we conducted sensitivity analyses to assess the impact of the assumptions to the range of dalys estimates. fortunately, the impact was relatively small because the portion of yld was relatively smaller than that of yll. however, it is necessary to estimate specific dws for covid-19/sars-cov-2 infection to reflect the exact level of disability in the near future. second, the kcdc only reported the number of deaths by sex and age group, we additionally confirmed data published by local governments and the public media. there was one inconsistent death case between the kcdc and the media in sex classification. the number of female and male was 114 and 126 in this study, whereas 113 and 127 in the kcdc data. the difference in sex caused different life expectancy, however the difference in ylls is small. after the epidemic stables, the data should be confirmed accurately. third, the results from this study are not final one because the epidemic is ongoing. we calculated the dalys of covid-19 even though the epidemic is ongoing because it is necessary to know the exact burden of covid-19 to make informed decisions. once the covid-19 epidemic has ended, we can estimate the final burden of disease due to covid-19, and in future it may be useful to estimate it annually. in conclusion, this is the first study to characterize the disease burden caused by covid-19 in korea using dalys. the methodological framework used in this study can be applied to other countries where disease notification data are collected by the government. determination of the dalys attributable to covid-19 in other countries could provide the basis for international comparisons and prioritization of healthcare resources to control the pandemic. most of the disease burden from covid-19 was derived from yll (89.7%); this indicates that decision-makers should focus and make an effort on reducing fatality for preparing the second wave of covid-19. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention central disaster and safety countermeasures headquarters. covid-19 regular briefing korea centers for disease control and prevention. cases of covid-19 in korea quantifying burden of disease to measure population health in korea global burden of disease and risk factors: the world bank the korean national burden of disease study: from evidence to policy covid-19 in south korea -challenges of subclinical manifestations disability weights measurement for 228 causes of disease in the korean burden of disease study 2012 population statistics based on resident registration trends and patterns of burden of disease and injuries in korea using disability-adjusted life years disability-adjusted life years for communicable disease in the korean burden of disease study 2012 clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study the covid-19 pandemic in the usa: what might we expect? covid-19 response team. severe outcomes among patients with coronavirus disease 2019 (covid-19)-united states case-fatality rate and characteristics of patients dying in relation to covid-19 in italy seventy two hours, targeting time from first covid-19 symptom onset to hospitalization global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017 global, regional, and national disability-adjusted life-years (dalys) for 359 diseases and injuries and healthy life expectancy (hale) for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017 years lived with disability (ylds) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the global burden of disease study 2010 disability-adjusted life years (dalys) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010 using psychoneuroimmunity against covid-19 treating the mental health effects of covid-19: the need for at-home neurotherapeutics is now clinical characteristics of coronavirus disease 2019 in china key: cord-349812-nw1nlc1y authors: jang, won mo; jang, deok hyun; lee, jin yong title: social distancing and transmission-reducing practices during the 2019 coronavirus disease and 2015 middle east respiratory syndrome coronavirus outbreaks in korea date: 2020-06-09 journal: j korean med sci doi: 10.3346/jkms.2020.35.e220 sha: doc_id: 349812 cord_uid: nw1nlc1y background: the absence of effective antiviral medications and vaccines increased the focus on non-pharmaceutical preventive behaviors for mitigating against the coronavirus disease 2019 (covid-19) pandemic. to examine the current status of non-pharmaceutical preventive behaviors practiced during the covid-19 outbreak and factors affecting behavioral activities, we compared to the 2015 middle east respiratory syndrome coronavirus (mers-cov) outbreak in korea. methods: this was a serial cross-sectional population-based study in korea with four surveys conducted on june 2 and 25, 2015 (mers-cov surveys), and february 4, and april 2, 2020 (covid-19 surveys). of 25,711 participants selected using random digit dialing numbers, 4,011 participants (aged ≥ 18 years) were successfully interviewed, for the 2020 covid-19 (n = 2,002) and 2015 mers-cov (n = 2,009) epidemics were included. participants were selected post-stratiﬁcation by sex, age, and province. the total number of weighted cases in this survey equaled the total number of unweighted cases at the national level. we measured the levels of preventive behaviors (social distancing [avoiding physical contact with others]), and practicing transmission-reducing behaviors such as wearing face mask and handwashing. results: between the surveys, respondents who reported practicing social distancing increased from 41.9%–58.2% (mers-cov) to 83.4%–92.3% (covid-19). the response rate for the four surveys ranged between 13.7% and 17.7%. practicing transmission-reducing behaviors (wearing face masks and handwashing) at least once during covid-19 (78.8%, 80.2%) also increased compared to that during mers-cov (15.5%, 60.3%). the higher affective risk perception groups were more likely to practice transmission-reducing measures (adjusted odds ratio, 3.24–4.81; 95 confidence interval, 1.76–6.96) during both covid-19 and mers-cov. conclusion: the study findings suggest markedly increased proportions of non-pharmaceutical behavioral practices evenly across all subgroups during the two different novel virus outbreaks in korea. strategic interventions are needed to attempt based on preventive behavior works. many countries are battling with the coronavirus disease 2019 (covid-19) pandemic because of the absence of effective antiviral medications and vaccines. to control the spread of covid-19, social distancing, wearing of face masks, and washing of hands, which are transmission-reducing behaviors, are being recommended as some of the most important measures. 1-3 because early transmission of the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is caused by pre-symptomatic-or pauci-symptomatic-infected individuals, these non-pharmaceutical preventive behaviors are getting more attention for the containment of the covid-19 pandemic. 4-6 these attempts at behavioral change are aimed at slowing down the spread of emerging infectious diseases and to flatten the epidemic curve. thus, the healthcare system resource capacity can be conserved while allowing time for the development of drugs and vaccines. social distancing (or spatial distancing), including avoidance of outdoor activities, public transportation, healthcare facilities, and crowded places with potential for physical contact between individuals, reduced the number of infections. 2, 3 wearing of face masks and washing of hands are also associated with reduced propensity of transmission. [5] [6] [7] [8] periodically, korea has experienced outbreaks including the severe acute respiratory syndrome (sars), influenza h1n1, middle east respiratory syndrome coronavirus (mers-cov), and covid-19 outbreaks in 2003, 2009, 2015 , and 2020, respectively. 9-11 differences occurred in epidemiologic outcomes (number of cases, fatality rates) of these novel infectious disease outbreaks in korea. only 3 confirmed cases and no death during sars, more than 100,000 confirmed cases and 260 deaths during influenza h1n1, and 185 confirmed cases and 36 deaths during mers-cov occurred. 9 since diagnosing the first covid-19 case in korea on 20 january, 2020, 10,738 cases have been confirmed, 243 deaths occurred, and 3,246 patients were isolated until 27 april, 2020. 12 in february 2020, korea became the worst affected country, aside from china, for a while, and had several surges in the number of cases. 13 however, the korea epidemic curve flattened without coercive restrictions following rapid interventions beginning in march 2020. 14 one possible explanation for the mitigation of the surge was the strong efforts implemented by the korean government and the citizens of korea to practice social distancing and transmission-reducing behaviors. resurgence in the emerging infectious disease provides opportunity for comparing individual's levels of practicing non-pharmaceutical preventive behaviors. however, no study has compared the proportion of practicing non-pharmaceutical preventive behaviors between covid-19 and 2015 mers-cov outbreaks. 2,3,7,15-18 the current study aimed to quantify and compare the individuals' adherence to social distancing and transmission-reducing behavioral practices during the covid-19 and mers-cov outbreaks in korea. factors influencing these practices were also determined. we hypothesized that there would be differences in the rate of adherence to the non-pharmaceutical preventive behaviors and the factors affecting these behaviors between the 2020 covid-19 and 2015 mers-cov outbreaks. the 95% confidence interval (ci), 0.025 desired margin of error, 0.2 behavioral response proportion of population. the 4,011 participants included 2,009 participants older than 19 years who were monitored during the mers-cov outbreak between june 2 and 25, 2015; and 2,002 participants, older than 18 years, who were investigated during covid-19 outbreak between february 4 and april 2, 2020. all surveys were conducted using mobile (85%) or landline (15%) random digit dialing numbers in 8 regions (nationally representative). participants were selected post-stratification by sex, age, and province and chosen independently by each survey. the total number of weighted cases in this survey equaled the total number of unweighted cases at the national level. the weights were normalized to calculate the proportions and ratios but not for estimating the subtotal populations. trained interviewers conducted all interviews using computer assisted telephone interviewing. surveys 3 and 4 began approximately 2 weeks after the index case occurred, while surveys 1 and 2 were conducted approximately a month after surveys 3 and 4. survey 1 was conducted just 10 days before the last confirmed patient of mers-cov on july 4, 2015. however, survey 2 was conducted when there were more than 100 confirmed cases. the surveys were conducted by gallup korea, an affiliation of gallup international. details, including period, number of respondents successfully interviewed, and response rate for each of the four surveys are provided in table 1 . sex, age, occupation, self-reported household economic status, residential area, presidential job approval rating, party identification, and affective risk perception as participants' characteristics, were investigated to identify factors influencing non-pharmaceutical preventive behaviors. age was classified into 5 levels (19-29, 30s, 40s, 50s, and 60 years and older). occupation was classified into five levels (unemployed, self-employed including farming/ forestry/fishery, blue-collar worker, white-collar worker, and full-time homemaker or student). self-reported household economic status was classified into five levels (lower, lower middle, middle, upper middle, and upper). participants were classified as either metropolitan or non-metropolitan residents. presidential job approval rating was assessed using the following options: "approval," "disapproval," or "no opinion." support for party identification was assessed based on alignment either with the ruling party, opposition party, or no opinion. affective risk perception was assessed using the options "worried" or "not worried." 19 the interviews were conducted on the two aspects of the non-pharmaceutical preventive behaviors, which are social distancing measures and transmission-reducing practices ( supplementary data 1 and 2) . social distancing was assessed using the following four questions: 1) "did you reduce or avoid outdoor activities or attend meetings this week because of mers-cov or covid-19?"; 2) "did you reduce or avoid using public transportation such as the bus or the subway this week because of mers-cov or covid-19?"; 3) "did you reduce or avoid using healthcare facilities such as the hospitals or public health centers this week because of mers-cov or covid-19?"; and 4) "did you reduce or avoid visiting crowded markets, departmental stores, or large discount stores this week because of mers-cov or covid-19?" transmission-reducing practice was assessed using the following two questions: 1) "do you wash your hands more often than usual because of mers-cov or covid-19?" and 2) "have you ever worn a face mask because of mers-cov or covid-19?" all the questions about the non-pharmaceutical preventive behaviors required "yes/no" responses. the development of the questionnaires on preventive behaviors had not gone through a validity procedure due to the urgency of the outbreak. we also imposed the survey items on existing questionnaire developed by gallup korea, an affiliation of gallup international. response rates according to preventive behaviors were calculated according to participants' characteristics. univariable analyses using χ 2 test were performed in the four surveys, entirely and respectively, to identify the relationships between practicing preventive behaviors and each demographic variable. missing values of any outcome variable were ≤ 3.6%. multivariable logistic regression analysis was performed to explore factors influencing preventive behaviors in the four surveys, entirely and respectively. we performed multivariable logistic regression model adjusted for sex, age, occupation, selfreported household economic status, residential area, presidential job approval, and party identification. 15 affective risk perception was excluded from survey 1 and survey 2 logistic regression models to attain comparability because no data existed for it in survey 2. on the avoidance of outdoors activities, extremely large number of events made the odds ratios (ors) in survey 2 logistic regression model unstable; therefore, surveys 1 and 2 logistic models were not reported. using logistic regression analysis for transmission-reducing measures and social distancing measures, "y = 1" was used when "yes" for preventive behaviors, otherwise "y = 0" was used. we analyzed with a 2-sided p value of less than 0.05 considered significant using sas version 9.4 (sas institute inc, cary, nc, usa). this study was reviewed and approved by the institutional review board (irb) of seoul metropolitan government-seoul national university boramae medical center (irb no. 20200403/07 -2020 -12/043). the need for informed consent was waived by the board. differences in participants' general characteristics between surveys 1 and 2 are shown in table 2 . overall, the practice rate of avoiding outdoor activities in survey 2 increased 1.7-fold compared to that in survey 1. depending on the general characteristic, avoiding outdoor activities' practice rate differed by as little as 28.2% (upper economic status) and as much as 54.6% (presidential job approval). overall, avoiding public transportation practice rate in survey 2 increased 2.1-fold compared to that in survey 1. depending on the general characteristic, avoiding public transportation' practice rate differed by as little as 29.3% (aged 30-39 years) and as much as 57.6% (no opinion of presidential job approval). overall, avoiding healthcare facilities' practice rate in survey 2 increased 1.6-fold compared to that in survey 1. depending on the general characteristic, avoiding healthcare facilities' practice rate differed by as little as 22.7% (opposition party identification) and as much as 49.9% (presidential job approval). overall avoiding crowded places' practice rate in survey 2 increased 1.8-fold compared to that in survey 1. depending on the general characteristic, avoiding crowded places' practice rate differed by as little as 4.4% (upper economic status) and as much as 49.3% (presidential job approval). there were no statistically significant differences between surveys with participants' characteristics except with occupation, self-reported household economic status, presidential job approval rating, and party identification. with occupation, higher proportions occurred in the unemployed and blue-collar workers in survey 2, while lower proportions occurred in white-collar workers and home makers or students. of the self-reported household economic status, survey 4 had higher proportions in the 'upper middle' and 'middle' status, while lower proportions occurred in 'low middle' and 'lower' status. with respect to the presidential job approval rating, the percentage of participants who reported obtaining 'approval' increased in survey 2 compared to survey 1. of the party identification, the proportion in the 'ruling party' in survey 2 were higher than that in survey 1. comparison of the general characteristics of the participants between surveys 3 and 4 are shown in table 3 . overall, wearing of face mask rate in survey 4 had increased by more than 5-fold compared to that in survey 3. depending on the general characteristic, the wearing of face mask rate differed by as little as 39.2% (upper economic status) and as much as 71.3% low middle economic status). overall, the washing of hands rate in survey 4 increased by 1.3fold compared to that in survey 3. depending on the general characteristic, washing of hands rate differed by as little as 12.0% (aged 19-29 years) and as much as 37.5% (upper economic status). there were definitively, statistically significant differences in the wearing of face masks rate in all subgroups between surveys 3 and 4. no significant differences occurred in participants' proportions between surveys, except with occupation, self-reported household economic status, presidential job approval rating, and party identification. with occupation, survey 4 had higher proportions of the unemployed and blue-collar workers, while had lower proportions of the self-employed and home makers or students. of the self-reported 6/11 https://jkms.org https://doi.org/10.3346/jkms.2020.35.e220 household economic status, survey 4 had a higher proportion of those in the 'middle' status, while had a lower proportion of those in the 'low middle.' with respect to presidential job approval rating, the percentage of participants who reported 'approval' increased when survey 4 was compared with survey 3. of the party identification, the proportion in the 'ruling party' in survey 4 were higher than that in survey 3. table 4 reports the association between variables and non-pharmaceutical preventive behaviors, social distancing and transmission-reducing behaviors. of social distancing behaviors, generally, none of the factors (characteristics) consistently affected any kinds of social distancing behaviors (avoiding public transportation, healthcare facilities, and crowded places) in both surveys 1 and 2. the results showed that sex, presidential job approval rating, and party identification were significantly associated with social distancing behaviors in survey 1, but not in survey 2. those aged 30 years and older were more likely to avoid public transportation in both surveys 1 and 2. participants aged 30-39 years were more likely to avoid healthcare facilities in survey 2 only. those aged 30-49 years were more likely to avoid crowded places in survey 1 only. only in survey 2 were residents of metropolitan cities identified to have practiced avoidance of public transportation behaviors less. in transmission-reducing behaviors, both surveys 3 and 4 reported that females were more likely to practice preventive behaviors (adjusted or [aor], 1.57-2.43; 95% ci, 1.04-3.78), which tended to be stronger in survey 4. the association of affective risk perception with transmission-reducing behaviors was also observed in both surveys 3 and 4. participants who reported being 'worried' were more likely to practice both the wearing of face masks and handwashing (aor, 3.24-4.81; 95% ci, 1.76-6.96). those living in metropolitan cities more frequently wore face masks in both surveys 3 and 4. participants aged 50 years and older practiced less wearing of face masks in survey 4 only. the results showed that presidential job approval rating and washing of hands were significant in survey 3, but not in survey 4. possibly, the current study is the first to explore changes in individuals' non-pharmaceutical preventive behaviors during two different consecutive emerging infectious disease outbreaks in korea. 2,3,7,15-17,20-22 first, our study showed a marked increase in non-pharmaceutical preventive behaviors such as social distancing, wearing of face masks, and washing of hands, evenly, across all subgroups during covid-19 compared to 2015 mers-cov. during the previous 2003 sars outbreak in hong kong, the level of preventive behavioral practice increased over time, but differences in level was not compared between outbreaks. 23 a possible explanation for the increase of preventive behavioral practices during covid-19 in korea could be due to previous experience of emerging infectious disease epidemic, intensifying the practice. 24 additional study is needed to examine why the preventive behavioral practice increased during covid-19 outbreak, and to understand how differences in preventive behavioral practices affected the transmission during repeated and different emerging infectious disease outbreaks. 25 however, there is need to investigate for further understanding, the association between risk perception (affective and cognitive) and preventive behaviors. 19 third, our results, showing that low level of trust in the president and identification of opposition party influenced preventive behavioral practice during 2015 mers-cov but not during 2020 covid-19 are inconsistent with those of previous studies. 15,17 differences in the korean government's responses to the two different emerging infectious disease epidemics could have affected how the public perceived the image of the president and the ruling party, as well as the trust in the government. 9,14,19,26-32 further research is needed to understand the conditions of trust in the president and identification of a party that could affect preventive behavioral practices. however, this study has some limitations. first, that this study used surveys on self-reported practices could mean that the data could be different from those obtained through observed practices. therefore, there could have been measurement errors. (i.e., social desirability bias, 'yes-saying' bias) however, surveys of observed practices are difficult to conduct during health crisis. second, this study used a cross-sectional design; hence, it could not establish causal relations. third, risk perception (affective and cognitive reactions) was not fully surveyed during the outbreaks, limiting the interpretation of findings. fourth, the current study could not evaluate the intensity of the preventive behaviors. finally, because of the unexpected rapidly evolving outbreak, this study could not examine the validity of the questionnaire using a test-retest design. in conclusion, the present study suggests, for the first time, the level of the practice rate of non-pharmaceutical preventive behaviors and influencing factors during 2020 covid-19 and 2015 mers-cov in korea. affective risk perception can increase practicing reducing transmission measures and it can be used to prevent the failure of preventive behavior management. to understand the mechanism of behavioral immunity, further exertions are needed behind the citizens, the governmental public health sector, as well as the academic society. strategic interventions to suppress the spread of infectious diseases based on preventive behaviors works through cooperation of individuals with regulations and will be a salient contribution to a quick end to covid-19 pandemic. thus, policies to guide such strategic interventions need to be developed. basic protective measures against the new coronavirus impact assessment of nonpharmaceutical interventions against coronavirus disease 2019 and influenza in hong kong: an observational study the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study virological assessment of hospitalized patients with covid-2019 social distancing against covid-19: implication for the control of influenza seventy-two hours, targeting time from first covid-19 symptom onset to hospitalization effectiveness of handwashing in preventing sars: a review mathematical modeling of the effectiveness of facemasks in reducing the spread of novel influenza a (h1n1) central government reform to improve national disease control severe acute respiratory syndrome epidemiological characteristics of imported influenza a (h1n1) cases during the 2009 pandemic in korea covid-19: surge in cases in italy and south korea makes pandemic look more likely korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from preventive behavioral responses to the 2015 middle east respiratory syndrome coronavirus outbreak in korea preventive behaviors by the level of perceived infection sensitivity during the korea outbreak of middle east respiratory syndrome in 2015 social distancing and transmission-reducing practices during covid-19 outbreak in korea 17. lee km, jung k. factors influencing the response to infectious diseases: focusing on the case of sars and mers in south korea adoption of personal protective measures by ordinary citizens during the covid-19 outbreak in japan influence of trust on two different risk perceptions as an affective and cognitive dimension during middle east respiratory syndrome coronavirus (mers-cov) outbreak in south korea: serial cross-sectional surveys perceived risk, anxiety, and behavioural responses of the general public during the early phase of the influenza a (h1n1) pandemic in the netherlands: results of three consecutive online surveys risk perception, preventive behaviors, and vaccination coverage in the korean population during the 2009-2010 pandemic influenza a (h1n1): comparison between high-risk group and non-high-risk group community-based risk communication survey: risk prevention behaviors in communities during the h1n1 crisis monitoring community responses to the sars epidemic in hong kong: from day 10 to day 62 social distance and sars memory: impact on the public awareness of 2019 novel coronavirus (covid-19) outbreak. medrxiv. forthcoming early assessment of anxiety and behavioral response to novel swine-origin influenza a(h1n1) institutional trust and misinformation in the response to the 2018-19 ebola outbreak in north kivu, dr congo: a population-based survey perception of hazards: the role of social trust and knowledge public health crisis response and establishment of a crisis communication system in south korea: lessons learned from the mers outbreak mers tarnishes korean president's image as leader middle east respiratory syndrome in south korea during 2015: risk-related perceptions and quarantine attitudes coronavirus in south korea: how 'trace, test and treat' may be saving lives how south korea flattened the curve we would like to thank gallup korea, an affiliation of gallup international, for supporting surveys and data collection for this manuscript. questionnaire (korean). 