key: cord-293500-z28bws23 authors: guan, wei-jie; liang, wen-hua; he, jian-xing; zhong, nan-shan title: cardiovascular comorbidity and its impact on patients with covid-19 date: 2020-04-27 journal: eur respir j doi: 10.1183/13993003.01227-2020 sha: doc_id: 293500 cord_uid: z28bws23 comorbid hypertension correlates with poorer outcomes in patients with covid-19. with . we truly appreciate the comments from sisnieguez et al., who have performed a further analysis on the potential association between cardiovascular comorbidities and the clinical outcomes of covid-19 (in particular, the mortality) [1] . we also applaud the suggestion to thoroughly adjust for the potential confounding factors when interpreting the association between specific categories of cardiovascular comorbidities (e.g., hypertension) and the clinical outcomes of covid-19. to this end, we have attempted to incorporate the cardiovascular diseases (including coronary heart disease) into the multivariate regression model [2] . findings of the model indicated a prominent collinearity between hypertension and coronary heart disease, and we have therefore elected to retain hypertension in the regression model for further analyses. like other comorbidities such as chronic obstructive pulmonary disease, the record of cardiovascular comorbidities was derived from the patient's self-report, which could not preclude under-reporting. therefore, the percentage of patients with cardiovascular diseases might have been underestimated given the urgency of data collection (history taking) within the wards during the outbreak. our findings could have also been attributed to the relatively low proportion of patients with co-existing hypertension and coronary heart disease in our study. nonetheless, the overall proportion of patients with comorbidities in our study [2] was in keeping with the previous publications [3] [4] [5] [6] [7] . our findings were likely to be generalizable to other population worldwide. the causes for the association between cardiovascular diseases and the poor clinical outcomes of covid-19 might be multifaceted, including but not limited to the interaction with the age, and the cardiac dysfunction due to viral infections. since our study was a crosssectional case study, causality could not be inferred from the current study design. dynamic monitoring of the cardiovascular symptoms, the cardiac function, and the laboratory markers might help unravel the underlying pathways linking cardiovascular diseases to the poor clinical outcomes of covid-19. arterial hypertension and the risk of severity and mortality of covid-19 comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis association of age and comorbidity on 2009 influenza a pandemic h1n1-related intensive care unit stay in massachusetts clinical features and short-term outcomes of 144 patients with sars in the greater toronto area prevalence of comorbidities in cases of middle east respiratory syndrome coronavirus: a retrospective study prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov) diabetes mellitus, hypertension, and death among 32 patients with mers-cov infection, saudi arabia key: cord-290378-h4cof32m authors: guy, tiphaine; créac'hcadec, audrey; ricordel, charles; salé, alexandre; arnouat, baptiste; bizec, jean-louis; langelot, marie; lineau, christine; marquette, david; martin, françoise; lederlin, mathieu; jouneau, stéphane title: high-flow nasal oxygen: a safe, efficient treatment for covid-19 patients not in an icu date: 2020-08-28 journal: eur respir j doi: 10.1183/13993003.01154-2020 sha: doc_id: 290378 cord_uid: h4cof32m sars-cov2 infected patients with non-hypercapnic acute hypoxemic respiratory failure can benefit from hfno outside an icu. the technique appears to be safe for hcws and could well liberate critical icu resources. the new severe acute respiratory syndrome coronavirus 2 (sars-cov-2) that causes coronavirus disease (covid-19), now recognized by the who as a pandemic, emerged in late 2019 in china (1) . patients infected with sars-cov-2 can develop severe pneumonia and respiratory failure, which often require treatment in intensive care units (icu) in western european countries (2) . oxygen therapy and supportive care are still the main forms of therapy for sars-cov-2 pneumonia until suitable anti-infective therapies become available. three large clusters of sars-cov-2 infected patients were detected in france at the end of february 2020, in the east (mulhouse, strasbourg), around paris (creil, compiègne), and in the west (auray and crac'h, near vannes in brittany). high-flow nasal oxygen (hfno, airvo2 tm , fisher and paykel healthcare) has been a standard therapy for non-hypercapnic acute hypoxemic respiratory failure in vannes hospital since the publication of the florali trial in 2015 (3) . this report describes the use of hfno to manage sars-cov-2 infected patients with respiratory failure on the pulmonology ward rather than in an icu. a total of 34 consecutive patients who tested positive for covid-19 by rt-pcr were admitted to the respiratory department. hfno was systematically initiated when the oxygen flow exceeded 5l/min, then 14 single rooms dedicated to hfno were rapidly set up ("hfno unit") with continuous monitoring of pulsed oxygen saturation. hfno was required by 27 of the 34 patients, therefore this report will focus on them. the median (iqr25-75) age of patients on hfno was 77 years (77-79), 81% (22/27) were men, and their median body mass index (bmi) was 25.9 kg/m² (23.3-29.4). they were admitted within a median of 7 days (3-8) after the first sars-cov2 symptoms appeared. the median pao2/fio2 ratio was 203 (198-286) at admission, and 124 (120/158) immediately prior to hnfo initiation. the median time from admission to hfno initiation was 2 days (1-3) and the median duration of hfno was 6 days (2-10). the median airvo2 tm total flow was 55l/min (50-60) and the median fio2 was 65% (60-70). we used « targeted » oxygen therapy to avoid over oxygenation, and our targeted spo2 was between 92 and 94%. as of march 31, 19 patients (70%) were weaned from hfno, 4 (15%) were still on hfno, and 4 (15%) had died ( figure 1 ). of the 19 patients weaned from hfno, 9 had returned home after a median hospital stay of 17 days (14-22), 6 were transferred to a rehabilitation unit, and 4 remained on the ward with reduced oxygen (less than 3l/min). of the 4 unweaned patients, 2 remained on hfno unit and 2 were transferred to the icu. of the 4 deceased patients, 1 died after 6 days of mechanical ventilation (decision to limit life sustaining therapy in icu), while the other 3 were not transferred to icu due to severe comorbidities. altogether, 7 out of 27 patients (26%) had their respiratory status deteriorated on hfno and were transferred to icu where they were mechanically ventilated for a median of 7 days (5-12). as hfno can generate infectious aerosols, all health care workers (hcws) in contact with patients treated with hfno were taught airborne precautions. the personal protection equipment (ppe) was composed offfp2 masks (reference m52010-wh, kolmi ® , st barthélemy d'anjou france), hospital suits (fabric pajamas changed every day), disposable gowns with waterproof aprons, gloves, overshoes, and eye and head protections. the patients themselves also wore surgical masks when an hcw entered their room. surgical masks have been mandatory for all hcws while they were on the vannes hospital site since march 2, 2020. only one of the 44 hcws (7 pulmonologists, 20 nurses, 12 caregivers, 3 physiotherapists, 1 dietitian, and 1 psychologist), a nurse, had become infected by april 5, 2020. however, domestic contamination is suspected since this nurse was living with his parents, who had previously been infected via the eastern france cluster. all three of them tested positive for sars-cov-2. no other hcw was absent from work or presented any symptoms of covid-19. the use of hfno in covid-19 raises two issues: its safety and its effectiveness. the theoretical risk of virus aerosolization resulted in early published reports of critically ill sars-cov-2-infected patients in china not recommending the use of hfno or non-invasive ventilation until the patient had been cleared of covid-19 (4). however, clinical evidence is scarce. recent guidelines for the clinical management of severe pneumonia following a sars-cov-2 infection do not exclude the use of hfno with maximal precautions to exclude airborne transmission (weak recommendation) (5) . and a 2012 meta-analysis found no increased risk of hcws being infected with sars when using hnfo (6) . in fact, hfno seemed to have a protective effect, suggesting that avoiding intubation reduced the risk of transmission. more recently, some have recommended using hfno for patients with moderately severe hypoxaemia, which might make intubation unnecessary, or at least delay it (7) . the only nurse infected with sars-cov-2 in the present study was probably contaminated by his parents. if so, none of the hcws on this 14-bed unit were infected with hfno after a 30-day follow-up. as the median incubation time is 5 days (8), is seems likely that using hfno to treat covid-19 patients requiring oxygen (> 5l/min) was safe for hcws at our institution. however, there is still a risk of aerosolization and all hcws were required to wear personal protective equipment, not just ffp2 masks, when using hfno. hydro-alcohol handwash and "social distancing" are also major tools for avoiding infection. above all, the experience of hcws with hfno management and continued training in anti-airborne precautions undoubtedly help minimize the risk of contamination in the respiratory unit. the results of this monocentric study (23/27 patients recovered, 19/27 weaned from hfno, including 9 discharged) suggest that hfno is effective. however, further confirmatory studies at other centres are urgently needed. our 15% in-hospital mortality rate is similar to the 14% recently published from a french 3-year multicenter prospective study which included adults admitted with influenza and influenza-like illness (9) . managing infected patients with hfno could save critical icu resources, including access to mechanical ventilation, in the context of a large-scale covid-19 outbreak. hfno allows patients to feed more easily than when on other forms of oxygen supplementation, particularly mechanical ventilation, and facilitates respiratory/bronchial physiotherapy and muscle rehabilitation. mechanical ventilation may require curarization and thus induce additional muscle loss. another positive feature of hfno is that patients can continue talking and interacting with their family and hcws. this is psychologically very important for everyone involved. while these results should be confirmed in larger studies, we believe that our data strongly suggest that sars-cov2 infected patients with non-hypercapnic acute hypoxemic respiratory failure can benefit from hfno outside an icu. the technique appears to be safe for hcws and could well liberate critical icu resources. who director-general's opening remarks at the media briefing on covid-19 -18 baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure staff safety during emergency airway management for covid-19 in hong kong surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review treatment for severe acute respiratory distress syndrome from covid-19 the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application non-influenza respiratory viruses in adult patients admitted with influenza-like illness: a 3-year prospective multicenter study key: cord-316058-eh4m5jqz authors: long, li; zeng, xiansheng; zhang, xu; xiao, wei; guo, e.; zhan, wenzhi; yang, xuejiao; li, chunyan; wu, caiyun; xu, tingting; zhan, chen; chen, yuehan; jiang, mei; zhong, nanshan; lai, kefang title: short-term outcomes of coronavirus disease 2019 and risk factors for progression date: 2020-04-20 journal: eur respir j doi: 10.1183/13993003.00990-2020 sha: doc_id: 316058 cord_uid: eh4m5jqz with a median follow-up time of 24.0 (17.5–30.0) days, progression occurred in 19.6% moderate, 27.8% severe, 66.7% critical covid-19. a neutrophil-to-lymphocyte ratio ≥2.973, age ≥50 years, male gender, and comorbidity were associated with progression. coronavirus disease 2019 (covid-19) has now become a worldwide health concern. the severity of covid-19 was classified as mild, moderate, severe and critical [1] . to date, there were a few studies focused on the clinical course and outcome of critical cases [2] [3] [4] . however, information regarding outcomes of mild to moderate cases are lacking, despite the fact that mild to moderate cases accounted for approximately 80% of laboratory-confirmed patients [1, 5] . this study aimed to investigate short-term outcomes of patients rated as different severities on admission, and to identify risk factors for progression, thereby, help the management of covid-19 in clinical practice. all consecutive patients with laboratory-confirmed covid-19 admitted to the first people's hospital of jingzhou and xiangyang central hospital, which were tertiary hospitals located in jingzhou city and xiangyang city, hubei province, between january 16 th and february 24 th , 2020 were unselectively enrolled. diagnosis of covid-19 was made according to the diagnosis and treatment scheme of covid-19 (interim version 5) released by china's national health commission [6] , and comply with world health organization interim guidance [7] . mild cases were defined when patients only presented with mild symptoms and did not have a radiographic appearance of pneumonia. moderate cases were defined when patients presented with fever and/or respiratory symptoms and have a radiographic appearance of pneumonia. severe cases were defined when patients presented with one of the followings, 1) respiratory distress, respiratory rate ≥ 30 breaths/minute; 2) finger oxygen saturation ≤ 93% at resting state; 3) partial pressure of arterial oxygen (pao 2 )/fraction of inspired oxygen (fio 2 ) ≤ 300mmhg. critical cases were defined when patients presented with one of the following, 1) respiratory failure occurs and requires mechanical ventilation; 2) shock occurs; 3) other organ failure occurs and should be admitted to the intensive care unit [6] . progression would be determined once the severity got worse, the date was recorded to calculate the interval between admission date and progression date. severe/critical disease condition on admission and unchanged severity at the endpoint assessment was not classified as progression. clinical features, laboratory findings, treatments, as well as clinical outcomes (ie. discharge, the severity of the disease, mortality, length of stay) of patients were recorded and monitored up to march 1 st , 2020. this study was approved by the ethics commissions of both hospitals (the first people's hospital of jingzhou 42016803-t, xiangyang central hospital 2020-001). written informed consent was waived due to the emergency of the covid-19 pandemic. a total of 301 confirmed cases were enrolled, 150 (49.8%) were male, the median age was 51.0 (iqr 36.0-63.0) years. on admission, the median disease duration was 6.0 (4.0-9.0) days, and the proportion of mild, moderate, severe, critical cases was 8 (2.6%), 245 (81.4%), 36 (12.0%), 12 (4.0%), respectively. a standard treatment protocol was applied. as for mild/moderate patients, 214 (84.6%) were treated only with medical treatment as initial therapy (antiviral therapy combined with as needed antibiotics, expectorant, chinese patent medicines, etc.), while 39 (15.4%) received both medical treatment and low-flow oxygen inhalation. all of the 48 severe/critical patients received both medical treatment and oxygen therapy, including 22 (45.8%) low-flow oxygen inhalation, 15 (31.3%) high-flow inhalation, 8 (16.7%) non-invasive ventilation, 3 (6.2%) invasive ventilation. by the final day of follow-up, the median observation time was 24.0 (17.5-30.0) days, and the median disease duration of the included patients was 30.0 (23.0-36.0) days. of the 301 included patients, 156 (51.8%) patients were treated only with medical treatment, and low-flow oxygen inhalation, high-flow oxygen inhalation, non-invasive ventilation, invasive ventilation, ecmo were given to 104 (34.6%), 42 (14.0%), 17 (5.6%), 4 (1.3%), 1 (0.3%) patients, respectively (some patients received more than one type of oxygen therapy). none of the mild cases had experienced progression. 48 (19.6%) out of the 245 moderate patients experienced progression during hospitalization, among them, 14 (5.7%) turned moderate, 6 (2.5%) were discharged, while 21 (8.6%) were severe, 2 (0.8%) were critical, 5 (2.0%) died at the endpoint. 10 (27.8%) out of the 36 severe cases had experienced progression, among them, 1 (2.8%) turned moderate, 1 (2.8%) were discharged while 2 (5.6%) were severe, 2 (5.6%) were critical, 4 (11.1%) died. as for the 12 critical cases, 1 (8.3%) turned moderate and 8 (66.7%) died. by the final day of follow-up, overall, 66 (21.9%) of patients had experienced progression. the proportion of discharged, mild, moderate, severe, critical and dead patients was 156 (51.8%), 5 (1.7%), 84 (27.9%), 34 (11.3%), 5 (1.7%) and 17 (5.6%), respectively. the median time from admission to disease progression was 6.0 (5.0-9.0) days, to discharge was 22.0 (16.0-25.0) days. assessing by roc curve, the optimal cut-off value of age for differentiating progression and no progression patients was 50 years (area under the curve: 0.7366, sensitivity: 81.8%, specificity: 58.3%), the optimal value of the neutrophil-to-lymphocyte ratio was 2.973 (area under the curve: 0.7338, sensitivity: 75.8%, specificity: 66.8%). variables including baseline characteristics, laboratory findings, and chest ct scan findings were analysed by univariate cox regression analyses, and sex, age, comorbidities, the neutrophil-to-lymphocyte ratio, eosinophil count, c-reactive protein level were identified as significant variables, which were then included into multivariate cox regression analyses. a neutrophil-to-lymphocyte ratio ≥ 2.973 (hazard ratio *95% ci+: 2.641 *1.421-4.908], p = 0.002), age ≥ 50 years (2.504 *1.202-5.215], p = 0.014), male gender (2.004 [1.101-3.647], p = 0.023), and with comorbidity (1.969 [1.085-3.571], p = 0.026) were identified as risk factors for progression by multivariate cox regression analyses. kaplan-meier curve was used to estimate time-dependent hazards categorized by the above risk factors (fig 1) . all patients who experienced progression during hospitalization had at least one of the risk factors. 54 (81.8%) of them were aged ≥ 50 years, 50 (75.8%) had a neutrophil-to-lymphocyte ratio ≥ 2.973, 46 (69.7%) had comorbidity, 44 (66.7%) were male. as far as we know, this is the first study that focuses on clinical outcomes of covid-19 patients rated as different severities on admission. considering a few of mild to moderate cases developed critically ill condition, we chose the progression of covid-19 as the primary outcome rather than a composite endpoint (one or more of death, admission to the icu, the use of mechanical ventilation). we believe findings in this study would be more helpful to prevent progression in an earlier stage for the general covid-19 patients, and could be a supplement to a recent study that reported patients with any comorbidity were more likely to achieve the composite endpoint than those without [8] . our study has some limitations. first, hospitals would give a priority to more severe patients, which might lead to a lower proportion of mild cases in this study. second, although we had a median follow-up time of 24.0 (17.5-30.0) days, at the endpoint, nearly half of the patients were still hospitalized. progression could occur in a part of patients who did not get worse during our observation period, thus, the actual progression rate might be higher than the results shown in the present study. in conclusion, with a median follow-up time of 24.0 (17.5-30.0) days, we found progression occurred in 19.6% of moderate cases, 27.8% of severe cases and 66.7% of critical cases during hospitalization. a neutrophil-to-lymphocyte ratio ≥ 2.973, age ≥ 50 years, male gender, and comorbidity were associated with progression. our thanks go to all doctors and nurses in the first people's hospital of jingzhou and xiangyang central hospital. time from admission to progression categorized by risk factors. a) age < 50 years vs age ≥ 50 years. b) neutrophil-to-lymphocyte ratio < 2.973 vs neutrophil-to-lymphocyte ratio ≥ 2.973. c) with comorbidity vs without comorbidity. d) female vs male. who-china joint mission. report of the who-china joint mission on coronavirus disease 2019 (covid-19) available from clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study 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 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention china's national heath commission. diagnosis and treatment scheme of 2019-ncov (interim version 5) clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected (ncov)-infection-is-suspected (date last accessed comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis key: cord-325565-cz9f65ca authors: heederik, dick j.j.; smit, lidwien a.m.; vermeulen, roel c.h. title: go slow to go fast: a plea for sustained scientific rigor in air pollution research during the covid-19 pandemic date: 2020-06-25 journal: eur respir j doi: 10.1183/13993003.01361-2020 sha: doc_id: 325565 cord_uid: cz9f65ca present studies on the role of air pollution and covid-19 spread and prognosis in patients do not fulfill quality criteria and are at present not sufficiently informative. the second study used european data and, based on simple correlation analyses, associated long term (jan-feb 2020) exposure to nitrogen oxides (nox) in the troposphere (resolution ~7*3.5km), assessed using satellite data, and absolute numbers of covid-19-related deaths. [4] the study made use of data from 66 administrative regions in france, germany, italy and spain. in this analysis no standardization or adjustments to basic variables as population size and age distributions were made. the result, which was strongly driven by a few data points from italy and spain, was interpreted as an association between nox levels and fatal covid-19 case counts. the third and smallest study associated levels of no x and ozone between 2018 and 2019 obtained from monitoring stations across england with covid-19 mortality in a mere 7 different english regions. [5] positive associations were seen between levels of nitrogen dioxide and nitrogen oxide and increased covid-19 mortality and reported number of cases, without adjustment for population size, age distribution or other confounding variables. a negative association was observed with ozone levels. the authors concluded that their study provided a useful framework to guide health policy in countries affected by the pandemic. all three so-called ecological studies rely on aggregate data, which can suffer from the well-known problem of ecological fallacy, where a misjudgment in interpretation occurs as inferences about individuals are reasoned from the group to which the individual belongs. [9] the study design is prone to potential confounding as on an aggregate level, many factors may vary and even co-vary between geographical entities. given the number of groups (i.e. counties) involved in the first study, and the higher quality of exposure assessment, ecological biases are clearly less likely than in the second and third study. the first study is also methodologically stronger because it is adjusted for a range of confounders at the county level, while in the two other studies, no adjustment for confounding factors was considered. however, a major issue, mostly ignored in these studies, resides in the complexity of a potential association between air pollution and covid-19 morbidity and mortality. in particular, the effect of air pollution on the spread of sars-cov-2 infection and on covid-19 prognosis should be distinguished. the dynamics of an epidemic are dependent on transmissibility, contact rates and duration of infectiousness summarized in the basic reproduction number or r 0 . this factor may differ between geographical regions and over time. changes in r 0 can occur over time as a result of the natural history of the epidemic and infection control measures being implemented, as is shown by the leveling off of epidemic curves in many countries where physical distancing is practiced. in particular, the reproduction number can be high in early stages of an epidemic when disease recognition and control measures are less adequate. whether air pollution affects the spread of an infectious disease, depends on whether the factors that determine the reproduction number; transmissibility, contact rates and duration of infectiousness, are influenced by air pollution. theoretically one can imagine that each of these variables can be influenced by air pollution, by changing host susceptibility, mobility and contact patterns and severity and duration of the infection. to explore whether air pollution influences r 0 , high resolution temporal and spatial data are required, preferably supported by virus sequencing data. this far exceeds the granularity of the data used in air pollution studies and most infectious disease outbreak studies. in particular the two ecological studies which crudely correlate reported numbers of covid-19 cases or mortality to regional air pollution levels ignored the time of introduction of covid-19 in the different areas, did not take into account disease dynamics in any way, and ignored basic epidemiologic principles by using inadequate measures of disease frequency. [10] to study the effect of air pollution on the spread of the pandemic in ongoing studies requires knowledge about the time of the virus introduction in the study area(s) and the dynamics of the pandemic in the study area(s). when comparing different study areas, the local outbreak size needs to be accounted for. the authors of the us study seem well aware of their study's limitations related to outbreak dynamics and acknowledged that using total population size in a county as a proxy for the local size of the outbreak in a given county, may result in unmeasured confounding through partial adjustment for outbreak size. [3] the updated study probably better adjusted for outbreak dynamics by including days since first covid-19 case reported and days since issuance of stay-at-home order for each state, resulting in a considerably smaller regression coefficient for pm 2.5 and covid-19 mortality. the fact that the epidemic had spread more evenly across the country, also to less urbanized areas, from almost 42% of counties with covid-19 deaths to almost 78% might also have contributed to a weaker association for pm 2.5 . a separate us study, associating covid-19 fatality rates and mortality to pm2.5 in a three pollutant model (pm 2.5 adjusted for 0 3 and no x ), showed a null association for pm 2,5 with covid-19 fatality rates and a marginally significant association with mortality. [11] the use of the case fatality rate instead of covid-19 mortality, and adjustments for epidemic timing of introduction and spread of covid-19 by adjusting for the time the 1 st and 100 th covid-19 case occurred, probably explains the marked difference in results for pm 2.5 with the other us study. the authors also indicate that control for spatial trends in exposure and residual autocorrelation in exposure between counties may also have contributed to the observed difference in pm 2.5 study results. the same study found positive and statistically significant associations for no x . however, it was concluded that no x air pollution level may act as a surrogate for urbanicity, despite of adjustment for population density. these studies together highlights that uncovering the effect of air pollution on the spread of sars-cov-2 represents an enormous challenge that will require multidisciplinary collaboration and highquality data. other approaches, among which air pollution time series studies need to be explored when the appropriate covid-19 data to perform such analyses become available. such approaches should also consider the effect of changes in air pollution levels. however, changes in air pollution also occurred after introduction of measures to mitigate the impact of the pandemic. here confounding still plays a major role as many additional factors changed at the same time (e.g. physical activity, stress, social economics, medical care visits) introducing other challenges in the data analyses. in the meantime, multiple other studies have been published, many of which can be found in a useful study repository. [12] however, many of these studies did not take into account covid-19 outbreak dynamics. this leads to similar biases are described here. the effect of air pollution on disease prognosis can be studied using more conventional approaches after covid-19 infection. for instance by following up in time confirmed patients in different regions with different levels of air pollution. however, even this type of study might be complicated by confounding: for instance disease severity and testing policies can differ by treatment center, and the fact that quality of care delivered by health care systems may differently vary across regions depending on the size of the local outbreak. these scenarios are more classical examples of confounding for which a range of solutions may be considered. the use of test-negative designs has been proposed in which risk factors are compared between subjects that test positive or negative to sars-cov-2. [13] such designs can eliminate some of the aforementioned concerns (access to testing etc.), but has other limitations, mainly related to shared risk factors for being tested regardless of the outcome (e.g. presence of respiratory disease). we certainly do not want to argue that air pollution does not play a role in the covid-19 pandemic. there is previous evidence from the sars coronavirus epidemic [14] (albeit that this study suffers from the same ecological problem as the current studies), similarities with a possible smoking contribution to the pandemic [15] , mechanistic evidence involving the angiotensin-converting enzyme 2 (ace-2) receptor in covid-19 pathology that could be influenced by air pollution [16] , and the fact that air pollution has previously been causally linked to risk of pneumonia and other comorbidities that contribute to covid-19 deaths. [17] however, determining if there is a causal effect and obtaining an accurate estimate of the effect requires rigorous and time consuming research. a final major point of criticism that we wish to make is that one of the aforementioned papers was accepted for publication after a 1-day review period [4] , while the other papers made headlines before the peer-review process based on preprint manuscripts. [3, 5, 16] it is important to ask why is this the way covid-19 air pollution research is being reviewed and communicated? research in this field may be of relevance for the spread of infectious disease and disease prognosis, but outcomes from air pollution research are unlikely to lead to changes in the implementation of pandemic control measures and in the clinical care of patients. instead, air pollution and infectious disease epidemiology research will have an impact in the longer term, as to fully understand etiology and cocontributing factors. thus, there seems little reason to abandon the rigorous peer review process and expedite manuscript publication for covid-19 air pollution studies. study quality is of great importance and all stakeholders, including the scientific community, policy makers and the general public, are served best by well-conducted and thoroughly appraised studies on air pollution and covid-19. we need to avoid creating myths that are diverting political and scientific attention from other urgent and actionable questions. the sentence go slow to go fast is used in industry to combat the short-sighted fixation on speed while sacrificing product quality and hence utility. in the case where research does not have immediate impact on clinical and societal interventions related to the current pandemic, we may want to adopt this philosophy. air pollution researchers and scientific journal editors have an important role in maintaining calm scientific rigor during this tumultuous time. of the global burden of disease project for lower respiratory infections, estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the global burden of disease study ers/ats workshop report on respiratory health effects of household air pollution exposure to air pollution and covid-19 mortality in the united states medrxiv assessing nitrogen dioxide (no2) levels as a contributing factor to coronavirus (covid-19) fatality links between air pollution and covid-19 in england. medrxiv air pollution linked to far higher covid-19 death rates, study finds air pollution may be 'key contributor' to covid-19 deaths -study, in the guardian exposure to air pollution and covid-19 mortality in the united states: a nationwide cross-sectional study medrxiv the ecological fallacy strikes back accurate statistics on covid-19 are essential for policy guidance and decisions urban air pollution may enhance covid-19 case-fatality and mortality rates in the united states covid-19 and air pollution analysis proposals for test-negative design and matched case-control studies during widespread testing of symptomatic persons for sars-cov-2 air pollution and case fatality of sars in the people's republic of china: an ecologic study. environ health clinical characteristics of coronavirus disease 2019 in china acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: angiotensin-ii type-i receptor as a molecular target of particulate matter exposure ambient particulate air pollution and acute lower respiratory infections: a systematic review and implications for estimating the global burden of disease we thank calvin ge for proof-reading and editing the editorial and marc chadeau-hyam for his critical and constructive comments. key: cord-333131-affb4yln authors: jacob, joseph; alexander, daniel; baillie, j. kenneth; berka, rosalind; bertolli, ottavia; blackwood, james; buchan, iain; bloomfield, claire; cushnan, dominic; docherty, annemarie; edey, anthony; favaro, alberto; gleeson, fergus; halling-brown, mark; hare, samanjit; jefferson, emily; johnstone, annette; kirby, myles; mcstay, ruth; nair, arjun; openshaw, peter j.m.; parker, geoff; reilly, gerry; robinson, graham; roditi, giles; rodrigues, jonathan c.l.; sebire, neil; semple, malcolm g.; sudlow, catherine; woznitza, nick; joshi, indra title: using imaging to combat a pandemic: rationale for developing the uk national covid-19 chest imaging database date: 2020 journal: eur respir j doi: 10.1183/13993003.01809-2020 sha: doc_id: 333131 cord_uid: affb4yln the national covid-19 chest imaging database (nccid) is a repository of chest x-ray, ct and mri images and clinical data from covid-19 patients across the uk, to support research and development of ai technology that may proffer insights into the disease. since the emergence of the novel coronavirus sars-cov-2 in wuhan, china in 2019(1), the resulting covid-19 disease has rapidly transitioned into a global pandemic with over 31,000 deaths and 215,000 infections in the uk as of 10th may 2020 (2) . confirmation of sars-cov-2 infection requires reverse-transcriptase polymerase chain reaction (rt-pcr) testing (3) . chest radiographic and/or computed tomography imaging is also central to diagnosis and management (4) . the scale of the covid-19 pandemic has resulted in the acquisition of huge volumes of imaging data. traditionally, research using imaging data constituted collation of data within single hospitals or groups of hospitals at most. endeavours on a local scale have the constraint that not all patient subgroups or disease manifestations might be captured in the collected data. it has long been recognised that there is an acute need to curate larger more comprehensive datasets to better understand a disease. covid-19 has arrived in an era where advances in computational power, aligned with an increased availability of big data and the development of self-learning neural networks have begun to redefine research in medicine. in recent years computer algorithms trained on imaging data, widely available on the internet, have been adapted to the task of medical image analysis (5, 6) . for computer algorithms to be successfully applied to medical image analysis, it is imperative that they train on large volumes and representative examples of imaging data. these are typically orders of magnitude larger than traditional imaging research datasets, and beyond the capacity of traditional research e-infrastructure. the national health service in the united kingdom has long sought national repositories of linked clinical and imaging data, which are essential for applications of artificial intelligence (ai) computing systems in healthcare. historically, logistical barriers to this have seemed insurmountable and progress has been notoriously slow. yet one aspect of the covid-19 response has been the issue of a notice under regulation 3(4) of the health service control of patient information regulations 2002 (copi notice) in the uk which has temporarily eased data sharing restrictions to facilitate covid-19specific public health research and scientific collaboration over the course of the emergency. the british society of thoracic imaging research network(7) began a multicentred covid-19 imaging study which grew into a partnership with nhsx to create the national covid-19 chest imaging database (nccid)(8). nccid has put in place mechanisms to collate all chest imaging and prespecified clinical data from every uk hospital where patients undergo a rt-pcr test for covid-19. this will include all rt-pcr positive patients and a representative sample of rt-pcr negative patients. the study aims to identify information in covid-19 imaging that may be inconspicuous to the human eye, but which is extractable by computer algorithms. such buried information may allow the early identification of patients at risk of deterioration thereby anticipating future intensive care needs. ai algorithms may also demonstrate how comprehensive characterisation of covid-19 may improve care/outcomes. the nccid data and image transfer solutions are robust and secure, including those having been adapted from techniques tried and tested on numerous research studies involving large-scale medical image collection (9) . to maximise efficient resource utilisation in busy hospitals during the course of the pandemic, we are linking our imaging data to the isaric who clinical characterisation protocol for severe emerging infection uk (isaric ccp-uk)(10) and aim to link to icnarc(11). isaric investigators are collating clinical information and biological samples for covid-19 cases of all ages admitted to hospitals, whilst icnarc collates detailed data from adults in the intensive care setting. the study has also been supported by health data research uk as part of its uk response to covidan endeavour of this scale, rarely attempted before in the nhs, can only succeed if the radiology and scientific community contribute their time, effort and available data. isaric has open source processes and already has established data and material sharing from uk covid-19 cases (12) . the nccid initiative will create an open, well-governed database for researchers from academia and industry to add to covid-19 knowledge collectively. public, patient and professional trust is vital to nccid and covid-19 in general, and we consider accessibility and feedback on data uses as central to good governance. the nccid data access committee aim to link to researchers who are asking related scientific questions, using complementary methodologies. nccid will also set aside a portion of its data to enable validation of ai models. this will maintain the highest standards of governance throughout the emergency and allow technology developers to validate their algorithms promptly. 1) chest radiographs: the united kingdom prioritised the use of chest radiographs in the clinical work-up of patients suspected of covid-19 (13) . the choice of chest radiographs as the primary diagnostic imaging test was pragmatic given the reported limited sensitivity of ct imaging in covid-19 diagnosis (14) . the choice also reflected concerns regarding seeding of infection via ct scanners contaminated with virus particles, as well as the limited numbers of ct scanners serving the uk population when compared with other european countries (15) . accordingly, a large proportion of imaging in nccid will consist of chest radiographs acquired at initial presentation of the patient to hospital and throughout the patients hospital stay (figure 1 ). nccid will collect chest radiographs in all rt-pcr covid-19 positive patients in hospitals throughout the uk. in addition, a number of chest radiographs from rt-pcr covid-19 negative patients will be collected from sites as a representative control population. 2) computed tomography chest imaging: nccid will collect all chest ct imaging in rt-pcr covid-19 positive patients. this will include non-contrast enhanced chest ct imaging, ct pulmonary angiograms and ct coronary angiograms. 3) for all rt-pcr covid-19 positive patients nccid will acquire all chest imaging performed in the previous 3 years. for rt-pcr covid-19 negative patients nccid will acquire any chest imaging performed in the previous 4 weeks. clinical data collected on rt-pcr covid-19 positive patients will include demographic information, patient co-morbidity, smoking and medication histories, clinical observations, admission blood test results and outcomes including time of intensive care unit admission and survival. the imaging will link to other clinical databases such as isaric to allow analyses against more detailed clinical information. we anticipate that in may 2020 the nccid data will be released to interested academic and commercial groups. given that the nccid will be of particular interest to ai researchers, a portion of the data will be segregated to allow rigorous and independent validation of ai models. data access will be initiated through online applications to be filled in and submitted according to the instructions on the website of nccid (8). applications will then be assessed by a central data access committee comprising scientific advisors, technology advisors, information-governance advisors, patient/ethics advisors, and system advisors to evaluate the positive impact on the nhs overall. successful applicants can access the data on a cloud-based amazon s3 bucket, and transfer it on to their computing infrastructure, required to fulfil high standards of it security. in these challenging times, research efforts necessary to better understand covid-19 cannot afford to be fragmented and uncoordinated. accelerating insights and discovery necessitates leveraging economies of scale and resource amongst researchers, institutions and companies. we believe nccid will quickly improve covid-19 understanding and patient care and build on early insights into covid-19 (16) (17) (18) . the scale of the current pandemic requires the best minds, data, algorithms and research programmes to come together quickly. we are fortunate in the uk to have an abundance of internationally recognised researchers working on covid-19. we hope that nccid provides a common uk resource to fuel international efforts in tackling covid-19 and allows better preparedness for similar future needs. unsupervised deep learning methods could help identify discrete covid-19 patient phenotypes that manifest differing disease courses. image analysis may also allow prediction of those patients that are likely to manifest chronic multisystem sequelae following their acute infection, which may inform future resource prioritisation in healthcare systems. clinical features of patients infected with 2019 novel coronavirus in wuhan strategies for the prevention and management of coronavirus disease 2019 an update on covid-19 for the radiologist -a british society of thoracic imaging statement clinically applicable deep learning for diagnosis and referral in retinal disease dermatologist-level classification of skin cancer with deep neural networks a uk-wide british society of thoracic imaging covid-19 imaging repository and database: design, rationale and implications for education and research optimam mammography image database: a large scale resource of mammography images and clinical data open source clinical science for emerging infections. the lancet infectious diseases a british society of thoracic imaging statement: considerations in designing local imaging diagnostic algorithms for the covid-19 pandemic chest ct findings in coronavirus disease-19 (covid-19): relationship to duration of infection healthcare resource statistics -technical resources and medical technology clinical and ct features of early stage patients with covid-19: a retrospective analysis of imported cases in high-resolution computed tomography features of 17 cases of coronavirus disease 2019 in sichuan province, china the clinical dynamics of 18 cases of covid-19 outside of wuhan, china key: cord-290490-u3mkfvxw authors: armstrong-james, darius; youngs, jonathan; bicanic, tihana; abdolrasouli, alireza; denning, david w.; johnson, elizabeth; mehra, varun; pagliuca, tony; patel, brijesh; rhodes, johanna; schelenz, silke; shah, anand; van de veerdonk, frank l.; verweij, paul e.; white, p. lewis; fisher, matthew c. title: confronting and mitigating the risk of covid-19 associated pulmonary aspergillosis (capa) date: 2020-07-23 journal: eur respir j doi: 10.1183/13993003.02554-2020 sha: doc_id: 290490 cord_uid: u3mkfvxw cases of covid-19 associated pulmonary aspergillosis (capa) are being increasingly reported and physicians treating patients with covid-19-related lung disease need to actively consider these fungal co-infections. the sars-cov-2 (covid19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities (1) . severe covid-19 is characterised acute respiratory distress syndrome (ards) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ecmo) (2) . clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with covid-19 received antimicrobial therapy (3) . however, the risk of fungal co-infection, in particular covid-19 associated pulmonary aspergillosis (capa), remains underappreciated. fungal disease consistent with invasive aspergillosis (ia) has been observed with other severe coronaviruses such as severe acute respiratory syndrome (sars-cov-2003) (4, 5) and middle east respiratory syndrome (mers-cov) (6) . from the outset of the covid-19 pandemic, there were warning signs of secondary invasive fungal infection; aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first covid-19 cohort from wuhan to be reported in any detail (2) and aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region (7) . more recently, retrospective case series from belgium (8), france (9) , the netherlands (10) and germany (11) have reported evidence of capa in an alarming 20-35% of mechanically ventilated patients. influenza-associated pulmonary aspergillosis (iapa) presents a known risk to critically unwell patients with influenza (12) (13) (14) and the clinical course of covid-19 shows many features that are shared with severe influenza infection. these include ards, lymphopenia, bilateral pulmonary infiltrates, systemic pro-inflammatory cytokine responses and sepsis leading to multiple organ failure (14, 15) . it is therefore reasonable to suspect that patients with severe covid-19 may be similarly susceptible to ia. corticosteroid use is an important acquired immunological risk factor for iapa (16) and, during the sars-2003 epidemic, there were case reports of patients developing sars-associated ia after corticosteroid use (5) . corticosteroid use has been reported in hospitalised patients with covid-19 (1) and may further contribute to the risk of capa. importantly, the recent finding by the uk recovery trial (isrctn50189673) (17) of a one-third mortality reduction conferred by dexamethasone in ventilated patients with covid-19, while leading to a crucial new therapeutic avenue, may increase the risk of patients acquiring capa and emphasises the need for enhanced fungal surveillance. table 1 summarises individual patient-level data in 33 cases of capa that have been reported to date. the median age of cases is 70 (iqr 57-75), of whom only 2 (6%) had an eortc host factor. of these 16 (48%) had exposure to inhaled or systemic corticosteroids, 10 (30%) diabetes and 9 (27%) underlying chronic lung disease; chronic obstructive pulmonary disease (n=5), asthma (n=3), bullous emphysema (n=1), pulmonary fibrosis (n=1) and post-radiotherapy for non-small-cell lung cancer ia is difficult to diagnose in critically unwell patients without traditional host factors because radiological changes are usually non-specific (e.g. infiltrates, consolidation or nodules), with features such as halo sign, air-crescent sign or cavitation being rare (19) . table 1 were 'proven', 11 'putative' and 17 might be considered putative but with caveats which have been described in the table. for example, in many cases a tracheal aspirate, rather than bal, provided the only mycological evidence of ia (in the absence of tracheobronchitis/cavitation). there should therefore be caution about over-estimating the incidence of capa from such case series, which may include some patients with aspergillus colonisation or contamination only. in the study by alanio et al. (9) which reported evidence of capa in 9/27 (33%) of ventilated patients who underwent bal/ tracheal aspirate (ta), one case was defined based on on a bal gm of 0.89 (below the usual cut-off of 1.0), two based on ta rather than bal culture, one based on a serum gm of 0.51 (cut-off being 0.50) and in four cases bal culture was positive but bal gm negative, which suggests a lack of tissue invasion. indeed, of seven cases that were not treated with antifungals, five survived. accordingly, larger, prospective, multi-site studies are needed to refine the aspicu criteria for patients with covid-19, as well as to estimate incidence and the impact of capa on survival (20, 21) . bearing these observations in mind, we argue that critically ill patients with covid-19 and progressive features should be screened for capa. we acknowledge that acquiring and handling clinical samples for microbiology is very challenging given the hazard group 3 (hg3) rating of the sars-cov-2 virus, alongside an overburdened critical care service (22) . ideally, screening for capa entails using a combination of ct chest imaging and aspergillus antigen tests on bal and serum including galactomannan (gm) elisa or lateral-flow tests (23), or aspergillus pcr (24) . whilst characteristic ct features of ia such as nodules with halo sign were seen in 17.6% of severely ill covid-19 patients, they were not confirmed to be ipa (25) . given the lack of typical ia features on ct in iapa, the absence of classical findings such as cavitation should not be used to exclude capa, however their presence can help support the diagnosis and reduce the burden of evidence placed on mycological investigations. in a study of 26 icu patients that were diagnosed with proven (non-capa/iapa) ipa post-mortem, serum gm had only 25% sensitivity in those that were not neutropenic (vs 70% in neutropenic patients) (26) . in contrast, bal gm was 88-90% sensitive in both groups. in the iapa study by schauwvlieghe et al. (13) serum gm testing performed better with 20/31 (65%) of cases positive, however bal gm remained superior at 67/76 (88%). in capa cases reported to date ( table 1) , bal culture and gm had a sensitivity of 72.7% and 66.7% respectively, but serum gm was positive in only 6/28 (21.4%). moreover, of the five cases of proven capa reported to date, four were serum gm negative [ table 1 ; (8) ], indicating that serum gm test performance might be inferior in diagnosing capa. therefore, bronchoscopy, including tracheobronchial inspection and bal sampling for culture and gm should be the diagnostic gold standards whenever capa is suspected, providing this is compatible with local infection prevention and control guidance for aerosol-generating procedures. a positive bal gm (index >1.0) would be indicative of capa, whereas if the index is <0.5, capa is much less likely (26) . a positive serum gm result (≥ 0.5) would be highly suspicious for capa but a negative result should not be used to exclude the diagnosis. novel lateral-flow antigen tests may represent a locally implementable alternative to gm elisa in the cl3 laboratory, but currently require validation in icu patients without eortc host factors including covid-19 (23) . an aspergillusspecific pcr test (24) may also be helpful and if positive could also lead to the application of molecular testing for the recognised markers of clinically or environmentally-derived azole-resistance (27) . there is a suspicion of ipa. although performance might be superior to serum aspergillus antigen testing for the detection of ipa in the icu (28), bdg negativity cannot be used to rule out infection, with a 77% sensitivity determined across a heterogeneous population of ia patients, and performance in capa as yet to be determined. bdg positivity can occur due to a number of reasons in this patient cohort, however serial positive tests increases specificity and should prompt a diagnostic work-up including ct and bronchoscopy and testing for aspergillus antigen as outlined above (29) . while initiating antifungal treatment pre-emptively based on of bdg positivity may be an improvement on empirical therapy, every effort should be made to utilise other more specific diagnostic tests to complement the bdg result. current guidelines advise against routine diagnostic bronchoscopy due to the risk of aerosol generation; recommending it only in patients in whom nasopharyngeal cultures are negative and bal sampling will change clinical management (30) . in practice many patients with suspected capa undergo endotracheal sampling or non-directed bal sampling only, and it is important that any case definition proposed for capa reflects this reality. to acknowledge this, we propose a screening and diagnostic algorithm for capa, which has clinical (respiratory) deterioration and/or positive aspergillus sputum, or tracheal aspirate culture as its entry point (figure 1) . although the host risk factors and clinical characteristics of capa are not yet understood, those individuals fulfilling the criteria for proven or probable aspergillosis (13, 14) should then be treated according to current guidelines (31, 32) . importantly, now that adjunctive use of dexamethasone is likely to become widespread in the treatment of patients with severe covid-19 (17) , intensified screening for ia is indicated to study the possible association between corticosteroid usage and capa. finally, the use of immunomodulatory drugs such as anakinra (recombinant il-1ra), tocilizumab (anti-il6) and janus kinase (jak) inhibitors, currently undergoing trials for covid19, may also predispose patients to capa. there is also an increased risk of aspergillus exposure for patients who are treated in hospital wards or makeshift 'hospital' facilities that do not meet icu specifications for appropriate room ventilation and air changes. it is also worth bearing in mind that pulmonary aspergillosis could develop into a chronic cavitary disease in a subset of patients, perhaps in those developing post-covid19 pulmonary fibrosis. for these reasons, clinicians following up patients manifesting chronic respiratory problems following their primary covid-19 infection should bear in mind longer-term fungal complications. fungal infections present an additional threat in the challenging task of managing covid-19 patients in outbreak conditions. the pandemic of sars-cov-2 virus will undoubtedly involve capa, and the use of immunomodulatory therapy and impact of overburdened critical care services during this pandemic may exaggerate its impact. more research is needed on the epidemiology and diagnosis of capa in patients with covid-19, a need that is partially met as ongoing prospective multi-site clinical studies are extended to include this cohort (e.g. aspiflu (20) ) or are launched (capa (21)) in response to pandemic covid-19. clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid-19 antimicrobial prescribing pulmonary pathology of severe acute respiratory syndrome in toronto fatal aspergillosis in a patient with sars who was treated with corticosteroids the emergence of the middle east respiratory syndrome coronavirus clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study van regenmortel n. covid-19-associated invasive pulmonary aspergillosis prevalence of putative invasive pulmonary aspergillosis in critically ill patients with covid-19 covid-19 associated pulmonary aspergillosis shimabukuro-vornhagen a. covid-19 associated pulmonary aspergillosis invasive pulmonary aspergillosis is a frequent complication of critically ill h1n1 patients: a retrospective study dutch-belgian mycosis study g. invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study dutch mycoses study g. influenza-associated aspergillosis in critically ill patients recovery: randomised evaluation of covid-19 therapy features of 16,749 hospitalised uk patients with covid-19 using the isaric who clinical characterisation protocol a clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients aspergillosis in patients with severe influenza or coronavirus dutch-=belgian mycosis study group: capa guidance: covid-19 safe handling and processing for samples in laboratories lateral flow assays for the diagnosis of invasive aspergillosis: current status diagnosis of aspergillosis by pcr: clinical considerations and technical tips coronavirus disease 2019 (covid-19): role of chest ct in diagnosis and management galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients azole resistance in aspergillus fumigatus: a side-effect of environmental fungicide use? comparison of 1,3-beta-dglucan with galactomannan in serum and bronchoalveolar fluid for the detection of aspergillus species in immunosuppressed mechanical ventilated critically ill patients beta-dglucan detection as a diagnostic test for invasive aspergillosis in immunocompromised critically ill patients with symptoms of respiratory infection: an autopsy-based study the use of bronchoscopy during the covid-19 pandemic: chest/aabip guideline and expert panel report practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america diagnosis and management of aspergillus diseases: executive summary of the 2017 escmid-ecmm-ers guideline. clinical microbiology and infection : the official publication of the covid-19 associated pulmonary aspergillosis invasive pulmonary aspergillosis in severe covid-19 pneumonia fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient prevalence of putative invasive pulmonary aspergillosis in critically ill patients with covid-19 invasive pulmonary aspergillosis complicating covid-19 in the icu -a case report covid-19-associated invasive pulmonary aspergillosis covid-19 associated pulmonary aspergillosis clinical and virological data of the first cases of covid-19 in europe: a case series invasive pulmonary aspergillosis complicating sars-cov-2 pneumonia: a diagnostic challenge under eortc criteria without histological evidence of 'proven' ipa a patient host factor (e.g. recent neutropenia, haematological malignancy) is required to meet the 'probable'/'possible' definition. corticosteroids must be given at ≥0.3 mg/kg for ≥3 weeks to classify as a host factor. key: cord-281193-sb7kgu24 authors: yang, hai-jun; zhang, yan-mei; yang, min; huang, xing title: re: predictors of mortality for patients with covid-19 pneumonia caused by sarscov-2: a prospective cohort study date: 2020-08-03 journal: eur respir j doi: 10.1183/13993003.02439-2020 sha: doc_id: 281193 cord_uid: sb7kgu24 we found that there were several issues which are worth clarifying in du r. h. et al.'s paper published in the european respiratory journal. with covid-19 pneumonia were associated with increased risk of death from this disease [1] . they further identified that cd3+cd8+ t-cells ⩽75 cells·μl −1 and cardiac troponin i especially ⩾0.05 ng·ml −1 could be used as predictors for mortality of patients with covid-19 pneumonia using matched case-control study [1] . with great interest, we have read the full text of the paper and found that there are several issues which are worth to clarifying. [2] . taken together, the findings of the study reported by du r et al are of great significance, though some possible error and inappropriate expression were found. we hope our comments will be helpful to improve the expression and increase the quality of the paper published by du r et al. predictors of mortality for patients with covid-19 pneumonia caused by sars-cov-2: a prospective cohort study methods for estimating the case fatality ratio for a novel, emerging infectious disease key: cord-307732-sdstnm9i authors: yang, kai; wang, lingwei; li, furong; chen, dandan; li, xi; qiu, chen; chen, rongchang title: the influence of preventive strategies on covid-2019 epidemic in shenzhen, china date: 2020-04-16 journal: eur respir j doi: 10.1183/13993003.00599-2020 sha: doc_id: 307732 cord_uid: sdstnm9i early identification of imported cases, prevention of family clustering transmission, preventive measures in the public area and strict infection control procedure in hospitals were crucial for successful prevention of covid-19 in shenzhen, china. hubei in december 2019, and spread to all provinces in china and more than 90 countries in the next 2 months [1] [2] [3] [4] [5] . by march 7, 2020, covid-19 has infected more than 90000 cases and led to more than 3000 deaths [6] . there are about 20 million people living in shenzhen, of which the external population from the internal area of china, including hubei province, account for a large proportion. high population density, high proportion of external population and high mobility may increase the possibility of covid-19 outbreak [7, 8] . the first covid-19 patient in shenzhen was admitted on january 9, 2020, and 419 cases have been confirmed by march 7, 2020 , which ranked the top cities outside wuhan. most of these patients were imported cases from hubei province, and there was no large-scale transmission and nosocomial infection in shenzhen until now. therefore, the purpose of this study was to analyze the epidemiology and preventive strategies in shenzhen in order to understand the main transmission route and effective preventive strategies in cities with risk of imported cases, which may provide clue for better preventing outbreak of potential respiratory infectious disease, such as covid-19 in cities with heavy population density and high proportion of external population. the data of this study were downloaded from the data open-platform of shenzhen government (https://opendata.sz.gov.cn). the number of confirmed cases of covid-19 began to be released daily on january 19, 2020, and 419 cases have been confirmed by march 7, 2020. compared with the reports from wuhan, hubei [9] , the age of infected population in shenzhen was younger and decreasing gradually, in which 33 patients were children. familial clustering was an important feature of covid-19 [10] . in shenzhen, 232 covid-19 patients (232/419, 55.4%) came from 86 families, 15 of which had more than 3 patients, indicating that local transmission in the family environment was important route of transmission. based on the daily new cases, three phases were classified: the slow increase phase from january 19 to january 28, the rapid increase and plateau phase from january 29 to february 5, and the decline phase since february 6 ( figure 1 ). almost all cases (61/63, 96.8%) in slow increase phage were patients from hubei, and 2 cases were family members of these patients, indicating that main source of covid-19 patients was imported from hubei province. compared with the previous period, majority of the patients (174/228, 76.3%) in the rapid increase and plateau phase were still from hubei, but infection related to contact with hubei patients (27/228, 11.8%), non-hubei patients (12/228, 5.3%) and no contact history (14/228, 6.1%) increased. in the decline phase, the number of daily new confirmed cases decreased all medical staff involved in the management of covid-19 patients implemented infection control procedures. for the general population, people entering the hospital were asked to wear masks and take body temperature. the hospital environment was disinfected timely and regularly, hand-washing equipment and disinfectants were equipped in multiple places, and indoor air ventilation was strengthened. as early as january 19, when the national health commission announced the first imported case in shenzhen, shenzhen began to take temperature for people in main city entrances to screen imported cases, which was also widely used in the prevention of other respiratory infectious diseases, such as influenza in united states and sars in china [11, 12] . after the release of the first (highest) level response to major public health emergencies in guangdong on january 23, all chinese new year's entertainments were cancelled, and many public places were temporarily closed in shenzhen, such as market, library, gymnasium. other necessary public places needed to be disinfected regularly, including airport, station, port, freeway entrance, urban traffic, community entrance. the employees in these places needed to have health examinations. people came to these places needed to wear masks and take body temperature. these measures were important for blocking the spread of covid-19 millions of people returned to shenzhen from all over the country after chinese new year's holiday, which may lead to the imported cases and potential transmission. therefore, strengthened measures were implemented in february 2, which included isolating all the new arrival people came from epidemic area for medical observation for 14 days, informing all people in the living communities once there were confirmed cases, using of big data and information technology to track the places in the last 14 days and identify the contacted persons of the confirmed cases. the preventive strategies and measures implemented in shenzhen were supposed to block the transmission of covid-2019. the newly diagnosed covid-19 cases reached its peak around january 31, which was 7 days after the peak date of cases arrived at shenzhen (mainly patients in incubation period from hubei) and around 10 days after the serial early preventive strategy implemented. taking account of the incubation period (mostly 3-7 days, with mean of 3.7 days) and the time between symptom onset and confirm of the diagnosis (6 day on average) [13, 14] epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside wuhan, china first case of 2019 novel coronavirus in the united states a novel coronavirus outbreak of global health concern. the lancet china novel coronavirus i, research t. a novel coronavirus from patients with pneumonia in china the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china epidemiology of imported infectious diseases emerging challenges and opportunities in infectious disease epidemiology clinical features of patients infected with 2019 novel coronavirus in wuhan, china. the lancet a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster entry screening for severe acute respiratory syndrome (sars) or influenza: policy evaluation clinical characteristics of 138 hospitalized patients with none declared. key: cord-327169-sz4ildnd authors: mondoni, michele; sferrazza papa, giuseppe francesco; rinaldo, rocco; faverio, paola; marruchella, almerico; d'arcangelo, francesca; pesci, alberto; pasini, simone; henchi, sonia; cipolla, giuseppe; tarantini, francesco; giuliani, lisa; di marco, fabiano; saracino, laura; tomaselli, stefano; corsico, angelo; gasparini, stefano; bonifazi, martina; zuccatosta, lina; saderi, laura; pellegrino, giulia; davì, matteo; carlucci, paolo; centanni, stefano; sotgiu, giovanni title: utility and safety of bronchoscopy during sars-cov-2 outbreak in italy: a retrospective, multicenter study date: 2020-08-28 journal: eur respir j doi: 10.1183/13993003.02767-2020 sha: doc_id: 327169 cord_uid: sz4ildnd utility and safety of bronchoscopy during sars-cov-2 outbreak funding: the work is funded by università degli studi di milano in the context of the registry for covid19 emergency (recover) electronic database severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection and the related disease (coronavirus disease -2019, covid-19) has been notified throughout italy since february 2020. intensive care unit (icu) admission rate increased following the high incidence of pneumonia-related respiratory failure [1] . the diagnosis of pneumonia relies on viral detection in respiratory samples and on the assessment of abnormal findings on chest x-ray, ultrasounds, and computed tomography (ct) [2] [3] [4] [5] . viral diagnosis based on naso/oropharyngeal swabs shows suboptimal accuracy (sensitivity: 32-63%), owing to wrong handling of the specimen, sample collection during the late phase of the disease or low viral load [5] [6] [7] . bronchoscopy increases the sensitivity of the molecular diagnosis in comparison with that associated with nasopharyngeal swabs [6] . furthermore, endoscopic techniques may be useful to manage serious pulmonary disorders (e.g., obstructive atelectasis, severe hemoptysis) [8] [9] [10] [11] [12] . however, bronchoscopy generates aerosol and may increase the risk of sars-cov-2 transmission [8] [9] 12] . limited data are available in the scientific literature on the role of bronchoscopy in cases of sars-cov-2 pneumonia [6] [7] [8] [9] [10] [11] [12] . the primary aim of the present study was to describe the diagnostic yield of bronchoscopy in patients with negative nasopharyngeal swab(s) and a clinical and radiological suspicion of covid-19 pneumonia. indications of bronchoscopy in cases of confirmed covid-19 patients and the assessment of the safety of bronchoscopy for healthcare workers (hcws) were also evaluated. an observational, retrospective, multicenter cohort study was carried out in italy. the study protocol was approved by the ethical committees of the participating hospitals. a written informed consent was signed by recruited patients. adult patients who underwent bronchoscopy between 1 st march 2020 and 15 th april 2020 were consecutively recruited in six italian hospitals. the indications of bronchoscopy were: -diagnosis of sars-cov-2 pneumonia in patients with previously negative nasopharyngeal swab (clinical and radiological suspicion of pneumonia); -need for undelayable procedures in covid-19 patients (e.g., massive hemoptysis, post-obstructive atelectasis). all bronchoscopies were performed according to the who guidelines: the number of persons in the room was decreased to achieve a size appropriate to the provision of adequate care and support (i.e., one physician and one nurse wearing ffp3 masks) [13] . the diagnosis of covid-19 was confirmed when molecular (i.e., real time pcr) results detected sars-cov-2 in any respiratory sample [4, 5] . the probability of covid-19 was high in case of a negative pcr and covid-19-related symptoms (i.e., fever, cough, fatigue, and/or shortness of breath), ct signs (i.e., ground-glass opacity, consolidation, reticulation/thickened interlobular septa, air bronchogram sign), with rapid clinical changes (progression or improvement in a short time period) [4, 7] . the diagnostic yield of bronchoscopy was calculated dividing the number of patients with a molecular diagnosis of sars-cov-2 infection following the collection of bronchoscopic specimens by the number of patients with a suspected diagnosis of covid-19 pneumonia. every hcw was carefully monitored for symptoms and clinical signs suggestive for covid-19 for at least 15 days after the procedure. an ad hoc electronic form was adopted to collect all study variables. qualitative and quantitative variables were summarized with absolute (relative) frequencies and means (standard deviations, sd), respectively. this is to our knowledge the largest study on the diagnostic yield of bronchoscopy in patients with negative nasopharyngeal swabs and a clinical/radiological suspicion of sars-cov-2 infection. an etiological diagnosis is crucial to prevent viral transmission to susceptible individuals and decrease clinical complications in infected patients [1, 2] . prompt respiratory isolation is needed to hamper the viral spread, whereas an early diagnosis of covid-19 related complications (i.e., respiratory failure) is crucial for a good prognosis [1, 2] . our findings show that bronchoscopy might be useful in patients with suspected covid-19 pneumonia and negative swabs, with an acceptable diagnostic performance of bal and bw. a recent study found a 71% detection rate of sars-cov-2 in 28 patients who underwent bronchoscopy in china, with 93% of positive pcr results in bal samples [6] . our study shows a lower diagnostic yield but we performed a bronchoscopy only in patients with two previous negative swabs [6] . despite bronchoscopy has been relatively contraindicated during the covid-19 pandemic, endoscopic procedures may not be postponed in some patient categories [11] . urgent/life-saving bronchoscopies were performed in 31 patients with a confirmed covid-19 diagnosis for obstructive atelectasis, suspected concomitant lower respiratory tract infections, severe hemoptysis, suspected tracheal lacerations in patients mechanically ventilated, tracheostomy complications, and suspected concomitant pulmonary tuberculosis. similar findings were recently described by torrego et al. in a spanish cohort of covid-19 patients who underwent bronchoscopy in icu [12] . few data are available on bacterial and fungal co-infections with sars-cov-2 [14] . lower respiratory tract co-infections were diagnosed with bal in 4 patients. prompt identification of co-infecting microorganisms is associated with an early prescription of antibiotics [14] . few bronchoscopy-related complications were recorded, with fever and mild respiratory failure being the most frequent. the above-mentioned side effects can occur following a bronchoscopic procedure, in the line with the scientific evidence published before the pandemic [15, 16] . neither severe complications nor deaths were described. the who recommendations on airborne precautions for aerosol-generating procedures were strictly followed in the study centers: hcws did not acquire any infections following the endoscopic procedures [13] . in conclusion, our study shows that bronchoscopy is a useful technique in the diagnostic pathway of covid-19 pneumonia when nasopharyngeal swabs are negative. urgent/life-saving procedures may be safely and successfully performed for diagnostic and therapeutic purposes in covid-19 patients. the risk of viral transmission to hcws is low following the who guidelines on airborne precautions for aerosol-generating procedures. covid-19 lombardy icu network. baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region covid-19 diagnosis and management: a comprehensive review covid-19): role of chest ct in diagnosis and management laboratory diagnosis of emerging human coronavirus infections -the state of the art detection of sars-cov-2 in different types of clinical specimens correlation of chest ct and rt-pcr testing in coronavirus disease 2019 (covid-19) in china: a report of 1014 cases the use of bronchoscopy during the covid-19 pandemic: chest/aabip guideline and expert panel report performing bronchoscopy in times of the covid-19 pandemic: practice statement from an international expert panel bronchoscopy to assess patients with hemoptysis: which is the optimal timing? american association for bronchology and interventional pulmonology (aabip) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed covid-19 infection bronchoscopy in covid-19 patients with invasive mechanical ventilation: a center experience infection prevention and control during health care when covid-19 is suspected bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid-19 antimicrobial prescribing british thoracic society bronchoscopy guideline group. british thoracic society guideline for diagnostic flexible bronchoscopy in adults: accredited by nice incidence of complications in bronchoscopy. multicentre prospective study of 20,986 bronchoscopies declaration of interests: all authors declare no competing interests the authors want to acknowledge dr. beatrice vigo, mrs. simona gentile, dr. filippo montanelli, dr bronchoscopic detection rate of sars-cov-2 in patients with previous negative swabs and in the presence of a clinical and radiological suspicion of covid-19 pneumonia, in the total cohort (78 patients) and according to bal and bw key: cord-296694-2js639bk authors: price, laura c; mccabe, colm; garfield, ben; wort, stephen j title: thrombosis and covid-19 pneumonia: the clot thickens! date: 2020-06-18 journal: eur respir j doi: 10.1183/13993003.01608-2020 sha: doc_id: 296694 cord_uid: 2js639bk pulmonary thrombosis appears to be common in covid-19 pneumonia and takes two forms, proximal pulmonary emboli and/or distal thrombosis. we hypothesise mechanisms and discuss clinical implications. at the end of last year, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2), resulted in an acute respiratory illness epidemic in wuhan, china [1, 2] . the world health organization (who) termed this illness coronavirus disease 2019 . the coronavirus family have been shown to enter cells through binding angiotensin-converting enzyme 2 (ace2), found mainly on alveolar epithelium and endothelium. activation of endothelial cells is thought to be the primary driver for the increasingly recognised complication of thrombosis. viral inclusion bodies have been identified in endothelial cells in a variety of organs, from lung to gastro-intestinal tract [3] . the immune dysregulation characteristic of severe covid-19 infection may be initiated by 'pyroptosis', a particularly pro-inflammatory form of apoptosis initially described in macrophages [4] , with rapid viral replication leading to massive release of inflammatory mediators. one of the most consistent findings is that of a raised d-dimer. although many inflammatory processes can influence d-dimer levels, it almost certainly reflects, to some extent, intra-vascular thrombosis in patients with covid-19 [5, 6] . in the early studies emerging from china, an elevated d-dimer (>1000 ng/ml) at admission was associated with increased risk of in-hospital death [7] . an elevated d-dimer continues to be one of the most consistent markers of poor outcome [8] . the true prevalence of thrombosis associated with covid-19 infection is unknown, as most studies to date do not include systematic and comprehensive investigation protocols. it appears that it is also important to consider the stage of the disease course and where the patient is tested, e.g. ward versus intensive care unit (icu). in addition, both of these factors will influence the amount of anticoagulation a patient may receive, which in turn may influence subsequent thrombosis. furthermore, most studies refer to pulmonary embolism (pe), whereas there is persuasive evidence to suggest much of this may be "in situ" pulmonary thrombosis [9] . two recent dutch studies have reported cumulative incidences of thrombotic events between 48 and 49% respectively in their icus in patients with covid-19 pneumonia [10, 11] . most thrombotic events are described as pe, for instance 87% in the paper by klok et al. [12] although it should also be noted that venous and arterial thrombosis is described [10] . in this edition of the european respiratory journal, bompard et al. refine this further by describing a 50% cumulative incidence of pulmonary embolism (pe), diagnosed by ct-pulmonary angiogram (pa), in covid-19 patients admitted to icu in two hospitals of the university of paris (erj ref bompard). it is important to note that all patients received thromboprophylaxis, which is a common theme in most reports. in fact, in one study 56% of patients already on full anticoagulation were diagnosed with pe [13] . several studies have compared rates of thrombosis in icu and non-icu populations [11, 14] also published in this edition of european respiratory journal, comparing dvt rates between icu patients (13%) and ward patients (4%) (erj ref criel). one obvious question is whether these rates of thrombosis are higher than we would expect? two studies have used a retrospective "comparative" non-covid icu population and report 3-6 times the expected rates of thrombosis in the covid populations [15, 16] . there also appeared to be a very high association with thrombosis in sars, another coronavirus, and higher than h1n1 for instance [17, 18] . however, the described rates are probably consistent with those reported in patients with severe sepsis or shock [19] . it may be that there are just many more very sick patients in this pandemic. however, it is also clear that we are likely to be underestimating the true prevalence. several other interesting observations have been described. firstly, in the study of lodigiani et al., around 50% of patients were diagnosed with thrombosis within 24 hours of admission, supporting the hypothesis that many patients are probably presenting with pe [14] . secondly, klok et al. describe a small population who happened to be on long-term anticoagulation at admission, who appeared to be protected from developing thrombosis, although, interestingly, not overall mortality [12] . thirdly, there is considerable anecdotal evidence that patients are dying after discharge and that this could be thrombosis related. in the accompanying editorial, huertas et al. elegantly describe the early pathogenesis in covid-19 pneumonia defined by a widespread endotheliilitis affecting multiple organ systems (erj ref huertas). as such, viral inclusion bodies are observed within endothelial cells accompanied by apoptosis, inflammatory cell infiltration and microvascular thrombosis [20] . at the same time, systemic inflammation is commonly observed, with elevated levels of crp, fibrinogen and cytokines such as il-6 [21] . although the exact mechanisms of covid-19 induced thrombosis have not been elucidated, at least some of the well-described mechanisms associated with infection/inflammation are likely to be relevant [22] . these include the increased production of tissue factor and amplification of the coagulation cascade, resulting in increased production of thrombin and consequently fibrin. small studies describing thromboelastography in patients with covid-19 suggest clot formation is extremely rapid and also resistant to breakdown [23] . this, in turn, is likely to relate to reduced fibrinolysis due to increased production of pai-1, again as a result of inflammation. deposition of components of the complement system such as c5b-9 in damaged vessels of covid-19 patients indicate that this may be another important pro-thrombotic mechanism as it has been observed in other conditions associated with microthrombosis such as anti-phospholipid syndrome [24] . furthermore, neutrophil extracellular traps (nets) have also been observed in vessels in autopsy specimens of patients with covid-19 [25] . these are associated with high circulating levels of cell-free dna and histones, which in turn can activate pro-thrombotic pathways leading to increased thrombin production [26] . in addition to ace2 mediated sars-cov-2 viral entry, recent reports of affinity of the sars-cov-2 spike protein and cd147, a membrane glycoprotein and extracellular matrix metalloproteinase inducer expressed on a variety of haematopoietic cell lines, suggest another potentially novel mechanism of thrombosis and inflammation in the arterial and venous circulations [27] . finally, the profound hypoxaemia that is often observed is a likely driver of vasoconstriction, inflammation and thrombosis. hypoxaemia will result in activation of hypoxia-inducible factors (hifs), which in turn will activate cytokines, tissue factor and pai-1 [28, 29] . overall, the high rate of pulmonary thrombosis in covid-19 conceivably lies in the confluence of three processes: firstly, the intense endothelial inflammation described above, leading to "in situ" thrombosis, including microvascular thrombosis; secondly, altered pulmonary blood flow in response to the parenchymal process, disturbing virchow's triad within the lung; and thirdly, classical dvt to pe transition, which may, in fact, be the minor partner [10] . as the recognition of the thrombotic complications of covid-19 increases, more guidelines are emerging on their prevention, investigation and management [30, 31] . as already stated, we are likely to be missing thrombotic complications in many patients. most guidance recognises the importance of keeping the balance between providing quick, pragmatic advice to worried physicians keen to do the best for their patients, with the recognition that evidence for full anticoagulation is of course lacking in this population. ideally, therefore, wherever practical, we believe the diagnosis of vte in patients with covid-19 should be made by traditional imaging modalities; ctpa and/or in the case of clinical suspicion of dvt, by compression venous doppler of the lower limb [31] . there should be a high suspicion for thrombotic complications and low threshold for definitive imaging, where possible. traditional d-dimer cut offs are unlikely to be useful in determining who should go on to have a ctpa due to an unacceptably low specificity which will be exacerbated by admission to icu [5, 32] . however, for many reasons imaging may be impossible. d-dimer has been used in some institutions to guide anticoagulation, even in the absence of imaging detected vte [31, 33] . the risks and benefits of an approach aimed at targeting both imaging detected vte as well as "presumed thrombosis" is yet to be determined but excess bleeding is an almost inevitable consequence [34] . whether this excess risk is offset by improvements in overall survival is yet to be seen. anticoagulation is clearly not the only treatment needed in patients with covid-19 and in many patients, on the sicker end of the spectrum, may be too late to alter outcome. the intimate association between inflammation and thrombosis would suggest an anti-inflammatory/anti-viral therapeutic approach should be considered in parallel to anticoagulation. furthermore, as the fibrinolytic potential of blood from patients with covid-19 is extremely low, even with anticoagulation, immediate consequences of thrombus may not be treated. we may just be preventing further thrombus. indeed, case reports describe the use of fibrinolytics in selected patients with shortterm benefits [35] , and trials are on-going. but how long will this beneficial effect last in the procoagulant covid-19 milieu? histology from autopsy specimens demonstrate platelet aggregates obstructing the microvasculature. thromboelastography and platelet function tests reveal that patients with covid-19 have activated platelets [36] , suggesting that there may be a role for anti-platelet therapy. here, the potential to do benefit may be theoretically greater but so is the chance of doing harm. clearly results of ongoing trials are urgently needed to further inform clinical practice on the use of anticoagulation. this includes both patients admitted to icus and those at risk on the general ward. with regards to non-icu patients, questions to be asked include: what are the triggers for more intense anticoagulation where imaging is not available? can this be done using d-dimer alone and what is the threshold to use? what do you do with patients when they are discharged? in the meantime, local and national advice is available and being constantly updated [21] . finally, with certainty, we can say that the more we know about covid-19, the more the clot thickens! when coronavirus 19 infects cells expressing the surface receptors angiotensin-converting enzyme 2 (ace2), active replication and release of the virus may cause the host cell to undergo pyroptosis (pro-inflammatory apoptosis) and release damage-associated molecular patterns (damps), activating oxidant stress, and generating proinflammatory cytokine and chemokine release from nearby epithelial cells, endothelial cells and alveolar macrophages. these proteins in turn attract inflammatory cells to the site of infection, promoting a pro-inflammatory feedback loop. tissue factor, usually hidden on the subendothelium, is upregulated on platelets, leucocytes and ec during inflammation, leading to activation of both the extrinsic and intrinsic coagulation pathways to make thrombin. complement activation is also relevant. thrombin binds to protease-activated receptors (e.g. par-1) to promote the formation of fibrin from fibrinogen, the activation of platelets and subsequent clot stabilization, also propagating further inflammation. natural anticoagulants and fibrinolytics may also be reduced in covid 19 infection. occluded small pulmonary blood vessels are likely to contain fibrin, platelets and coagulation factors, as well as neutrophils that become trapped in 'nets' as they pass through the lung. ongoing inflammation provides a positive feedback loop. additional procoagulant stimuli include lung hypoxia, for example via upregulation of pai-1 through suppression of fibrinolysis. in this prothrombotic pneumonitis or ards, whether similar mechanisms promote both microthrombosis as well as larger vessel pulmonary embolic disease is not known. abbreviations: ace2 angiotensin receptor type 2, ec endothelial cell, ards acute respiratory distress syndrome, nets neutrophil extracellular traps, par proteinase-activated receptor, pai plasminogen activator inhibitor 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 endothelial cell infection and endotheliitis in covid-19 pro-inflammatory programmed cell death acute pulmonary embolism in covid-19 patients on ct angiography and relationship to d-dimer levels prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study covid-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up attention should be paid to venous thromboembolism prophylaxis in the management of covid-19 incidence of thrombotic complications in critically ill icu patients with covid-19 incidence of venous thromboembolism in hospitalized patients with covid-19 confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid -19: an updated analysis high incidence of venous thromboembolic events in anticoagulated severe covid-19 patients venous and arterial thromboembolic complications in covid-19 patients admitted to an academic hospital in pulmonary embolism in covid-19 patients: awareness of an increased prevalence high risk of thrombosis in patients with severe sars-cov-2 infection: a multicenter prospective cohort study acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars diagnosis vte incidence and risk factors in patients with severe sepsis and septic shock endothelial cell infection and endotheliitis in covid-19 clinical and immunological features of severe and moderate coronavirus disease 2019 covid-19 and its implications for thrombosis and anticoagulation hypercoagulability of covid-19 patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis complement associated microvascular injury and thrombosis in the pathogenesis of severe covid-19 infection: a report of five cases neutrophil extracellular traps in covid-19 targeting potential drivers of covid-19: neutrophil extracellular traps sars-cov-2 invades host cells via a novel route: cd147-spike protein hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis the stimulation of thrombosis by hypoxia isth interim guidance on recognition and management of coagulopathy in covid-19 bts guidance on venous thromboembolic disease in patients with covid-19 venous thromboembolism in the icu: main characteristics, diagnosis and thromboprophylaxis emergence of institutional antithrombotic protocols for coronavirus predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review tissue plasminogen activator (tpa) treatment for covid-19 associated acute respiratory distress syndrome (ards): a case series chinese expert consensus on diagnosis and treatment of coagulation dysfunction in covid-19 key: cord-299679-6z9e5gi6 authors: rello, jordi; storti, enrico; belliato, mirko; serrano, ricardo title: clinical phenotypes of sars-cov-2: implications for clinicians and researchers date: 2020-05-21 journal: eur respir j doi: 10.1183/13993003.01028-2020 sha: doc_id: 299679 cord_uid: 6z9e5gi6 patients with covid-19 present a broad spectrum of clinical presentation. whereas hypoxaemia is the marker of severity, different strategies of management should be customised to five specific individual phenotypes. many intubated patients present with phenotype 4, characterised by pulmonary hypoxic vasoconstriction, being associated with severe hypoxaemia with “normal” (>40 ml·cmh(2)o(−1)) lung compliance and likely representing pulmonary microvascular thrombosis. phenotype 5 is often associated with high plasma procalcitonin and has low pulmonary compliance, which is a result of co-infection or acute lung injury after noninvasive ventilation. identifying these clinical phenotypes and applying a personalised approach would benefit the optimisation of therapies and improve outcomes. the clinical spectrum of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection is broad, ranging from asymptomatic infection to flu-like illness (sometimes with digestive disturbances) to viral pneumonia. patients with pneumonia may have only minor opacification with near normal chest radiographs but have the potential to develop an acute respiratory failure with severe hypoxaemia of quick progression. the need for mechanical ventilation can be identified by increases in respiratory rates and requirement of high oxygen concentrations to maintain arterial oxygen saturation >90%. however, due to the scenario of the crisis with limited resources, many patients have experienced intubation delay after failure of continuous positive airway pressure, noninvasive ventilation or high-flow nasal oxygen therapy. thus, the estimation of risk factors for mechanical ventilation have not been well identified due to the lack of standardisation of practices. this article reports clinical experience from the sars-cov-2 surge acquired from different hospitals in italy and spain (on 27 march 2020) and is supported by clinical observations. further validation with stronger evidences is required. as with influenza, reverse transcriptase-pcr for sars-cov-2 is associated with frequent false-negative results [1] . therefore, patients may be diagnosed by a characteristic computed tomography (ct) scan. it is important to advise that high procalcitonin should not exclude the diagnosis, because it has been often reported in children and young adults and often suggests co-infection with a bacterial pathogen [2] . ageing, hypertension and diabetes have been consistently reported as risk factors for death or severity, whereas pregnancy does not seem to be a risk factor like in influenza [3] . current reported information may have different profiles beyond china, affecting younger or obese subjects due to differences in prevalence and socialisation. in china, sars-cov-2 has not shown a more severe disease in immunocompromised patients. that is in contrast with other respiratory viral agents, such as influenza, respiratory syncytial virus, adenovirus or rhinovirus; possibly because in coronavirus the host innate immune response appears to be the main driver of lung tissue injury during viral infection [4] . caution should still be advised with immunocompromised patients as the total number of reported cases in this subgroup remains low. clinical and laboratory features are characteristic with lymphocytopenia, elevation of lactate dehydrogenase, high plasma c-reactive protein and low procalcitonin [5] . many patients have hypercoagulability with complement mediated micro-angiopathy, increasing the risk of deep venous thrombosis, pulmonary artery micro-thrombosis, distal arterial micro-thrombosis affecting fingers, and cardiovascular events such as myocardial ischaemia, ischaemic stroke and pulmonary embolisms. in severe cases there can be dramatic elevation of d-dimer values, reduced fibrinogen with a high international normalised ratio and low platelet count, associated with the induction of tissue factor expression. some intensive care unit patients in china reported by zhang et al. [6] showed antiphospholipid autoimmune responses that led to thrombotic events, but lupus anticoagulant was not detected. endothelial damage leading to inflammation and thrombosis plays a big role. thus, all coronavirus 2019 (covid-19) hospitalised patients are tributary of benefit from prophylactic anticoagulation, unless they have severe thrombocytopenia or active bleeding. long chain (unfractionated) heparin would theoretically be preferable because of their anti-inflammatory effects. prescribing heparin to those patients with 6-fold levels of d-dimers above upper normal ranges has been associated with significantly reduced 28-day mortality rates (52% versus 32%, p=0.01) among 449 patients with severe sars-cov-2 infection in china [7] . this scenario may suggest an alteration of the microvascular endothelium or a secondary complement mediated micro-angiopathy activated by the virus or by an associated cytokine storm. zhou et al. [5] reported 54 nonsurvivors with median serum ferritin >1400 ng·l −1 . a few of these patients require bone marrow aspirate and may develop hemophagocytic lymphohistiocytosis syndrome, requiring γ-globulins and high-dose dexamethasone. as the current experience with endemic human coronavirus pneumonia is that it may double 12-month mortality [8] , patients should be monitored after clinical cure to assess for persistent hyperinflammation or hypercoagulability and consideration for preventive interventions. in an era of precision medicine, it is important to identify the main phenotypes in order to customise therapy in a personalised approach [9] . a variety of proposed anti-viral, anti-inflammatory, anticoagulant and anti-fibrotic strategies may be beneficial or harmful depending on the state of disease. recognition of different phenotypes of sars-cov-2 is therefore critical to clinicians and researchers for timely, effective and safe therapeutic interventions. the most benign phenotype ( phenotype 1) is the most common and only symptomatic therapy needs to be considered, which is characterised by fever, headache or mild respiratory symptoms (like cough or sore throat) and malaise, but the chest radiograph is normal and hypoxaemia is not present. phenotype 2 represents 80% of hospitalisations and is characterised by the presence of hypoxaemia or small opacities on chest radiographs and these patients should be referred for close respiratory monitoring ( particularly respiratory rate and oxygen saturation measure by pulse oximetry) because they are at risk of rapid deterioration progressing to death if intubation is not timely instituted. these patients are typically hyper-inflamed and remain hypovolemic at presentation to the hospital. thus, restriction of furosemide use should be considered, except if they have received a huge volume infusion. phenotype 3 represented 15% of hospitalisations in china [10] and presents with greater hypoxaemia and higher respiratory rates (30 breaths·min −1 or 25 breaths·min −1 in those aged >55 years of age or healthy subjects <55 years of age, respectively). patients may present as phenotype 3 or progress from phenotype 2 because hypoxaemia progresses quickly. high interleukin-6 is a biomarker which may help to differentiate these two phenotypes. phenotypes 2 and 3 are good candidates for randomised clinical trials to assess the efficacy of drugs with either anti-viral activity (to block replication very early), anti-inflammatory drugs or anti-fibrotic drugs. in our opinion, delaying intubation using noninvasive ventilation may induce acute lung injury. given the good lung compliance and low work of breathing, these patients may avoid mechanical ventilation despite requirement for high inspiratory oxygen fraction, using awake prone position whereas they have spontaneous breathing. arterial oxygen tension/inspiratory oxygen fraction ratios should not be a criteria for intubation. intubation should be clinically considered in the presence of respiratory alkalosis with progressive hyperventilation when delivering high oxygen concentrations. phenotype 4 is characterised by severe hypoxaemia requiring intubation, under strict measures to limit aerosolisation. ct scans document oedema in the lower lobes. angio-ct in patients with multiple ground-glass opacities often show micro-embolic lesions. lung ultrasonography is consistent with interstitial injury with b lines (white lung) [11] . in the presence of reduced sliding and multiple subpleural opacities, intubation should not be delayed, particularly when bb coalescent lines are present in all evaluated zones or in the majority (more than three fields explored). this phenotype is characterised by an organising pneumonia with hypoxic vasoconstriction associated with severe hypoxaemia. nitric oxide or prostacyclin, when available, should be considered as potential rescue therapies. this phenotype has "normal" (>40 ml·cmh 2 o −1 ) lung compliance and likely does not represent acute respiratory distress syndrome. the target should be to maintain a venous oxygen saturation >90%, avoiding ventilatory asynchronies. high positive end-expiratory pressure (peep) in patients with normal compliance may have detrimental effects on haemodynamics [12] . peep should be enough to be maintained at 8-10 cmh 2 o, with higher levels compromising cardiovascular stability. most patients had prior hyperinflammation and hyperpyrexia, and are hypovolemic. under these conditions, peep values >10 cmh 2 o may be harmful, often being associated with a need for high dose vasopressors and acute kidney injury, thus complicating management. respiratory rate should be <20 beats·min −1 . recruitment manoeuvres are not beneficial and are contraindicated. prone positioning/supine cycles are of little benefit in this phenotype, contributing to increased risks of contamination and fatigue of healthcare workers. in this phenotype, tidal volumes >6 ml·kg −1 are likely to be less harmful than in typical acute respiratory distress syndrome. gattinoni et al. [12] suggest that tidal volumes of 6-9 ml·kg −1 may be allowed in order to control hypercapnia because the risk of ventilator-induced lung injury may be better tolerated if high lung compliances are maintained. these observations are consistent with a preliminary analyses of 16 patients [13] . phenotype 5 is less common than phenotype 4 (table 1) and it is an advanced stage with associated acute lung injury. co-infection or acute lung injury is associated with increased plasma procalcitonin levels, which may help to distinguish it. in our experience, this phenotype was rarely documented in patients who underwent rapid intubation (table 2) . typically, it was present in patients with sars-cov-2 infection who were started on noninvasive ventilation (via helmet in italy or facemask in china) but less common in patients started on ventilation promptly [14] . oxygenation should be assessed measuring the shunt fraction. lung compliance showed values <40 ml·cmh 2 o −1 . this phenotype may benefit from high peep values and prone positioning, with a similar management strategy to acute respiratory distress syndrome. the potential benefit of immunomodulatory agents at this stage may result in the emergence of severe adverse events which complicate management, such as systemic super infections (viremia by cytomegalovirus and bacterial sepsis). in summary, patients with covid-19 present a broad spectrum of clinical presentations. whereas hypoxaemia is the marker of severity, different strategies of management should be customised to the specific individual phenotypes (table 1) . applying a personalised approach would benefit the optimisation of therapies and improve outcomes. testing for respiratory viruses in adults with severe lower respiratory infections clinical and ct features in pediatric patients with covid-19 infection: different points from adults severe 2009 a/h1n1v influenza in pregnant women in spain coronaviruses and immunosuppressed patients. the facts during the third epidemic clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study coagulopathy and antiphospholipid antibodies in patients with covid-19 anticoagulant treatment is associated with decreased mortality in severe coronavirus disease in patients with coagulopathy endemic human coronaviruses in hospitalized adults with community-acquired pneumonia: results from the louisville pneumonia study towards precision medicine in sepsis: a position paper from the european society of clinical microbiology and infectious diseases coronavirus disease 2019 (covid-19): a critical care perspective beyond china utility of point-of-care lung ultrasound for initial assessment of acute respiratory distress syndrome patients in the emergency department covid-19 pneumonia different respiratory treatment for different phenotypes? covid-19 does not lead to a "typical" acute respiratory distress syndrome sars-cov-2 in spanish intensive care: early experience with 15-day survival in vitoria conflict of interest: j. rello has nothing to disclose. e. storti has nothing to disclose. m. belliato reports personal fees for lectures from hamilton medical, swiss and bonaduz, outside the submitted work. r. serrano has nothing to disclose. key: cord-301318-9g547s2n authors: zhang, zhi-jiang; yu, xue-jie; fu, tao; liu, yu; jiang, yan; yang, bing xiang; bi, yongyi title: novel coronavirus infection in newborn babies under 28 days in china date: 2020-04-09 journal: eur respir j doi: 10.1183/13993003.00697-2020 sha: doc_id: 301318 cord_uid: 9g547s2n previous studies described the clinical features of covid-19 in adults and infants under 1 year of age. little is known about features, outcomes and intrauterine transmission potential in newborn babies aged 28 days or less. through systematical searching, we identified 4 infections in newborn babies in china as of march 13. the age range was 30 h to 17 days old. three were male. two newborn babies had fever, 1 had shortness of breath, 1 had cough and 1 had no syndromes. supportive treatment was provided for all 4 newborn babies. none required intensive unit care or mechanical ventilation. none had any severe complications. three newborn babies recovered by the end of this study and had been discharged with 16, 23, and 30 days of hospital stay. all 4 mothers were infected by sars-cov-2, 3 showing symptoms before and 1 after delivery. cesarean section was used for all 4 mothers, 3 at level iii hospitals and 1 at a level ii hospital. three newborn babies were separated from mothers right after being born and were not breastfed. in summary, newborn babies are susceptible to sars-cov-2 infection. the symptoms in newborn babies were milder and outcomes were less severe as compared to adults. intrauterine vertical transmission is possible but direct evidence is still lacking. the outbreak of coronavirus disease 2019 (covid-19) spreads rapidly [1] [2] [3] [4] [5] [6] [7] [8] . on january 31, the world health organization declared covid-19 a public health emergency of international concern. by march 13, covid-19 have been confirmed in 127 countries with 145,166 cases and 5,428 deaths worldwide. at the earlier stage of the epidemic, older adults were reported to be more likely to be infected [1] [2] [3] [4] [5] [6] [7] [8] . subsequently, infections in infants under 1 year of age [8] and children were reported. to date, little is known about the infection in newborn babies. furthermore, data regarding intrauterine transmission are scarce [9] . we identified all infected newborn babies in china by march 13 and described the clinical features, treatment, outcomes and intrauterine transmission potential. for this retrospective study, we identified all neonatal infections of sars-cov-2 between dec 8, 2019 and march 13, 2020 in china. the summary number of new infections was released by the national health commission on daily basis in china [10] . we systematically explored all the laboratory-confirmed 81,026 cases by march 13, as described previously [8] . in short, we retrieved the summary data from the central government and local health departments and screened for newborn babies <28 days of age. local hospitals, administrative offices and families of patients were interviewed through telephone or online communication tools. this study was approved by the institutional review board of wuhan university school of health sciences. informed consent was waived as part of a public health outbreak investigation. data on the demographics, disease onset, diagnosis, treatment, and outcomes were collected using standard forms. to analyze the intrauterine transmission potential, mother's disease onset (symptoms, timing of symptoms onset relative to delivery), diagnosis, wuhan linkage (living in or visited wuhan, or directly contacting visitors from wuhan), delivery (delivery methods, hospital level, protection level, gestational age at delivery), mother-child contact (separation, breastfeeding) were collected. to detect neonatal infection, nasopharyngeal swabs or annals swabs were collected during hospitalization. quantitative real-time polymerase chain reaction was used according to the recommended protocol [11] . for mothers of the newborn babies, ct scanning was used for preliminary screening. abnormal results included ground-glass opacity and bilateral patchy shadowing. suspected infection was defined as abnormal results on ct scanning coupled with typical clinical symptoms, including fever, cough, headache, sore throat, shortness of breath, sputum production. nasopharyngeal swabs was collected for detection of sars-cov-2 nucleic acid. based on the data sources we used in this retrospective study, 4 nucleic acid-confirmed neonatal infections were identified through systematic and comprehensive searching among the 81,026 confirmed cases in china as of march 13 (table) . all 4 patients were hospitalized. three were male. the age range was 30 hours to 17 days old. two newborn babies had fever, 1 had shortness of breath, 1 had cough and 1 had no noticeable syndromes. the onset of disease occurred in hospital for 2 newborn babies and home for 2 newborn babies. two newborn babies were at isolation and 2 were not at isolation at the time of disease onset. nucleic acid detection was performed using nasopharyngeal swabs for 2 newborn babies and annals swabs for 2 newborn babies. four newborn babies tested positive in nucleic acid detection. ct scans were performed in 3 newborn babies. all showed increased lung marking. time between dates of admission/symptoms and diagnosis was 0-2 day. supportive treatment was provided for all 4 newborn babies. none required intensive unit care or mechanical ventilation. none had any severe complications. three newborn babies were deemed to recover after two consecutive negative nucleic acid tests (separated by ≥24h). the hospital stay was 16, 23, and 30 days, respectively. all the 4 newborn babies' mother was diagnosed to be infected. three mothers showed symptoms before delivery and 1 after delivery. the most common symptoms in mothers were fever, followed by cough, appetite decline and oil intolerance. ct scans were performed for all 4 mothers, with 3 before and 1 after delivery. abnormal findings were reported for all mothers. nucleic acid detection was performed for all 4 mothers, with 3 after delivery and 1 before delivery. all 4 mothers tested positive for nucleic acid. cesarean section was used for all 4 mothers, 3 at level ⅲ hospitals and 1 at a level ⅱ hospital. the protection level was ⅲ for 3 mothers and ⅱ for 1 mother. three newborn babies were separated from mothers right after being born and were not breastfed; one neonate had not been separated from mother and was breastfed for 16 days until symptom onset. based on the sources of data used in this study, 4 nucleic acid-confirmed infections were identified in newborn babies. severe clinical complications or deaths were reported, as compared to fatality rates of 4%~15% in adults [1] [2] [3] [4] . note that infants <1 year of age also presented mild or no symptoms and rarely severe complications [8] . it is encouraging that newborn babies and infants appear to be less vulnerable to sars-cov-2. on the other hand, mild or no symptoms in the youngest make it difficult to detect and prevent further transmission. the number of neonatal infections is 4, as compared to 9 infections in infants aged between 28 days and 1 year [8] . proportionately, the infection rate might be significantly higher in newborn babies than infants. different exposure chance may explain the difference, if any, between the infection rates, but transmission routes may also be different. it is possible that vertical transmission is an additional route for neonatal infections, although a previous study of 6 pregnant women did not find any direct evidence [9] . findings of the present study support intrauterine transmission potential. all 4 newborn babies were delivered through cesarean section and 3 were under level ⅲ protection. the possibility of intrapartum mother-to-child transmission by vaginal delivery was excluded. except for patient 2 having contact with an infected visitor, all the other 3 newborn babies were at isolation when symptoms occurred. no mother-child contact or breastfeeding occurred in the 3 newborn babies. time between birth and diagnosis was limited, ranging between 30 hours and 5 days. taken together, the chance of infection through ways other than intrauterine transmission is deemed to be low. however, there are other explanations for neonate infections. first, possibility of nosocomial infection cannot be completely ruled out. second, nasopharyngeal and annals swabs cannot directly indicate intrauterine infection, and no viral particles were found in amniotic fluid or cord blood from 6 patients [9] . third, number of neonatal infections is small although incomplete identification is possible. fourth, sars-cov, another coronavirus with similar genome sequence [12] , was not found to be vertically transmitted [13, 14] . further research is warranted. there are limitations to the present study. first, although a systematic and comprehensive searching was made for sars-cov-2 infection in newborn babies <28 days of age, incomplete identification of cases is possible. second, the present study identified mostly symptomatic patients. however, asymptomatic infection exists for covid-19 [8, 15] . third, intrauterine tissue samples were not collected for these 5 newborn babies. direct detection of sars-cov-2 is not possible in the present study. in summary, newborn babies are susceptible to sars-cov-2 infection. the symptoms in newborn babies were milder and outcomes were less severe as compared to adults. intrauterine vertical transmission is possible but direct evidence is still lacking. 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 clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiologic features and clinical course of patients infected with sars-cov-2 in singapore clinical characteristics of coronavirus disease 2019 in china novel coronavirus infection in hospitalized infants under 1 year of age in china clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records national health commission of the people's republic of china coronarvirus diesease (covid-19) technical guidance: laboratory testing for 2019-ncov in humans a novel coronavirus from patients with pneumonia in china infants born to mothers with severe acute respiratory syndrome pregnancy and perinatal outcomes of women with severe acute respiratory syndrome a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster all authors declared they had none conflicts of interest. level ⅲlevel ⅲlevel ⅱ level ⅲ level ⅲlevel ⅱ level ⅲlevel ⅲ key: cord-274282-hvx5m2bx authors: liu, yang; mao, bei; liang, shuo; yang, jia-wei; lu, hai-wen; chai, yan-hua; wang, lan; zhang, li; li, qiu-hong; zhao, lan; he, yan; gu, xiao-long; ji, xiao-bin; li, li; jie, zhi-jun; li, qiang; li, xiang-yang; lu, hong-zhou; zhang, wen-hong; song, yuan-lin; qu, jie-ming; xu, jin-fu title: association between ages and clinical characteristics and outcomes of coronavirus disease 2019 date: 2020-04-27 journal: eur respir j doi: 10.1183/13993003.01112-2020 sha: doc_id: 274282 cord_uid: hvx5m2bx age significantly determined the clinical features and prognosis of the disease. the prognosis was worse in patients older than 60 years, calling for clinicians to pay more attention to patients on this special age. https://bit.ly/34dti05 different age. this study showed that clinical features and prognosis of the disease vary among patients of different ages and a thorough assessment of age may help clinicians worldwide to establish risk stratification for all covid-19 patients. patients over 60 years showed heavier clinical manifestations, greater severity and longer disease courses compared with those under 60 years. closer monitoring and more medical interventions may be needed for the elder. the rapid outbreak of novel coronavirus 2019 (covid-19) has been a matter of international concern as the disease is spreading fast [1, 2] . considering that the contagious disease has led to an enormous impact globally, there is an urgent need to identify the risk populations with poor prognosis. aging is associated with certain changes in pulmonary physiology, pathology and function, during the period of lung infection. therefore, the age-related differences in responsiveness and tolerance become obvious and lead to the worse clinical outcome in elderly individuals [3] . previous studies mentioned that older covid-19 patients are at an increased risk of death [4] [5] [6] [7] . however, the ages related clinical characteristics, diseases courses and outcomes other than death in covid-19 patients remain unclear. totally, 221 covid-19 patients who were diagnosed by the fever clinics of designated hospitals were included in this study. they were administratively admitted to shanghai public health clinical center to receive medical care. the diagnosis was based on the positive response to the viral nucleic acid detection according to the updated versions of the guideline for the diagnosis and treatment of 2019 novel coronavirus-infected pneumonia issued by the national health commission of china [8] . data on demographics, symptoms, disease severity and course, radiologic and laboratory examination were analyzed in our study. a unified observation endpoint date was set (march 7, 2020) in our study, primary outcome of the disease course and second outcome of respiratory failure rate for all covid-19 patients in both groups were compared. all 221 covid-19 patients were divided into two groups when taking 60 years old as the threshold. the age distribution for all patients was shown in figure1a. 136 cases (61.5%) were under 60 years old (<60), and other cases were over 60 years old (≥60). in total, 176 patients (79.6%) had fever, other common symptoms included cough (48.0%), sputum (25.8%), sore throat (8.6%), and diarrhea (5.4%), among which only sore throat showed a significant difference between two groups (11.8% vs 3.5%, p=0.034). the significant negative correlations between ages of patients and lymphocyte counts (r=-0.432, p<0.001) as well as albumin levels (r=-0.569, p<0.001) were observed in our study (figure 1b (figure 1f ). in turn, the utilization of antibiotic therapy, intravenous corticosteroids, and assisted ventilation were more common in those over 60 ( figure 1g ). longer disease courses and higher proportion of cases with respiratory failure in patients over 60 were observed (figure 1h ). the median time of disease courses was significantly longer in patients over 60 years (24.0 vs 21.5 days, p=0.026) (figure 1i ). interestingly, this difference was markedly significant in male patients (25.0 vs 21.0 days, p=0.036) but not in female patients (figure 1i) . big difference of courses was observed in cases with respiratory failure in two ages groups, although it showed no statistical significance (38.0 vs 30.0 days, p=0.100) (figure 1i ). this is the first study to systematically evaluate the impact of age on the clinical characteristics and important outcomes for covid-19 patients, thus helping clinicians to establish risk stratification of covid-19 patients as early as possible. sporadic studies mentioned that the elderly people may tend to die after infection [5, 7, 9] , calling on the public to pay more attention to protecting the elder from the virus. in this study, we demonstrated that the clinical characteristics and outcomes of 221 covid-19 patients were closely related to the different ages. this study provided clear evidence of relationship between disease severity and the age, which other studies did not refer to. comprehensive analysis of these indicators provided physicians worldwide with important information for the disease perception, the condition assessment and the effective treatments for covid-19. the proportions of patients with the usage of antibiotics were higher in patients≥60 years than those in patients <60 years, possibly due to the higher proportion of patients with bacteria co-infection in this group. besides, older patients showed more serious illness, leading to higher frequency of adjuvant therapies including corticosteroids and assisted ventilation in this group of patients. contrastive analysis with recent reports [10, 11] , older patients presented significantly lower level of lymphocyte than young patients. lymphocytes are generally elevated in response to common viral infections, while abnormally decreased in sars and covid-19 [12] [13] [14] . although the underlying mechanism is still unclear, the low level of lymphocyte could be a key indicator of disease severity in covid-19. furthermore, other serological indexes, such as albumin level, blood urea nitrogen, lactate dehydrogenase and inflammatory indicators also showed a progressive trend with age. the phenomenon is obvious, however, we cannot identify whether these indicators changed result in or result from the differences of the diseases severity with age. although most patients had favorable prognosis in this study, some patients required longer periods of treatment, which might turn worse under the high risk of hospital-acquired or iatrogenic infections. age was one of the risk factors in disease severity and mortality of viral infections studies [5, 9] , while the data about age in those studies are rough. our study found that covid-19 patients over 60 years had a higher rate of respiratory failure and needed prolonged treatment than those at age below 60 years, demonstrating that elderly covid-19 patients were much more severe and showed poorer response to treatments than the younger. the cure rate of patients over 60 years old (89.4%) was relatively lower than that of patients under 60 years old (95.6%), especially in male and those with respiratory failure. previous study had indicated that there might be a sex predisposition to covid-19, with men more prone to be affected, but no evidence of an association between the severity of covid-19 and the male sex [15] . more attention needs to be paid on these old patients with respiratory failure, and aggressive early intervention should be made to improve their prognosis. with more cases being examined from different ethnic and genetic backgrounds, the findings related to the age in this study may be approved by physicians worldwide. in conclusion, the clinical features and prognosis of the disease vary among patients of different ages and a thorough assessment of age may help clinicians worldwide to establish risk stratification for all covid-19 patients. patients over 60 years showed heavier clinical manifestations, greater severity and longer disease courses compared with those under 60 years. closer monitoring and more medical interventions may be needed for the elder. outbreak of coronavirus disease strategies for the prevention and management of coronavirus disease 2019 age-related changes in immunological and physiological responses following pulmonary challenge 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 risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease predictors of mortality for patients with covid-19 pneumonia caused by sars-cov-2: a prospective cohort study guidelines for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 5 updated understanding of the outbreak of 2019 novel coronavirus (2019-ncov) in wuhan clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of coronavirus disease 2019 in china effects of severe acute respiratory syndrome (sars) coronavirus infection on peripheral blood lymphocytes and their subsets clinical characteristics of 140 patients infected with sars-cov-2 in wuhan clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov-2 sex difference and smoking predisposition in patients with covid-19 the authors would like to express our sincere thanks to all the staff of all the hospitals, and also the patients for their contributions to the study. the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data, review, or approval of the manuscript; and decision to submit the manuscript for publication. no authors have been paid to write this article by any pharmaceutical companies or agencies. all authors declare that they have no competing interests. key: cord-290080-hxte1gc1 authors: tadolini, marina; garcía-garcía, josé-maría; blanc, françois-xavier; borisov, sergey; goletti, delia; motta, ilaria; codecasa, luigi ruffo; tiberi, simon; sotgiu, giovanni; migliori, giovanni battista title: on tuberculosis and covid-19 co-infection date: 2020-06-25 journal: eur respir j doi: 10.1183/13993003.02328-2020 sha: doc_id: 290080 cord_uid: hxte1gc1 covid-19 may boost tuberculosis given infection and mortality, further studies are needed dear editor, we wish to thank, alkesh khurana and deepak aggarwal [1] for their interest in our research letter and comments [1] . in their correspondence, the authors raised two important issues, namely the possible association between tuberculosis (tb) and covid-19 (can infection by sars-cov-2 reactivate tb?) and the effects of tb on early mortality in co-infected patients. our research letter reported the first cohort of patients with diagnosis of tb (including posttreatment sequelae) and covid-19. the article was aimed at reporting what was observed at the beginning of the epidemic among some of the most affected countries. this explains the small numbers described and the countries involved. at the time the article was submitted several countries in africa, europe and latin america represented in the global tuberculosis network (gtn) had no tb/covid-19 patients to report. in the absence of previous cohorts and scientific information on the tb/covid-19 coinfection, we have described the timing of diagnosis of the two diseases, observing that one third had covid-19 diagnosed prior to tb and 18% were diagnosed simultaneously. we agree, it is possible that the diagnosis of covid was made before tb because of acute onset of symptoms caused by sars-cov2 in addition to the alarm generated by the covid-19 pandemic, which determined rapid access to radiological examinations and subsequent discovery of underlying tuberculosis. in fact we commented this in point 3 of our article [2] , and we abstained from making any clear statement about causal association. however, we could not exclude that the infection by sars-cov-2 or the drugs utilized might have accelerated the progression of a pre-existing tb infection to disease. however, apart from the speculation on what disease comes first, it is evident that the coexistence of tb and covid-19 poses a challenge in differential diagnosis [2] . the study was observational, and based on a relatively small cohort, and therefore we fully agree that larger prospective studies are necessary to shed further light on this to establish whether there is an association or not. the authors [1] also raised the important question whether tb has a real effect or 'weight' in increasing the probability of death in covid-19 patients. the issue has been described in a second article [3] which reports the findings of 69 patients from our original cohort plus a second cohort [4] which was managed in a reference hospital in northern italy. the patients likelier to die were those of older age with pre-existing co-morbidities [3] . it is important to emphasise that the cohort of young migrants without co-morbidities reported elsewhere [3, 4] experienced a milder form of covid-19 with no deaths. however, in countries where risk factors for mortality are highly prevalent among young individuals (smoking, alcohol and substance abuse, hiv co-infection, among others), particularly in the presence of drug-resistance and difficult access to diagnosis (delayed diagnosis), the impact of mortality may be higher. we agree that in resource-limited settings poverty and malnutrition might play an important role in increasing morbidity and mortality. furthermore, we do agree that the population of individuals with post-tb treatment sequelae deserves further evaluation, given the potential effect of both tb and covid-19 on quality of life and subsequent need for rehabilitation [5] [6] [7] . in order to better understand the implication of tb and covid-19 co-infection the study is continuing: more countries and a larger sample size will help answering some of the questions left open by our original study [2] . we will be happy to collaborate with all interested colleagues. the (in)significance of tb and covid-19 co-infection active tuberculosis, sequelae and covid-19 co-infection: first cohort of 49 cases covid-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts. pulmonology clinical characteristics of covid-19 and active tuberculosis co-infection in an italian reference hospital pulmonary rehabilitation is effective in patients with tuberculosis pulmonary sequelae the increasing threat of respiratory tract infections to global health security -covid-19 and tuberculosis tuberculosis in the time of covid-19: quality of life and digital innovation the article is part of the scientific activities of the global tuberculosis network ( key: cord-322075-e6whegrf authors: guglielmetti, lorenzo; chiesi, sheila title: covid-19 in italy passing through bitter waters date: 2020-05-22 journal: eur respir j doi: 10.1183/13993003.01812-2020 sha: doc_id: 322075 cord_uid: e6whegrf the covid-19 epidemic in italy has shown many shortcomings of the national health care system but it also represents a historic opportunity to reinforce the central health care governance and reduce inequalities across the country the catastrophic impact of the coronavirus disease 2019 (covid-19) epidemic in italy has been described previously. [1, 2] in a recent editorial, nava and co-authors pay a well-deserved tribute to the almost 200 health care workers who succumbed to covid-19 in the country in less than 3 months since the first case was reported. [3] we would like to contribute with some considerations on the shortcomings of italy's response to the pandemic. around the first covid-19 cluster in northern italy, between the regions of lombardy and emilia-romagna, the explosion in the caseload has been abrupt. [4] soon, resources became insufficient to provide adequate assistance to all patients who required it. [5] as the system got progressively overwhelmed, the death toll started to rise. during these weeks working among the communities paying the highest price to the epidemic, we have witnessed the relentless commitment of health care personnel at all levels. it was at once moving and disheartening to observe them struggling to cope with unbearable workloads in a system which was not prepared to support them. faced with exhausting shifts and often without adequate personal protective equipment, health care workers have been unsurprisingly affected by high rates of infection and death. [6] indeed, as shown by nava and co-authors, 65% of the casualties among medical doctors occurred in the two aforementioned regions. [3] an obvious reason for italy's inadequate outbreak response can be found in years of neglect for the public sector, increased private expenditure, and health care budget cuts by governments of all political affiliations. [7] other major shortfalls stem, in our opinion, from the extreme regionalization of health care, which has led to fragmentation of the decision-making process, increased inequalities, and lack of national coordination. [8] for instance, covid-19 testing policies vary widely in italy, where some regions perform mass contact tracing and outreach activities, while others prioritize severely-sick patients. the role of general practitioners in outbreak response activities is also differing substantially across the country. this heterogeneity, coupled with ambiguous communication, has generated inefficiencies and confusion. resource allocation in the emergency was similarly impacted, in particular for the management of intensive care unit needs. as previously highlighted, italy already had a modest number of intensive care unit beds. [9] during the last years, this number has been progressively tapered due to budget necessities, ignoring repeated warning by experts, [10] and leading to complete unpreparedness to handle the burden of patients who required intensive support. major differences between regions, even neighboring ones, in terms of respiratory equipment availability were obvious on everyday news. nevertheless, inter-regional collaboration was limited. most patient transfers to relieve overwhelmed intensive care units were indeed performed inside the same region, or towards foreign countries. finally, the lack of standardization also affected patient management, which was guided by regional -not national -guidelines. moreover, participation to clinical trials and access to investigational drugs were easier for bigger centers and university hospitals, where greater research experience and manpower facilitated their implementation. quoting a famous colleague, doctor van helsing from bram stoker's dracula, we will have to pass through the bitter waters before reaching the sweet. once there, though, this historic opportunity for reform should be seized: strengthening our public health care system, reinforcing a central governance, reducing inequalities across regions, and going back from "aziende ospedaliere" (hospital companies) to just hospitals. only then, we will be ready to react efficiently to next pandemic threat while protecting adequately our health care workers. [1] at the epicenter of the covid-19 pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation facing covid-19 in italy -ethics, logistics, and therapeutics on the epidemic's front line an italian sacrifice to covid-19 epidemic covid-19 and italy: what next? the toughest triage -allocating ventilators in a pandemic integrated surveillance of covid-19 in italy the italian health system and the covid-19 challenge economic crisis, decentralisation and health inequalities: the case of italy, universal health coverage. aida isabel tavares intechopen what other countries can learn from italy during the covid-19 pandemic cassandra's curse and covid-19: why do governments listen to businesses over doctors? key: cord-323480-h6z3vim0 authors: li, shao-qiang; guo, wen-liang; liu, hao; wang, tao; zhou, yuan-yuan; yu, tao; wang, chong-yang; yang, yong-ming; zhong, nan-shan; zhang, nuo-fu; li, shi-yue title: clinical application of intelligent oropharyngeal-swab robot: implication for covid-19 pandemic date: 2020-07-16 journal: eur respir j doi: 10.1183/13993003.01912-2020 sha: doc_id: 323480 cord_uid: h6z3vim0 clinical application on the safety and effectiveness of intelligent oropharyngeal-swab robot for the implication for covid-19 pandemic coronavirus disease 2019 , caused by infection of severe acute respiratory syndrome coronavirus-2 (sars-cov-2), is transmitted through respiratory droplets and close contact. [1] [2] [3] [4] to diagnose covid-19, oropharyngeal-swab (op-swab) sampling is widely used for viral nucleic acid detection. [3] however, healthcare workers who perform op-swab are at high risk of infection due to aerosol from patients during the process of sampling. and the quality of manual op-swabs is inconsistent among different collectors, which may lead to misdiagnosis. [5] remote controlled opswab robot has the potential to avoid close contact between healthcare workers with patients, and thus reduce the risk of sars-cov-2 infection during sampling. here, we invented a robotic sampling (rs) system and evaluated the safety and efficacy of this system on op-swab sampling during the period of pandemic. first-generation semi-automatic op-swab robot jointly developed by shenyang institute of automation of the chinese academy of science and first affiliated hospital of guangzhou medical university was used to take op-swabs in this study ( figure 1a to figure1d). the exposure of op-swab sampling using robot is classified according to the visible structures as follows: class i, soft palate, fauces, uvula, pillars; class ii. soft palate, fauces, uvula; class iii, soft palate, base of uvula; class iv, soft palate not visible at all. class i was defined good field of view (fov) of posterior pharyngeal wall, and class ii-iv was defined limited fov of posterior pharyngeal wall. research protocol was registered (chictr2000030861) and approved by ethics committee of the first affiliated hospital of guangzhou medical university (2020-46).suspected covid-19 patients were determined based on criteria of national health commission of china. [6] sampling parameters, safety and effectiveness of op-swab robot were investigated in 20 healthy individuals using four different sampling forces (10-60 g). effectiveness was determined in terms of sampling success rate (completion in first attempt), and swab quality was determined based on the threshold cycle (ct) value for glyceraldehydes 3-phosphate dehydrogenase (gapdh) by rt-pcr [8] . op-swabs with ct values of ≤37 and >37 was considered as qualified and unqualified samples respectively. sampling adverse reactions were determined in terms of retching, sore throat, pharyngeal congestion, or injury of posterior pharyngeal wall after sampling. comparison study of the safety and effectiveness between rs and ms was performed in 30 healthy individuals in crossover trials. clinical application study was performed in 20 consecutive suspected covid-19 patients from a fever clinic to compare the pathogen test results of the two methods. op-swab sample collection in ms group was achieved through wiping of posterior pharyngeal wall with sterile cotton swab by experienced collectors. data normality was tested via kolmogorov-smirnov test and presented as mean ± sd or median (iqr). two-sided independent sample t-test,one way anova or fisher's exact test were used as appropriate, a p<0.05 was considered statistically significant. sampling success rate was 95% in 20 healthy subjects with different force groups when using rs-system. the ct values showed 97% specimens as qualified, and no significant difference in the quality of the specimens was found in the four sampling force groups based on the sample gadph ct value. (group 10-30 g: 31.50 ±3.5; group 20-40 g: 32.93 ±2.9; group 30-50 g: 32.37 ±2.1; and group 40-60 g: 32.97 ±2.1, p= 0.346). there was no pharyngeal congestion or injury in any participant, however, incidence of sore throat was higher when the sampling force is > 40g (15.8%, 6/38) when compared to low-force (≤ 40 g) group (0/38; p= 0.025). thus, 20-40 g force was selected for op-swab robot sampling in subsequent experiments. next, we compared rs and ms system and showed 95% and 100% success rates respectively when measuring gapdh in the swab samples in the crossover study. all specimens were qualified based on gapdh ct values of ≤37, however, variation of ct value from ms specimens was more significant compared to rs specimens (27.14 ± 2.0 vs. 27.86 ± 2.02, p = 0.008). however, the difference in ct values from the data did not exceed 1, and although there was statistical difference, no clinical significance was indicated. no significant differences in adverse reactions were observed between the two groups. swab quality was affected by limited fov as ct value of swab specimens with good fov group was significantly lower than the limited fov group (ct value of good fov group: 27.33 ± 1.99; ct value of limited fov group: 28.61 ± 1.87;p = 0.018). there were 7 and 9 cases of limited fov in ms and rs groups respectively,. however, after eliminating the influence factor of limited fov, no significant difference in swab quality was found between the ms and rs methods (27.05 ± 2.0 vs. 27.61 ± 1.97, p = 0.156). rs sampling time (9 ±4.1 s) was significantly shorter than ms group (18 ±5.1 s; p= 0.032). there was no significant difference in adverse reactions between the rs and ms groups(10% vs 10%，p=1). lastly, op swabs were collected using ms and rs in 20 suspected covid-19 patients, including 8 males and 12 females with the mean age of 45 ±15 years. op swab samples were subjected to pathogen testing. sars-cov-2 nucleic acid was negative for all suspected cases. the results of viral and mycoplasma tests were negative. there were two cases tested positive for bacteria, including one case of staphylococcus infection and another case of moraxella catarrhalis infection. the consistency of the pathogen discovery results between the two sampling methods for the 20 suspected cases of covid-19 reached 95% (kappa= 0.875). no differences in the success rate, swab quality, and pathogen discovery results were found between the oropharyngeal-swab robot and manual sampling methods. standard sampling of op swab, including the precise delivery of swab to target tissue, appropriate force and touch avoidance of surrounding tissue, has confirmed to be prerequisite for the enhancement of positive detection rate. [9] [10] [11] ms swab sampling may potentially lead to falsenegative results due to lack of experience and psychological anxiety on sampling personnel due to sars-cov-2 contagious nature. [5] op-swab robot with remote camera can help medical staffs to have clear vision during sampling without close contact to patients, thus resulting in collection of highquality swab specimens consistently. though greater force is believed to be capable of collecting higher number of cells in swab, however, our results showed that there was no correlation between the quality of swab specimens and sampling force. thus, the rs system showed advantage in the quality control of op swab sampling, and have the potential to minimize the risk of infection to healthcare workers. [11] time from research and development to application was pressed in light of the crisis of the emerging infectious disease. therefore, the first generation of pharyngeal swab robots still required medical assistants to manually replace the isolation sleeves and swabs after collecting the specimens, which would minimize but not avoid the exposure to sars-cov-2. however, ultraviolet disinfection and air disinfectant machine were performed for sterilization after each specimen collection to avoid the exposure risk to the outmost extent. additionally, in view of this situation the second-generation intelligent robot has been developed to achieve intelligent movement and automatically replace the swab and protective cover, and is currently preparing for the next phase of clinical trials. it can further improve the intelligence and reduce the degree of manual participation. though this was a preliminary, single-center study in limited covid-19 patients, the sampling process of the intelligent oropharyngeal-swab robot is safe, with a high success rate of sampling. the quality of op swabs and the detection rate of pathogens were not interior to those collected manually. the oropharyngeal-swab robot presents a safe and effective sampling method, and could avoid cross infection to the operators. during epidemics or pandemics, the oropharyngeal-swab robot has a good application prospect in clinical practice. the authors declare no conflicts of interest and alone are responsible for the content and the writing of the manuscript. wuhan coronavirus has strong ability to infect humans national health commission of the people's republic of china key: cord-277603-hpn1ovgo authors: strapazzon, giacomo; hilty, matthias p.; bouzat, pierre; pratali, lorenza; brugger, hermann; rauch, simon title: to compare the incomparable: covid-19 pneumonia and high-altitude disease date: 2020-06-25 journal: eur respir j doi: 10.1183/13993003.01362-2020 sha: doc_id: 277603 cord_uid: hpn1ovgo covid-19 pneumonia is a viral infection; high-altitude pulmonary oedema is a non-cardiogenic oedema. some clinicians have found the clinical features similar. it is important to clarify such misconceptions to prevent erroneous treatment strategies https://bit.ly/2kobi3f to compare the incomparable: covid-19 pneumonia and high-altitude disease to the editor: the coronavirus disease 2019 (covid-19) pandemic is overwhelming healthcare systems worldwide. there is no evidence from randomised clinical trials that any potential therapy improves outcome in covid-19 pneumonia, and therapeutic strategies have been based on a progressively increasing knowledge of the clinical presentation of the disease. some clinicians have found the clinical features of covid-19 pneumonia to be similar to high-altitude pulmonary oedema (hape) [1] , and such theory has been amplified via social media. we question this relationship. covid-19 pneumonia shows diffuse alveolar damage and airway inflammation, reflecting a true virus-related pathology [2] , as shown by the first report of pathological findings from autopsies in covid-19 decedents published at the beginning of april 2020 [1] . since the end of february 2020, as clinicians from northern italy and other european countries, we have faced the management of several hundreds of critically ill patients, similarly to other colleagues [3, 4] . most of the patients with covid-19 pneumonia who require hospitalisation and intensive care meet the acute respiratory distress syndrome (ards) criteria specified in the berlin definition, but with an unusual clinical manifestation. hypoxaemia is the main characteristic of all patients with covid-19 pneumonia and ards, but some patients run an unusual course of the disease and show specific abnormalities on chest imaging. these patients show a dissociation between relatively well-preserved lung mechanics and the severity of hypoxaemia. in contrast to classic ards, lung volume and dead space in covid-19 patients are often normal, consolidations absent and pulmonary and chest wall elastance preserved, but a severe capillary leak dominates the initial phase. whether this severe leak is secondary to virus-triggered inflammation, endothelial cell injury, or direct virus-induced cell destruction, is the subject of ongoing trials. gattinoni et al. [5] have hypothesised two different phenotypes of covid-19 pneumonia: a phenotype l, characterised by low elastance, low recruitability, low response to positive end-expiratory pressure (peep) and low ventilation/perfusion matching; and a phenotype h (similar to classic ards) with high elastance, higher shunt, high recruitability and higher peep response. despite the assumption that patients may progress from phenotype l to phenotype h over time, and that this evolution could be disease-and/or therapy-driven, further evidence is needed to prove this hypothesis. the assumption that the clinical features of covid-19 pneumonia are similar to hape [1] may rely on the initial clinical presentation of covid-19 patients, showing profound hypoxaemia with no respiratory distress, similar to patients with acute high-altitude disease that have a chemoreceptor dysfunction. hape is a non-cardiogenic pulmonary oedema caused by exaggerated hypoxic pulmonary vasoconstriction and abnormally high pulmonary artery pressure and capillary pressure [6] . these high pressures lead to a non-inflammatory and haemorrhagic alveolar capillary leak in the earlier stages of the disease [7] . over time, haemorrhagic alveolar capillary leak may also evoke a secondary inflammatory response in hape patients [7] . the pathogenesis of the two diseases (hape and covid-19 pneumonia) is clearly different, despite similarities in clinical features, chest imaging and bronchoalveolar lavage findings in later stages, as has recently been emphasised by luks et al. [8] . due to the different pathogenesis, adoption of prevention and treatment strategies from hape for the treatment of patients with covid-19 pneumonia could lead to potential pitfalls. patients with covid-19 pneumonia often require intensive care, whereas hape is a life-threatening condition that almost never needs intensive care, as it can be reversed by oxygen administration, exposure to a relatively hyperbaric environment or transfer to lower altitude [9] . the use @erspublications covid-19 pneumonia is a viral infection; high-altitude pulmonary oedema is a non-cardiogenic oedema. some clinicians have found the clinical features similar. it is important to clarify such misconceptions to prevent erroneous treatment strategies https://bit.ly/2kobi3f of supplemental oxygen in covid-19 pneumonia does not counteract the underlying pathogenic mechanisms in the way it does in hape [9] , but only increases oxygen availability. systemic pulmonary vasodilators such as nifedipine and phosphodiesterase-5 inhibitors could critically worsen ventilation/ perfusion mismatch or cause hypotension in covid-19 patients, where there is no hypoxic pulmonary vasoconstriction like in hape [6] but rather a dysregulation of lung perfusion and impaired hypoxic vasoconstriction. despite its established role in prevention and treatment of hape [9] , corticosteroid use in covid-19 pneumonia is still under debate in the scientific community [10] and currently not advised by the world health organization. we consider it important to clarify such misconceptions, in order to prevent the spreading of erroneous treatment strategies when caring for covid-19 patients. covid-19 disease has been reported to affect high-altitude areas [11] and, interestingly, the spread of the disease in certain areas of northern italy has started from villages in mountainous areas that are popular with tourists. this does not implicate any coincidence between the diseases. clinicians should focus on the development of therapeutic strategies based on the pathogenesis of the disease, and should remember that covid-19 pneumonia is a viral infection primarily leading to diffuse alveolar damage and airway inflammation. rationale for their utilization as adjunctive countermeasures in the treatment of coronavirus disease 2019 (covid-19) covid-19 autopsies covid-19 does not lead to a "typical" acute respiratory distress syndrome baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region covid-19 pneumonia: different respiratory treatments for different phenotypes? high-altitude pulmonary edema is initially caused by an increase in capillary pressure pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor covid-19 lung injury is not high altitude pulmonary edema clinical practice: acute high-altitude illnesses clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury clinical and imaging features of covid-19 patients: analysis of data from high-altitude areas this version is distributed under the terms of the creative commons attribution non-commercial licence 4 key: cord-331497-mipg4mg7 authors: mcquaid, c. finn; mccreesh, nicky; read, jonathan m.; sumner, tom; houben, rein m. g. j.; white, richard g.; harris, rebecca c. title: the potential impact of covid-19-related disruption on tuberculosis burden date: 2020-06-08 journal: eur respir j doi: 10.1183/13993003.01718-2020 sha: doc_id: 331497 cord_uid: mipg4mg7 before the covid-19 pandemic, over 4000 people were dying from tuberculosis (tb) every day [1]. as with past emergencies [2], the impact of covid-19 on tb outcomes is a serious cause for concern [3] but is currently unknown. health systems overload, due to high numbers of covid-19 cases, as well as interventions necessary to limit the transmission of sars-cov-2, could result in severe reductions in health service availability and access for the detection and treatment of tb cases [4]. however, physical distancing interventions could also limit mycobacterium tuberculosis transmission outside of households, where most transmission occurs [5]. this has not been adequately explored in existing work [6–8], and it is currently unclear whether social distancing could compensate for disruptions in tb services, and what the impact of these combined covid-19 disruption effects on tb burden is likely to be. before the covid-19 pandemic, over 4000 people were dying from tuberculosis (tb) every day. [1] as with past emergencies [2] , the impact of covid-19 on tb outcomes is a serious cause for concern [3] but is currently unknown. health systems overload, due to high numbers of covid-19 cases, as well as interventions necessary to limit the transmission of sars-cov-2, could result in severe reductions in health service availability and access for the detection and treatment of tb cases. [4] however, physical distancing interventions could also limit mycobacterium tuberculosis transmission outside of households, where most transmission occurs. [5] this has not been adequately explored in existing work, [6] [7] [8] and it is currently unclear whether social distancing could compensate for disruptions in tb services, and what the impact of these combined covid-19 disruption effects on tb burden is likely to be. we used a mathematical model of tb with an age-specific contact matrix calibrated to data from china, india and south africa, [9] key high tb burden countries accounting for approximately 40% of global tb cases, [1] to estimate the relative impact of reductions in social contacts and health services due to covid-19 on tb burden. we considered three scenarios for reductions in different forms of social contact, reweighting contact rates between age groups to reflect large reductions in the number of contacts per day occurring in schools (0%, 50%, and 100% in the low, medium, and high scenarios respectively), transport (30%, 60%, 80%) and leisure settings (50%, 70%, 80%), and smaller reductions in contacts occurring in workplaces (20%, 30%, 50%), which are within the range of already observed reductions. [10, 11] we assumed that mean numbers of contacts occurring within home settings did not change, although we did not model households explicitly. we also considered three scenarios for tb health service disruption, which could be a result of a number of factors such as decreases in diagnostic activities and clinic visits, delays in diagnosis and treatment initiation, and reduced treatment support. these were modelled as reductions in the proportion of incident tb cases detected and detected cases successfully treated: a 20%, 50% or 80% relative reduction in both simultaneously. although our scenarios are in line with initial evidence on reductions in tested and notified cases [12, 13] , we examined a wide range of disruptions here as the scale of these is, as yet, largely unknown.. both reductions in social contact and in health service parameters were implemented from early 2020, and were assumed to last for six months. we estimated the cumulative change in tb incidence and deaths over 5 years for each combination of these scenarios compared to a baseline with no change. results suggest that any potential 'benefit' of social distancing on tb burden is likely to be larger for tb disease incidence, than for tb deaths (fig1 a-c vs d-f). such that in some scenarios where health services are less affected, lower numbers of tb cases may occur over this period. however, this is not considered the most plausible scenario based on current anecdotal information in most low and middle income settings. in addition, this potential reduction in the impact on tb burden tends not to be true for tb deaths, which show a net increase in deaths in all scenarios with some level of health service disruption. in scenarios with substantial health service disruption, we project an increase in both tb cases and deaths, regardless of the level of social distancing. in our worst case scenario, where covid-19 interventions to reduce social contacts are minimal, but tb health services are badly affected, results suggest an increase in tb deaths of 23,516 (range 18,560-27,940), 149,448 (85,000-233,602) and 28,631 (19,963-40,011) in china, india and south africa, respectively between 2020-2024, totalling 201,595 (123,523-301,553) additional tb deaths in these three countries alone. this would be an increase of 8-14% in cumulative tb deaths for that period. however, if these countries are able to minimise the impact on tb health service delivery, major reductions in social contacts could keep the number of additional tb deaths comparatively low. these impacts on tb burden are likely to be felt globally, particularly for tb mortality in the short term. however, our results suggest that the setting-specific nature of the tb epidemic and differences in changing social contacts and service delivery could create highly he terogeneous changes to long-term tb incidence. for example, higher proportions of tb resulting from reactivation in china [14] suggest that reductions in social contacts may have less influence on incidence than elsewhere. further important factors for consideration include that health service declines are likely to have a greater impact on patients with drug-resistant tb (which we do not consider here). indeed, a more detailed analysis of health service availability than our simplified consideration of case detection and treatment success, while not yet possible due to the lack of data, is necessary to understand and mitigate for these changes. our model is also limited in its consideration of each country as a whole, when disruptions are likely to be geographically heterogeneous and specific to local measures. meanwhile external factors such as increases in poverty and reductions in access to antiretroviral therapy in settings with a high hiv prevalence could also increase rates of progression to tb disease. in addition, we estimate the impact of a six month disruption, but given subsequent pandemic waves are anticipated, [15] and are likely to require further mitigation measures, estimates presented here could be considered conservative. finally, the as-yet-unknown potential for an increase in risk of severe covid-19 in patients with active or previous tb, as well as an increase in risk of exposure to sars-cov-2, could have major implications for tb burden. [16, 17] it is, however, imperative that continued access to tb diagnosis and care is ensured, together with the collection and regular reporting of tb indicators, to allow the impact on tb to be both measured and mitigated. research, guidance and funding are urgently required to identify, prioritize and deliver those intervention that could best alleviate the impact of covid-19-related disruptions. these will differ by timescale. interventions necessary to prioritize during disruptions, such as digital adherence technologies to support patient treatment remotely, will be different to those to prioritize afterwards, such as active case finding activities focused on the household, where social contacts and transmission may have been concentrated. it is vital that decision-makers and funders recognise the importance of this issue and act to ensure that innovative approaches to peoplecentered tb care are rapidly scaled up, so that the fight to end one pandemic does not worsen another. world health organization effects of response to 2014-2015 ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa tackling two pandemics: a plea on world tuberculosis day impact of covid-19 on tuberculosis control in china whole genome sequencing shows a low proportion of tuberculosis disease is attributable to known close contacts in rural malawi report 19 -the potential impact of the covid-19 epidemic on hiv, tb and malaria in low-and middle-income countries predicted impact of the covid-19 pandemic on global tuberculosis deaths in 2020. medrxiv the potential impact of the covid-19 response on tuberculosis in high-burden countries: a modelling analysis potential impact of new tuberculosis vaccines in china, south africa and india and implications for vaccine development age profile of susceptibility, mixing, and social distancing shape the dynamics of the novel coronavirus disease 2019 outbreak in china. medrxiv google covid-19 community mobility reports impact of covid-19 intervention on tb testing in south africa. national institute for communicable diseases the tb response is heavily impacted by the covid-19 pandemic age -targeted tuberculosis vaccination in china and implications for vaccine development: a modelling study the global impact of covid-19 and strategies for mitigation and suppression active tuberculosis, sequelae and covid-19 co-infection: first cohort of 49 cases tuberculosis, covid-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts key: cord-339934-g6ufz29l authors: yu, hai-qiong; sun, bao-qing; fang, zhang-fu; zhao, jin-cun; liu, xiao-yu; li, yi-min; sun, xi-zhuo; liang, hong-feng; zhong, bei; huang, zhi-feng; zheng, pei-yan; tian, li-feng; qu, hui-qi; liu, de-chen; wang, er-yi; xiao, xiao-jun; li, shi-yue; ye, feng; guan, li; hu, dong-sheng; hakonarson, hakon; liu, zhi-gang; zhong, nan-shan title: distinct features of sars-cov-2-specific iga response in covid-19 patients date: 2020-05-13 journal: eur respir j doi: 10.1183/13993003.01526-2020 sha: doc_id: 339934 cord_uid: g6ufz29l humoral immune response to sars-cov-2 showed an early response of iga, instead of igm, in covid-19 patients. as highlighted by our study, enhanced iga responses observed in severe covid-19 might confer damaging effects in severe covid-19. to the editor: in comparison to severe acute respiratory syndrome coronavirus (sars-cov), sars-cov-2 appears to be more contagious [1] , and coronavirus disease 2019 patients demonstrate varied clinical manifestations distinct from those seen in patients with sars-cov and middle east respiratory syndrome coronavirus (mers-cov) infections [2] . collective results from the clinical and epidemiological observations suggest a distinct viralhost interaction in covid-19 patients. profiling of the antibody response during sars-cov-2 infection may help improve our understanding of the viral-host interaction and the immunopathological mechanisms of the disease. studies on humoral responses to infections have been mainly geared toward the production of high-affinity igg antibodies that efficiently resolve an infection. it has been well recognized, however, that humoral immune response to infection can be a double-edged sword that either serves as a protective mechanism to resolve the infection or aggravates the tissue injury, e.g. igg response causes fatal acute lung injury by skewing inflammationresolving response in sars [3] . in the case of respiratory infection, while igm and igg isotypes have been the primary emphasis in characterizing immunity, mucosal and systemic iga responses that may play a critical role in the disease pathogenesis, have received much less attention. this study was designed to better understand the timing and patterns of humoral the present study showed that the levels of specific igm antibody were significantly lower than those of iga in both severe and non-severe patents. this pattern of humoral immune response is different in case of sars-cov infection, in which igm and iga showed similar chronological profiles in terms of both seroconversion time and antibody titres [5] , in line with the knowledge that viremia is common in sars. as a mucosal targeted virus, sars-cov-2 would be expected to generate secretory iga (siga) and induce strong mucosal immunity. indeed, the mucosal anti-viral immunity has been shown to result in part from the iga-mediated interactions with the pathogenic microorganisms to prevent pathogens from adhering to the cell surface [6] . however, recent studies also found that siga is able to induce interleukin (il)-6, il-8, monocyte chemoattractant protein (mcp)-1 and granulocyte-macrophage colony stimulating factor (gm-csf) production by normal human lung fibroblasts (nhlfs) [7] . it is also proposed that siga may have synergistic effects with igg in promoting antibody-dependent cellular cytotoxicity (adcc) [8] . in contrast to mucosal iga, the role of serum iga have been relatively unexplored. previous studies have shown that iga mediates either pro-or antiinflammatory effects in innate immune cells and suggested a plausible role of iga as a driver of autoimmune diseases and regulator of immune hyperactivation [9] . monomeric binding of serum iga to the fc alpha receptor (fcαri) has been suggested to mediate inhibitory function via the receptor inhibitory signals in a variety of myeloid cells [10] . in contrast, crosslinking of the fcαri by iga and pathogen is able to transmit activating signals leading to phagocytosis, respiratory burst, adcc, increased antigen presentation, degranulation, and cytokine release [11] . cytokines including transforming growth factor beta (tgf-β) and il-10 can induce antibody isotype switching [12] . upregulated iga production may be the result of increased levels of tgf-β and il-10 that promote antibody switching in sars-cov-2 infection. considering the roles of mucosal and systemic iga in covid-19, inducing iga production, e.g. using lactoferrin to activate canonical tgf-β signaling [13] , or retinoic acid to enhance lactoferrin-induced iga responses [14] , has been proposed as novel therapies for severe covid-19. however, as highlighted by our study, enhanced iga responses observed in severe covid-19 might confer damaging effects in severe covid-19. as a result, we hypothesize that severe covid-19 might be at least in part an iga-mediated disease (related to iga deposition and vasculitis), which helps to explain common organ injuries in covid-19, e.g. acute pulmonary embolism, kidney injury, etc. [15] we acknowledge the limitations of this study, including no measurement of local iga, and limited number of patients. high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 a novel coronavirus outbreak of global health concern anti-spike igg causes severe acute lung injury by skewing macrophage responses during acute sars-cov infection guidelines for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 7) chronological evolution of igm, iga, igg and neutralisation antibodies after infection with sars-associated coronavirus role of secretory iga in infection and maintenance of homeostasis secretory immunoglobulin a induces human lung fibroblasts to produce inflammatory cytokines and undergo activation secretory iga antibodies synergize with igg in promoting adcc by human polymorphonuclear cells, monocytes, and lymphocytes immunomodulatory properties of human serum immunoglobulin a: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cells monomeric and polymeric iga show a similar association with the myeloid fcαri/cd89 the unexplored roles of human serum iga at celldependent mechanism for the induction of human mucosal homing immunoglobulin a-secreting plasmablasts lactoferrin causes iga and igg2b isotype switching through betaglycan binding and activation of canonical tgfβ signaling retinoic acid enhances lactoferrin-induced iga responses by increasing betaglycan expression acute pulmonary embolism and covid-19 pneumonia: a random association? key: cord-290712-flj352ql authors: bi, jianping; ma, hong; zhang, dongsheng; huang, jing; yang, dongqin; wang, yajie; verma, vivek; zhang, tao; hu, desheng; mei, qi; han, guang; li, jian title: does chemotherapy reactivate sars-cov-2 in cancer patients recovered from prior covid-19 infection? date: 2020-09-04 journal: eur respir j doi: 10.1183/13993003.02672-2020 sha: doc_id: 290712 cord_uid: flj352ql recovered covid-19 cancer patients remain negative for sars-cov-2 after delivery of chemotherapy to the editor: cancer patients are particularly vulnerable to coronavirus disease 2019 (covid-19) (1) (2) (3) . these individuals are not only more susceptible to this infection, but also more frequently develop severe pneumonia during the disease course (1) (2) (3) . one factor associated with an increasing risk for developing severe events in this population is oncologic therapy, especially cytotoxic chemotherapy. therefore, some oncologists and societies recommend that chemotherapy should generally not be started until covid-19 symptoms have completely resolved and viral testing becomes negative (3, 4) . additionally, some cancer patients who have recovered from infection are recommended to withhold, postpone, or switch to alternative routes of chemotherapy (e.g. oral instead of intravenous [iv] infusion) until the end of the covid-19 pandemic (3, 4) . llhbch2020lw-006). the median age was 57 years (iqr: 46-63) and the median follow-up from initial administration of chemotherapy was 116 days (iqr: 100-125). prior to chemotherapy administration, all patients were negative for sars-cov-2, and all had at least one positive result for anti-sars-cov-2 antibodies. in total, 5 (13%) patients were negative for immunoglobulin g (igg -) and positive for immunoglobulin m (igm + ), 30 (77%) were igg + igm -, and 4 (10%) were igg + igm + . among this cohort, lung cancer was the most frequent neoplasm (9 [23%] patients), followed by breast cancer (8 [21%] ) and colorectal cancer (7 [18%]). fifteen (38%) patients had stage iv disease with distant organ metastasis. twenty-seven (69%) patients had received chemotherapy prior to initially developing covid-19, and 12 (31%) patients were chemotherapy-naïve. thirty-three (85%) patients received multi-agent chemotherapy or a combination of chemotherapy and targeted therapies (including 5 patients with intravenous chemotherapy plus a pd-1 inhibitor); 6 (15%) received either orally administered drugs or a combination of targeted drug therapies (table 1) . at the time of last follow-up, all patients remained negative for sars-cov-2, without suspicious changes on chest ct. twenty-two (56%) patients experienced altered immunoglobulin test results; specifically, twelve (31%) patients who were initially igg + igmbecame igg -igmafter the median 57 days (iqr: 36-66) from initial administration of chemotherapy. among the four (10%) patients who were initially igg + igm + , three patients became igg -igm + , and one became igg + igmrespectively after 54, 65, 101, and 23 days of chemotherapy. two (5%) patients who was initially igg + igmbecame igg + igm + after 55, 72 days of chemotherapy. three patients who was initially igg -igm + became igg -igmafter 59, 94 and 101 days of chemotherapy and only one patient initially igg -igm + became igg + igm -. treatments were tolerated well in this cohort. at least one therapy-associated adverse event was registered in 31 (79%) patients and all adverse events were of grades i or ii, except for four cases of grade iii-iv neutropenia which returned to normal after treatment with granulocyte colony-stimulating factor (g-csf). potential re-emergence of covid-19 in recovered patients receiving immunosuppressive chemotherapy is a major oncologic and public health concern. concerns of reactivation of a prior infection are not limited to covid-19. previous studies have shown that reactivation of hepatitis b virus (hbv) occurs in nearly 20% of cancer patients undergoing chemotherapy, and may result in varying degrees of liver damage (6, 7) . there has also been a report that chemotherapy may cause reactivation of tuberculosis (8) . additionally, many studies have illustrated (in the recovered covid-19 population) that chemotherapy is associated with a higher risk of developing severe events (e.g. pneumonitis), as compared to cancer patients without receipt of recent chemotherapy (1, 2). however, not all studies have supported such conclusions; some have found no significant effect on mortality for patients having undergone chemotherapy within the prior four weeks (9, 10) . those studies mainly addressed whether chemotherapy could predict for hospitalization, severe disease, and mortality in cancer patients with covid-19 infection. however, limited information is known about the outcome of chemotherapy for cancer patients with prior covid-19 infection. to address this knowledge gap, this study's findings suggest that administering chemotherapy to this population is associated with a very low short-term risk of sars-cov-2 reactivation. further work is required to prospectively follow these subjects in the longer term. many studies have indicated that patients with covid-19 have varying degrees of multiple organ dysfunction (11) (12) (13) , especially those who are critically ill (13) . the rate of liver dysfunction, acute kidney injury, and cardiac injury were as high as 29%, 29% and 23%, respectively (13) . to date, it is unknown whether chemotherapy would make cancer patients with prior covid-19 infection more vulnerable to organ damage. although our data demonstrate that this population does not demonstrate an overtly increased susceptibility to organ dysfunction in the short term, corroboration with longer-term prospective data is required for firmer conclusions. our study has several limitations. first, according to the updated covid-19 diagnostic criteria (7th edition) (14) , viral serum antibody-based tests are indeed valid for diagnosis; however, false positive and false negative test results can occur. the sensitivity and specificity of the colloidal gold immunoassay utilized herein for igg, igm, and igg/igm was 83%/74%/84% and 99%/97%/95%, respectively (15) . second, the number of cases in this study is relatively small, and retrospective assessment can never exclude biases in patient selection. third, the duration of follow-up in this study was relatively short and it may take a longer period of time to determine immune-related alterations caused by chemotherapy in cancer patients who have recovered from covid-19 infection. nevertheless, when conservatively interpreted, our study indicates no overt short-term increase in the risk for sars-cov-2 reactivation following immunosuppressive chemotherapy in this uniquely vulnerable population. to our knowledge, this is the first study reporting that recovered covid-19 cancer patients remain negative in the short-term for sars-cov-2 after delivery of chemotherapy. the knowledge/experience gained from this study may aid guidelines on delivering chemotherapy to cancer patients recovered from covid-19 infection during this pandemic as well as to address potential "second waves" in the future. cancer patients in sars-cov-2 infection: a nationwide analysis in china clinical characteristics of covid-19-infected cancer patients: a retrospective case study in three hospitals within wuhan a practical approach to the management of cancer patients during the novel coronavirus disease 2019 (covid-19) pandemic: an international collaborative group covid-19) resources for the cancer care community positive rt-pcr test results in patients recovered from covid-19 frequency of hepatitis b virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors hepatitis b reactivation in patients receiving cytotoxic chemotherapy: diagnosis and management reactivation of pulmonary tuberculosis during cancer treatment clinical impact of covid-19 on patients with cancer (ccc19): a cohort study covid-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study covid-19 and liver dysfunction: a systematic review and meta-analysis of retrospective studies cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) mar 27;e201017 clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study new coronavirus pneumonia prevention and control program diagnostic efficacy of anti-sars-cov-2 igg/igm test for covid-19: a meta-analysis we thank tian tang (renmin hospital of wuhan university, wuhan, hubei, china) for her assistance in the study and we thank all patients involved in the study. all other authors declare no competing interests. all authors had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. key: cord-307279-1yei5ifs authors: nagra, deepak; russell, mark; yates, mark; galloway, james; barker, richard; desai, sujal r.; norton, sam title: covid-19: opacification score is higher in the right lung and right lung involvement is a better predictor of icu admission date: 2020-10-02 journal: eur respir j doi: 10.1183/13993003.02340-2020 sha: doc_id: 307279 cord_uid: 1yei5ifs in covid-19 the right lung has higher degree of opacification on plain radiograph than the left lung. right lung opacificiation is a stronger predictor for critical care admission and death. dear editor, the global response to covid-19 has resulted in a wealth of research. the accrual of data through electronic health records (ehr) facilitates the efficient interrogation of datasets. indeed, many issues of relevance to the covid-19 response have been explored in this way, the impact of ethnicity or ace inhibition on outcomes, to name but two (1, 2) . large teaching hospitals in the capital were at the forefront of the uk covid-19 outbreak in the united kingdom with over a thousand patients admitted in under one month. research teams mobilised quickly to understand this new and unprecedented disease. we extracted data from our ehr to build a risk score that predicted critical care admission or death. the model included demographics, laboratory data and chest radiographic (cxr) severity (3). the extent of cxr abnormality was scored using an adapted radiographic assessment of lung oedema for covid-19, as proposed by wong et al (4) . the severity score attributes a number between 0-4 to each lung depending on extent of consolidation or ground-glass opacification as follows: 0 = no disease, 1 = <25% extent, 2 = 25-49%, 3 = 50-75%, 4 = >75%). admission cxrs on 1,389 consecutive patients admitted with covid-19 were evaluated. the first 200 radiographs were assessed by two independent scorers: there was high (90.5%) inter-rater concordance. subsequent review of between lung scores demonstrated moderate agreement (r = 0.72; κ=0.52). a polychoric correlation comparing the degree of opacification by lung showed significant differences (p<0.0001). the striking differences were in the most severe categories. the right lung was more likely to be assigned the maximum extent score of 4: 11% versus 6% in the left lung. in addition, opacification of the right lung was a stronger predictor of admission to critical care or die (see figure) . this finding has not been reported previously or with other imaging modalities. we acknowledge important limitations in our work. we did not account for projectional image quality (e.g. anterior or posterior views). the scoring was done by acute physicians rather than radiologists. the explanation for the apparent differential lung involvement in covid-19 is unclear. if the finding is confirmed, it may offer insights into the pathobiology of covid-19 in the lungs. the explanation may lie in anatomy: the right lung is anatomically larger than the left, with a larger main bronchus diameter and more segmental bronchi, possibly increasing viral delivery to respiratory epithelial surfaces. conversely, it is also possible that the lung scoring is subject to perception bias with the cardiac silhouette distracting from left lung abnormalities. to our knowledge asymmetrical radiographic involvement in interstitial lung disease has not been previously reported. opensafely: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult nhs patients use of renin-angiotensin-aldosterone system inhibitors and risk of covid-19 requiring admission to hospital: a case-population study a clinical risk score to identify patients with covid-19 at high risk of critical care admission or death: an observational cohort study frequency and distribution of chest radiographic findings in covid-19 positive patients as a research group with an interest in machine learning, it is interesting to reflect on the power of human observation. we look forward to this pattern being explored in other cohorts using tools such as volumetric ct. c. key: cord-322580-7ohso8hl authors: stochino, claudia; villa, simone; zucchi, patrizia; parravicini, pierpaolo; gori, andrea; raviglione, mario carlo title: clinical characteristics of covid-19 and active tuberculosis co-infection in an italian reference hospital date: 2020-06-01 journal: eur respir j doi: 10.1183/13993003.01708-2020 sha: doc_id: 322580 cord_uid: 7ohso8hl the covid-19 infection rate was high in patient with active tuberculosis. major clinical complications were seen only in two patients thus requiring ex novo oxygen supply, one of whom with advanced tuberculosis died. nasal swab viral clearance was rapid. risk factors such as advanced age and some co-morbidities, such as diabetes and chronic respiratory diseases, are associated with poor outcomes in both tb and covid-19. 3 however, only limited information about covid-19 and active tb co-infection has been reported so far. [4] [5] [6] concerns remain that covid-19 could have a negative impact on the clinical course of tb and its ultimate outcome. 7, 8 this study describes clinical, radiological, and laboratory characteristics of a series of covid-19 patients with concurrent active tb in a hospital in sondrio province, region lombardy in northern italy. patients with active tb admitted to the hospital were analysed to assess the impact of covid-19 on their clinical course as well as radiologic and laboratory consequences of the co-infection. tb diagnosis relied mainly on xpert mtb/rif and chest radiography (cxr) followed by culture confirmation and phenotypic and genotypic drug susceptibility testing (dst). at the time of tb diagnosis, patients were also tested for human immunodeficiency virus (hiv). covid-19 diagnosis was based on the results of the real-time, reverse transcriptase-polymerase chain reaction (rrt-pcr) for sars-cov-2 from nasopharyngeal swabs. radiological results at covid-19 diagnosis were compared with the most recent radiographs available prior to the onset of covid-19 to assess any change in pulmonary tb (ptb)-related lesions. a patient was considered covid-19 laboratory-negative if two consecutive swabs, ≥24 hours apart, were negative. follow-up swabs were performed after 14 days from diagnosis and then every 7 days. 9 clinical data were recorded during a followup period of 6-41 days following the first positive swab. the study was approved by the nineteen patients (95%) had ptb and, among them, three (p11,p13-14) had also extrapulmonary involvement: two patients (p11 and p13) had renal and neurological (p11 with tb meningeal abscess and small brain granulomas; p13 with tb meningitis and encephalitis) localization; whereas one (p14) patient had a disseminated form with pericardial, pleural, splenic, and bone tb. tb was diagnosed using xpert mtb/rif (18/19;95%); in 14 patients, the diagnosis was confirmed by culture. in one case diagnosis was confirmed by bone biopsy (1/19;5%). at admission, cxr showed a multilateral involvement in 12/19 (63%) cases. only one patient (p19) had an exclusively extrapulmonary tb (abdominal lymph nodes) that was diagnosed through needle aspiration. five patients (p07,p10,p17-18,p20) were infected with a drug-resistant strain: three were isoniazid resistant (through genotypic dst in p10) and two were multidrug-resistant. the standard anti-tb treatment regimen (isoniazid, rifampicin, ethambutol, and pyrazinamide) was used in 14 cases, while in six patients therapy was tailored based on clinical characteristics and dst results. hydroxychloroquine (200 mg twice a day) was administered to all patients with covid-19 co-infection and was well tolerated. no antiviral therapy was administered since no patient met the condition of intensive case admission for its use. patients requiring second-line anti-tb drugs (pretomanid, linezolid, terizidone, and clofazimine) for treatment of multidrug-resistant forms (p18 and p20) were monitored through electrocardiogram and no qt interval prolongation was observed. the median time from tb diagnosis and sars-cov-2 detection was 30 (range 19-69) days. the comparison of cxr after covid-19 diagnosis with the latest available one (on average 32 [range 7-88] days earlier) showed that in 12 patients (63%) tb lesions were reduced (on average 30 [range 7-88] days before), whereas seven patients (35%) had worsening tb lesions (on average 32 [range 14-57] days earliest) and in one with eptb there was no change. at cxr, three patients (15%) (p02, p06, p20) had mild-to-moderate interstitial thickening associated with covid-19, and one (p13) had ground glass pattern compatible with covid-19 on computed tomography (ct) scan. a general lymphocytopenia (total lymphocyte count <1,500/mm 3 ) was detected in 13 patients (65%) and one patient (p18) had thrombocytopenia (platelet count <150x10 3 /mm 3 ). increased serum levels of transaminase (both aspartate aminotransaminase and alanine aminotransaminase) was observed in two cases (p19 and p20) who were known to have previously suffered from anti-tb drug-induced hepatitis. nineteen (95%) patients high ddimer levels (>250 ng/ml)-but only five (p01, p04, p06-07, p11) more than 2,000 ng/mland 11 of them (58%) had an increased ferritin concentration (>300 ng/ml). one patient, p19, affected by sickle cell anaemia, had a level of 5,036 ng/ml attributed to frequent blood transfusions. oxygen supplementation was required in four patients at admission (p02, p05, p08, p17); in three patients (p02,p08,p17) it was soon discontinued and in one reduced from 2 to 1 l/min (p05). during hospitalization, three patients required ex novo oxygen supply (p06, p11, p13) due haemoglobin desaturation below 95%. among them, two had respiratory complications: one had a pneumothorax due to subpleural blebs rupture (p11) which required temporary oxygen supplementation until thoracic drainage, and one elderly patient (p06), with advanced ptb and cachexia, developed covid-19 pneumonia and severe hypoxia (requiring 10l/min oxygen supplementation) dying 6 days after covid-19 diagnosis. our study requires some final comments. first, the low rate of clinical and radiological deterioration in our series may be associated to the young age of most patients, low frequency of other co-morbidities including hiv infection, low prevalence of mdr-tb, and the quality of healthcare services. second, clinical symptoms may have been partly underestimated due to cultural and linguistic barriers as the vast majority of patients were recent immigrants. third, lung lesions caused by covid-19 might have been over-looked due to the use of portable cxr at patient's bed instead of ct scan given the decision to prevent further nosocomial. 10 finally, the duration of follow-up was limited to a few weeks thus not allowing assessment of longer-term outcomes which will be, however, assessed later. in conclusion, the impact of covid-19 on active tb appears to be clinically manageable with proper care. rigorous infection control practices and personal protection devices are fundamental to prevent the risk of in-hospital transmission especially when dealing with a highly vulnerable population. $ at covid-19 diagnosis compared to the last available cxr result; ^ isoniazid-resistance was detected only through genotypic drugsusceptibility test; * lung pattern at chest radiography; ** lung pattern at chest computed tomography scan; £ ferritin was n ot routinely assessed but was part of a set of exams to perform only in patients affected by covid-19, however, due to the lag obtaining the swab results for sars-cov-2 it was not included; & frequent blood transfusions to treat severe anaemia due to sickle cell disease; ‡ o2 supply ex novo; § o2 supply at admission ad then stopped; # oxygen supply was required temporarily due to pleural blebs rupture and consequent pneumothorax. the early phase of the covid-19 outbreak in case-fatality rate and characteristics of patients dying in relation to covid-19 in italy predictors of mortality for patients with covid-19 pneumonia caused by sars-cov-2: a prospective cohort study active tuberculosis, sequelae and covid-19 co-infection: first cohort of 49 cases tuberculosis, covid-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts considerations for tuberculosis (tb) care new diseases and old threats: lessons from tuberculosis for the covid-19 response quesiti scientifici relativi all'infezione da coronavirus sars-cov-2 a role for ct in covid-19? what data really tell us so far european centre for disease prevention and control. using face masks in the community key: cord-330093-asba80bi authors: leung, janice m.; sin, don d. title: smoking, ace-2 and covid-19: ongoing controversies date: 2020-07-16 journal: eur respir j doi: 10.1183/13993003.01759-2020 sha: doc_id: 330093 cord_uid: asba80bi smoking increases severity of covid-19 https://bit.ly/2ywp3jb and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection. j am heart assoc 2020; 9: e016219. copyright ©ers 2020. this version is distributed under the terms of the creative commons attribution non-commercial licence 4.0. to the editor: we have read with great interest the paper by leung et al. [1] published in the european respiratory journal, the correspondence by russo et al. [2] , and also the subsequent comment by the first group [3] . both research teams are reporting increased angiotensin-converting enzyme 2 (ace-2) expression in airways of current smokers and those with copd, with important implications for coronavirus disease 2019 (covid-19) patients. since ace-2 has been shown to be the main receptor utilised by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) to enter the host cells [2] , the authors conclude that nicotine is a risk factor for covid-19. russo et al. [2] have shown that nicotine upregulates ace-2 through α7-nachrs which are present in neuronal and non-neuronal cells. leung et al. [3] provided further evidence in support of this hypothesis and propose the repurposing of α7-nachr antagonists for the pandemic (e.g. methyllycaconitine, α-conotoxin), expecting that such treatment will alter ace-2 expression and prevent sars-cov-2 entry. while this hypothesis is based on laboratory experiments, it is not supported by clinical data. recent observations on the prevalence of smoking among hospitalised covid-19 patients have raised some important issues. many studies, while based on preliminary data and subject to several limitations (e.g. lack of adjustment for confounding factors, possibility for inability to report, inaccurate recording or under-reporting of the smoking status), suggest that the proportion of hospitalised covid-19 patients who are current smokers is by far lower than expected based on population smoking rates [4, 5] . in one study, smoking was associated with lower odds of hospitalisation for covid-19 after adjusting for covariates [6] . to further address this issue, we calculated the pooled prevalence of current smoking in 11 published case series (table 1) , nine from china and two from the usa [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] , and compared it to the expected prevalence based on gender-adjusted and gender-and age-adjusted population smoking rates in each country by estimating the prevalence odds ratio (por) using random effects meta-analysis. due to the lack of data on patients' age distribution, the age-adjustment for the expected smoking prevalence was calculated by assuming that all patients were aged ⩾65 years, since lower smoking prevalence is observed in the elderly compared to younger adult age groups. population smoking prevalence information was derived from the world health organization 2018 global adult tobacco survey [16] for china, and from the us centers for disease control and prevention (for gender adjustment) [17] and statista (for gender and age adjustment) [18] . the pooled prevalence of smoking was 5.3% (95% ci 3. in conclusion, the observations of a low smoking prevalence among hospitalised covid-19 patients, despite the important limitations, together with the hypothetical links between dysfunction of the nicotinic cholinergic system and clinical manifestations of the disease raise some important research questions, considering that nicotine is a cholinergic agonist. the interaction between sars-cov-2 and the nicotinic cholinergic system should be further examined and any proposal for the repurposing of α7-nachr antagonists should be approached with caution, since it could potentially propagate the cytokine storm and adversely affect the prognosis. obviously, smoking cannot be considered protective for covid-19 (or any other disease), but pharmaceutical nicotine products are widely available and their role in covid-19 should be explored. covid-19 and vaping: risk for increased susceptibility to sars-cov-2 infection? to the editor: with great interest we read and commend the study done by russo et al. [1] , highlighting their findings that nicotine induces an increase in angiotensin-converting enzyme 2 (ace-2) expression in human bronchial epithelial cells (hbepc) and is mediated by α7-subtype nicotinic receptors (α7-nachr). it raises the concern that all electronic nicotine-delivery systems may put users at greater risk of succumbing to coronavirus disease 2019 (covid-19). we [2] , along with leung et al. [3] , have shown that ace-2 expression is upregulated in the small airway epithelia of smokers and patients with copd. in particular, we observed increased ace-2 expression in type-2 pneumocytes and alveolar macrophages along with the small airway epithelium of smokers compared to healthy never-smokers [2] . similar studies are yet to be done in the context of electronic cigarettes (e-cigarettes), heat-not-burn devices (iqos) or waterpipe exposure to human airways. ace-2 is the binding site for severe acute respiratory syndrome coronavirus 2 (sars-cov-2), mediating entry of the virus into cells [4] . binding affinity between the spike proteins of the virus and ace-2 on respiratory cells has been identified to be much higher than any previously identified human coronavirus. the significance of such overexpression of ace-2 in smokers should not be ignored. covid-19 and progression of severe pneumonia may be more likely to occur in smokers, particularly in those that have smoking-related comorbidities [5] . we are beginning to elucidate the role of traditional cigarette smoking and nicotine-driven changes to the lungs in the context of coronavirus transmission and susceptibility. cigarette smoke has been identified and linked to increasing expression of the binding site for the cause of the 2020 pandemic (sars-cov-2) via mediating nicotine receptors. with this, an avoidable and potentially gigantic risk-factor has emerged for covid-19, as the pandemic continues to claim ultimate grasp over the year of 2020. here, we bring to the discussion whether the increased susceptibility and virulence of sars-cov-2 via α7-nachr and the upregulation of small airway ace-2 expression may also be relevant for those who vape using nicotine-based e-cigarettes. e-cigarette vapour studies, although in their infancy, have already shown that they can enhance the virulence and inflammatory profile of pathogens such as streptococcus pneumoniae, among other deleterious biological effects [6] . vaping intensifies pneumococcal adherence through an increase in platelet-activating factor receptor expression, ultimately rendering those who vape with an increased risk of pneumonia [7, 8] . we, among others, have previously shown that e-cigarettes and iqos are not "safer", as having a vast pro-inflammatory response [9] . we compared cigarette smoke versus e-cigarette and iqos on airway epithelial and smooth muscle cells [9] . all tested pathological biomarkers were elevated in cells exposed to e-cigarette aerosols and iqos, which included chemokine cxcl8, extracellular matrix proteins and markers of mitochondrial dysfunction. we found these products toxic to the cells, evident from decreased cellular viability and integrity. more devastatingly, vaping also interfered with cellular energetics. our results further substantiate current research that e-cigarettes and @erspublications absolute cessation of any tobacco product in any form: implications for covid-19 https://bit.ly/ 3cyk9ra ioqs are indeed detrimental with increases in oxidative stress, inflammation, infections and airway remodelling in the lungs of these device users. as the scientific evidence mounts, confirming the fears that e-cigarettes and iqos are strongly associated with the development and progression of debilitating lung diseases [10] , now may be the prime time to include all electronic nicotine delivery systems in the vocalisation of concerns concerning tobacco-related death and disease. we recirculate the simple notion that the lungs are not designed for the chronic inhalation of anything but air and that the indication for a smoking-and nicotine-induced increase in ace2 is more evidence to the stacking weight of toxicity that tobacco is for humanity. given the role of the nicotine receptor, vaping may also lead to the upregulation of ace-2. research in this area will be invaluable in the development of e-cigarette research and providing trusted, peer-reviewed and real evidence for the youth of the 2020s. we strongly recommend that the world health organization and countries act to advance their efforts to reduce smoking, vaping and waterpipe use. during a pandemic it is difficult to focus on anything other than the immediate threat. the "primacy of rescue" has overwhelmed preventive action. additional research into the relationship of smoking, and all electronic nicotine delivery systems to the infection, transmission and progression of covid-19 is required. progress towards easily identifying those susceptible to severe disease or capable of asymptomatic transmission are important goals for managing the disease at a community level. covid-19 is a dress rehearsal for the next pandemic, and the next, and the one after that: the new norm. from the authors: the three letters from d. lutchman, k.d. mcalinden and co-workers, and k. farsalinos and co-workers together capture the divergence in opinion on the impact of smoking on coronavirus disease 2019 (covid-19) and whether the angiotensin-converting enzyme 2 (ace-2) receptor mediates this relationship. at the heart of this controversy is whether smoking reduces or increases the risk of contracting covid-19. k. farsalinos and co-workers, through analysis of the pooled prevalence of current smoking across 11 case series determined that current smoking status was significantly lower than expected gender-and age-adjusted prevalence in covid-19 patients. that smoking could potentially be protective against covid-19 has not gone unnoticed by the public. since late april, multiple media outlets have reported on this possibility, prompting the world health organization (who) to release a warning on 4 may, 2020, on tobacco use during this pandemic [1] . while we do not dispute that the prevalence of smoking in covid-19 cases has been surprisingly low across the world, we would echo who's advice, based on emerging evidence that outcomes in covid-19 are worse in patients who do smoke. an analysis conducted by killerby et al. [2] , of 220 hospitalised and 311 nonhospitalised patients with covid-19 patients across six acute care hospitals and associated outpatient clinics in metropolitan atlanta, georgia, for instance, demonstrated that smoking was an independent risk factor for covid-19 hospitalisation, carrying an odds ratio of 2.3 (95% ci 1.2-4.5). a recent meta-analysis has also shown that smokers have a relative risk of 1.34 (95% ci 1.07-1.67) of having more severe disease or experiencing refractory or progressive disease [3] . while smoking may not necessarily increase one's risk for contracting covid-19, the biological and inflammatory cascade that occurs upon severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection may be particularly devastating for a smoker. k.d. mcalinden and co-workers raise the possibility that a similar effect could be occurring in patients who vape. certainly, the risks of significant pulmonary injury with vaping are now well-described in the literature [4] , and the multiple ways that vaping can cause cellular damage and impede the lung's response to infection are clearly delineated by the authors. the theoretical possibility that vaping could prime the lung for sars-cov-2 infection is still hypothetical, given that to date none of the epidemiological studies have reported on vaping prevalence amongst their covid-19 patients. several demographic factors, however, make such estimates unlikely to be obtained with much precision. for instance, consider the landscape of e-cigarette use in china, the first epicentre of covid-19. a 2018 survey of 10 233 individuals in five chinese cities found that only 0.9% had used e-cigarettes within the past 30 days [5] . only 0.2% of those 65 years and older reported e-cigarette use within the past 30 days compared to 1.5% of those in the 15-24 year age range. similarly, in 2016, of 32 931 adults included in the us national health interview survey, 1.0% of those over 65 years reported current e-cigarette use compared to 4.6% of the 18-44 year age group [6] . older age groups, the ones more likely to have severe covid-19, present to a hospital, and therefore be captured by epidemiologists in their surveys, are therefore less likely to report current vaping. on the other hand, it may be difficult to ascertain the prevalence of vaping in younger age groups who are much more likely to vape, but also much more likely to have mild or asymptomatic covid-19 infections that are not captured, either for their failure to present to a healthcare provider or the constraints placed on available tests in resource-limited settings. nonetheless, we would argue for hospitals to capture these data as best they can and hope that data for mild cases in younger outpatients begin to be reported from around the world. similar to smoking, it is possible that vaping may still be associated with worse outcomes, if not necessarily being a risk factor for contracting infection in the first place. finally, as d. lutchman notes, if the culprit player for worse outcomes in smokers in this pandemic is the heightened ace-2 receptor in the airway epithelium, soluble ace-2 might be a therapeutic option. indeed, we would agree with the excitement for this approach as this was the subject of a recent study by monteil et al. [7] , which showed that human recombinant soluble ace-2 (hrsace-2) reduced sars-cov-2 viral loads in infected vero-e6 cells by a factor of 1000-5000. hrsace-2 also inhibited sars-cov-2 infections of kidney and vascular organoids. hrsace-2 is now under phase 2 investigation in europe as a therapeutic agent for covid-19 (clinicaltrials.gov: nct04335136). whether such a therapy will be helpful for the smokers and patients with copd who display higher levels of ace-2 in their airways and may suffer worse outcomes from covid-19 remains to be determined. ace-2 expression in the small airway epithelia of smokers and copd patients: implications for covid-19 covid-19 and smoking: is nicotine the hidden link? covid-19 and nicotine as a mediator of ace-2 systematic review of the prevalence of current smoking among hospitalized covid-19 patients in china: could nicotine be a therapeutic option? preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -united states factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city clinical characteristics of coronavirus disease 2019 in china clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of refractory covid-19 pneumonia in wuhan, china clinical characteristics of 140 patients infected with sars-cov-2 in wuhan, china clinical features and treatment of covid-19 patients in northeast chongqing analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease clinical features of patients infected with 2019 novel coronavirus in wuhan, china epidemiological, clinical characteristics of cases of sars-cov-2 infection with abnormal imaging findings world health organization. global adult tobacco survey tobacco product use and cessation indicators among adults -united states percentage of adults in the us who were current cigarette smokers as of 2016, by age and gender. www. statista.com/statistics/673619/smoking-prevalence-among-men-us-by-age/ date last accessed covid-19 and smoking: is nicotine the hidden link? smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus sars-cov-2 (covid-19) ace-2 expression in the small airway epithelia of smokers and copd patients: implications for covid-19 cryo-em structure of the 2019-ncov spike in the prefusion conformation analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease electronic cigarette vapour increases virulence and inflammatory potential of respiratory pathogens e-cigarette vapour enhances pneumococcal adherence to airway epithelial cells new therapeutic targets for the prevention of infectious acute exacerbations of copd: role of epithelial adhesion molecules and inflammatory pathways iqos exposure impairs human airway cell homeostasis: direct comparison with traditional cigarette and e-cigarette there can be smoke without fire: warranted caution in promoting electronic cigarettes and heat not burn devices as a safer alternative to cigarette smoking tobacco users may be at an increased risk of #covid19, both in contracting the disease and complications characteristics associated with hospitalization among patients with covid-19 impact of smoking status on disease severity and mortality of hospitalized patients with covid-19 infection: a systematic review and meta-analysis hospitalizations and deaths associated with evali use of electronic nicotine delivery systems (ends) in china: evidence from citywide representative surveys from five chinese cities in 2018 changes in electronic cigarette use among adults in the united states inhibition of sars-cov-2 infections in engineered human tissues using clinical-grade soluble human ace2 this version is distributed under the terms of the creative commons attribution non-commercial licence 4 key: cord-275858-46jzw94p authors: leung, janice m.; niikura, masahiro; yang, cheng wei tony; sin, don d. title: covid-19 and copd date: 2020-08-13 journal: eur respir j doi: 10.1183/13993003.02108-2020 sha: doc_id: 275858 cord_uid: 46jzw94p copd patients have increased risk of severe pneumonia and poor outcomes when they develop covid-19. this may be related to poor underlying lung reserves or increased expression of ace-2 receptor in small airways. https://bit.ly/37dsb8l nonetheless, there is increasing evidence that copd may be a risk factor for more severe covid-19 disease [57] . an analysis of comorbidities in 1590 covid-19 patients across china found that copd carried an odds ratio of 2.681 (95% ci 1.424-5.048; p=0.002) for icu admission, mechanical ventilation or death, even after adjustment for age and smoking [13] ; 62.5% of severe cases had a history of copd (compared with only 15.3% in non-severe cases) and 25% of those who died were copd patients (compared with only 2.8% in those who survived). in a multicentre chinese study, copd patients made up 15.7% of the critically ill patients, but only 2.3% of moderately ill patients ( p<0.001) [16] . other studies have found similar, if statistically weaker, differences in copd rates between icu admissions and non-icu admissions (8.3% versus 1.0%; p=0.054) [10] , severe and non-severe cases (4.8% versus 1.4%; p=0.026) [17] , and between non-survivors and survivors (7% versus 1%; p=0.047) [11] . why copd patients appear to suffer worse outcomes upon contracting covid-19 (even if their risk of contracting to begin with may not be high) is worth some speculation. first, recent evidence that copd patients and smokers may display the machinery required for sars-cov-2 cellular entry differently has come to light. similar to sars-cov (which was responsible for the 2002-2003 sars pandemic) [58] , sars-cov-2 bears an envelope spike protein that is primed by the cellular serine protease tmprss2 to facilitate fusion of the virus with the cell's angiotensin-converting enzyme 2 (ace-2) receptor and subsequent cell entry (figure 1) [59] [60] [61] [62] . our group has recently demonstrated that in three separate cohorts with available gene expression profiles from bronchial epithelial cells, ace-2 expression was significantly elevated in copd patients compared to control subjects [63] . current smoking was also associated with higher ace-2 expression compared with former and never smokers, an observation which has subsequently been validated by other groups in separate cohorts of lung tissue and airway epithelial samples [64] [65] [66] and supported by additional evidence linking ace-2 expression with nicotine exposure [67, 68] . it is important to note, though, that ace-2 expression alone has not been shown yet to confer increased susceptibility or increased severity of disease. moreover, the relatively low expression of ace-2 in the bronchial epithelium in comparison to the nasal epithelium [69] has unclear implications for disease susceptibility in patients with predominantly small airways pathology. the management of copd patients during the covid-19 pandemic two challenges of clinical care in copd have emerged during this pandemic: 1) whether the usual algorithms of pharmaceutical management in copd still apply and 2) how to weather the dramatic curtailments in non-pharmaceutical interventions this pandemic has wrought. although our understanding of covid-19 has substantially increased in a short period of time, these problems have largely been the domain of expert opinion rather than being guided by rigorous scientific evidence. questions remain about the effects of common respiratory medications used by our copd patients such as inhaled (ics) and systemic corticosteroids, short-and long-acting β 2 -agonists, and short-and long-acting muscarinic antagonists in either mitigating or exacerbating covid-19 infections. the epidemiological data emerging from china and other early epicentres have not yet provided the necessary granularity required to determine whether these medications are harmful or beneficial in covid-19 patients with copd. peters et al. [70], however, have recently shown that ace-2 expression in airway epithelial cells obtained from asthmatic patients was decreased in those taking ics compared to those who were not on ics, raising the possibility that ics exposure could decrease viral entry. whether the same relationship holds true in the copd airway, in which the predisposition to pneumonia following ics use is well-documented, has not yet been established. for now, in the absence of data demonstrating definitive [105] to show ace2 expression, with the respiratory system highlighted in red. c) the renin-angiotensin system (ras) and the proposed sars-cov-2 action. the generation of angiotensin ii from angiotensin i by angiotensin-converting enzyme (ace) induces vasoconstriction of blood vessels and pro-inflammatory effects through the binding of angiotensin ii receptor type 1 (at 1 r), while the receptor type 2 (at 2 r) may negatively regulate this pathway. ace inhibitors (acei) and angiotensin ii receptor blockers (arbs) are very successful anti-hypertensives by promoting vasodilation of blood vessels. ace-2 inhibits the activity of angiotensin ii by converting angiotensin i to angiotensin 1-9 and angiotensin ii to angiotensin 1-7, which binds to the mas1 proto-oncogene (mas) receptor with anti-inflammatory effects. upon sars-cov-2 binding to ace-2, there is a shift in the ace/ace-2 balance towards a predominance of ace, resulting in increased pro-inflammatory effects and tissue damage. https://doi.org/10.1183/13993003.02108-2020 harm or benefit, ics and other long-acting inhalers should not be routinely withdrawn nor should their use be escalated as a preventative measure for copd patients during this pandemic [71] . of greater concern is the use of systemic corticosteroids, the backbone of copd exacerbation treatment. on balance, the historical evidence for systemic corticosteroids in viral pandemics has not been entirely favourable. lessons from the sars and middle east respiratory syndrome (mers) pandemics suggest potential harm, in fact. in sars, while the majority of studies were inconclusive, four studies showed harm, including delayed viral clearance and increased rates of psychosis [72] . in mers, corticosteroid use was associated with increased mortality [73] and delayed viral clearance [74] . so far, the most promising preliminary data on corticosteroids and covid-19 are from a randomised controlled trial of dexamethasone (recovery) performed in the uk, which demonstrated a one-third reduction in mortality [75] . published data, however, are derived from small retrospective studies and appear mixed, with two studies showing no benefit [76, 77] and two studies showing improvements in rates of death and escalation of care [78, 79] . because of the results of the recovery trial, however, it is likely that dexamethasone will become standard of care treatment for covid-19 patients including those with copd. the impact of the pandemic has been keenly felt by copd patients in myriad aspects of their lives. face-to-face clinic visits with their physicians have been curtailed, as have pulmonary rehabilitation sessions and copd home visit programmes. patients who may have normally presented to the hospital during an exacerbation might choose to stay home for fear of exposure, resulting in delayed care, as has occurred in other conditions like myocardial infarction [80, 81] . the long-term effects of this pause in routine care have yet to be measured. for now, healthcare systems have had to adapt to these conditions by augmenting telehealth and virtual visits. fortunately, multiple randomised controlled trials assessing telehealth for copd patients have demonstrated its feasibility and at least non-inferiority to usual care when it comes to exacerbations, hospitalisations and quality of life [82] [83] [84] [85] [86] . moreover, online pulmonary rehabilitation programmes appear to be as effective as in-person sessions [87] [88] [89] . in the event that social distancing measures remain in place for many more months, we advocate for the establishment of these virtual programmes to ensure our patient population can continue to receive optimal care. specifically, we will have to address the following questions on covid-19 as they pertain to copd: • does the burden of disease, clinical manifestations, and outcomes of covid-19 in copd patients differ from the general population and if so, how? • given the multiple phenotypes associated with the term "copd" (i.e. frequent exacerbators, emphysema-predominant, eosinophilic-predominant, asthma overlap), does covid-19 infection in each of these phenotypes present and behave differently? • are routine medications used in copd such as inhaled and systemic corticosteroids, β 2 -agonists, muscarinic antagonists and chronic azithromycin protective or harmful in the setting of covid-19 infection? • what will the impact of post-covid-19 infection disability be in copd patients and what resources will be required to adequately support the transition of copd patients from the hospital to home after covid-19? • how can we manipulate the unique airway pathology of copd patients and the ace-2 system to identify novel therapeutics? • what is the role of inhaled substances (e.g. tobacco, cannabis and e-cigarettes) and air pollution in increasing the susceptibility of copd patients to covid-19? • what can we learn from the experience of virtual care to copd patients during this pandemic that can be applied in future scenarios to reach isolated patient populations and resource limited settings? these research questions can best be answered by developing standards for transparent data reporting across the globe and harnessing the power of international networks that can quickly collate the data of covid-19 copd patients. similarly, the efforts of translational research scientists at the laboratory bench who are working to characterise the pathophysiology of covid-19 infections in the 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-a systematic echocardiographic study hospitalization and mortality among black patients and white patients with covid-19 characteristics and outcomes of coronavirus disease patients under nonsurge conditions characteristics and clinical outcomes of adult patients hospitalized with covid-19 -georgia covid-19 testing, hospital admission, and intensive care among 2 united states veterans aged 54-75 years baseline characteristics and outcomes of patients with covid-19 admitted to intensive care units in vancouver, canada: a case series single-cell rna-seq data analysis on the receptor ace2 expression reveals the potential risk of different human organs vulnerable to 2019-ncov infection key: cord-259453-1njd0c0x authors: nusair, samir title: abnormal carbon monoxide diffusion capacity in covid-19 patients at time of hospital discharge date: 2020-07-23 journal: eur respir j doi: 10.1183/13993003.01832-2020 sha: doc_id: 259453 cord_uid: 1njd0c0x on recovery from covid-19 it is important to draw attention to the co diffusion test and the actual meaning of the findings when considering the values of d(lco) and d(lco)/v(a) put together https://bit.ly/36k2o2q it is important to give emphasis here that by using carbon monoxide, d lco represents the gas diffusion capacity across the alveolar-capillary barrier and is in fact a mathematical product of the rate constant representing alveolar carbon monoxide uptake efficiency (d lco /v a ) multiplied by alveolar volume (v a ) [3] . thus, when d lco /v a is normal or near normal, d lco may still be low because of reduced alveolar volume, which means that complete acini with alveoli and blood vessels surrounding them are affected [3, 4] . in the remaining functionally available alveolar volume, the actual carbon monoxide uptake is normal as the diffusion through the alveolar-capillary barrier is not impaired and the blood volume within the pulmonary capillary bed is not reduced. interstitial abnormalities or pulmonary vascular abnormalities are associated with reduced d lco /v a which accompanies reduced d lco [4] . in the discussion of their findings, the authors cite previous studies describing follow-up of severe acute respiratory syndrome (sars) patients having impaired d lco as the most common abnormality, with affected proportion of patients ranging from 15.5% to 43.6%. it would be important to describe how impaired d lco was defined in those studies, citing values as % of predicted and comparing that with the findings of the present study. the conclusion which can be obtained from this study is that low d lco is caused mainly by reduced alveolar volume, and not residual interstitial abnormalities or pulmonary vascular abnormalities caused by covid-19. the latter is important, since the proposed pathogenic mechanism describes an initial abnormality induced by covid-19 similar to the effect of sars and consists of a microvascular injury with some interstitial thickening with clear lungs on imaging and physical examination accompanied by profound hypoxaemia [5, 6] , followed by development of alveolar abnormalities with consequent gradual loss of the alveolar spaces [6] . the filling of the alveoli with exudate at a later stage causes the loss of lung volume and reduced pulmonary compliance [7] . the finding of decreased alveolar volume on discharge may be explained by transient changes in mechanical properties of the chest wall and respiratory muscles after critical illness and may well address the concerns about a possible long lasting pulmonary parenchymal dysfunction post-covid-19 [2] . in conclusion, the authors presented very useful data, but it is important to draw attention to the up-to-date manner in which we look at the carbon monoxide diffusion test and the actual meaning of the findings when considering the results of d lco and d lco /v a together. impaired pulmonary function in discharged patients with covid-19: more work ahead we are grateful for the opportunity to respond to the letter by s. nusair, whom we thank for his interest and thoughtful remarks about our study on the abnormal pulmonary function in coronavirus disease 2019 (covid-19) patients [1] . @erspublications impairment of diffusion capacity is the most common abnormality in discharged patients with covid-19. both decreased alveolar volume and k co contribute to the pathogenesis of impaired diffusion capacity. more follow-up work is needed. https://bit.ly/2yl2eak diffusing capacity of the lung for carbon monoxide (d lco ) reflects the capacity of carbon monoxide transfer from the environment to the pulmonary capillary blood, which is the most clinically useful routine methodology to evaluate the function of the lung to exchange gas. k co is the rate constant for carbon monoxide uptake from alveolar gas, which is influenced mostly by the thickness and area of the alveolar capillary membrane, the volume of blood in capillaries supplying ventilated alveoli, and the concentration and properties of haemoglobin in the alveolar capillary blood. d lco is mainly determined by k co and the alveolar volume (v a ). mathematically, k co can be calculated as d lco /v a under body temperature, ambient pressure, saturated with water vapour conditions [2] . we agree with s. nusair that it should be noted that d lco /v a is not a simple ratio and in fact the relationship between lung volume and carbon monoxide uptake is linear and certainly less than 1:1 [3] . recent studies have tended to use k co instead of d lco /v a , as it may be inferred from the use of the term d lco /v a that d lco can be normalised for v a . the 2017 european respiratory society/american thoracic society standards for single-breath carbon monoxide uptake in the lung recommends that the term of k co is preferred to d lco /v a [2] . however, in practice, many pulmonary function test reports from different manufacturers still present with d lco /v a and not k co . besides, in order for an easier and direct comparison with some previous studies on pulmonary function in patients with severe acute respiratory syndrome (sars) [4, 5] , d lco /v a was kept in our report. it is important to understand the interpretation of k co and d lco /v a , but the term of k co is recommended for more popular use in future. decreased k co occurs in alveolar-capillary damage, microvascular pathology or anaemia. causes of low v a include reduced alveolar expansion, alveolar damage or loss, or inspired gases maldistributed with airflow obstruction. when k co turns normal, in the presence of a low d lco it is associated with low v a . because only the functional alveolar units had been sampled, a biased picture toward more preserved areas of the lungs is thereby provided [3] . crucially, the same d lco may occur with various combinations of k co and v a , each suggesting different pathologies. it is difficult to interpret which is the predominant role because both decreased alveolar volume and k co contribute to the pathogenesis of impaired diffusion capacity. d lco gives an overall assessment of gas exchange for the lung, while the alveolar-capillary membrane diffusing capacity for carbon monoxide (d mco ) only dependents on molecular diffusion of the membranes. however, d mco can be calculated using different equations but is not yet standardised, and as such is not a commonly used gas diffusing parameter [6] . in our study, 51 patients with covid-19 had impaired d lco , including 29 patients who showed both impaired d lco and k co . the number of patients with both impaired d lco and k co (29/51) was 24% larger than the number of patients with impaired k co alone (22/51). moreover, the percentage of patients with decreased total lung capacity was less than the percentage of patients with decreased k co . furthermore, vascular injury and thrombosis have been demonstrated to be important contributing factors in the pathogenesis of covid-19. sars coronavirus 2 infects the endothelial cells via angiotensin-converting enzyme 2. the recruitment of immune cells to the endothelial cells facilitates the induction of endotheliitis in several organs, which contributes to systemic impaired microcirculatory function [7] . acute pulmonary embolism has been reported during the clinical course [8] . post mortemstudies have reported vascular injury and thrombi in multiple organs [7, 9] . ackermann et al. [10] compared the lung pathology of covid-19 with h1n1. the result showed that patient with covid-19 presented distinctive vascular features, consisting of severe endothelial injury associated with the disruption of intercellular junctions, cell swelling and a loss of contact with the basal membrane. from the above, it is probable that the effect of membrane lesion plays an important role on the impaired diffusion capacity in patients with covid-19. our study showed that, similar to d lco , d lco /v a (representing the transfer factor of carbon monoxide) also showed an association with the disease severity: as the patients progressed to a more severe condition, the mean value of d lco /v a compared to predicted values was lower. since the standard deviation values suggest that individual differences have effects on lung function, we also provided the distribution of the d lco /v a of predicted in patients with different severities. 42% of the subjects with severe pneumonia had a d lco /v a of less than 80% of predicted, compared to only 27% in the patients with pneumonia and 13% in patients with mild illness, respectively. in previous follow-up studies of sars, impaired d lco was defined as when d lco was <80% of the predicted value, irrespective of k co or the alveolar volume. in follow-up studies of rehabilitating sars patients ranging from 0.5 to 2 years, the impaired d lco was the most common abnormality, accounting for 15.5% to 43.6% [11] [12] [13] . the mean d lco ranged from 77.7% to 93.8% pred in the studies above, with the longest follow up of 2 years. our study showed a mean d lco of 78.2% pred at time of discharge but follow-up data is not available yet. it is unclear how the impaired diffusion capacity changes in survivors of covid-19, as well as how the changes may be reflected on chest computed tomography (ct). in one study, where surviving sars patients were seen 6 months after admission, 43(75.4%) of patients showed radiological abnormalities, including 62.8% who had abnormal d lco [11] . thus, the lung function impairment findings are consistent with the ct images of sars survivors showing persistent ground glass opacity, reticular opacities and traction bronchiectasis suggesting the fibrosis [14] . likewise, in discharged patients with covid-19, wang et al. [15] reported that 94% (66/70) of patients who were discharged from hospital at the end of the study still had mild to substantial residual lung abnormalities on their last ct scans. our study was a pilot study which first described the impaired pulmonary function in patients with covid-19 at time of discharge. impairment of diffusion capacity is the most common abnormality followed by restrictive ventilatory defects. however, more follow-up work is needed to assess the longitudinal variation of these deficits. abnormal pulmonary function in covid-19 patients at time of hospital discharge pulmonary fibrosis secondary to covid-19: a call to arms? examination of the carbon monoxide diffusing capacity (dlco) in relation to its kco and va components diffusing capacity, specific diffusing capacity and interpretation of diffusion defects immune mechanisms of pulmonary intravascular coagulopathy in covid-19 pneumonia pulmonary pathology of early-phase 2019 novel coronavirus (covid-19) pneumonia in two patients with lung cancer clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study abnormal pulmonary function in covid-19 patients at time of hospital discharge ers/ats standards for single-breath carbon monoxide uptake in the lung incorporating lung diffusing capacity for carbon monoxide in clinical decision making in chest medicine 1-year pulmonary function and health status in survivors of severe acute respiratory syndrome follow-up study on pulmonary function and lung radiographic changes in rehabilitating severe acute respiratory syndrome patients after discharge standardisation and application of the single-breath determination of nitric oxide uptake in the lung endothelial cell infection and endotheliitis in covid-19 acute pulmonary embolism and covid-19 pneumonia: a random association? neuropathology of covid-19: a spectrum of vascular and acute disseminated encephalomyelitis (adem)-like pathology pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 six month radiological and physiological outcomes in severe acute respiratory syndrome (sars) survivors the 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors the long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section ct temporal changes of ct findings in 90 patients with covid-19 pneumonia: a longitudinal study this version is distributed under the terms of the creative commons attribution non-commercial licence 4 key: cord-335198-qp964238 authors: kotsimbos, t.; humbert, m. title: pandemic treatments on trial: the bigger picture date: 2020-08-03 journal: eur respir j doi: 10.1183/13993003.02281-2020 sha: doc_id: 335198 cord_uid: qp964238 the tension between immediately using any potentially useful novel therapy in covid19 and trialling all novel therapies as rigorously as possible is addressed from a bigger picture perspective. given the stated extremes above, there is a clear trade-off between "doing all that one can for individual patients with currently available information in a timely manner and despite significant uncertainty" and "group treatment of individuals to be enrolled in properly conducted but costly (effort, time and money) clinical trials for specific therapeutic approaches that will help inform the evidence-base for future patients". in many ways this is a false dichotomy as both are necessary frameworks with clearly defined validity and purpose, which should ideally sit comfortably next to each other. the lack of a clear transition zone between these two frames of reference necessitates ambidextrous frame-shifts. ideally, frame-shifting would be sensitive and responsive to the prevailing environment when health-care provision is at its best for any level of resource constraint. although this may be difficult to define in positive terms of agility, dynamic range and contextual fit across and within multiple frames, it is most easily identifiable by its absence. this absence is even more obvious when the "in-between" situation is excessively encroached upon as some sort of compensatory way forward. here, therapies are prescribed to patients for varying reasons that can only be partly rationalized on the basis of either individual or group interests. the resultant case series and uncontrolled observational studies therefore quickly transition from a reasonable, adaptive initial response to explore large efficacy and safety signals in poor clinical outcome settings to efforts that are maladaptive when excessive. at best, these efforts minimally progress either individual patient care decisions or the broader evidence-base necessary to inform integrating guidelines. at worst, unchecked biases may lead to false positive results whilst simultaneously diverting resources from potentially more useful strategies. that there has been an excess of small and uncontrolled trials in the setting of a covid19 pandemic which itself is very much an "n of 1" situation is therefore worthy of further reflection and exploration. whose needs are being met? how do we best explore and exploit our overall clinical management and scientific research approach during the covid19 pandemic? there is little argument with the upholding the public health principles and standards of supportive care in relatively mild community cases that are likely to recover without ill effect. but how do we minimize the risks of progression in more severe hospitalized cases, particularly older patients with risk factor co-morbidities? how do we maximize compassionate use of available, potentially useful but unproven therapies when no other alternatives exist? how do we minimize the risks of these very same therapies for individual patients? and how do we quickly establish and conduct difficult and costly randomized, controlled clinical trials for the most promising old and new therapies where there is a clear equipoise between possible benefits and potential risks? all these questions so far turn on what is hopefully an impartial assessment of what is in the best interests of the patient. however, there are also other potential factors at play, albeit very difficult to quantify. these include (in no specific order): i) the difficult research environment that would necessarily follow from health care systems that are overwhelmed in a pandemic setting; ii) specific resource and funding constraints in such systems; iii) widespread fear and anxiety at all levels of the community including healthcare providers; iv) clinician-researcher and other interested party belief systems and potential "savior" mentalities; v) potential pharma industry interests regarding expanding re-purposed drug possibilities; vi) potential biotech start-up/pharma interests regarding new agent fast tracking opportunities; vii) potential political and economic interests; and viii) potential media and socio-cultural factors. although it is impossible to quantify in any meaningful way the magnitude of these factors and how they may all interact with each other, an enlightened awareness of all these possibilities is an essential first step to both prevention and any countering response. it is also the quintessential function that underpins all drug evaluating regulatory agencies/processes that we discard or bypass at our peril. in the midst of a pandemic that has overwhelmed many health-care systems globally it is indeed very impressive that several, large collaborative clinical trials have already been established to meaningfully assess potential covid19 therapies including the world health organisation's "solidarity" trial (see below). ideally this list should be extended to all other therapies where there may be a potential benefit seemingly counterbalanced by potential risk. however, at all points decisions will need to be weighed and taken. which drugs to trial? which patients? what disease severity? what dose? what to measure?, and how?, and why? which endpoints? how to adjust for confounder variables? how many patients? additionally, analytic integrity is all. not enough design control and internal validity is threatened, too much and there will be a problem with external validity. even with well-controlled rcts for specific agents uncertainty can never be completely eliminated. the best we can hope for is to optimally quantify key uncertainties thereby elevating our certainty base for future decision-making. the more iterative this process can be, the better. notwithstanding this however, there will always be a tension between the ideal of increasingly covering all testing possibilities for completeness and the practicalities of getting on with the real-time demands of work to be done. paradoxically, the almost immediate establishment of a well-designed rct to test the combination antiviral treatment lopinavir-ritonavir in wuhan, china during the beginning of the pandemic exemplified this tension in a most unusual way when trial recruitment ceased early due to falling covid19 case numbers (7). it is clearly not possible to immediately perform a well-controlled rct on all potentially useful therapies. hence, in trying to do everything one can for individual patients with severe disease who are likely to die it is compassionate and reasonable to empirically trial available products off-label where the existing information base suggests potential benefit outweighing any potential harm. this of course all turns on our shared understanding of "likely to die", "likely to benefit" and "potential for harm" at the very least. the more we use these therapies however in patients with less severe illness, where the uncontrolled benefit signal may be significantly "overcalled" by a positive natural history and the risks of harm may become increasingly unacceptable, the more it behoves us to go down the path of a properly controlled and conducted rct. excellence here is not the enemy of "good enough" as may be argued in the exceptional circumstances of a pandemic or indeed any uniquely uncertain area of clinical medicine but the standard that should always be aspired to. indeed, an enlightened view of excellence would expand its horizon to embrace "good enough" in the most excellent way possible for any specific situation. anything less than this is professionally and personally diminishing as it quickly contracts down to no-risk comfort zones and sets us down the murky path of "good enough for who" questions and excusable actions that are answerable to noone. under pandemic conditions of overwhelming health-care system stress and understandable urgencies to try untested therapies, the introduction of novel therapeutic practices may therefore take on a life of its own and become disproportionately uncoupled from any primary purpose. hence, randomly collected case series and uncontrolled smaller trials may proliferate without necessarily being in the best interests of either individual patients or specific patient cohorts. the example of hydroxychloroquine/chloroquine is a case in point where some early in vitro evidence of efficacy against sars-cov2 has been taken both "too far" and "not far enough". hence, it has been used empirically in a large, number of small and uncontrolled "trials" around the world despite its potential for cardiac toxicity, and in one larger, poorly controlled observational study no significant benefit and potential for significant harm signal (8) was inconclusive thereby paving the way for rationalizing any position you may wish to take. more recently, the controversial results of a multinational registry study examining the risk/benefit ratio of hydroxychloroquine/chloroquine with or without macrolide for treatment of covid19 also weighed into the evidence debate only to now be retracted by the authors (9) . add to this a heady mixture of high profile, celebrity supporters and trial by media and you have a recipe for compounding one crisis with another. also, very illuminating is the story of the antiviral remdisivir. from early, uncontrolled results that reported a clinical improvement in 68% of 53 "analyzable" patients (10) through to a negative rct study result involving 236 patients which was stopped early due to reduced case numbers in china resulting in a trial with reduced power to detect any smaller clinically significant benefit with any certainty (11) to further preliminary reports of potentially positive results in larger trials sponsored by the remdisivir patent holder (12) . similar stories abound for many other therapies being used to manage hospitalized patients with more severe covid19 related illness including various respiratory support strategies and their combinations, a range of anticoagulation protocols, novel immunotherapeutic agents including the anti-il6 receptor monoclonal antibody tocilizumab, and various combination strategies and therapies (13) (14) (15) (16) (17) (18) (19) (20) (21) . at the other end of the spectrum are the much more inclusive, simplified and highly "capturing" rct approaches such as the who solidarity international clinical trial across multiple countries (22) and the oxford university led recovery trial in the uk (23)both designed to compare different treatment options against usual of care for as many hospitalised covid patients as possible within their jurisdictions. with large number of enrolments helping to counter the large degree of individual case heterogeneity that comes with a simplified approach, the solidarity trial's international steering committee discontinued the trial's hydroxychloroquine and lopinavir/ritonavir arms in early july 2020 as interim trial results for both these treatment arms showed little or no reduction in the mortality of hospitalised covid19 patients (22) . the large recovery trial in the uk (n> 11,800 as of 29 th june 2020) almost simultaneously confirmed these findings for both hydroxychloroquine and lopinavir/ritonavir, and by contrast, revealed that low dose dexamethasone (6 mg given once daily for up to ten days) reduces the risk of death by about one-third among patients receiving ventilation and by one-fifth in those requiring oxygen alone (with no benefit among those not requiring ventilatory support) (23, 24) . other treatment arms in the recovery trial include azithromycin, tocilizumab and convalescent plasma (23) . a closer look at what transpired during the 2009 influenza a h1n1(09) pandemic -our most recent pandemic prior to covid19, is very salient. patients were frequently treated for pandemic influenza viral pneumonia with drugs not specifically registered for this indication and rarely under circumstances of high-quality data capture. this resulted in experimental drugs being used largely on compassionate grounds with no real improvement in our understanding of the potential benefits and harms of specific treatments. however, further reflections on the above outcomes led some clinician-researchers to a unifying multicentre embrace of master protocols, adaptive trial platforms and overarching statistical plans. these are designed to build operational "checks and balances" into a modular study framework that remains congruent across time and space and promotes a culture of learning as you go. hence, although remap-cap was originally designed to study severe pneumonia requiring icu management in over 160 sites across many countries, it was quickly adapted after the hin1(09) pandemic be pandemic influenza ready making it relatively easy to switch its focus to the current covid19 pandemic. a key feature of adaptive trial design is that researchers are required to add and remove treatment groups as the trial is running in order to minimize the diluting effects of futile treatments and maximize the signal to noise ratio of more promising treatments according to certain trigger thresholds. and so, no algorithmic approach can completely substitute for imaginatively insightful, thoughtfully rational and well-equilibrated ethical thinking. additionally, there is the increasing appreciation that although adaptive trial designs for treatments is a great start, they may not go far enough. given the extensive variation in clinical outcomes with covid19 infection in the population at large, we may well need to also integrate some well-chosen deeper phenotype and genotype factors into our adaptive trial designs and analyses. the benefits of any such extended approach will of course need to be weighed up against the potential for greatly increasing the logistic complexity of adaptive trials beyond what is practically manageable even with the potential help of enhanced machine learning protocols, and of course the inexorable law of diminishing returns. as always, appropriately managing individual patient case priorities is a central pillar of ethical clinical practice. this is true both within an exploratory n of 1 framework and in exploiting n of many rcts. hence, although the uncontrolled, compassionate use of specific off-label therapies may be acceptable in one framework, a completely different framework is required to generate a quality evidence base for improved pandemic management practices now and in the future. additionally, within framework discussions matching rights and responsibilities is generally much more comfortable than between frameworks. and yet, individuals and the society they belong to are irrevocably intertwined and interdependent. negotiating the deep chasm between frameworks is a key challenge for treating clinicians so that we don't get lost in a multitude of poorly controlled studies but leap towards a hierarchy of larger clinical trials arranged according to likelihood of success based on early but uncertain signals in smaller numbers of patients. ethical leadership therefore requires us to be agile, proportionate and adaptive in aligning, balancing and contextualising patient needs across many dimensions both simultaneously and separately. during a pandemic these fundamentals are unchanged, although our responses now have to be both speedier and as complete as possible with a varying emphasis on either depending on the guiding framework and associated driving purpose. with this in mind, doing the most right thing, at the most right time, in the most right way for the one and the many is the ethicist's embrace of epistemological excellence and the flourishing of all. references: thoracic society of australia and new zealand h1n1 influenza 09 task force. influenza a/h1n1_09: australia and new zealand's winter of discontent clinical and epidemiological profile of patients with severe h1n1/09 pandemic influenza in australia and new zealand: an observational cohort study influenza epidemiology in patients admitted to sentinel australian hospitals in 2018: the influenza complications alert network (flucan) the role of chest imaging in patient management during the covid-19 pandemic: a multinational consensus statement from the fleischner society systematic review of clinicaltrials.gov infectious disease trials treating influenza infection, from now and into the future. front immunol a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 observational study of hydroxychloroquine in hospitalized patients with covid-19 :nejm. oa2012410 hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis compassionate use of remdesivir for patients with severe covid-19 actt-1 study group members.remdesivir for the treatment of covid-19 -preliminary report asian critical care clinical trials group. intensive care management of coronavirus disease 2019 (covid-19): challenges and recommendations emerging pharmacotherapies for covid-19 tsiodras s; escmid study group for respiratory viruses. review of trials currently testing treatment and prevention of covid-19 how did we rapidly implement a convalescent plasma program? transfusion trials and tribulations: so many potential treatments, so few answers off-label use of tocilizumab for the treatment of sars-cov-2 pneumonia in successful recovery from severe covid-19 pneumonia after kidney transplantation: the interplay between immunosuppression and novel therapy including tocilizumab effective treatment of severe covid-19 patients with tocilizumab triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with covid-19: an open-label, randomised, phase 2 trial solidarity" clinical trial for covid-19 treatments: 6 th why haven't others delivered more results? kai kupferschmidt effect of dexamethasone in hospitalized patients with covid-19 -preliminary report medrxiv 22 nd key: cord-285897-ahysay2l authors: wu, guangyao; yang, pei; xie, yuanliang; woodruff, henry c.; rao, xiangang; guiot, julien; frix, anne-noelle; louis, renaud; moutschen, michel; li, jiawei; li, jing; yan, chenggong; du, dan; zhao, shengchao; ding, yi; liu, bin; sun, wenwu; albarello, fabrizio; d'abramo, alessandra; schininà, vincenzo; nicastri, emanuele; occhipinti, mariaelena; barisione, giovanni; barisione, emanuela; halilaj, iva; lovinfosse, pierre; wang, xiang; wu, jianlin; lambin, philippe title: development of a clinical decision support system for severity risk prediction and triage of covid-19 patients at hospital admission: an international multicenter study date: 2020-07-02 journal: eur respir j doi: 10.1183/13993003.01104-2020 sha: doc_id: 285897 cord_uid: ahysay2l background: the outbreak of the coronavirus disease 2019 (covid-19) has globally strained medical resources and caused significant mortality. objective: to develop and validate machine-learning model based on clinical features for severity risk assessment and triage for covid-19 patients at hospital admission. method: 725 patients were used to train and validate the model including a retrospective cohort of 299 hospitalised covid-19 patients at wuhan, china, from december 23, 2019, to february 13, 2020, and five cohorts with 426 patients from eight centers in china, italy, and belgium, from february 20, 2020, to march 21, 2020. the main outcome was the onset of severe or critical illness during hospitalisation. model performances were quantified using the area under the receiver operating characteristic curve (auc) and metrics derived from the confusion-matrix. results: the median age was 50.0 years and 137 (45.8%) were men in the retrospective cohort. the median age was 62.0 years and 236 (55.4%) were men in five cohorts. the model was prospectively validated on five cohorts yielding aucs ranging from 0.84 to 0.89, with accuracies ranging from 74.4% to 87.5%, sensitivities ranging from 75.0% to 96.9%, and specificities ranging from 57.5% to 88.0%, all of which performed better than the pneumonia severity index. the cut-off values of the low, medium, and high-risk probabilities were 0.21 and 0.80. the online-calculators can be found at www.covid19risk.ai. conclusion: the machine-learning model, nomogram, and online-calculator might be useful to access the onset of severe and critical illness among covid-19 patients and triage at hospital admission. in december 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2; earlier named as 2019-ncov), emerged in wuhan, china [1] . the disease caused by sars-cov-2 was named coronavirus disease 2019 (covid19) . as of may 15, 2020, more than 4 490 000 covid-19 patients have been reported globally, and over 300 000 patients have died [2] . the outbreak of covid-19 has developed into a pandemic [3]. among covid-19 patients, around 80% present with mild illness whose symptoms usually disappear within two weeks [4] . however, around 20% of the patients may proceed and necessitate hospitalization and increased medical support. the mortality rate for the severe patients is around 13.4% [4] . therefore, risk assessment of patients preferably in a quantitative, non-subjective way, is extremely important for patient management and medical resource allocation. general quarantine and symptomatic treatment at home or mobile hospital can be used for most non-severe patients, while a higher level of care and fast track to the intensive care unit (icu) is needed for severe patients. previous studies have summarized the clinical and radiological characteristics of severe covid-19 patients, while the prognostic value of different variables is still unclear [5, 6] . several scoring systems that are in common clinical use (e.g. sequential organ failure assessment score, confusion-urea-respiratory rate-blood pressure-age 65, acute physiology and chronic health evaluation, etc.) could be applied to the triage problem, albeit each with their own problems and limitations, such as the need for laboratory variables that are hard to obtain at hospital admission [7] . the pneumonia severity index (psi) stands out as it is used to assess the probability of severity and mortality among adult patients with community-acquired pneumonia and to help hospitalization management [8] . a better solution could possibly be found using machine-learning, a branch of artificial intelligence that learns from past data in order to build a prognostic model [9] . in recent years, machine learning has been developed as a useful tool to analyze large amounts of data from medical records or images [10] . previous modeling studies focused on forecasting the potential international spread of covid-19 [11] . therefore, our objective is to develop and validate a prognostic machine-learning model based on clinical, laboratory, and radiological variables of covid-19 patients at hospital admission for severity risk assessment during hospitalization, and compare the performance with that of psi as a representative clinical assessment method. our ambition is to develop a multifactorial decision support system with different datasets to facilitate risk prediction and triage (home or mobile hospital quarantine, hospitalization, or icu) of the patient at hospital admission. the institutional review board approved this study (2020-71), which followed the standards for reporting of diagnostic accuracy studies statement [12] , and the requirement for written informed consent was waived. 299 adult confirmed covid-19 patients from the central hospital of wuhan were included consecutively and retrospectively between december 23, 2019 and february 13, 2020. the inclusion criteria were: (1) patients with a confirmed covid-19 disease, (2) patients present at hospital for admission. the exclusion criteria were: (1) patients already with a severe illness at hospital admission; (2) time interval > 2 days between admission and examinations; and (3) no data available or delayed results as described below. the patients included from this center were divided into two datasets according to the entrance time of hospitalization, 80% for training (239 patients from december 23, 2019, to january 28, 2020) and 20% for internal validation (60 patients from january 29 to february 13, 2020). the five test datasets were collected between february 20, 2020 and march 31, 2020 from other eight centers (supplementary) in china, italy, and belgium under the same inclusion and exclusion criteria (figure 1 ). patients were labelled as having a "severe disease" if at least one of the following criteria were met during hospitalization [6, 13] : (a) respiratory failure requiring mechanical ventilation; (b) shock; (c) icu admission; (d)organ failure; or (e) death. patients were labelled as having a "non-severe disease" if none of the abovementioned criteria were met during the whole hospitalization process until deemed recovered and discharged from the hospital. clinical, laboratory, radiological characteristics and outcome data were obtained in the case record form shared by the international severe acute respiratory and emerging infection consortium from the electronic medical records [14] . a confirmed case with covid-19 was defined as a positive result of high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction assay for nasal and pharyngeal swab specimens. after consultation with respiratory specialists and review of the recent covid-19 literature, a set of clinical, laboratory, and radiological characteristics was identified and the data collected from the electronic medical system. the clinical characteristics included basic information (5 variables), comorbidities (11 variables), and symptoms (13 variables). all clinical characteristics were obtained when the patients were admitted to hospital for the first time. 42 laboratory results were recorded, including complete blood count, white blood cell differential count, d-dimer, c-reactive protein (crp), cardiac enzymes, procalcitonin, liver function test, kidney function test, b-type natriuretic peptide and electrolyte test. the arterial blood gas was not taken into account due to missing data for most early-stage patients. the metric conversion of laboratory results was performed using an online conversion table [15] . a detailed list of variables can be found in tables 1 and 2 . the semantic ct characteristics (including ground-glass opacity, consolidation, vascular enlargement, air bronchogram, and lesion range score) were independently evaluated on all datasets by two radiologists (py [a radiologist with 5 years' experience in chest ct images] and yx [a radiologist with 20 years' experience in chest ct images]), who were blinded to clinical and laboratory results. any disagreement was resolved by a consensus read. lesion range was identified as areas of ground-glass opacity or consolidation and was graded all feature selection and model training were performed in the training dataset alone to prevent information leakage. an overview of the functions used is given in supplementary table s1. in order to reduce feature dimensionality, features showing high pairwise spearman correlation (r > 0.8) and the highest mean correlation with all remaining features were removed, followed by application of the boruta algorithm to select important features [16] . the boruta algorithm combines feature rank based on the random forest classification algorithm and selection frequency based on multiple iterations of the feature selection procedure. recursive feature elimination based on bagged tree models with a cross-validation technique (10 folds, 10 times) was performed to select the best performing combination of features. in order to balance the positive and negative sample size, an adaptive synthetic sampling approach for imbalanced learning (adasyn) was used during feature selection and modeling [17] . the feature selection process was used for clinical, laboratory, and ct semantic models alone, and in combination. the prognostic performances of the best model were compared with other models on the training dataset, due to a bigger sample size. the performance of the best model and psi scoring were gauged on the datasets via the receiver operator characteristic (roc) and confusion matrix. in order to gauge the level of overfitting, the outcomes were randomized on the best model and the entire process repeated, from feature selection to model building and evaluation. the patients from the training datasets were divided into low, medium and high risk according to the first quartile (25th percentile) and the third quartile (75th percentile) of probabilities from the best performing model. nomograms and on-line calculators were used to provide the interpretability of the best trained models. the test datasets were used to gauge the prognostic performance and the validity for the best model. baseline data were summarized as median, and categorical variables as frequency (%). differences between the severe group and the non-severe group were tested using the mann-whitney test for continuous data and fisher's exact test for categorical data. feature correlations were measured using the spearman correlation coefficient. we determined the area under the roc curve (auc) with its 95% confidence interval (ci) and tested auc difference between models 1-3 and model 4 by the delong method [18] , measures of prognostic performance included the auc, and metrics derived from the confusion matrix -accuracy, sensitivity, specificity, positive prediction value (ppv), and negative prediction value (npv). a calibration-plot based on the hosmer-lemeshow test was used to estimate the goodness-of-fit and consistency of the model on the test datasets. all p values were two-sided, and p < 0.05 was regarded as significant. all statistical analyses, modeling, and plotting were performed in r (version 3.5.3), and the detailed package characteristics are listed in supplementary table s1 . of 299 hospitalized covid-19 patients in retrospective cohort, the median age was 50.0 years (interquartile range, 35.5-63.0; range, 20-94 years) and 137 (45.8%) were men. all the clinical characteristics and ct findings are summarized in table 1 , and more details of laboratory findings can be seen in table 2 . of 426 hospitalized covid-19 patients in 5 cohorts as test datasets, the median age was 62.0 years (interquartile range, 50.0-72.0; range, 19-94 years) and 236 (55.4%) were men. among the clinical features, age, hospital employment, body temperature, and the time of onset to admission were selected. lymphocyte (proportion), neutrophil, (proportion), crp, lactate dehydrogenas (ldh), creatine kinase (ck), urea, and calcium were selected from the laboratory feature set. only the lesion range score was selected from ct semantic features. when putting these three category features together to select features, age, lymphocyte (proportion), crp, ldh, ck, urea and calcium were finally included in the combination model. model performance was as follows. the model 1 based on age and hospital employment showed an auc of model 4 was validated on the five test datasets, which showed aucs ranging from 0.84 to 0.93 with accuracies ranging from 74.4% to 87.5%, sensitivities ranging from 75.0% to 96.9%, specificities ranging from 57.5% to 88.0%, ppvs ranging from 71.4% to 84.1%, and npvs ranging from 73.9% to 93.9% ( table 3) . the roc, confusion-matrix, and calibration plots are shown in figure 3 . the results of randomizing the outcomes and rerunning the analysis yielded auc of 0.50 (95% ci, 0.44-0.55) for the model 4. based on the selected features from the best models, a nomogram was established to quantitatively assess the severity risk of illness (figure 4) . the developed online-calculators can be found at www.covid19risk.ai. compared to psi scoring, model 4 showed higher aucs, accuracies, sensitivities, and npvs on the five test datasets ( table 3) . there were significant difference for the proportion of severe patients among low, medium, and high-risk groups in the five test datasets (figure 5 ). this international multicenter study analyzed individually and in combination, clinical, laboratory and radiological characteristics for covid-19 patients at hospital admission, to retrospectively develop and prospectively validate a prognostic model and tool to assess the severity of the illness, and its progression, and to compare these with psi scoring. we found that covid-19 patients that developed a severe illness were often of an advanced age, accompanied by multiple comorbidities, presenting with chest tightness, and had abnormal laboratory results and broader lesion range on lung ct on admission. using simpler linear regression models yielded better prognostic performance than psi scoring in the test datasets. we believe these models could be useful for risk assessment and triage. previous studies have reported that age and underlying comorbidities (such as hypertension, diabetes, and cardiovascular diseases) may be risk factors for the covid-19 patients requiring intensive care unit (icu) [19 20] . in this study, we found that the elderly covid-19 patients who were male, non-hospital staff, suffering from hypertension, diabetes, cardiopathy disease, chronic obstructive pulmonary disease, cerebrovascular disease, renal disease, hepatitis b virus infection, lower body temperature, and chest tightness were more vulnerable to develop a severe illness in the early stages of the disease. among these features, age, hospital staff, body temperature, and the time of onset to admission had certain prognostic abilities. age was the most important feature, which may interact with other features, which was why only age was selected into our combination model (model 4) from these features. zhou and colleagues have confirmed that sars-cov-2 uses the same cell entry receptor (angiotensin-converting enzyme ii [ace2]) with sars-cov [21] . however, whether covid-19 patients with hypertension and diabetes have higher severe illness risk, which is due to treatment with ace2-increasing drugs is still unknown [22] . hospital staff had a lower risk of progression, possibly due lower age, higher levels of education, and more medical knowledge once infected although the unbalanced nature of this type of data has to be taken into account. furthermore, early studies have shown that covid-19 patients with severe illness had more laboratory abnormalities such as crp, d-dimer, lymphocyte, neutrophil, and ldh, than those patients with non-severe illness, which were associated with the prognosis [19, 20, 23] . in our study, we also found that the severe group had numerous laboratory abnormalities in complete blood cell count, white cell differential count, d-dimer, crp, liver function, renal function, procalcitonin, b-type natriuretic peptides, and electrolytes. among these abnormalities, lymphocyte proportion, neutrophil proportion, crp, ldh, ck, urea, and calcium were significant prognostic factors, which suggest that covid-19 may cause damage to multiple organ systems when developing into a severe illness. however, current pathological findings of covid-19 suggest that there is no evidence that sars-cov-2 can directly impair the other organs such as liver, kidney and heart [24] . current reports have shown that thin-slice chest ct is a powerful tool in clinical diagnosis due to the high sensitivity and the ability to monitor the development of the disease [25, 26] . in addition, a previous study reported that ground-glass opacity and consolidation were the most common ct findings for covid-19 patients with pneumonia, while being nonspecific [27] . clinical observations showed that there were significantly more consolidation lesions in icu patients on admission, while more ground-glass opacity lesions were observed in non-icu patients [28] . in our study, we found that vascular enlargement, air-bronchogram, and lesion range score differ significantly between non-severe and severe groups. among these features, only the lesion range score had prognostic power, but not enough to be selected for the combination model. this indicates that while these early stage ct semantic features could have diagnostic value, they have limited ability to prognose the onset of severe illness in covid-19 patients. the chinese national health committee added some warning indicators for severe or critical cases in the updated diagnosis and treatment plan for covid-19 patients (version 7) [29] , which includes progressive reduction of peripheral blood lymphocytes, a progressive increase of il-6, crp and lactate, and rapid progression of lung ct findings in a short period. in this study, we used age, lymphocyte fraction, crp, ldh, ck, urea, and calcium scores from clinical, laboratory, and radiological exams recorded at hospital admission to train a model for the prediction of the onset of severe illness. our model combining these features from multiple sources showed a favorable performance when validated in the five external datasets from china, italy, and belgium. in addition, the model is able to stratify covid-19 patients into low, medium, and high-risk groups for developing severe illness. we propose that this model with its higher prediction performance and simplicity than psi score could be used for a preliminary screening and triage tool at hospital admission for the potential to develop severe illness. furthermore, the model could be used for the selection and/or stratification of patients in clinical trials in order to homogenize the patient population. follow-up laboratory tests are needed to assess the severity risk with a higher accuracy. as one of the coronaviruses family infecting humans, sars-cov-2 has similar etiologic, clinical, radiological and pathological features to those of severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus [23, 30, 31] . therefore, we believe that developing a reliable early warning model based on presently clinical, radiological, and pathological data is necessary for current outbreaks and possible future outbreaks of coronaviruses. our study has several limitations. first, selection bias is unavoidable and the limited and unbalanced sample size. second, patients from different races and ethnicities may have diverse clinical and laboratory results, and the self-medication of patients before admission may affect the clinical and laboratory results. third, the threshold to go to the hospital and hospitalization management can vary from country to country, we are also aware that rna viruses can mutate rapidly and that could have an impact of the performance of the models. we therefore propose that those models should be continuously updated to achieve a better performance for example using privacy-preserving distributed learning approaches [32, 33] . fourth, the ct features used for this study are semantic features from the first ct scan, and radiomics or deep learning approaches may improve its prognostic performance, and follow-up ct scan may yield more information. fifth, due to the large number of predictors included in the analysis, and the complexity of feature selection and modelling, overfitting is always possible. we have mitigated this with the use of external validation cohorts, and by rerunning the analysis on randomized outcomes to arrive at a "chance" (auc=0.5) result. elderly covid-19 patients and non-hospital staff seem more vulnerable to develop a severe illness after hospitalization as per defining criteria, which can cause a wide range of laboratory and ct anomalies. furthermore, our model based on lactate dehydrogenase, c-reactive protein, calcium, age, lymphocyte proportion, urea, and creatine kinase might be a more useful preliminary screening and triage tool than pneumonia severity index for risk assessment of covid-19 patients at hospital admission. role of the funder/sponsor: the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. chest ct scans were performed using one of the ct scanners (uct 780, united imaging, china and brilliance ict 128, philips medical systems, the netherlands) with patients in the supine position. the scanning range was from the level of the upper thoracic inlet to the inferior level of the costophrenic angle. for ct acquisition, the tube voltage was 120kvp with automatic tube current modulation, a field of view (fov) of 350 × 350 mm, and a matrix size of 512 × 512. all images were reconstructed into a slice thickness of 1 mm and an interval of 1 mm. coronavirus disease (covid-19) outbreak who. coronavirus disease 2019 (covid-19) situation report -116 who. report of the who-china joint mission on coronavirus disease epidemiologic features and clinical course of patients infected with sars-cov-2 in singapore clinical characteristics of coronavirus disease 2019 in china acute physiology and chronic health evaluation ii score as a predictor of hospital mortality in patients of coronavirus disease a prediction rule to identify low-risk patients with communityacquired pneumonia machine learning in medicine radiomics: the bridge between medical imaging and personalized medicine nowcasting and forecasting the potential domestic and international spread of the 2019-ncov outbreak originating in wuhan, china: a modelling study towards complete and accurate reporting of studies of diagnostic accuracy: the stard initiative. standards for reporting of diagnostic accuracy diagnosis and treatment of adults with community-acquired pneumonia. an official clinical practice guideline of the american thoracic society and infectious diseases society of america labcorp feature selection with the boruta package adaptive synthetic sampling approach for imbalanced learning comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach clinical features of patients infected with 2019 novel coronavirus in wuhan clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china a pneumonia outbreak associated with a new coronavirus of probable bat origin are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 pathological findings of covid-19 associated with acute respiratory distress syndrome novel coronavirus (2019-ncov) pneumonia temporal changes of ct findings in 90 patients with covid-19 pneumonia: a longitudinal study ct imaging features of 2019 novel coronavirus (2019-ncov) radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study national health commission & state administration of traditional chinese medicine short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (sars) middle east respiratory syndrome systematic review of privacy-preserving distributed machine learning from federated databases in health care distributed learning on 20 000+ lung cancer patients -the personal health train key: cord-293691-ewerquin authors: sauerhering, lucie; kupke, alexandra; meier, lars; dietzel, erik; hoppe, judith; gruber, achim d.; gattenloehner, stefan; witte, biruta; fink, ludger; hofmann, nina; zimmermann, tobias; goesmann, alexander; nist, andrea; stiewe, thorsten; becker, stephan; herold, susanne; peteranderl, christin title: cyclophilin inhibitors restrict middle east respiratory syndrome coronavirus via interferon λ in vitro and in mice date: 2020-07-02 journal: eur respir j doi: 10.1183/13993003.01826-2019 sha: doc_id: 293691 cord_uid: ewerquin rationale: while severe coronavirus infections, including middle east respiratory syndrome coronavirus (mers-cov) cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use. objectives: we elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin a (csa) and alisporivir (alv) restrict mers-cov to validate their suitability as readily-available therapy in mers-cov infection. methods: calu-3 cells and primary human alveolar epithelial cells (haec) were infected with mers-cov and treated with csa or alv or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nfat, or map kinases. novel csa-induced pathways were identified by rna sequencing and manipulated by gene knockdown or neutralising antibodies. viral replication was quantified by qrt-pcr and tcid(50). data were validated in a murine mers-cov infection model. results: csa and alv both reduced mers-cov titers and viral rna replication in calu-3 and haec improving epithelial integrity. while neither calcineurin nor nfat inhibition reduced mers-cov propagation, blockade of c-jun n-terminal kinase diminished infectious viral particle release but not rna accumulation. importantly, csa induced interferon regulatory factor 1 (irf1), a pronounced type-iii-interferon (ifnλ) response and expression of antiviral genes. down-regulation of irf1 or ifnλ increased mers-cov propagation in presence of csa. importantly, oral application of csa reduced mers-cov replication in vivo, correlating with elevated lung ifnλ levels and improved outcome. conclusions: we provide evidence that cyclophilin inhibitors efficiently decrease mers-cov replication in vitro and in vivo via upregulation of inflammatory, antiviral cell responses, in particular ifnλ. csa might therefore represent a promising candidate to treat mers-cov infection. saudi arabia [1] and led to recurring human infections with more than 2,500 laboratory-confirmed cases and high case fatality rates of about 35% [2] . in ex vivo infection of human lung tissue, mers-cov targets bronchial and alveolar epithelial cells (aec) and leads to a detachment and apoptosis of aec [3] . recent reports analyzing autopsy material of deceased mers-cov-infected patients showed mers-cov antigen in aec and epithelial multinucleated syncytial cell conglomerates in vivo [4, 5] . accordingly, severe human infection presents as pneumonia with progression to acute respiratory distress syndrome [4, 5] . to date, no vaccine or specific treatment for mers-cov -or the recently ongoing pandemic caused by the novel severe acute respiratory syndrome cov 2 (sars-cov-2) -is approved and therapy relies on supportive measures only [2, 6] . while in vitro studies and experiments in non-human primates demonstrated benefits of a combination of type-i-interferon and antiviral compounds including ribavirin against mers-cov [7] [8] [9] , results from retrospective patient cohorts applying similar treatment regimens remain controversial [10] [11] [12] . cyclosporin a (csa) has been found to inhibit several human-pathogenic cov in cell lines originating from kidney or liver epithelia [13] [14] [15] [16] . however, the molecular mechanisms by which csa affects cov, including mers-cov, particularly in its primary target cells, the pulmonary epithelium, remain elusive. moreover, preclinical studies addressing the effect of csa or related compounds on mers-cov replication in vivo have been lacking to date. csa is known to block the peptidyl-prolyl cis-trans isomerase (ppi) activity of cyclophilins that is involved in diverse cellular processes (e.g. protein folding, 17). additionally, csa forms together with cyclophilin a (cypa) and calcineurin (cna) a ternary complex which blocks the cna-dependent activation of nfat (nuclear factor of activated t-cells), a process which accounts for the immunosuppressive effect of csa [18] . in addition, csa has also been shown to inhibit the map kinases jnk (c-jun n-terminal kinase) and p38 [19, 20] . here, we aimed to elucidate the distinct signaling pathways by which csa affects mers-cov in clinically relevant models such as primary human aec and a murine mers-cov infection model [21, 22] . we demonstrate that csa blocks mers-cov infectious particle egress, which is dependent on jnk. moreover, we for the first time provide evidence that csa triggered the activation of an antiviral defense state in lung epithelial cells. we show that csa is a potent inducer of interferon regulatory factor 1 (irf1), type-iii-ifn (ifnλ) and multiple interferon-stimulated genes (isgs). additionally, we demonstrate that oral application of csa induced a robust ifnλ response in vivo and, importantly, significantly reduced mers-cov replication and improved disease progression in infected mice. experiments with mers-cov were performed under biosafety level 4 conditions at the institute of virology, philipps-university of marburg, germany. human alveolar epithelial cells (haec) were isolated and cultured as previously described [23] . human lung tissue was obtained from patients who underwent lobectomy after informed written consent (departments of pathology and surgery, university of giessen, approved by the university of giessen ethics committee; az.58/15). calu-3 or haec were infected at a multiplicity of infection (moi) of 0.1 diluted in dmem/f12 without fcs at 37°c for 1 h. cells were washed with dmem/f12 with 10% fcs and supplemented with stimulatory/ inhibitory reagents as indicated. 24 h after infection (pi) cells were processed for quantitative pcr (maxima-sybr/rox qpcr-mastermix, thermo fisher) and supernatant was harvested for virus titration as described previously [24] . all animal experiments were performed in accordance with the german animal protection laws and were authorized by the regional authorities (g73/2017). c57bl/6 mice were purchased from charles river laboratories and housed under pathogenfree conditions. mice were intratracheally inoculated with adenovirus-hdpp4-mcherry (cloned at viraquest inc.) as described [21, 25] . five days post transduction, mice were infected intranasally with 1.5x10 5 tcid 50 /ml mers-cov (emc/2012). 50 mg/kg/day csa diluted in dmso or dmso alone were mixed with a nut/chocolate-creme, and offered to the mice for voluntary uptake. uptake was controlled daily. csa feeding started 2 days before mers-cov challenge. mice were sacrificed 4 or 7 days post mers-cov infection. all data are given as mean ± sem. statistical significance was analyzed by unpaired two-tailed student's t-test or by 1-way anova and post-hoc multicomparison tests as indicated in the respective figures. a p value of less than 0.05 was considered significant. *p < 0.05; **p < 0.01; ***p < 0.005. further experimental details can be found in the online supplement. to address the previously proposed antiviral activity of csa in clinically relevant cells, we infected the human bronchial epithelial cell line calu-3 and primary human alveolar epithelial cells (haec) with mers-cov and analyzed intracellular viral rna and infectious particle release in presence of dmso or csa ( figure 1 ). in both calu-3 and haec, csa treatment led to a >95% decrease of viral rna ( figure 1a ) and a reduction of viral titers in the supernatant by 2.6-2.8 log 10 , respectively ( figure 1b) . interestingly, and in accordance with reports from autopsy material of mers-cov patients [4] , mers-cov-infected calu-3 and primary haec both showed apoptotic cell loss and formation of multinucleated cell foci ( figure 1c ). addition of csa reduced cell foci formation and significantly reduced apoptosis induction ( figure 1c , d). in line, both cftr (cystic fibrosis transmembrane conductance regulator; figure 1e ) and enacβ (epithelial sodium channel beta; supplement fig.e1) protein expression was improved after addition of csa to mers-cov-infected calu-3. moreover, epithelial structural integrity and ability for vectorial water transport were reduced in mers-cov-infected control cells and significantly improved to normal levels in mers-cov-infected, csa-treated cells ( figure 1f , g). csa is known to act via multiple signaling pathways including cyclophilin ppiase activity, the cna-nfat axis as well as map kinase signaling [17] [18] [19] [20] . using specific inhibitors, we aimed to interfere with csa-affected pathways to identify relevant molecular signaling events involved in the csa-mediated reduction of mers-cov infection. inhibition of cna by its specific inhibitor calcineurin inhibitory peptide (cip), as well as inhibition of the downstream transcription factor nfat resulted in minor, statistically non-significant changes in mers-cov viral titers in both calu-3 and haec (figure 2a , b). the non-immunosuppressive derivate of csa, alisporivir (alv), that binds the ppiase but does not induce ternary complex formation of cypa with cna, reduced viral titers to a similar extent as csa, suggesting that the cypa-ppiase activity elicits the restrictive effect on mers-cov replication rather than ternary complex-mediated signaling events. moreover, alv reduced cell foci formation and loss of epithelial integrity to a similar extent as csa (supplement fig. e2 ). applying specific mapk inhibitors against jnk and p38, we revealed that inhibition of the map kinase jnk, but not of p38 reduced mers-cov titers in both calu-3 and haec ( figure 2a our data suggest that, as opposed to its well-known cna/nfatfigure 4c ). these data indicate that csa treatment mounts a distinct interferon-driven antiviral response in lung epithelial cells. to better understand the transcriptional programs leading to ifnλ induction in csa-treated cells, we analyzed the regulation of interferon regulatory factors (irfs). our data reveal significant upregulation of irf1 mrna levels upon csa treatment, but not of irf3, irf7 or irf9 ( figure 5a ). irf1 is known to be a specific activator of ifnl gene expression [26] . accordingly, we identified a significantly increased number of irf1-expressing cells in csa-stimulated calu-3 cells by immunofluorescence ( figure 5b ). in line, irf1 sirna knockdown significantly reduced ifnl mrna levels in csa treated calu-3 cells ( figure 5c ). accordingly, irf1 knockdown inhibited ifnλ release by more than 75 % as compared to control ( figure 5d ). to understand the extent to which the inhibition of mers-cov propagation in csa treated cells was mediated by irf1-mediated production of ifnλ, we performed knockdown of irf1 or neutralized cell-free ifnλ, respectively. our data demonstrated that silencing of irf1 but not treatment by control sirna lead to a significant increase in mers-cov released viral particles in csa-treated cells ( figure 6a , b). moreover, neutralizing antibodies directed against ifnλ1, ifnλ2 and ifnλ3 or against the less induced ifnβ were applied ( figure 6b ). neutralization of ifnβ had no significant impact on mers-cov replication after csa treatment, whereas application of anti-ifnλ1/2/3 treatment significantly increased mers-cov viral titers by 1.05 log 10 level ( figure 6b ). these data indicate that the antiviral effects of csa were at least partially mediated by an irf1-ifnλ signaling axis, and independent of type-i-ifn. as no specific treatment is approved for mers-cov or sars-cov(-2), current treatment strategies are supportive [29, 30] . treatments including recombinant type-i-ifn and antivirals (e.g. lopinavir/ritonavir) have been applied off-label to treat mers-cov and yielded only moderate efficacy with controversial results in retrospective studies, and data from prospective studies or randomized controlled trials are lacking [29, [31] [32] [33] . due to its receptor specificity to the human dpp4, only few animal models to study mers-cov pathogenesis and mers-cov-directed antiviral compounds have been accessible to date. for this study, mers-cov infection in the mouse was facilitated via intratracheal delivery of a human dpp4encoding adenovirus, that might cause low-level inflammation itself and inhomogeneous receptor distribution within the lung, present for a limited time frame. however, even if this model might not fully recapitulate the native cellular distribution or density of the receptor as seen in the human lung, high transduction efficiencies (≥ 95%, data not shown) allow efficient viral spread in the upper and lower respiratory airways with quick progression to severe lung injury [22] and with moderate changes in morbidity [34] . thus, model-specific neurotropism as seen in some of the transgenic hdpp4 mice [35] or the necessity to adapt virus isolates via multiple passages, which might potentially affect its susceptibility to interventional strategies, are circumvented. while prior exposure to adenovirus evokes moderate histological changes including perivascular and bronchiolar lymphocytic infiltration (data not shown), mers-cov infection led to a clearly distinguishable granulocytic, necrotizing interstitial pneumonia with alveolar edema formation as described previously [22] . moreover, we demonstrate that inhibition of cypa via csa or alv, which both potently block the cypa ppiase activity at the used concentrations [42] , results in a pronounced upregulation of type-iii-ifn on both mrna and protein level, which was mediated via irf1 and was accompanied by expression of antiviral isgs. among those, especially ifit1 (interferon-induced protein with tetratricopeptide repeats 1), has been reported to influence the pathogenesis of mers-cov, highlighting the relevance of our findings [43] . of note, type-iii-ifns have recently emerged as key antiviral players in the innate immune response to viral infections at mucosal and epithelial surfaces [44] [45] [46] [47] . they efficiently restrict different respiratory viruses, and act e.g. by limiting spread from the upper to the lower airways [44, [46] [47] [48] . as opposed to type-i-ifn, type-iii-ifn do not trigger detrimental immune responses that contribute to immunopathology in influenza infection [23, 25, 44, 49] . this might prove to be pivotal in the context of csa-dependent stimulation of ifnλ during cov, as severe human cov infections, like mers-cov and-while data are still limitedalso sars-cov-2, are characterized by an immunopathology with a strong cytokine induction [5, 50, 51] . in addition to defining a novel pro-inflammatory, antiviral expression profile induced by csa on lung epithelial cells, this study also demonstrated for the first time gen. virol. 2017. statistical significance was calculated using unpaired two-way student's t-test (a, b, c, d, g) with *p < 0.05. onestep rt-pcr system (invitrogen life technologies) as described previously [2, 3] . intracellular localization of endogenous irf1 protein was analyzed 3 and 4 hour post csa stimulation. dmso-treated cells were used as negative control. stimulated cells were fixed with 4% pfa and permeabilized with methanol/acetone for 10 min. cells were incubated with a rabbit monoclonal-anti-irf1 (1:100; cell signaling) and an alexafluor 594-conjugated secondary antibody (1:400; dianova). cell nuclei were counterstained with dapi. the samples were mounted in fluoprep (biomérieux) and images were recorded with a confocal laser scanning microscope (leica sp5). calu3 cells were seeded in 0.4µm pore size transwell cell culture dishes (corning) and cultured until achieving electrochemical resistances (ter) of ≥800ω /cm 2 as measured by millicell-ers2 device. cells were infected apically with mers-cov at ; as reported previously [4] . for quantification of mers-cov induced apoptosis a caspase 3/7 gloassay® sds-page and western blot was analyzed as described previously [5] . calu-3 cells were infected with mers-cov using a moi of 0.1 and stimulated with csa 1 hour after virus adsorption. 24 h pi cells were scratched off with 500 µl pbs supplemented with protease-inhibitor mix (calbiochem) and centrifuged for 5 min at 5,000 rpm. cell pellets were resuspended in sample buffer [6] containing 4% sds and boiled at 100°c for 10 min. after discharge of the probes out of the bsl4 laboratory another 10 min boiling step was performed before the samples were separated using an 7,5 % sds-gel. after blotting on a nitrocellulose membrane and blocking using pbsdef with 5% milk powder first antibodies (anti-cftr antibody, clone mm13-4 and mouse monoclonal anti-vinculin antibody both sigma-aldrich; enacβ antibody (e-10), sc-48428; santa cruz biotechnology) diluted in pbsdef with 1% milk powder were incubated overnight followed by secondary antibody-incubation for 1 h (goat anti-mouse/hrp and swine anti-rabbit/hrp; both dako). for visualization of the signals image lab software was used. all animal experiments were performed in accordance with the regulations of german animal protection laws and as authorized by the regional authorities for histopathological analyses of formalin-fixed, paraffin-embedded murine lung tissues, sections of 2 µm thickness were cut from four to six evenly distributed planes throughout the entire lungs and mounted on adhesive glass slides. the slides were stained with hematoxylin and eosin and coverslipped. histopathological evaluation was performed using an established four grade scoring scheme [7] including the following parameters: affected area, severity and distribution of interstitial inflammation, infiltration of macrophages, lymphocytes and granulocytes, necrosis, alveolar hemorrhage and edema as well as formation of bronchus-associated lymphoid tissue (balt) and perivascular, lymphocytic cuffing. figure onestep rt-pcr kit as described previously [2, 3] . quantification was carried out using a standard curve based on 10-fold serial dilutions of appropriately cloned rna ranging from 10 2 to 10 5 copies. bar graphs in represent mean ± sem of n = 4 isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus (mers-cov) dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-emc ultrastructural findings of a fatal case of middle east respiratory syndrome coronavirus infection in the united arab emirates histopathology of middle east respiratory syndrome coronovirus (mers-cov) infection -clinicopathological and ultrastructural study middle east respiratory syndrome treatment with lopinavir/ritonavir or interferon-β1b improves outcome of mers-cov infection in a nonhuman primate model of common marmoset treatment with interferon-α2b and ribavirin improves outcome in mers-cov-infected rhesus macaques inhibition of novel β coronavirus replication by a combination of 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the ifnλ receptor to regulate antiviral activity against hcv and coronaviruses impact and regulation of lambda interferon response in human metapneumovirus infection interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology activation signals for interleukin-2 production involve activation of mkk6-p38 and mkk7 signaling pathways sensitive to cyclosporin a variability of interferon-λ induction and antiviral activity in nipah virus infected differentiated human bronchial epithelial cells of two human donors a highly immunogenic and protective middle east respiratory syndrome coronavirus vaccine based on a recombinant measles virus vaccine platform. perlman s, editor protective efficacy of recombinant modified vaccinia virus ankara delivering middle east respiratory syndrome coronavirus spike glycoprotein. perlman s, editor macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection serine-arginine protein kinase 1 regulates ebola virus transcription multivesicular bodies as a platform for formation of the marburg virus envelope spectrum of pathogen-and model-specific histopathologies in mouse models of acute pneumonia work with live mers-cov was performed in the bsl-4 facility of the philipps university, marburg, germany. we thank julia spengler, larissa hamann, stefanie jarmer, dirk becker and marc ringel for excellent technical and experimental assistance. we thank ralf bartenschlager for providing alisporivir. key: cord-296440-18vpg419 authors: beurnier, antoine; jutant, etienne-marie; jevnikar, mitja; boucly, athénaïs; pichon, jérémie; preda, mariana; frank, marie; laurent, jérémy; richard, christian; monnet, xavier; duranteau, jacques; harrois, anatole; chaumais, marie-camille; bellin, marie-france; noël, nicolas; bulifon, sophie; jaïs, xavier; parent, florence; seferian, andrei; savale, laurent; sitbon, olivier; montani, david; humbert, marc title: characteristics and outcomes of asthmatic patients with covid-19 pneumonia who require hospitalisation date: 2020-07-30 journal: eur respir j doi: 10.1183/13993003.01875-2020 sha: doc_id: 296440 cord_uid: 18vpg419 background: viral respiratory infections are the main causes of asthma exacerbation. the susceptibility of asthmatics to develop an exacerbation when they present with severe pneumonia due to sars-cov-2 infection is unknown. the objective of this study was to investigate the characteristics and outcomes of asthmatic patients with covid-19 pneumonia who required hospitalisation during the spring 2020 outbreak in paris, france. methods: a prospective cohort follow-up was carried out from march 15 to april 15, 2020 in bicêtre hospital, university paris-saclay, france. all hospitalised patients with a sars-cov-2 infection who reported a history of asthma were included. results: among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. patients were mainly female (70%), non-smokers (85%), with a median age of 54 years (interquartile range, iqr 42–67). none of them presented with an asthma exacerbation. twenty-two (59%) had major comorbidities and 31 (84%) had a body mass index ≥25 kg·m(−2). the most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). all patients had a confirmed diagnosis of covid-19 pneumonia on computed tomography of the chest. eosinopenia was a typical biologic feature with a median count of 0/mm3 (iqr 0–0). eleven patients (30%) were admitted in intensive care unit with three death (8.1%) occurring in the context of comorbidities. conclusion: asthmatics were not overrepresented among patients with severe pneumonia due to sars-cov-2 infection who required hospitalisation. worst outcomes were observed mainly in patients with major comorbidities. viral respiratory infections are the main causes of asthma exacerbations in both adults and children. coronaviruses are commonly isolated in the respiratory tract of these patients [1] . as the world faces the coronavirus disease 2019 (covid-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection, concerns have arisen about a possible increased risk of asthma exacerbations. indeed, sars-cov-2 is well known for its respiratory tropism that can lead to severe pneumonia and potentially fatal acute respiratory distress syndrome (ards) [2] . however, the prevalence of asthma among inpatients with covid-19 remains debated. in wuhan, authors pointed out a rate of 0.9% [3] , markedly lower than that in the local population; in another study investigating the clinical characteristics and allergy status of 140 patients infected by sars-cov-2 in wuhan, no patient were reported as being asthmatic [3] . conversely, other authors found that asthmatics accounted for 12.5% of total covid-19 inpatients in new york [4] . beside those conflicting statistics, the characteristics and the outcomes of asthmatic patients infected with sars-cov2 have not yet been described in detail. in france, the great paris region (ile-de-france) has been particularly affected by the epidemic. on march 14, 2020, the regional health agency issued a statement underscoring the rapid spread of sars-cov-2 in the region with 376 new daily confirmed cases [5] ; the number of regional hospitalizations for covid-19 eventually reached a peak on april 1st [6] . from march 15, 2020 to april 15, 2020 we carried out a prospective study in bicêtre hospital, university paris-saclay, france. the objective of this study was to investigate the characteristics and outcomes of asthmatic patients with covid-19 pneumonia who required hospitalization. a prospective monocentric cohort follow-up was initiated in bicêtre hospital, france. all adult patients hospitalized from march 15, 2020 to april 15, 2020 with a diagnosis of sars-cov-2 infection and reporting a history of asthma were included. decision of hospitalization was based on a concerted decision algorithm that has been locally implemented into clinical practice during the french covid-19 outbreak (supplementary figure 1 ) . covid-19 was first suspected on the basis of compatible symptoms: in suspected cases, both sars-cov-2 reverse transcription polymerase chain reaction (rt-pcr) on nasopharyngeal swab and computed tomography (ct) of the chest were systematically performed. diagnosis was confirmed in the presence of positive sars-cov-2 rt-pcr and/or typical ct abnormalities (i.e ground-glass opacities and/or consolidation in the lung periphery) [7] . a random control group of 75 non-asthmatic patients hospitalized for covid-19 pneumonia in our hospital during the same period has been included and analyzed. patients received written information about data collection. after inclusion, all data regarding the clinical status, main outcomes, biological and radiological features were recorded in an anymous database registred to the national commission on informatics and liberty (n° 2217978). the following data were collected after patient-centered interviews: comorbid conditions (obesity, hypertension, diabetes, renal failure, coronary heart disease); current smoking status ("non-smokers" referring to both former and never smokers); history of asthma; asthma controller treatment with classification from step 1 to 5 according to the last 2020 global initiative for asthma (gina) report [8] ; when feasable, we also clarified with the patient or his family whether asthma diagnosis had been confirmed by a pulmonologist or not. in addition, the following laboratory tests were analyzed at admission: sars-cov-2 rt-pcr result, blood count, cardiac biomarkers, liver function, arterial blood gas, c-reactive protein (crp), fibrinogen, d-dimers, creatine phosphokinase (cpk), lactate dehydrogenase (ldh), ferritin. ct of the chest was analyzed by a radiologist and a pulmonologist and the extent of lesions was classified as mild (< 10%), moderate (10-24%), severe (25-49%), very severe (50-74%), and critical (≥ 75%). the following management strategies were detailed: use of systemic corticosteroids (cs), short-acting beta-agonists (saba), antibiotics, adjustement of asthma controller, oxygen flow, intensive care unit (icu) admission, and mechanical ventilation requirement. finally, the main outcomes (mortality, length of icu stay and total length of hospital stay) were investigated after a one-month follow-up. quantitative data were expressed as median (interquartile range) (iqr, presented as first quartilethird quartile). qualitative data were expressed as number of occurrence, n (%). in case of missing data, the number of patients with available informations was provided next to each variable. when this number was not specified, data of entire population was available and analyzed. student's t test or mann-whitney u test (if not normally distributed) were used to compare the continuous variables between two groups. pearson's chi-square (χ2) test or fisher's exact tests if appropriate, were used to compare discrete variables between two groups. among 768 hospitalized covid-19 patients, 37 (4.8%) reported a history of asthma. thirtyone asthmatics had positive sars-cov-2 rt-pcr on nasopharyngeal swab (84%). the remaining six were diagnosed on the basis of clinical presentation and radiological patterns [7] . asthmatic patients were mainly female (70%), non-smokers (85%), with a median age of 54 years (42-67) and a median body mass index (bmi) of 28.3 kg/m² (26.8-31.5) . in 85% of cases the diagnosis of asthma had been previously confirmed by a pulmonologist. eleven patients (30%) were gina step 5, receiving high doses inhaled cs (ics) with long-actingbeta agonists (laba), associated with low dose oral cs in one case, and long-term omalizumab therapy in two (supplementary table 1 ).thirty-one asthmatics (84%) had a bmi ≥ 25 kg/m². twenty-two (59%) had at least one major comorbidity. the most common comorbid conditions were obesity (36%), hypertension (27%) and diabetes (19%). fifteen (41%) had multimorbidities ( table 1 ). the median time from onset of symptoms to admission in the emergency room was 6 days (3-8). fifty percent of patients had an initial peripheral oxygen saturation below 95% while breathing room air and 25% had a respiratory rate above 30/min. none of them presented with an asthma exacerbation. wheezing, mostly reported as mild, was reported at admission in only 6 cases (16%) ( table 2) . non-asthmatic controls are presented in tables 1 and 2. all differences pointed to worst covid-19 pneumonia in non-asthmatics, as evidenced by older age, higher male/female gender rate, and a trend to more comorbidities. laboratory values in the emergency room are summarized in table 3 . among asthmatics, lymphopenia was a frequent finding (median 1,205/mm3, iqr 738-1,476) ( figure 1a) . patients also presented with a marked eosinopenia, 78% having a blood eosinophils count equal to zero ( figure 1b) . n-terminal pro-b-type natriuretic peptide (nt-pro bnp) was measured in 21 patients and normal value (< 300 ng/l) was found in 81% of cases. of 31 available data, 6 patients (19%) had increased high-sensitive cardiac troponin t (≥ 14 ng/l); however, none of these patients demonstrated consistent evidence of serious myocardial injury. elevation of d-dimers was commonly observed (median 810 µg/l, iqr 483-1,180), as well as increased crp levels (median crp 51 mg/l, iqr 27-116). arterial blood gas while breathing room air was available in 29 patients : hypoxaemia was a common finding (median arterial partial pressure of oxygen (pao 2 ) 68 mmhg, iqr 62-83) with hypocapnia (median arterial partial pressure of carbon dioxide (paco 2 ) 34 mmhg, iqr 32-38). non-asthmatic controls are presented in table 3 . there was a trend for more pronounced lymphopenia and worst crp, d-dimers, ldh, liver transaminases levels, with more severe hypoxemia. all asthmatics underwent a ct of the chest ( table 4) . peripheral or mixed ground glass opacities were the most frequent ct patterns (95% of cases), expanding over more than 10 percent of lung parenchyma in 76% of cases. consolidations were observed in 26 patients (70%) and crazy-paving pattern in 13 patients (35%). in 51% of cases, lesions predominated in inferior lobes. based on clinical judgement or prediction rules [9] , four patients had initial ct pulmonary angiography (ctpa), demonstrating two cases of acute pulmonary embolisms (pe) at admission. eight additional ctpa were performed during hospital stays for clinical deterioration, leading to another acute pe diagnosis. in this small cohort of patients, higher inhaled corticosteroid exposure was not associated with higher proportion of severe radiological pneumonia; mild pneumonia tended to be more frequent in asthmatics with higher doses of ics (supplementary figure 2) . all non-asthmatic controls had imaging of the chest at admission (66 ct and 9 chest x ray). the results of ct of the chest are presented in table 4 . as compared to asthmatics, there was more sereve-to-critical radiological presentation in the non-asthmatics. as shown in table 5 , 30 (81%) asthmatics received oxygen with use of high-concentration masks in 10 patients. when nasal oxygen was used, the median oxygen flow-rate was 2 l/min. in two patients, oxygen had to be maintained after discharge. thirty-one (84%) received at least one antibiotic. saba as needed was prescribed using a pressurized metereddose inhaler (p-mdi) with a spacer chamber and previous inhaled treatments were maintained. five patients received oral cs before admission, one of them in the context of self-medication. three additional patients received intravenous cs during hospital stay: refractory ards was the main cause of cs prescription in two cases and bronchospasm occurring in the context of mechanical ventilation in one case. eleven patients were admitted in icu, six of them requiring invasive mechanical ventilation. there was a trend for more aged and comorbid patients among patients admitted in icu ( table 6) . a flowchart of the main outcomes is presented in figure 2 . as shown in figure 3 , asthmatics without multimorbidities were discharged at home earlier. two deaths occurred at one-month follow-up and one additional death was later noted, thus leading to a mortality rate of 8.1% in asthmatics (as compared to 14.6% in non-asthmatics, p=0.381). the first patient was a 68 year-old woman treated for asthma by her pulmonologist with fluticasone/salmeterol 500/50 µg daily (medium doses, gina step 4). she had several comorbidities including obesity (bmi = 31.2 kg/m²), diabetes, current chemotherapy for ovarian cancer, dyslipidemia and sleep apnea syndrome. at admission, no wheezing was reported, she was eosinopenic (0/mm 3 two patients were treated with anti-immunoglobulin e monoclonal antibody (omalizumab) for severe allergic asthma. the first one was a 53 year-old woman treated with budesonide/formoterol 800/12 µg daily, montelukast 10 mg/j and subcutaneous omalizumab at a monthly dose of 300 mg. she had no sign of asthma exacerbation before admission, but took a short course of oral prednisone (40mg/day) during five days as self medication that was this prospective monocentric cohort describes clinical, biological and radiological characteristics and outcomes of asthmatics with covid-19 pneumonia who require hospitalization. during the spring 2020 outbreak, asthmatics accounted for less than 5% of total hospitalized patients in our institution. the most recent data available in france indicate that 6.4% of individuals have a current diagnosis of asthma [10] . in line with previous reports [11] , our results suggest that asthmatics were thus not over-represented among covid-19 inpatients. in addition, no patient was hospitalized for a covid-19 related asthma exacerbation during the outbreak and very few developed an asthma attack while hospitalized, which is consistent with data recently reported in strasbourg, france [12] . this contrasts sharply with viral respiratory infections, including other types of coronavirus, being the main causes of asthma exacerbations [1] . several mechanisms may explain this apparent paradox. first, a lower expression of sars-cov-2 cellular receptor angiotensin-converting enzyme-2 (ace2) has been described in airways cells of patients with respiratory allergy and/or asthma, and it was also found that ace2 expression was inversely associated with type 2 biomarkers [13] . of note, severe eosinopenia was a typical biologic feature in our cohort, 78% of hospitalized asthmatics having no detectable blood eosinophils at admission. this finding is unusual in hospitalized asthmatics receiving neither systemic cs nor anti-interleukin 5 (il-5) therapy. similar findings were reported in a mostly non-asthmatic covid-19 population in wuhan, china, where eosinopenia was described in 53% of hospitalized subjects [14] and in 81% of fatal cases [15] . as suggested by others [16] , eosinopenia in covid-19 may be a marker of more severe disease. in addition, one may speculate that it reflects a down-regulation of type 2 inflammation that might decrease the risk of asthma exacerbation orchestrated by type 2 responses. of note, it has been recently showed that severe covid-19 is driven by inappropriate inflammatory response defined by low levels of type i and iii interferons juxtaposed to elevated chemokines and high expression of il-6, supporting the concept that reduced innate antiviral defenses coupled with exuberant proinflammatory cytokine production are the defining and driving features of covid-19 [17] . further studies are needed, describing the cytokine profile of asthmatics in response to sars-cov-2 infection. furthermore, there is in vitro evidence to support a protective effect of ics on coronaviruses infections [18] . indeed, sputum analysis showed that ace2 expression levels are significantly lower in asthma patients taking ics than in those not taking ics, especially when high doses are administrated [19] . randomized control trials are needed to test the effect of ics on covid-19 in both asthmatics and non-asthmatics patients. we observed a female predominance (70%) in our cohort, whereas previous works demonstrated an increased risk of sars-cov-2 infection in males [20] . this might be explained by age-related sex ratio differences, asthma being more prevalent in female adults [21] [22] . moreover, obesity, hypertension and diabetes were the most common comorbidities observed in our cohort of hospitalized asthmatics with covid-19, which is consistent with earlier research in other patient groups [4] [23] . interestingly, obesity has been associated with asthma in women [24] and severe forms of covid-19 in both genders [25] [26] . asthmatic patients with covid-19 pneumonia who required hospitalization presented with radiological characteristics similar to those described previously, with a predominance of peripheral ground glass opacities [27] . interestingly, three patients had a diagnosis of acute pe (8.1 %) on ctpa at admission or during hospitalization. at the start of the covid-19 outbreak, the first-line imaging tool in our centre relied on non-contrast ct of the chest [7] . however, more concern has been recently raised about thrombosis and pulmonary embolism in covid-19 patients [28] , underscoring that this complication may be more prevalent in this patient population. asthma therapy was unchanged in all patients, including biologics, as recommended by the french asthma and allergy working group (g2a) [29] . interestingly, two patients were on omalizumab therapy prior to covid-19. in one patient, the planned omalizumab injection has been administrated while she was under mechanical ventilation, experiencing severe bronchospasm and ards. no adverse events were observed and successful extubation was possible five days later. our study included a control group of covid-19 pneumonia hospitalized in the same hospital during the same period. as compared to controls, asthmatics were younger, more likely to be female and they tended to be less comorbid, which may explain at least in part, the better outcomes in this population. however, it is interesting to note that mild pneumonia tended to be more frequent in asthmatics with higher doses of ics (supplementary figure 2 ). further studies are needed to investigate the possible positive effect of inhaled corticosteroids on covid-19 pneumonia as previously showed with dexamethasone in the recovery trial [30] . the ongoing inhasco trial (nct04331054) is investigating this research question. one of the study limitations is the relative small number of asthmatic patients being investigated. however, all patients were identified prospectively by an expert team of asthma specialists in a large university hospital hosting a severe asthma clinic, allowing systematic analysis of relevant information and meticulous follow-up. in a state of emergency, misdiagnoses of both asthma and covid-19 cannot be excluded. regarding asthma, it could be underdiagnosed, as diagnosis was based on self-report and pulmonary function tests could not be performed during the outbreak. asthma might also be overdiagnosed, as previously reported in industrialized countries especially in obese individuals [31] . nevertheless, asthma diagnosis had been previously confirmed by a pulmonologist in 85% of cases. a covid-19 overdiagnosis is also unlikely, with positive sars-cov-2 rt-pcr on nasopharyngeal swab in 84% of cases. rt-pcr was negative in only six patients who presented with a high clinical suspiscion of covid-19 and consistent ct of the chest during the outbreak [7] . in conclusion, our data indicate that asthmatics were not over-represented in a large group of hospitalized pneumonia during the spring 2020 covid-19 outbreak in paris, france. in addition, covid-19 pneumonia was not associated with asthma exacerbation at admission and at one-month follow-up in patients who did not modify their asthma treatment including gina step 5 (high doses ics with laba, low dose oral cs, and long-term omalizumab). large multicenter cohort studies are needed to confirm these data and explore the reasons why sars-cov-2 does not seem to trigger as many asthma exacerbations, as previously seen with other respiratory viruses. a. a ct of the chest at the emergency department; hospitalization the microbiology of asthma clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china risk factors for severity and mortality in adult covid-19 inpatients in wuhan clinical characteristics of covid-19 in covid-19) : points de situation the role of chest imaging in patient management during the covid-19 pandemic: a multinational consensus statement from the fleischner society esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the european respiratory society (ers)the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology (esc) prévalence et prise en charge de l'asthme de l'adulte en france en 2018 : enquête do chronic respiratory diseases or their treatment affect the risk of sars-cov-2 infection? sars-cov-2 pneumonia in hospitalized asthmatic patients did not induce severe exacerbation association of respiratory allergy, asthma and expression of the sars-cov-2 receptor, ace2 clinical characteristics of 140 patients infected with sars-cov-2 in wuhan, china clinical features of 85 fatal cases of covid-19 from wuhan: a retrospective observational study eosinophil responses during covid-19 infections and coronavirus vaccination imbalanced host response to sars-cov-2 drives development of covid-19 inhaled corticosteroids and covid-19: a systematic review and clinical perspective covid-19 related genes in sputum cells in asthma: relationship to demographic features and corticosteroids epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study the relationship of sex to asthma prevalence, health care utilization, and medications in a large managed care organization asthma over the adult life course: gender and hormonal influences comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis obesity may increase the incidence of asthma in women but not in men: longitudinal observations from the canadian national population health surveys high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation obesity a risk factor for severe covid-19 infection: multiple potential mechanisms radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study effect of dexamethasone in hospitalized patients with covid-19: preliminary report overdiagnosis of asthma in obese and nonobese adults key: cord-337889-90q4py0j authors: guan, wei-jie; liang, wen-hua; zhao, yi; liang, heng-rui; chen, zi-sheng; li, yi-min; liu, xiao-qing; chen, ru-chong; tang, chun-li; wang, tao; ou, chun-quan; li, li; chen, ping-yan; sang, ling; wang, wei; li, jian-fu; li, cai-chen; ou, li-min; cheng, bo; xiong, shan; ni, zheng-yi; xiang, jie; hu, yu; liu, lei; shan, hong; lei, chun-liang; peng, yi-xiang; wei, li; liu, yong; hu, ya-hua; peng, peng; wang, jian-ming; liu, ji-yang; chen, zhong; li, gang; zheng, zhi-jian; qiu, shao-qin; luo, jie; ye, chang-jiang; zhu, shao-yong; cheng, lin-ling; ye, feng; li, shi-yue; zheng, jin-ping; zhang, nuo-fu; zhong, nan-shan; he, jian-xing title: comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis date: 2020-03-26 journal: eur respir j doi: 10.1183/13993003.00547-2020 sha: doc_id: 337889 cord_uid: 90q4py0j background: the coronavirus disease 2019 (covid-19) outbreak is evolving rapidly worldwide. objective: to evaluate the risk of serious adverse outcomes in patients with coronavirus disease 2019 (covid-19) by stratifying the comorbidity status. methods: we analysed the data from 1590 laboratory-confirmed hospitalised patients 575 hospitals in 31 province/autonomous regions/provincial municipalities across mainland china between december 11(th), 2019 and january 31(st), 2020. we analyse the composite endpoints, which consisted of admission to intensive care unit, or invasive ventilation, or death. the risk of reaching to the composite endpoints was compared according to the presence and number of comorbidities. results: the mean age was 48.9 years. 686 patients (42.7%) were females. severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. the most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. after adjusting for age and smoking status, copd [hazards ratio (hr) 2.681, 95% confidence interval (95%ci) 1.424–5.048], diabetes (hr 1.59, 95%ci 1.03–2.45), hypertension (hr 1.58, 95%ci 1.07–2.32) and malignancy (hr 3.50, 95%ci 1.60–7.64) were risk factors of reaching to the composite endpoints. the hr was 1.79 (95%ci 1.16–2.77) among patients with at least one comorbidity and 2.59 (95%ci 1.61–4.17) among patients with two or more comorbidities. conclusion: among laboratory-confirmed cases of covid-19, patients with any comorbidity yielded poorer clinical outcomes than those without. a greater number of comorbidities also correlated with poorer clinical outcomes. since november 2019, the rapid outbreak of coronavirus disease 2019 (covid19) , which arose from severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection, has recently become a public health emergency of international concern [1] . covid-19 has contributed to an enormous adverse impact globally. hitherto, there have been 109,577 laboratory-confirmed cases and 3,809 deaths globally as of march 10 th , 2020 [2] . the clinical manifestations of covid-19 are, according to the latest reports [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] , heterogeneous. on admission, 20-51% of patients reported as having at least one comorbidity, with diabetes (10-20%), hypertension (10-15%) and other cardiovascular and cerebrovascular diseases (7-40%) being most common [3, 4, 6] . previous studies have demonstrated that the presence of any comorbidity has been associated with a 3.4-fold increased risk of developing acute respiratory distress syndrome in patients with h7n9 infection [13] . similar with influenza [14] [15] [16] [17] [18] , severe acute respiratory syndrome coronavirus (sars-cov) [19] and middle east respiratory syndrome coronavirus (mers-cov) [20] [21] [22] [23] [24] [25] [26] [27] [28] , covid-19 more readily predisposed to respiratory failure and death in susceptible patients [4, 5] . nonetheless, previous studies have been certain limitations in study design including the relatively small sample sizes and single center observations. studies that address these limitations is needed to explore for the factors underlying the adverse impact of our objective was to evaluate the risk of serious adverse outcomes in patients with covid-19 by stratification according to the number and type of comorbidities, thus unraveling the sub-populations with poorer prognosis. this was a retrospective case study that collected data from patients with covid-19 throughout china, under the coordination of the national health commission which mandated the reporting of clinical information from individual designated hospitals which admitted patients with covid-19. after careful medical chart review, we compiled the clinical data of laboratory-confirmed hospitalized cases from 575 hospitals (representing 31.7% of the certified hospitals for admitting patients with between december 11 th , 2019 and january 31 st , 2020. the diagnosis of covid-19 was made based on the world health organization interim guidance [29] . because of the urgency of data extraction, complete random sampling could not be applied in our settings. all clinical profiles outside hubei province were centrally provided by the national health commission. three respiratory experts from guangzhou were dispatched to wuhan for raw data extraction from wuhan jinyintan hospital where most cases in wuhan were located. our cohort included 132 patients from wuhan jinyintan hospital, and one each from 338 hospitals. our cohort represented the overall situation as of jan 31 st , taking into account the proportion of hospitals (~ one fourth) and patient number (13.5%, 1,590/11,791 cases) as well as the broad coverage (covering all major provinces/cities/autonomous regions). confirmed cases denoted the patients whose high-throughput sequencing or real-time reverse-transcription polymerase chain reaction (rt-pcr) assay findings for nasal and pharyngeal swab specimens were positive [3] . see online supplement for further details. the interval between the potential earliest date of transmission source (wildlife, suspected or confirmed cases) contacts and the potential earliest date of symptom onset (i.e., cough, fever, fatigue, myalgia) was adopted to calculate the incubation period. in light that the latest date was recorded in some patients who had continuous exposure to contamination sources, the incubation periods of less than 1.0 day would not be included in our analysis. the incubation periods were summarized based on the patients who had delineated the specific date of exposure. the clinical data (including recent exposure history, clinical symptoms and signs, comorbidities, and laboratory findings upon admission) were reviewed and extracted by experienced respiratory clinicians, who subsequently entered the data into a computerized database for further double-check of all cases. manifestations on chest x-ray or computed tomography (ct) was summarized by integrating the documentation or description in medical charts and, if available, a further review by our medical staff. major disagreement of the radiologic manifestations between the two reviewers was resolved by consultation with another independent reviewer. because the disease severity reportedly predicted poorer clinical outcomes of avian influenza [13] , patients were classified as having severe or non-severe covid-19 based on the 2007 american thoracic society / infectious disease society of america guidelines [30], taking into account its global acceptance for severity stratification of community-acquired pneumonia although no validation was conducted in patients with viral pneumonia. the predictive ability of the need for icu admission and mortality has been validated previously [31, 32] . briefly, severe cases denoted at least one major criterion (septic shock requiring vasoactive medications, or respiratory failure requiring mechanical ventilation), or at least three minor criteria (respiratory rate being 30 times per minute or greater, oxygen index being 250 or lower, multiple lobe infiltration, delirium or loss of consciousness, blood urea nitrogen level being 20 mg/dl or greater, blood leukocyte count being 4,000 per deciliter or lower, blood platelet count being 100,000 per deciliter or lower, body temperature being lower than 36 degrees, hypotension necessitating vasoactive drugs for maintaining blood pressure). comorbidities were determined based on patient's self-report on admission. comorbidities were initially treated as a categorical variable (yes vs. no), and subsequently classified based on the number (single vs. multiple). furthermore, comorbidities were sorted according to the organ systems (i.e. respiratory, cardiovascular, endocrine). comorbidities that were classified into the same organ system (i.e. coronary heart disease, hypertension) would be merged into a single category. the primary endpoint of our study was a composite measure which consisted of the admission to intensive care unit (icu), or invasive ventilation, or death. this composite measure was adopted because all individual components were serious outcomes of h7n9 infections [13] . the secondary endpoint was the mortality rate. statistical analyses were conducted with spss software version 23.0 (chicago, il, usa). no formal sample size estimation was made because there has not been any published nationwide data on covid-19. nonetheless, our sample size was deemed sufficient to power the statistical analysis given its representativeness of the national patient population. continuous variables were presented as means and standard deviations or medians and interquartile ranges (iqr) as appropriate, and the categorical variables were presented as counts and percentages. in light that no random sampling was conducted, all statistical analyses were descriptive and no p values would be presented for the statistical comparisons except for the cox proportional hazards regression model. cox proportional hazards regression models were applied to determine the potential risk factors associated with the composite endpoints, with the hazards ratio (hr) and 95% confidence interval (95%ci) being reported. our findings indicated that the statistical assumption of proportional hazards analysis was not violated. moreover, cox regression model was considered more appropriate than logistic regression model because it has taken into account the potential impact of the various duration of follow-up from individual patients. the age and smoking status were adjusted for in the proportional hazards regression model because they have been recognized as the risk factors of comorbidities even in the general population. the smoking status was stratified as current smokers, ex-smokers and never smokers in the regression models. the national health commission has issued 11,791 patients with laboratory-confirmed covid-19 in china as of january 31 st , 2020. at this time point for data cut-off, our database has included 1,590 cases from 575 hospitals in 31 province/autonomous regions/provincial municipalities (see online supplement for details). of these 1,590 cases, the mean age was 48.9 years. 686 patients (42.7%) were females. 647 (40.7%) patients were managed inside hubei province, and 1,334 (83.9%) patients had a contact history of wuhan city. the most common symptom was fever on or after hospitalization (88.0%), followed by dry cough (70.2%). fatigue (42.8%) and productive cough (36.0%) were less common. at least one abnormal chest ct manifestation (including ground-glass opacities, pulmonary infiltrates and interstitial disorders) was identified in more than 70% of patients. severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints during the study ( table 1) . overall, the median follow-up duration was 10 days (interquartile range: 8, 14) . of the 1,590 cases, 399 (25.1%) reported having at least one comorbidity. the prevalence of specific we have further identified 130 (8.2%) patients who reported having two or more comorbidities. two or more comorbidities were more commonly seen in severe cases than in non-severe cases (40.0% vs. 29.4%). patients with two or more comorbidities were older (mean: 66.2 vs. 58.2 years), were more likely to have shortness of breath (55.4% vs. 34.1%), nausea or vomiting (11.8% vs. 9.7%), unconsciousness (5.1% vs. 1.3%) and less abnormal chest x-ray (20.8% vs. 23.4%) compared with patients who had single comorbidity ( table 2) . non-severe cases. furthermore, comorbidities were more common patients treated in hubei province as compared with those managed outside hubei province as well as patients with an exposure history of wuhan as compared with those without ( table 3) . overall, 131 patients (8.3%) reached to the composite endpoints during the study. 50 patients (3.1%) died, 99 patients (6.2%) were admitted to the icu and 50 patients (3.1%) received invasive ventilation. the composite endpoint was documented in 77 (19.3%) of patients who had at least one comorbidity as opposed to 54 (4.5%) patients without comorbidities. this figure was 37 cases (28.5%) in patients who had two or more comorbidities. significantly more patients with hypertension (19.7% vs. 5.9%), cardiovascular diseases (22.0% vs. 7.7%), cerebrovascular diseases (33.3% vs. 7.8%), diabetes (23.8% vs. 6.8%), copd (50.0% vs. 7.6%), chronic kidney diseases (28.6% vs. 8.0%) and malignancy (38.9% vs. 7.9%) reached to the composite endpoints compared with those without ( table 3) . patients with two or more comorbidities had significantly escalated risks of reaching to the composite endpoint compared with those who had a single comorbidity, and even more so as compared with those without (all p<0.05, figure 1 ). after adjusting for age and smoking status, patients with copd (hr 2.68, 95%ci 1.42-5.05), diabetes (hr 1.59, 95%ci 1.03-2.45), hypertension (hr 1.58, 95%ci 1.07-2.32) and malignancy (hr 3.50, 95%ci 1.60-7.64) were more likely to reach to the composite endpoints than those without (figure 2) . results of unadjusted analysis was presented in table e1 -2. overall, findings of unadjusted and adjusted analysis were not materially altered. as compared with patients without comorbidity, the hr (95%ci) was 1.79 (95%ci 1.16-2.77) among patients with at least one comorbidity and 2.59 (95%ci 1.61-4.17) among patients with two or more comorbidities (figure 2 ). subgroup analysis by stratifying patients according to their age (<65 years vs. ≥65 years) did not reveal substantial difference in the strength of associations between the number of comorbidities and mortality of covid-19 (table e3 ). our study is the first nationwide investigation that systematically evaluates the impact of comorbidities on the clinical characteristics and prognosis in patients with covid-19 in china. circulatory and endocrine comorbidities were common among patients with covid-19. patients with at least one comorbidity, or more even so, were associated with poor clinical outcomes. these findings have provided further objective evidence, with a large sample size and extensive coverage of the geographic regions across china, to take into account baseline comorbid diseases in the comprehensive risk assessment of prognosis among patients with covid-19 on hospital admission. overall, our findings have echoed the recently published studies in terms of the commonness of comorbidities in patients with covid-19 [3] [4] [5] [6] [7] . despite considerable variations in the proportion in individual studies due to the limited sample size and the region where patients were managed, circulatory diseases (including hypertension and coronary heart diseases) remained the most common category of comorbidity [3] [4] [5] [6] [7] . apart from circulatory diseases, endocrine diseases such as diabetes were also common in patients with covid-19. notwithstanding the commonness of circulatory and endocrine comorbidities, patients with covid-19 rarely reported as having comorbid respiratory diseases (particularly copd). the reasons underlying this observation have been scant, but could have arisen from the lack of awareness and the lack of spirometric testing in community settings that collectively contributed to the under-diagnosis of respiratory diseases [33] . it should be stressed that the observed frequency of comorbidity may also reflect the transmission dynamics within particular age groups, case detection or testing practices or hospital admission policies during the early phases of the epidemic. consistent with recent reports [3] [4] [5] [6] [7] , the percentage of patients with comorbid renal disease and malignancy was relatively low. our findings have therefore added to the existing literature the spectrum of comorbidities in patients with covid-19 based on the larger sample sizes and representativeness of the whole patient population in china. a number of existing literature reports have documented the escalated risks of poorer clinical outcomes in patients with avian influenza [14] [15] [16] [17] [18] , sars-cov [19] and mers-cov infections [20] [21] [22] [23] [24] [25] [26] [27] [28] . the most common comorbidities associated with poorer prognosis included diabetes [25, 29] , hypertension [28], respiratory diseases [19, 28] , cardiac diseases [19, 28] , pregnancy [16] , renal diseases [28] and malignancy [19] . our findings suggested that, similar with other severe acute respiratory outbreaks, comorbidities such as copd, diabetes, hypertension and malignancy predisposed to adverse clinical outcomes in patients with covid-19. the strength of association between different comorbidities and the prognosis, however, was less consistent when compared with the literature reports [16, 19, 25, 28] . for instance, the risk between cardiac diseases and poor clinical outcomes of influenza, sars-cov or mers-cov infections was inconclusive [16, 19, 25, 28] . except for diabetes, no other comorbidities were identified to be the predictors of poor clinical outcomes in patients with mers-cov infections [25] . few studies, however, have explored the it has been well accepted that some comorbidities frequently co-exist. for instance, diabetes [35] and copd [36] frequently co-exist with hypertension or coronary heart diseases. therefore, patients with co-existing comorbidities are more likely to have poorer baseline well-being. importantly, we have verified the significantly escalated risk of poor prognosis in patients with two or more comorbidities as compared with those who had no or only a single comorbidity. our findings implied that both the category and number of comorbidities should be taken into account when predicting the prognosis in patients with covid-19. our findings suggested that patients with comorbidities had greater disease severity compared with those without. furthermore, a greater number of comorbidities correlated with greater disease severity of covid-19. the proper triage of patients should be implemented by carefully inquiring the medical history because this will help identify patients who would be more likely to develop serious adverse outcomes of covid-19. moreover, better protection should be given to the patients with coivd-19 who had comorbidities upon confirmation of the diagnosis. a main limitation was the self-report of comorbidities on admission. under-reporting of comorbidities, which could have stemmed from the lack of awareness and/or the lack of diagnostic testing, might contribute to the underestimation of the true strength of association with the clinical prognosis. under-reporting of comorbidities could also lead to over-estimation of strength of association with adverse outcome. however, significant under-reporting was unlikely because the spectrum of our report was largely consistent with existing literature [3] [4] [5] [6] [7] and all patients were subject to a thorough history taking after hospital admission. the relatively low age might help explain the low prevalence of copd in our cohort. moreover, the duration of follow-up was relatively short and some patients remained in the hospital as of the time of writing. more studies that explore the associations in a sufficiently long time frame are warranted. caution should be exercised when extrapolating our findings to other countries where there are outbreaks of covid-19 since the prevalence of comorbidities may differ among different countries. therefore, future studies that include an external validation of the results would be desirable. although the temperature and systolic blood pressure differed between some subgroups, they were unlikely to be clinically relevant. finally, because of the rapid evolving outbreak globally, ongoing studies with the inclusion of more patients would be needed to increase the statistical power and lend support to subgroup analyses stratified by the specific comorbidities (i.e. copd) and their association with the risk of death. data are mean ± standard deviation, n/n (%), where n is the total number of patients with available data. copd=chronic obstructive pulmonary disease. icu = intensive care unit. data are mean ± standard deviation, n/n (%), where n is the total number of patients with available data. copd=chronic obstructive pulmonary disease. icu = intensive care unit data are mean ± standard deviation, n/n (%), where n is the total number of patients with available data. copd=chronic obstructive pulmonary disease. icu = intensive care unit cox proportional hazard regression models were applied to determine the potential risk factors associated with the composite endpoints, with the hazards ratio (hr) and 95% confidence interval (95%ci) being reported. shown in the figure are the hazards ratio (hr) and the 95% confidence interval (95%ci) for the risk factors associated with the composite endpoints (admission to intensive care unit, invasive ventilation, or death). the comorbidities were classified according to the organ systems as well as the number. the scale bar indicates the hr. cox proportional hazard regression models were applied to determine the potential risk factors associated with the composite endpoints, with the hazards ratio (hr) and 95% confidence interval (95%ci) being reported. the model has been adjusted with age and smoking status a b comorbidity and its impact on 1,590 patients with covid-19 in china: a nationwide analysis world health organization. novel coronavirus (2019-ncov) situation reports clinical features of patients with 2019 novel coronavirus in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province clinical findings in a group of patients infected with the 2019 novel coronavirus (sars-cov-2) outside of wuhan, china: retrospective case studies a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster high-resolution ct features of 17 cases of corona virus disease 2019 in sichuan province, china the clinical dynamics of 18 cases of covid-19 outside of wuhan, china epidemiological characteristics of 2019-ncov infections in shaanxi clinical characteristics of coronavirus disease 2019 in china clinical findings in 111 cases of influenza a (h7n9) virus infection association of age and comorbidity on 2009 influenza a pandemic h1n1-related intensive care unit stay in massachusetts the burden of influenza complications in different high-risk groups differences in the epidemiological characteristics and clinical outcomes of pandemic (h1n1) 2009 influenza, compared with seasonal influenza risk factors associated with severe outcomes in adult hospitalized patients according to influenza type and subtype effect of vaccination, comorbidities and age on mortality and severe disease associated with influenza during the season 2016-2017 in a spanish tertiary hospital clinical features and short-term outcomes of 144 patients with sars in the greater toronto area prevalence of comorbidities in cases of middle east respiratory syndrome coronavirus: a retrospective study prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov) risk factors for fatal middle east respiratory syndrome coronavirus infections in saudi arabia: analysis of the who line list diabetes mellitus, hypertension, and death among 32 patients with mers-cov infection, saudi arabia impact of comorbidity on fatality rate of patients with middle east respiratory syndrome a comparative study of clinical presentation and risk factors for adverse outcome in patients hospitalised with acute respiratory disease due to mers coronavirus or other causes chongqing yunyang county people's hospital, ankang central hospital, chenzhou second people's hospital, datong fourth people's hospital, dengzhou people's hospital, fengjie people's hospital, foshan first people's hospital, fuyang second people's hospital, gongyi people's hospital, guangshan people's hospital, guoyao dongfeng general hospital, hainan people's hospital, the second affiliated hospital of hainan medical college, the first people's hospital of xiaoshan district, hangzhou, huaihua first people's hospital, jiashan first people's hospital, lu'an people's hospital, affiliated hospital of qingdao university, qingyuan people's hospital, quanzhou county people's hospital, rizhao people's hospital, shaodong people's hospital, shiyan xiyuan hospital, tongling people's hospital, wenzhou people's hospital, wenzhou central hospital, the second affiliated hospital of wenzhou medical university, wuxi fifth people's hospital zhijiang people's hospital, people's hospital of dianjiang county, chongqing, chongqing jiulongpo first people's hospital, chongqing shizhu tujia autonomous county people's hospital, the first people's hospital of wanzhou district, chongqing, yongchuan hospital affiliated to chongqing medical university, anguo hospital, the third hospital of peking university, peking university shenzhen hospital , boluo people's hospital, changde lixian people's hospital, changde second people's hospital, chenzhou central hospital, chengjiang people's hospital, dalian central hospital, danzhou people's hospital, dengzhou central hospital hangzhou first people's hospital, hangzhou lin'an district people's hospital, nanpi county hospital of traditional chinese medicine of hebei province, henan people's hospital, hefeng county central hospital, hohhot first hospital, huludao central hospital, the first affiliated hospital of hunan medical college, shenzhen union hospital of huazhong university of science and technology, huaibei people's hospital, huangshi second hospital, huangchuan people's hospital jiangyou infectious diseases hospital, jieyang people's hospital, jinhua central hospital, jinzhong pingyao people's hospital, jingjiang people's hospital, the second affiliated hospital of kunming medical university, laifeng county central hospital, yueqing people's hospital, lijiang people's hospital, lixin people's hospital, the fourth people's hospital of lianyungang, linqu county people's hospital xuanwu hospital of capital medical university, sichuan mianyang 404 hospital, sixian hospital of traditional chinese medicine, suihua first hospital, suiping county people's hospital, tianjin fourth central hospital, tianjin haihe hospital, tiantai county people's hospital, tongchuan mining bureau central hospital, tongren people's hospital, weihai central hospital, the first affiliated hospital of wenzhou medical university, wuzhou third people's hospital, armed police hubei provincial general team hospital, xixian people's hospital, longshan county people's the first affiliated hospital of xinjiang medical university, xinmi hospital of traditional chinese medicine, xinxiang county people's hospital, xinye people's changsha eighth hospital, changsha first people's hospital, 921st hospital of the joint service support force of the chinese people's liberation army, central theater general hospital of the chinese people's liberation army, the first affiliated hospital of china medical university, the third affiliated hospital of zhongshan university, zhongshan second people's hospital, chongqing chengkou people's hospital, chongqing hechuan district people's hospital, chongqing red cross hospital, zhoushan women's and children's hospital, zhoukou infectious diseases hospital, zhuzhou first people's hospital, zhumadian central hospital, anlong people's hospital, anxi county hospital, anyang fifth people's hospital, anyang people's hospital, anyuan people's hospital, badong county ethnic hospital, wuyuan county people's hospital of bayannur city, baise people's hospital, the first affiliated hospital of bengbu medical college, baoding first central hospital, changping district hospital of beijing municipality, changping district hospital of traditional chinese and western medicine of beijing chizhou people's hospital, chongxin county people's hospital, chongyi people's hospital, affiliated hospital of north sichuan medical college, dazhou central hospital, dali first people's hospital, the second affiliated hospital of dalian medical university, the first affiliated hospital of dalian medical university, danyang people's hospital, daocheng people's hospital, deqing people's hospital, dezhou second people's hospital, dezhou people's hospital, dezhou qingyun people's hospital fuzhou fifth people's hospital, fuzhou dongxiang district people's hospital, fuyang district first people's hospital, ganzhou longnan county people's hospital, gaolan county people's hospital, gongcheng yao autonomous county people's hospital, gushi people's hospital, guang'an people's hospital, guangdong hospital of traditional chinese medicine, guangzhou eighth people's hospital, guangzhou 12th people's hospital, shenzhen hospital of guangzhou university of traditional chinese medicine, people's hospital of guiding county, hanjiang hospital of sinopharm, harbin acheng district people's hospital, nangang district people's hospital of harbin, the first affiliated hospital of harbin medical university, haikou people's hospital, hainan west central hospital, handan sixth hospital, handan central hospital, hanshan people's hospital, hangzhou dingqiao hospital, the third people's hospital of yuhang district, hangzhou, the first people's hospital of yuhang district, hangzhou, minzhou people's hospital, hefei sixth people's hospital (hefei infectious diseases hospital), he xian memorial hospital, hebei chest hospital, hechi people's hospital, hejin people's hospital, the first affiliated hospital of henan university of science and technology, zhangye people's hospital affiliated to hexi university, heyuan people's hospital, heze municipal hospital, heilongjiang provincial hospital , south yunnan central hospital of honghe prefecture, hulunbuir manzhouli hospital, hunan youxian people's hospital, the first affiliated hospital of hunan university of traditional chinese medicine, china resources wisco general hospital, huaihua chenxi county people's hospital, huai'an fourth people's hospital, huainan mashan infectious disease hospital, huangshan people's hospital, huangshi fifth hospital, huichang people's hospital, huining county people's hospital, huizhou first people's hospital, jixi people's hospital, qianan county people's hospital of jilin province, jinan fourth people's hospital, jining second people's hospital, affiliated hospital of jining medical college laixi people's hospital, the second hospital of lanzhou university, lancang second people's hospital, leping people's hospital, leshan people's hospital, lengshuijiang people's lianjiang county hospital, the first people's hospital of lianyungang, liaoning chaoyang disease control center hospital, liaocheng people's hospital, linshui people's hospital key: cord-012010-5h2ox3hu authors: bos, lieuwe d.j.; sinha, pratik; dickson, robert p. title: response to “covid-19 conundrum: clinical phenotyping based on pathophysiology as a promising approach to guide therapy in a novel illness” and “strengthening the foundation of the house of cards by phenotyping on the fly” and “covid-19 phenotypes: leading or misleading?” date: 2020-08-03 journal: eur respir j doi: 10.1183/13993003.02756-2020 sha: doc_id: 12010 cord_uid: 5h2ox3hu we argue that phenotyping of covid-19 related ards should be done using careful, data-driven approaches. in their letter, drs. cherian et al. take issue with our interpretation of the respiratory physiology of covid-19, arguing that it is based merely on "small cohort studies," instead arguing that "a high proportion of mechanically ventilated covid-19 patients exhibit near-normal lung compliance." [1] yet the low respiratory compliance of covid19 patients has now been extensively demonstrated by studies totaling more than 800 covid-19 patients [2] [3] [4] [5] [6] [7] [8] , including a direct comparison with non-covid ards patients that revealed no difference in respiratory compliance. [8] in contrast, the three case series cited by the correspondents in support of their claim comprise cohorts of, respectively, 16, 10 and 26 patients [9] [10] [11] . further, even these case series report average respiratory compliance in covid-19 of 40-45 ml/cmh 2 o, which is in fact abnormal and far from "near-normal compliance". [12, 13] as an informative comparison, the anzics cohort of ards patients used to derive the berlin definition of ards had an average respiratory compliance of 40 ± 15 ml/cmh 2 o. [14] we thus find no evidence in the authors' citations (or elsewhere) to support their empirical claim that many or most covid-19 patients present with "normal" or "near-normal" respiratory compliance. drs. cherian et al. also assume a temporal progression from "early" covid-19 physiology (characterized by normal respiratory compliance) to "late" physiology (characterized by impaired respiratory compliance). yet three published studies comprising nearly 350 mechanically ventilated covid-19 patients have reported serial measurements of respiratory compliance [2, 4, 7] , and none has shown any temporal trend towards decreased compliance in the days following initiation of mechanical ventilation. further, a recent report from haudebourg et al. demonstrated no correlation between duration of symptoms and respiratory compliance in covid-19 patients ( figure 1a ) [8] . we have since validated this observation using our own clinical data ( figure 1b ). figure 1c , gattinoni et al. recently published their own data countering these findings [15] . importantly, when data from all three cohorts are combined and analysed together, no temporal trend is present (p=0.50, r 2 =0.005). closer inspection reveals that the purported correlation in one of the cohorts is entirely attributable to two patients with low respiratory compliance and more than three weeks of symptoms, a duration of disease irrelevant to considerations of acute pathogenesis and rarely 2) the instability of statistical inferences using small, single variable, data sources; and 3) the predictable correction of initial human intuitions when more data emerge. a final, under-appreciated and unmeasurable pitfall of premature phenotyping raised in our editorial, and one that the multitude of publications addressing these purported phenotypes are substantiating, is the opportunity cost to research resources caused by high-profile yet unsupported speculation. this factor is all the more pertinent in the face of an unforgiving pandemic in which clinical icu workload is highly demanding and clinical research is a zero-sum game. further, clinicians have even less time than usual to critically evaluate scientific literature. therefore, it is incumbent as clinician-scientists that whilst our data gathering may be agile and creative, its interpretation should be cautious and deliberate. while we agree with drs. cherian regarding the potential pathophysiologic importance of endothelial injury in covid-19, the data at hand are simply insufficient to declare if this aspect of pathogenesis is a central mediator of disease progression and lung injury in covid-19. for example, it is worth noting that while endothelial injury has been described in post-mortem histopathological evaluations, it is not ubiquitous. epithelial injury and diffuse alveolar damage, however, are. [16, 17] our editorial did not take a position on the pathophysiology of covid-19, nor do we dispute the need to identify more homogenous biological pathways. frankly, we do not believe in "typical ards," as the syndrome encompasses diverse etiologic pathways with only partially intersecting clinical and histopathological "bottlenecks." we are merely arguing that the currently postulated phenotypes are unconvincing, and insufficient to justify a widespread change in clinical management (as proposed by the correspondents). in his response to our editorial, dr. rajendram reveals a curious misinterpretation of our editorial: "thus, whilst the net effect of the ardsnet protocol is beneficial at the level of the study population, theoretically, it may harm select patients… contrary to the opinions of the surviving sepsis campaign, and bos and colleagues, the ardsnet protocol is not a panacea." putting aside the wishful thinking of a supportive intervention functioning as a "panacea" for a condition with persistent mortality of 30-40%, the correspondent (along with drs. cherian et al.) seems to think that we dispute the heterogeneity of ards, and advocate for a "one-size-fits-all" approach to its clinical management. quite the opposite: we strongly believe that ards represents a pathophysiologically heterogenous syndrome and have argued the same for covid-19 related ards. [18] until well-defined biological subgroups are identified, the ceiling of effective interventions is likely to remain supportive. we also strongly suspect there are likely considerable biological differences between covid-19 and non-covid-19 ards. [19] where we differ with our correspondents, we suspect, is in our lack of confidence that clinicians can identify meaningful subphenotypes using underpowered cohorts and bedside intuitions and then recommend effective interventions without testing them in a scientific study. this was the central point of our editorial and is illustrated with two examples in this response (the "normal compliance" of covid-19 and its purported temporal worsening). as a contrast, the correspondents may consider recent pre-covid-19 research identifying hypoinflammatory and hyperinflammatory subphenotypes in ards (to which we have contributed). [9, 20] these ards subphenotypes were derived using unsupervised clustering of more than 3,000 rigorously adjudicated and extensively characterized patients. [21] the ards subphenotypes have been consistently validated across multiple cohorts and research groups [22] [23] [24] . in contrast, the high-compliance "l" phenotype, for the reasons detailed above, seems inherently unstable. whereas it was initially described as constituting 70-80% of covid-19 ards cases [20] , it now is defined as a rarely encountered extreme of a one-dimensional physiologic continuum. [25] in comparison, the previously identified ards subphenotypes represent distinct clinical "clusters" of patients, informed by measurements across organ systems and physiologic domains in secondary analyses of well curated cohorts of patients. [21] yet despite this robustness, we would recommend that any therapeutic interventions for which benefits have been observed in these hyperinflammatory and hypoinflammatory phenotypes require testing in prospective trials before they are implemented into clinical practice, as they were derived using secondary analyses. the objective of our editorial was to challenge the subclassification of patients with covid-19 that frequently occurred in the early weeks of the pandemic based on "discussions" and "close observations" before they became entrenched dogmas. [1] an unintended consequence of such a challenge may be that it evokes negative emotions with the reader, especially in these troubling and polarising times. we were, therefore, saddened to learn that our editorial caused irritation among gattinoni et al. [25] . while we vehemently disagree that "observations of bos and colleagues are expressed with a tone which goes beyond healthy and reasonable scientific debate," we acknowledge that our essay was interpreted as such by the correspondents and that is regrettable. we would like to clarify that the particular quoted sentences from our editorial that prompted the authors' irritation and concern were aimed at premature phenotyping in general. it is an unfortunate misunderstanding that the authors assumed we were speaking directly and exclusively about them. for the reasons outlined above, however, we stand by our editorial. drs. gattinoni et al. state that "the 'l & h' phenotypes were not intended to be tightly descriptive nor mutually exclusive 'bins' into which each patient falls," yet this is what is usually implied by disease "subphenotypes" or "endotypes". [26] as described in our editorial, for phenotypes to be purposeful, they should be discrete, robust, generalizable, easily-identifiable, and ideally, have an actionable intervention. seemingly, almost none of these conditions are met in the current case. as an illustration, the problem with loosely-defined phenotypes, as described by the correspondents, emerges when we try to precisely identify, at the bedside, who the patients are that the correspondents "hoped to help prevent use of high peep when there is no benefit, and equally important, to avoid maintaining low pressures when higher pressures can be beneficial." it is difficult to conceive how these phenotypes would be identifiable using quantifiable variables and when precisely to intervene, given that the authors themselves concede that these phenotypes are temporally dynamic, neither mutually-exclusive nor discrete, and that "usually, there is overlap". we agree entirely with the correspondents that ventilator management should be individualized to each patient's physiology, and have never argued otherwise. in the theoretical "limit case" of a patient with normal lung compliance and minimal lung recruitability, we would similarly discourage use of high levels of peep, as surely would most practicing intensivists. we merely disagree with the correspondent's conclusions regarding the prevalence of these theoretical patients based on data from 16 patients [20] , as well as their subsequent recommendations to deviate from safe ventilatory practice for covid-19 patients based on this limited data. [27] as catalogued above, the available data show that this purported "phenotype" is rarely encountered in covid-19 ards. unexpectedly, the correspondents request evidence from us that their efforts at phenotyping have caused harm. basic scientific convention, however, mandates that before they implore the field to deviate from usual practice, the burden is rather on them to demonstrate the benefits and safety of their proposed phenotyping scheme and linked interventions using robust scientific studies. thankfully for our patients, that is how best medical science works -primum non nocere. putting aside the complete absence of efficacy data, the validity of the physiological basis for their proposed interventions for these phenotypes has also been recently questioned. [28, 29] we hope our response clarifies for the correspondents and readers that we in no way dispute the underlying heterogeneity of ards, nor the uniqueness of covid-19, nor the need for patient-tailored therapy; indeed, much of our research is focused on attaining this. we merely insist that phenotyping be done using careful, data-driven approaches. to paraphrase dr. rajendram, rather than strengthening a house of cards, we should instead aspire to build a foundation out of sturdier, more lasting materials: in this case agile, yet robust, scientific studies using a responsible, data-informed approach. at this stage of the pandemic, sufficient data points exist to equip us to advance from anecdotebased intuitions to evidence-informed science. covid-19 conundrum: clinical phenotyping based on pathophysiology as a promising approach to guide therapy in a novel illness covid-19 in critically ill patients in the seattle region -case series subphenotyping ards in covid-19 patients: consequences for ventilator management respiratory pathophysiology of mechanically ventilated patients with covid-19: a cohort study icu and ventilator mortality among critically ill adults with coronavirus disease epidemiology, clinical course, and outcomes of critically ill adults with covid-19 in new york city: a prospective cohort study respiratory mechanics and gas exchange in covid-19 associated respiratory failure respiratory mechanics of covid-19 vs. non-covid-19 associated acute respiratory distress syndrome does not lead to a "typical" acute respiratory distress syndrome potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease clinical phenotypes of sars-cov-2: implications for clinicians and researchers reference values for dynamic and static pulmonary compliance in men pulmonary mechanics during general anaesthesia. the influence of mechanical irritation on the airway acute respiratory distress syndrome: the berlin definition postmortem examination of patients with covid-19 pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 covid-19 related acute respiratory distress syndrome: not so atypical is a "cytokine storm" relevant to covid-19? covid-19 pneumonia: different respiratory treatments for different phenotypes? subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis stability of ards subphenotypes over time in two randomised controlled trials covid-19 phenotypes: leading or misleading? toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design management of covid-19 respiratory distress covid-19-associated acute respiratory distress syndrome: is a different approach to management warranted? caution about early intubation and mechanical ventilation in covid-19 key: cord-335465-sckfkciz authors: gupta, rishi k.; marks, michael; samuels, thomas h. a.; luintel, akish; rampling, tommy; chowdhury, humayra; quartagno, matteo; nair, arjun; lipman, marc; abubakar, ibrahim; van smeden, maarten; wong, wai keong; williams, bryan; noursadeghi, mahdad title: systematic evaluation and external validation of 22 prognostic models among hospitalised adults with covid-19: an observational cohort study date: 2020-09-25 journal: eur respir j doi: 10.1183/13993003.03498-2020 sha: doc_id: 335465 cord_uid: sckfkciz background: the number of proposed prognostic models for covid-19 is growing rapidly, but it is unknown whether any are suitable for widespread clinical implementation. methods: we independently externally validated the performance candidate prognostic models, identified through a living systematic review, among consecutive adults admitted to hospital with a final diagnosis of covid-19. we reconstructed candidate models as per original descriptions and evaluated performance for their original intended outcomes using predictors measured at admission. we assessed discrimination, calibration and net benefit, compared to the default strategies of treating all and no patients, and against the most discriminating predictor in univariable analyses. results: we tested 22 candidate prognostic models among 411 participants with covid-19, of whom 180 (43.8%) and 115 (28.0%) met the endpoints of clinical deterioration and mortality, respectively. highest areas under receiver operating characteristic (auroc) curves were achieved by the news2 score for prediction of deterioration over 24 h (0.78; 95% ci 0.73–0.83), and a novel model for prediction of deterioration <14 days from admission (0.78; 0.74–0.82). the most discriminating univariable predictors were admission oxygen saturation on room air for in-hospital deterioration (auroc 0.76; 0.71–0.81), and age for in-hospital mortality (auroc 0.76; 0.71–0.81). no prognostic model demonstrated consistently higher net benefit than these univariable predictors, across a range of threshold probabilities. conclusions: admission oxygen saturation on room air and patient age are strong predictors of deterioration and mortality among hospitalised adults with covid-19, respectively. none of the prognostic models evaluated here offered incremental value for patient stratification to these univariable predictors. coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (sars-cov-2), causes a spectrum of disease ranging from asymptomatic infection to critical illness. among people admitted to hospital, covid-19 has reported mortality of 21-33%, with 14-17% requiring admission to high dependency or intensive care units (icu) [1] [2] [3] [4] . exponential surges in transmission of sars-cov-2, coupled with the severity of disease among a subset of those affected, pose major challenges to health services by threatening to overwhelm resource capacity [5] . rapid and effective triage at the point of presentation to hospital is therefore required to facilitate adequate allocation of resources and to ensure that patients at higher risk of deterioration are managed and monitored appropriately. importantly, prognostic models may have additional value in patient stratification for emerging drug therapies [6, 7] . as a result, there has been global interest in development of prediction models for covid-19 [8] . these include models aiming to predict a diagnosis of covid-19, and prognostic models, aiming to predict disease outcomes. at the time of writing, a living systematic review has already catalogued 145 diagnostic or prognostic models for covid-19 [8] . critical appraisal of these models using quality assessment tools developed specifically for prediction modelling studies suggests that the candidate models are poorly reported, at high risk of bias and over-estimation of their reported performance [8, 9] . however, independent evaluation of candidate prognostic models in unselected datasets has been lacking. it therefore remains unclear how well these proposed models perform in practice, or whether any are suitable for widespread clinical implementation. we aimed to address this knowledge gap by systematically evaluating the performance of proposed prognostic models, among consecutive patients hospitalised with a final diagnosis of covid-19 at a single centre, when using predictors measured at the point of hospital admission. we used a published living systematic review to identify all candidate prognostic models for covid19 indexed in pubmed, embase, arxiv, medrxiv, or biorxiv until 5 th may 2020, regardless of underlying study quality [8] . we included models that aim to predict clinical deterioration or mortality among patients with covid-19. we also included prognostic scores commonly used in clinical practice [10] [11] [12] , but not specifically developed for covid-19 patients, since these models may also be considered for use by clinicians to aid risk-stratification for patients with covid19 . for each candidate model identified, we extracted predictor variables, outcome definitions (including time horizons), modelling approaches, and final model parameters from original publications, and contacted authors for additional information where required. we excluded scores where the underlying model parameters were not publicly available, since we were unable to reconstruct them, along with models for which included predictors were not available in our dataset. the latter included models that require computed tomography imaging or arterial blood gas sampling, since these investigations were not routinely performed among unselected patients with covid-19 at our centre. our study is reported in accordance with transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (tripod) guidance for external validation studies [13] investigations were routinely performed. data were collected by direct extraction from electronic health records, complemented by manual curation. variables of interest in the dataset included: demographics (age, gender, ethnicity), comorbidities (identified through manual record review), clinical observations, laboratory measurements, radiology reports, and clinical outcomes. each chest radiograph was reported by a single radiologist, who was provided with a short summary of the indication for the investigation at the time of request, reflecting routine clinical conditions. chest radiographs were classified using british society of thoracic imaging criteria, and using a modified version of the radiographic assessment of lung edema (rale) score [14, 15] . for each predictor, measurements were recorded as part of routine clinical care. where serial measurements were available, we included the measurement taken closest to the time of presentation to hospital, with a maximum interval between presentation and measurement of 24 hours. for models that used icu admission or death, or progression to 'severe' covid-19 or death, as composite endpoints, we used a composite 'clinical deterioration' endpoint as the primary outcome. we defined clinical deterioration as initiation of ventilatory support (continuous positive airway pressure, non-invasive ventilation, high flow nasal cannula oxygen, invasive mechanical ventilation or extra-corporeal membrane oxygenation) or death, equivalent to world health organization clinical progression scale  6 [16] . this definition does not include standard oxygen therapy. we did not apply any temporal limits on (a) the minimum duration of respiratory support; or (b) the interval between presentation to hospital and the outcome. the rationale for this composite outcome is to make the endpoint more generalisable between centres, since hospital respiratory management algorithms may vary substantially. defining the outcome based on level of support, as opposed to ward setting, also ensures that it is appropriate in the context of a pandemic, when treatments that would usually only be considered in an icu setting may be administered in other environments due to resource constraints. where models specified their intended time horizon in their original description, we used this timepoint in the primary analysis, in order to ensure unbiased assessment of model calibration. where the intended time horizon was not specified, we assessed the model to predict in-hospital deterioration or mortality, as appropriate. all deterioration and mortality events were included, regardless of their clinical aetiology. participants were followed-up clinically to the point of discharge from hospital. we extended follow-up beyond discharge by cross-checking nhs spine records to identify reported deaths post-discharge, thus ensuring >30 days' follow-up for all participants. for each prognostic model included in the analyses, we reconstructed the model according to authors' original descriptions, and sought to evaluate the model discrimination and calibration performance against our approximation of their original intended endpoint. for models that provide online risk calculator tools, we validated our reconstructed models against original authors' models, by cross-checking our predictions against those generated by the web-based tools for a random subset of participants. for all models, we assessed discrimination by quantifying the area under the receiver operating characteristic curve (auroc) [17] . for models that provided outcome probability scores, we assessed calibration by visualising calibration of predicted vs. observed risk using loess-smoothed plots, and by quantifying calibration slopes and calibration-in-the-large (citl citl, but allowed us to examine the calibration slope in our dataset. we also assessed the discrimination of each candidate model for standardised outcomes of: (a) our composite endpoint of clinical deterioration; and (b) mortality, across a range of pre-specified time horizons from admission (7 days, 14 days, 30 days and any time during hospital admission), by calculating time-dependent aurocs (with cumulative sensitivity and dynamic specificity) [18] . the rationale for this analysis was to harmonise endpoints, in order to facilitate more direct comparisons of discrimination between the candidate models. in order to further benchmark the performance of candidate prognostic models, we then computed aurocs for a limited number of univariable predictors considered to be of highest importance a priori, based on clinical knowledge and existing data, for prediction of our composite endpoints of clinical deterioration and mortality (7 days, 14 days, 30 days and any time during hospital admission). the a priori predictors of interest examined in this analysis were age, clinical frailty scale, oxygen saturation at presentation on room air, c-reactive protein and absolute lymphocyte count [8, 19] . decision curve analysis allows assessment of the clinical utility of candidate models, and is dependent on both model discrimination and calibration [20] . we performed decision curve analyses to quantify the net benefit achieved by each model for predicting the intended endpoint, in order to inform clinical decision making across a range of risk:benefit ratios for an intervention or 'treatment' [20] . in this approach, the risk:benefit ratio is analogous to the cut point for a statistical model above which the intervention would be considered beneficial (deemed the 'threshold probability'). net benefit was calculated as sensitivity × prevalence -(1specificity) × (1prevalence) × w where w is the odds at the threshold probability and the prevalence is the proportion of patients who experienced the outcome [20] . we calculated net benefit across a range of clinically relevant threshold probabilities, ranging from 0 to 0.5, since the risk:benefit ratio may vary for any given intervention (or 'treatment'). we compared the utility of each candidate model against strategies of treating all and no patients, and against the best performing univariable predictor for in-hospital clinical deterioration, or mortality, as appropriate. to ensure that fair, head-to-head net benefit comparisons were made between multivariable probability based models, points score models and univariable predictors, we calibrated each of these to the validation dataset for the purpose of decision curve analysis. probability-based models were recalibrated to the validation data by refitting logistic regression models with the candidate model linear predictor as the sole predictor. we calculated 'delta' net benefit as net benefit when using the index model minus net benefit when: (a) treating all patients; and (b) using most discriminating univariable predictor. decision curve analyses were done using the rmda package in r [21] . we handled missing data using multiple imputation by chained equations [22] , using the mice package in r [23] . all variables and outcomes in the final prognostic models were included in the imputation model to ensure compatibility [22] . a total of 10 imputed datasets were generated; discrimination, calibration and net benefit metrics were pooled using rubin's rules [24] . all analyses were conducted in r (version 3.5.1). we recalculated discrimination and calibration parameters for each candidate model using (a) a complete case analysis (in view of the large amount of missingness for some models); (b) excluding patients without pcr-confirmed sars-cov-2 infection; and (c) excluding patients who met the clinical deterioration outcome within 4 hours of arrival to hospital. we also examined for non-linearity in the a priori univariable predictors using restricted cubic splines, with 3 knots. finally, we estimated optimism for discrimination and calibration parameters for the a priori univariable predictors using bootstrapping (1,000 iterations), using the rms package in r [25] . the pre-specified study protocol was approved by east midlands -nottingham 2 research ethics committee (ref: 20/em/0114; iras: 282900). we identified a total of 37 studies describing prognostic models, of which 19 studies (including 22 unique models) were eligible for inclusion (supplementary figure 1 and table 1 ). of these, 5 models were not specific to covid-19, but were developed as prognostic scores for emergency department attendees [26] , hospitalised patients [12, 27] , people with suspected infection [10] or communityacquired pneumonia [11] , respectively. of the 17 models developed specifically for covid-19, most (10/17) were developed using datasets originating in china. overall, discovery populations included hospitalised patients and were similar to the current validation population with the exception of one study that discovered a model using community data [28] , and another that used simulated data [29] . a total of 13/22 models use points-based scoring systems to derive final model scores, with the remainder using logistic regression modelling approaches to derive probability estimates. a total of 12/22 prognostic models primarily aimed to predict clinical deterioration, while the remaining 10 sought to predict mortality alone. when specified, time horizons for prognosis ranged from 1 to 30 days. candidate prognostic models not included in the current validation study are summarised in supplementary table 1 . during the study period, 521 adults were admitted with a final diagnosis of covid-19, of whom 411 met the eligibility criteria for inclusion (flowchart shown in supplementary figure 2 ). median age of the cohort was 66 years (interquartile range (iqr) 53-79), and the majority were male (252/411; 61.3%). figure 4) . for all models that provide probability scores for either deterioration or mortality, calibration appeared visually poor with evidence of overfitting and either systematic overestimation or underestimation of risk ( figure 1 ). supplementary figure 5 shows associations between prognostic models with pointsbased scores and actual risk. in addition to demonstrating reasonable discrimination, the news2 and curb65 models demonstrated approximately linear associations between scores and actual probability of deterioration at 24 hours and mortality at 30 days, respectively. next, we sought to compare the discrimination of these models for both clinical deterioration and mortality across the range of time horizons, benchmarked against preselected univariable predictors associated with adverse outcomes in covid-19 [8, 19] . we recalculated time-dependent aurocs for each of these outcomes, stratified by time horizon to the outcome ( supplementary figures 6 and 7) . these analyses showed that aurocs generally declined with increasing time horizons. admission oxygen saturation on room air was the strongest predictor of in-hospital deterioration (auroc 0.76; 95% ci 0.71-0.81), while age was the strongest predictor of in-hospital mortality (auroc 0.76; 95% ci 0.71-0.81). we compared net benefit for each prognostic model (for its original intended endpoint) to the strategies of treating all patients, treating no patients, and using the most discriminating univariable predictor for either deterioration (i.e. oxygen saturation on air) or mortality (i.e. patient age) to stratify treatment (supplementary figure 8) . although all prognostic models showed greater net benefit than treating all patients at the higher range of threshold probabilities, none of these models demonstrated consistently greater net benefit than the most discriminating univariable predictor, across the range of threshold probabilities (figure 2 ). recalculation figure 9) . finally, internal validation using bootstrapping showed near zero optimism for discrimination and calibration parameters for the univariable models (supplementary table ) . in this observational cohort study of consecutive adults hospitalised with covid-19, we systematically evaluated the performance of 22 prognostic models for covid-19. these included models developed specifically for covid-19, along with existing scores in routine clinical use prior to the pandemic. for prediction of both clinical deterioration or mortality, aurocs ranged from 0.56-0.78. news2 performed reasonably well for prediction of deterioration over a 24-hour interval, achieving an auroc of 0.78, while the carr 'final' model [31] also had an auroc of 0.78, but tended to systematically underestimate risk. all covid-specific models that derived an outcome probability of either deterioration or mortality showed poor calibration. we found that oxygen saturation (auroc 0.76) and patient age (auroc 0.76) were the most discriminating single variables for prediction of inhospital deterioration and mortality respectively. these predictors have the added advantage that they are immediately available at the point of presentation to hospital. in decision curve analysis, which is dependent upon both model discrimination and calibration, no prognostic model demonstrated clinical utility consistently greater than using these univariable predictors to inform decision-making. while previous studies have largely focused on novel model discovery, or evaluation of a limited number of existing models, this is the first study to our knowledge to evaluate systematically-identified candidate prognostic models for covid-19. we used a comprehensive living systematic review [8] to identify eligible models and sought to reconstruct each model as per the original authors' description. we then evaluated performance against its intended outcome and time horizon, wherever possible, using recommended methods of external validation incorporating assessments of discrimination, calibration and net benefit [17] . moreover, we used a robust approach of electronic health record data capture, supported by manual curation, in order to ensure a high-quality dataset, and inclusion of unselected and consecutive covid-19 cases that met our eligibility criteria. in addition, we used robust outcome measures of mortality and clinical deterioration, aligning with the who clinical progression scale [16] . a weakness of the current study is that it is based on retrospective data from a single centre, and therefore cannot assess between-setting heterogeneity in model performance. second, due to the limitations of routinely collected data, predictor variables were available for varying numbers of participants for each model, with a large proportion of missingness for models requiring lactate dehydrogenase and d-dimer measurements. we therefore performed multiple imputation, in keeping with recommendations for development and validation of multivariable prediction models, in our primary analyses [32] . findings were similar in the complete case sensitivity analysis, thus supporting the robustness of our results. future studies would benefit from standardising data capture and laboratory measurements prospectively to minimise predictor missingness. thirdly, a number of models could not be reconstructed in our data. for some models, this was due the absence of predictors in our dataset, such as those requiring computed tomography imaging, since this is not currently routinely recommended for patients with suspected or confirmed covid-19 [15] . we were also not able to include models for which the parameters were not publicly available. this underscores the need for strict adherence to reporting standards in multivariable prediction models [13] . finally, we used admission data only as predictors in this study, since most prognostic scores are intended to predict outcomes at the point of hospital admission. we note, however, that some scores are designed for dynamic in-patient monitoring, with news2 showing reasonable discrimination for deterioration over a 24-hour interval, as originally intended [27] . future studies may integrate serial data to examine model performance when using such dynamic measurements. despite the vast global interest in the pursuit of prognostic models for covid-19, our findings show that none of the covid-19-specific models evaluated in this study can currently be recommended for routine clinical use. in addition, while some of the evaluated models that are not specific to covid-19 are routinely used and may be of value among in-patients [12, 27] , people with suspected infection [10] or community-acquired pneumonia [11] , none showed greater clinical utility than the strongest univariable predictors among patients with covid-19. our data show that admission oxygen saturation on air is a strong predictor of clinical deterioration and may be evaluated in future studies to stratify in-patient management and for remote community monitoring. we note that all novel prognostic models for covid-19 assessed in the current study were derived from single-centre data. future studies may seek to pool data from multiple centres in order to robustly evaluate the performance of existing and newly emerging models across heterogeneous populations, and develop and validate novel prognostic models, through individual participant data meta-analysis [33] . such an approach would allow assessments of between-study heterogeneity and the likely generalisability of candidate models. it is also imperative that discovery populations are representative of target populations for model implementation, with inclusion of unselected cohorts. moreover, we strongly advocate for transparent reporting in keeping with tripod standards (including modelling approaches, all coefficients and standard errors) along with standardisation of outcomes and time horizons, in order to facilitate ongoing systematic evaluations of model performance and clinical utility [13] . we conclude that baseline oxygen saturation on room air and patient age are strong predictors of deterioration and mortality, respectively. none of the prognostic models evaluated in this study offer incremental value for patient stratification to these univariable predictors when using admission data. therefore, none of the evaluated prognostic models for covid-19 can be recommended for routine clinical implementation. future studies seeking to develop prognostic models for covid-19 should consider integrating multi-centre data in order to increase generalisability of findings, and should ensure benchmarking against existing models and simpler univariable predictors. mews = modified early warning score; qsofa = quick sequential (sepsis-related) organ failure assessment; rems = rapid emergency medicine score; news = national early warning score; tactic = therapeutic study in pre-icu patients admitted with covid-19; avpu = alert / responds to voice / responsive to pain / unresponsive; crp = c-reactive protein; ldh = lactate dehydrogenase; rale = radiographic assessment of lung edema; ards = acute respiratory distress syndrome; icu = intensive care unit; ecmo = extra-corporeal membrane oxygenation. units, unless otherwise specified, are: age in years; respiratory rate in breaths per minute; heart rate in beats per minute; blood pressure in mmhg; temperature in °c; oxygen saturation in %; crp in mg/l; ldh in u/l; neutrophils, lymphocytes, total white cell count and platelets x 10^9/l; d-dimer in ng/ml; creatinine in μmol/l; estimated glomerular filtration rate in ml/min/1.73 m2, albumin in g/l. ^clinician-defined obesity. for each model, performance is evaluated for its original intended outcome, shown in 'primary outcome' column. auroc = area under the receiver operating characteristic curve; ci = confidence interval. for each plot, the blue line represents a loess-smoothed calibration curve from the stacked multiply imputed datasets and rug plots indicate the distribution of data points. no model intercept was available for the caramelo or colombi 'clinical' models; the intercepts for these models were calibrated to the validation dataset, by using the model linear predictors as offset terms. the primary outcome of interest for each model is shown in the plot sub-heading. for each analysis, the endpoint is the original intended outcome and time horizon for the index model. each candidate model and univariable predictor was calibrated to the validation data during analysis to enable fair, head-to-head comparisons. delta net benefit is calculated as net benefit when using the index model minus net benefit when: (1) treating all patients; and (2) using the most discriminating univariable predictor. the most discriminating univariable predictor is admission oxygen saturation (spo2) on room air for deterioration models and patient age for mortality models. delta net benefit is shown with loess-smoothing. black dashed line indicates threshold above which index model has greater net benefit than the comparator. individual decision curves for each candidate model are shown in supplementary figure 8 . for each model, performance is evaluated for an approximation of its original intended outcome, shown in 'primary outcome' column. auroc = area under the receiver operating characteristic curve; ci = confidence interval. score primary outcome auroc (95% ci) calibration slope (95% ci) calibration in the large (95% ci) deterioration (1 day presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the features of 20 133 uk patients in hospital with covid-19 using the isaric who clinical characterisation protocol: prospective observational cohort study critical care utilization for the covid-19 outbreak in lombardy, italy report 17 -clinical characteristics and predictors of outcomes 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data-driven prediction of coronavirus clinical severity consortium n & mc-19 r. development and validation of a survival calculator for hospitalized patients with covid-19 covid-19 for the cmteg for. development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid-19 prediction of the clinical outcome of covid-19 patients using t lymphocyte subsets with 340 cases from wuhan, china: a retrospective cohort study and a web visualization tool clinical decision support tool and rapid point-of-care platform for determining disease severity in patients with covid-19 predicting mortality risk in patients with covid-19 using artificial intelligence to help medical decision-making machine learning-based ct radiomics model for predicting hospital stay in patients with pneumonia associated with sars-cov-2 infection: a multicenter study a machine learning model reveals older age and delayed hospitalization as predictors of mortality in patients with covid-19 evaluating a widely implemented proprietary deterioration index model among hospitalized covid-19 patients machine learning to predict mortality and critical events in covid-19 positive toward a covid-19 score-risk assessments and registry association of radiologic findings with mortality of patients infected with 2019 novel coronavirus in wuhan risk assessment of progression to severe conditions for patients with covid-19 pneumonia: a single-center retrospective study logistic regression carr et al [31] ' carr [47] , and thus were included in the present study. $ no model intercept was available; the intercepts for these models were therefore calibrated to the validation dataset, using the model linear predictors as offset terms.^using oxygen scale 1 for all participants, except for those with target oxygen saturation ranges of 88-92%, e.g. in hypercapnic respiratory failure, when scale 2 is used, as recommended [12] . all candidate models included in a living systematic review were considered at high risk of bias [1] . ards = acute respiratory distress syndrome; icu = intensive care unit; ct = computed tomography. optimism is calculated using bootstrapping with 1,000 iterations. auroc = area under the receiver operating characteristic curve; ci = confidence interval. dxy = somers' delta, which is a measure of agreement between pairs of ordinal variables, ranging from -1 (no agreement) to +1 (complete agreement). dxy key: cord-347046-u764muk6 authors: morice, alyn h. title: correlation and causality: a covid conundrum date: 2020-08-28 journal: eur respir j doi: 10.1183/13993003.03174-2020 sha: doc_id: 347046 cord_uid: u764muk6 i read with interest the two contributions by james chalmers et al. to the 1st july edition of the journal. in a reply to correspondence [1] concerning the ics withdrawal controversy they suggest [2] that alvar agusti succumbs to the fallacy of post hoc, ergo, proctor hoc i.e. a occurred, then b occurred: therefore, a caused b. however, as we know, correlation is not causality. i read with interest the two contributions by james chalmers et al. to the !st july edition of the journal. in a reply to correspondence [1] concerning the ics withdrawal controversy they suggest [2] that alvar agusti succumbs to the fallacy of post hoc, ergo, proctor hoc i.e. a occurred, then b occurred: therefore, a caused b. however, as we know, correlation is not causality. yet, in their original research article [3] lonergan and chalmers perpetrate the same error is in spades. they use the trajectory of deaths from covid-19 from around the world to estimate the consequences of easing lockdown measures. they assume the current fall in the rate of covid-19 related mortality is a consequence of lockdown; but is it? there is much we do not know about the virus, but if it behaves like other coronaviruses then there will be a marked seasonal variation [4] . did europe recover because sumer is icumen in? what we need is a control group. there is one european country where a much lighter application of social measures, well short of full lockdown, is practiced. that is sweden. if we compare by eye the weekly covid-19 related mortality figures from sweden with that of a similarly afflicted country such as the uk then in both countries there is a marked fall as spring turns into summer, albeit a bit slower in sweden (figure) . if the mortality curves have a similar shape despite large differences in social measures adopted then this must infer that such measures can only have had a minor effect on the epidemiology of this phase of the pandemic. it is surely incorrect to then to apply complex statistical modeling to mortality rates from 89 countries whose surety of data collection varies widely. lonergan and chalmers treat the reader to a detailed, and to me at least, indecipherable account of their "simple" modeling and its outcomes. the pitfalls of using such tools in covid-19 research have been highlighted recently [5] the results from the models used to predict the initial onslaught of the virus differed hugely leading to panic buying of ventilators and the creation of overflow (nightingale in the uk) hospitals which were never used. even the best model is prey to the assumptions made in its construction. the belief that we know the contribution that social measure have made to the evolution of the pandemic is wrong and so advising "[our] estimates are incompatible with a return to previous activities post "lockdown." is hubris which may have greater socio-economic and thus clinical consequences than the virus itself. withdrawal of inhaled corticosteroids in copd withdrawal of inhaled corticosteroids in copd estimates of the ongoing need for social distancing and control measures post-"lockdown" from trajectories of covid-19 cases and mortality coronavirus infections: epidemiological, clinical and immunological features and hypotheses wrong but useful -what covid-19 epidemiologic models can and cannot tell us key: cord-352502-vdm55zvq authors: salton, francesco; geri, pietro; confalonieri, marco title: response to: factors limiting the utility of bronchoalveolar lavage in the diagnosis of covid-19 date: 2020-09-17 journal: eur respir j doi: 10.1183/13993003.03383-2020 sha: doc_id: 352502 cord_uid: vdm55zvq we aimed at evaluating not the diagnostic yield of bal in covid-19, but the agreement between negative upper respiratory tract swabs and bal to exclude covid-19, stressing that bal is likely negative if swabs and chest ct are concordantly negative. francesco salton 1 , pietro geri 1 deepak and colleague misreported that bal was negative for sars-cov-2 rrt-pcr in majority of cases, including 38 patients with "strong clinical and radiological suspicion for covid-19". indeed, we reported that, among those patients who underwent chest ct scan, 38 revealed radiological signs compatible with an ongoing viral infection but not necessarily typical features of covid-19. on the contrary, in the only 2 cases of our series in which ct scan showed typical signs of covid-19 infection according to a recently published international consensus statement [2] , bal was positive for sars-cov-2 despite previous negative upper respiratory tract swabs. moreover, we reported that, when chest ct scan was normal, then both upper respiratory tract swabs and bal were rrt-pcr-negative for sars-cov-2. these findings support our main observation that bal is likely to be negative if one or more upper respiratory tract specimens and thoracic imaging are concordantly negative, therefore it should be only reserved for those cases in which a high clinical and radiological suspicion for covid-19 stands despite negative upper respiratory tract swabs. deepak and colleague also deem that our results might imply a high false negative rate of rrt-pcr for sars-cov-2 in bal samples. however, our study aimed at evaluating not the diagnostic yield of bal in covid-19, but the agreement (test concordance) between negative upper respiratory tract swabs and bal to exclude covid-19. this is a fundamental concept that we believe may be of valuable support to clinical practice in times of pandemics, when excessive demands for bal confirmation of repeatedly negative upper respiratory swabs expose operators to a high infectious risk while being clinically futile. in fact, bal has an unquestioned role in the diagnosis of pneumonia when non-invasive methods are not sufficient for an etiologic characterization; however, concerning sars-cov-2, we showed that bal is most likely to be negative if upper respiratory swabs and chest ct are concordantly negative. we obviously agree with deepak and varinder that clinical performance of a diagnostic test varies not only in light of its sensitivity but also of pretest probability, that is affected by several factors among which disease prevalence. nevertheless, it is not possible to calculate a true pretest probability for covid-19 at the moment, as the actual prevalence of sars-cov-2 infection is still not known. [3] finally, deepak and colleague claim insight details about our study population with regard to alternate diagnoses, clinical outcomes and their correlation with rrt-pcr test performance on upper and lower respiratory tract. unfortunately, this is out of the main focus of this study and it would need much more space than allowed by the journal for this manuscript format to be elucidated. the authors have no conflicts of interest to declare. we aimed at evaluating not the diagnostic yield of bal in covid-19, but the agreement between negative upper respiratory tract swabs and bal to exclude covid-19, stressing that bal is likely negative if swabs and chest ct are concordantly negative. limited role for bronchoalveolar lavage to exclude covid-19 after negative upper respiratory tract swabs: a multicenter study radiological society of north america expert consensus statement on reporting chest ct findings related to covid-19. endorsed by the society of thoracic radiology, the american college of radiology, and rsna. radiol. cardiothorac. imaging false negative tests for sars-cov-2 infection -challenges and implications key: cord-349440-jxigsdzh authors: gattinoni, luciano; camporota, luigi; marini, john j. title: covid-19 phenotypes: leading or misleading? date: 2020-07-02 journal: eur respir j doi: 10.1183/13993003.02195-2020 sha: doc_id: 349440 cord_uid: jxigsdzh comment to an editorial where we invite the authors to express with clarity the risks they are referring to and how their argument is furthering the cause of patients and clinicians. we read the editorial by bos et al [1] with a mixture of interest, irritation and serious concern. our interest derives from a simple fact: the debate on terms like 'typical ards' or 'atypical ards' is not just question of semantics, but these terms represent concepts linked to specific clinical, mechanical and radiological criteria, and not merely based on the severity of gas exchange. it should not be a surprise to the authors that different radiological patterns and mechanical characteristics should suggest different ventilatory strategies, each with possible benefits and harm. the management of individual patients needs to take into consideration various factors, and not just the gas exchange that currently defines ards. this is precisely the point of bringing attention to the novel 'l & h' phenotypes of covid-19 that bracket the extremes of the clinical encounter [2] . usually, there is overlap, depending in large part on disease duration. the 'l & h' were not intended to be tightly prescriptive nor mutually exclusive 'bins' into which each patient falls, as we clearly stated [3] . rather, the object was to alert clinicians in order to avert potential harm from assuming usual ards associations between hypoxemia and mechanics at all stages. in so doing, we hoped to help prevent use of high peep when there is no benefit, and equally important, to avoid maintaining low pressures when higher pressures can be beneficial. the irritation derives from the fact the authors seem to have deliberately decided to ignore the pathophysiological 'evidence' readily available and ventured into a philosophical and semantic discourse against 'premature phenotyping', and in so doing committing the greater sin of 'premature adjudication'. after reading sentences such as "…by needlessly clouding the clinical picture, false phenotypes … upon inspection of patient data, simply do not exist" , it is not clear to us -and without a doubt to most readers -what sort of clear, and self-evident truth we (and other authors) have been trying to cloud. the fact that covid-19 patients with similar oxygenation efficiency may have markedly different compliance (and vili risk) is apparent to any clinician who has ever looked after a number of these patients. the reasoning put forward by the editorialists seems purely argumentative and inflammatory, as it seems to imply that what we propose is based on non-existent data, i.e., a perception that we invented. our concern derives from noting that the observations of bos and colleagues are expressed with a tone which goes beyond healthy and reasonable scientific debate. we note also with concern the conclusions of the editorial: "by prematurely phenotyping patients with covid-19, we expose ourselves and our patients to considerable and preventable risk" and we invite the authors to express with clarity the risks they are referring to and how their argument is furthering the cause of patients and clinicians. time and emerging literature will undoubtedly demonstrate where "truth" lies. the perils of premature phenotyping in covid: a call for caution covid-19 pneumonia: different respiratory treatments for different phenotypes? management of covid-19 respiratory distress key: cord-351349-ypaevb8b authors: van koningsbruggen-rietschel, silke; dunlevy, fiona; bulteel, veerle; downey, damian; dupont, lieven title: sars-cov2 disrupts clinical research the role of a rare disease-specific trial network date: 2020-08-07 journal: eur respir j doi: 10.1183/13993003.02114-2020 sha: doc_id: 351349 cord_uid: ypaevb8b rare disease patients may suffer delayed access to new drugs as sars-cov-2 is disrupting clinical trials. our survey demonstrates that the european cystic fibrosis clinical trials network is ideally placed to track and address such disruption. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has disrupted clinical trials worldwide [1] . this could delay the approval of new medicines and reduce access to investigational treatments via clinical trials. this particularly impacts patients with rare diseases such as cystic fibrosis (cf). here we present the results of several surveys performed within the european cf society clinical trials network (ecfs-ctn) that aimed to assess how the pandemic disrupted cf clinical trials and to rapidly share useful information about operational mitigation measures by clinical trial teams across europe. we also monitored continued access, via trial participation, to cf transmembrane conductance regulator (cftr) modulators as diseasemodifying treatments in cf. these modulators restore cftr transcellular chloride transport caused by pathogenic variants in the cftr gene, demonstrating marked improvements in lung function and quality of life [2] . licensing and reimbursement of cftr modulators varies by country and around 450 cf patients across ecfs-ctn sites currently access cftr modulators via clinical trials. trial and treatment interruption could result in clinical deterioration and a reduced quality of life for these participants. four surveys were answered by clinical trial investigators and research coordinators in the 58 ecfs-ctn sites between march-may 2020 (weeks 1, 2, 4 and 6). each survey contained the same core questions; other questions were added/removed as the situation evolved. two responses from the same site were included if they represented adult and pediatric clinics. if multiple responses were received from the same adult/pediatric clinic within a site, consistency was checked, and the lead investigator response was included for result calculations. following data cleaning, there were 55-63 evaluable responses for each survey (representing 40-49 sites and 12-16 countries). the week 1 survey was performed just before initial fda and ema guidance in mid-march 2020 [3, 4] and showed that many sites had already prohibited new enrolment into trials and onsite monitoring visits ( table 1) . existing trial participants could mostly continue attending onsite trial visits in person, although remote "tele-visits" were also encouraged. patients were reluctant to attend around 25% of clinics for trial visits; other clinics reported that patients were willing to attend trial visits if precautions were implemented, or if it was to continue receiving cftr modulators. home delivery of study drug increased over time, which helped avoid onsite visits. most sites received adequate guidance from trial sponsors from week 1 onwards. procedures to set up new trials continued in around half of clinics, but site initiation visits were generally prohibited. encouragingly, patient rollover from phase 3 trials of cftr modulators to openlabel extension studies was mostly possible, guaranteeing continued treatment with cftr modulators. in week 4, reduced availability of clinical trial staff was reported by 41% of clinics (median [range] reduction: 50% [10-90%]), due to staff reassignment to clinical duties (50%) or covid-19 trials (42%), or illness/quarantine (26%). similar trends were observed at week 6. additionally, 42% of clinics reported that contingency measures such as shipment of medication, telephone visits and remote monitoring took longer than normal procedures. survey results were returned to sites several hours after the survey closed to share knowledge about how teams (both adult and pediatric) were handling trial conduct, and ensuring patient safety. we shared summary results with trial sponsors; we also surveyed sponsors about their mitigation efforts. our aerial view of the cf clinical trial landscape in europe did not detect any systemic issues (e.g. closure of trial sites) requiring our intervention. we are compiling the crowd-sourced learnings from these surveys into practical mitigation advice for future crises, that sites can adapt to their local situations. we are also following-up the various telehealth options reported by sites such as video calls, electronic consenting, home spirometry to identify and address any associated gaps in evidence, guidance or training. the pandemic caused major disruption to clinical trials, which could delay therapeutic progress in cf. the enforced healthcare measures and focus on new treatments for sars-cov2 should not stall development of treatments for cf and other rare diseases. ecfs-ctn's mission is to intensify clinical research in cf and get new medicines to patients faster [5] . we hope that the rapid collection and sharing of information between sites facilitated by this survey helped sites deal with the myriad of challenges posed by the pandemic and will help them better prepare for future crises. we believe that disease specific ctns are an effective way for rare disease clinical trial sites to learn from each other and overcome obstacles such as the current pandemic, while working towards the goals of effective treatments for rare diseases. preserving clinical trial integrity during the coronavirus pandemic impact of cftr modulator use on outcomes in people with severe cystic fibrosis lung disease date last accessed date last accessed disease-specific clinical trials networks: the example of cystic fibrosis key: cord-338351-y1t9emu1 authors: ora, josuel; puxeddu, ermanno; cavalli, francesco; giorgino, federica maria; girolami, andrea; chiocchi, marcello; sergiacomi, giaunluigi; federici, massimo; rogliani, paola title: does bronchoscopy help the diagnosis in covid-19 infection? date: 2020-06-11 journal: eur respir j doi: 10.1183/13993003.01619-2020 sha: doc_id: 338351 cord_uid: y1t9emu1 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is the agent responsible for the recent coronavirus disease 2019 (covid-19) pandemic. this virus is predominantly spread through large droplets. the clinical features of covid-19 are varied, ranging from asymptomatic to acute respiratory distress syndrome and multi-organ dysfunction [1]. to the editor: dear editor, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is the agent responsible for the recent coronavirus disease 2019 pandemic. this virus is predominantly spread through large droplets. the clinical features of covid-19 are varied, ranging from asymptomatic to acute respiratory distress syndrome and multi-organ dysfunction 1 . the diagnosis of covid-19 is mainly based on typical symptoms, history of exposure to an infected person and bilateral involvement on chest radiographs, and it is confirmed by a positive nucleic acid test for sars-cov-2 from numerous types of specimens including oropharyngeal (op) and nasopharyngeal (np) swabs, anal swabs, stool, urine and bronchoalveoalr lavage fluid (balf) 1,2 . reverse-transcriptase-polymerase-chain-reaction (rt-pcr) that targets the rdrp, n, or e genes is the most common method for sars-cov-2 detection 3 . op and np swabs are the most frequently used samples, but it has been demonstrated that their sensitivity is limited, 32% and 63% respectively while balf is reported to be positive in 93% of patients 4 . however the role of bronchoscopy in ruling out suspected covid-19 patients is under debate. according to several guidelines 5,6 , bronchoscopy is relatively contraindicated mainly because of its high risk of spreading the infection to the staff involved in the procedure. it is primarily recommended in immunocompromised patients, if there is the strong suspicion of superinfection or mucus plugging, or in life saving conditions, and it is not strictly recommended in the covid-19 diagnostic algorithm. nevertheless, some cases of negative op and np swabs in which balf tested positive for sars-cov-2 by rt-pcr were reported 7, 8 . there are two main problems in negative swab patients with ct scans and clinical picture suggestive for covid-19: firstly, according to the sensitivity of the swabs, misdiagnosing a sars-cov-2 positive patient may be a great risk for public health, secondly, an alternative diagnosis may be required for patients' appropriate treatment. here we report our experience from a covid-19 hospital in rome, italy, where patients with typical symptoms of the disease, suggestive ct scans and three np/op negative swabs performed on consecutive days and igg and igm serology negative for sars-cov-2 underwent bronchoscopy with bal to define the diagnostic issue. in the period between march 13 th and april 30 th 2020, 28 patients (age 65 ±16yrs, 16male and 12 female) with the described characteristics, discussed by the multidisciplinary clinicalradiological team, underwent bronchoscopy with bal. all the patients performed a nonantibiotic therapy was modified in 13 patients according to the microbiological findings. in these pandemic times, the low sensitivity of rt-pcr can miss many diagnoses of covid-19, representing a far too high risk for infection transmission. on the other hand, even if ct scan has a higher sensitivity (97%), its lower specificity (25%) 2 makes alternative diagnosis more likely and bronchoscopy with balf is the recommend procedure to rule out any doubts. our findings suggest that three negative swabs done in three different days and a negative serology are sufficient to rule out covid-19, even in patients with highly suggestive ct scans and clinical features compatible with the disease. differently than other reports 7,8 , we performed three op/np swabs and serology tests before performing the bronchoscopy, instead of just one or two op/np swabs. this conduct allowed to detect some patients who resulted positive at the third swab or at serology, avoiding unnecessary procedures, therefore reducing the risk of transmission to healthcare workers. bronchoscopies were performed with disposable devices and with the recommended personal protective equipment 6 . even if our results are very reassuring about the safety of this procedure in patients with three negative swabs and negative serology, the risk for the staff still remains high and we strongly suggest to maintain all the recommended precaution to minimize the risk of possible disease transmission. interestingly, balf was positive for other pathogens in 46% of patients, reinforcing its role in finding alternative diagnoses. in conclusion, our findings demonstrate that three negative swabs along with negative antibodies, despite a suggestive ct scan, can safely rule out the sars-cov-2 infection in suspected patients, hence to proceed in alternative diagnosis process. bronchoscopy should not be used for the confirmation of sars-cov-2 infection alone, but it can be very useful in resolving diagnostic complexity. this study was supported by institutional funding (university of rome "tor vergata", rome, italy) clinical characteristics of coronavirus disease 2019 in china correlation of chest ct and rt-pcr testing in coronavirus disease interim guidelines for collecting, handling, and testing clinical specimens from patients under investigation (puis) for comparison of nasopharyngeal and oropharyngeal swabs for sars-cov-2 detection in 353 patients received tests with both specimens simultaneously summarizing societal guidelines regarding bronchoscopy during the covid-19 pandemic american association for bronchology and interventional pulmonology (aabip) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed covid-19 infection negative nasopharyngeal and oropharyngeal swabs do not rule out covid-19 association of radiologic findings with mortality of patients infected with 2019 novel coronavirus in wuhan, china evolution of ct manifestations in a patient novel coronavirus (2019-ncov) pneumonia in wuhan, china ct manifestations of two cases of 2019 novel coronavirus (2019-ncov) pneumonia novel coronavirus (2019-ncov) pneumonia key: cord-351407-7vx9lzi0 authors: mehta, puja; ciurtin, coziana; scully, marie; levi, marcel; chambers, rachel c. title: jak inhibitors in covid-19: need for vigilance regarding increased inherent thrombotic risk date: 2020-07-06 journal: eur respir j doi: 10.1183/13993003.01919-2020 sha: doc_id: 351407 cord_uid: 7vx9lzi0 there is accumulating evidence that covid-19 is a hypercoagulable state. reports of thrombotic events and autopsy findings of pulmonary thrombotic microangiopathy [1] in patients with covid-19 are rising. bompard et al. recently reported a cohort study of 137 patients with covid-19 pneumonia, in which retrospective review of computed tomography pulmonary angiography (ctpa) scans demonstrated a cumulative incidence of pulmonary emboli (pe) of 24% overall and 50% in intensive care [2]. although it was initially thought that insidious venous thromboembolic events (vte) were mainly confined to ventilated patients [3], we now understand thrombotic risk to be a wider problem in covid-19. an overexuberant host inflammatory response, in selected patients with severe covid-19, may contribute to the high mortality. we recently recommended screening for virally-driven hyperinflammation in covid-19 and proposed that immunomodulation in this subgroup of patients, may improve outcomes [4]. there are several ongoing, randomised controlled trials evaluating the therapeutic potential of janus kinase inhibitors (jaki) in severe covid-19 (table 1). jaki have a purported advantage over other immunomodulatory strategies in covid-19, as they may exert dual anti-inflammatory (blockade of multiple, pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis [5, 6]) and have convenient oral administration, with relatively short half-lives. jaki may interrupt the signalling of several pro-inflammatory cytokines implicated in the pathogenesis of hyperinflammation, including interleukin (il)-6, which has been the focus of several clinical trials in covid-19. jaki may also inhibit the entry of the sars-cov-2 virus into the at2 alveolar epithelial cells; baricitinib (a jak1/2 inhibitor), is a numb-associated kinase (nak) inhibitor, with a particularly high affinity for ap2-associated protein kinase 1 (aak1), a pivotal regulator of clathrin-mediated viral endocytosis [5]. we recommend vigilance to the potentially increased thrombotic risk associated with jaki, given the hypercoagulability of covid-19 and our recent thromboprophylaxis recommendations for all hospitalised patients with covid-19 [7]. there is accumulating evidence that covid-19 is a hypercoagulable state. reports of thrombotic events and autopsy findings of pulmonary thrombotic microangiopathy 1 in patients with covid-19 are rising. bompard et al recently reported a cohort study of 137 patients with covid-19 pneumonia, in which retrospective review of computed tomography pulmonary angiography (ctpa) scans demonstrated a cumulative incidence of pulmonary emboli (pe) of 24% overall and 50% in intensive care 2 . although it was initially thought that insidious venous thromboembolic events (vte) were mainly confined to ventilated patients 3 , we now understand thrombotic risk to be a wider problem in covid-19. an overexuberant host inflammatory response, in selected patients with severe covid-19, may contribute to the high mortality. we recently recommended screening for virally-driven hyperinflammation in covid-19 and proposed that immunomodulation in this subgroup of patients, may improve outcomes 4 . there are several ongoing, randomised controlled trials evaluating the therapeutic potential of janus kinase inhibitors (jaki) in severe covid-19 (table 1) . jaki have a purported advantage over other immunomodulatory strategies in covid-19, as they may exert dual anti-inflammatory (blockade of multiple, pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis 5, 6 ) and have convenient oral administration, with relatively short half-lives. jaki may interrupt the signalling of several pro-inflammatory cytokines implicated in the pathogenesis of hyperinflammation, including interleukin (il)-6, which has been the focus of several clinical trials in covid-19. jaki may also inhibit the entry of the sars-cov-2 virus into the at2 alveolar epithelial cells; baricitinib (a jak1/2 inhibitor), is a numb-associated kinase (nak) inhibitor, with a particularly high affinity for ap2-associated protein kinase 1 (aak1), a pivotal regulator of clathrin-mediated viral endocytosis 5 . we recommend vigilance to the potentially increased (table 1) . it is unclear whether the presumed prothrombotic risks are dependent on jak selectivity, drug specificity, dose or treatment duration or are confounded by indication. whilst there is evidence of dose-dependent increased thrombotic risk associated with tofacitinib (five-fold increased risk of pe compared with tumour necrosis factor therapy in ra) 8 , a recent meta-analysis did not show an overall jaki class pro-thrombotic signal 9 . although a significantly increased incidence of thrombotic events (dvt and pe) was reported with bariticitinb in ra trials 10 , this has not been observed in extension studies and recent trials in atopic dermatitis 11 . post-marketing surveillance may delineate the true risk and whether this is disease-specific. it is unclear which jak isoform (selectivity) confers impact on the efficacy or influences safety of these therapies for their licenced indications (e.g. rheumatoid arthritis) or in the new disease setting of covid-19. it is important to note that at high doses, jaki can become 'pan-jak' inhibitors and exhibit non-selectivity 12 discussion continues regarding whether jaki have a causal role in thrombotic events, or whether this represents a higher background thrombotic risk 13 . indeed vte risk in ra (0.3-0.7 /100 patient years) is greater compared with the general population (0.1-0.4 / 100 patient years) 13 . intriguingly, ruxolitinib, unlike baricitinib, does not carry a vte warning, despite both being selective jak 1/2 inhibitors. conversely there is a suggestion that ruxolitinib may lower the inherently raised thrombotic risk in myeloproliferative neoplasms 14 . extrapolating this reassurance for ruxolitinib to covid-19 is inappropriate as data for baricitinib and ruxolitinib is derived from different disease populations and their respective safety signals may be confounded by indication. clinical trials in covid-19 using immunomodulation, including jaki, intend to recruit patients with the most severe disease, and it is hypothesised that these patients are more hypercoagulable. we recommend risk mitigation strategies including consideration of exclusion of patients with high thrombotic risk, treatment with standard or intermediate-dose low molecular weight heparin prophlyaxis 7 during hospitalisation and consideration of increased thrombotic risk associated with jaki, given the hypercoagulability of covid-19. covid-19 and its implications for thrombosis and anticoagulation pulmonary embolism in patients with covid-19 pneumonia venous thromboembolism in sars-cov-2 patients: only a problem in ventilated icu patients, or is there more to it? covid-19: consider cytokine storm syndromes and immunosuppression covid-19: combining antiviral and anti-inflammatory treatments baricitinib as potential treatment for 2019-ncov acute respiratory disease coagulation abnormalities and thrombosis in patients with covid-19 increased risk of blood clots in lungs and death with higher dose of xeljanz (tofacitinib) for rheumatoid arthritis impact of janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials cardiovascular safety during treatment with baricitinib in rheumatoid arthritis baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase iii trials the emerging safety profile of jak inhibitors in rheumatic disease thromboembolism with janus kinase (jak) inhibitors for rheumatoid arthritis: how real is the risk? the impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis pm drafted the manuscript. all authors contributed to discussions, revised and approved the manuscript. pm is an mrc-gsk eminent clinical training fellow with project funding outside the submitted work. pm receives co-funding by the nihr university college london hospitals biomedical research centre (uclh brc). cc, ms, ml have nothing to disclose. rcc reports grants from ukri mrc, grants from glaxosmithkline, grants from nihr ulch brc outside the submitted work. key: cord-354290-o5i4a7nl authors: li, jie; fink, james b.; ehrmann, stephan title: author's reply on high-flow nasal cannula for covid-19 patients: low risk of bio-aerosol dispersion date: 2020-08-28 journal: eur respir j doi: 10.1183/13993003.03136-2020 sha: doc_id: 354290 cord_uid: o5i4a7nl we appreciate the comments of elshof et al.'s on our article “high-flow nasal cannula for covid-19 patients: low risk of bio-aerosol dispersion” [1] and agree that further research is warranted to reduce risk of virus transmission from infected patients. the presented in vitro data [2] from a light detection of smoke dispersion distance and velocity model suggesting that high-flow nasal cannula (hfnc) generates larger dispersion distance than nonbreather mask and venturi mask is in contrast to reports from hui et al., using a similar model [3]. presumably because the smoke used by elshof et al. is larger (0.3–2.5 µm) [2] than that used by hui et al. (≤1 µm) [3], the larger particles dispersing differently. it should be noted that smoke in both models represents only a small fraction of the range of bioaerosols generated by patients during breathing, speaking, coughing or sneezing [4]. using the same size airway model, the authors observed that the dispersion distance decreased from 71 cm to 25 cm by changing the nasal cannula size from small to large when hfnc flow was set at 30 l·min(−1), however, when hfnc flow was set at 60 l·min(−1), the medium size nasal cannula generated shorter distance than both small and large nasal cannulas. this raises the role of proper fit of prong to nares and highlights the limitations of modelization. regardless of the sizes of nasal cannula, the dispersion distance was higher with 60 l·min(−1) than 30 l·min(−1), which is inline with hui et al. results [3] and may be expected, as higher velocity of the gas may carry exhaled smoke to a further distance. however, this effect of total flow did not occure when testing the the venturi mask. strangely, the venturi mask with large open holes and total gas flow of 40 l·min(−1) generated shorter dispersion distance than normal breathing. these inconsistencies are difficult to interpret without comprehensive peer reviewe of extensive methods and results. whether smoke imaging models truly reflect the natural features of the transportation and dispersion of bioaerosols generated by patients has not been established and results from these studies should be interpreted cautiously. we appreciate the comments of elshof et al"s on our article "high-flow nasal cannula for covid-19 patients: low risk of bio-aerosol dispersion" 1 and agree that further research is warranted to reduce risk of virus transmission from infected patients. the presented in vitro data 2 from a light detection of smoke dispersion distance and velocity model suggesting that high-flow nasal cannula (hfnc) generates larger dispersion distance than nonbreather mask and venturi mask is in contrast to reports from hui et al, using a similar model 3 . presumably because the smoke used by elshof et al is larger (0.3-2.5 µm) 2 than that used by hui et al (≤ 1 µm), 3 the larger particles dispersing differently. it should be noted that smoke in both models represents only a small fraction of the range of bioaerosols generated by patients during breathing, speaking, coughing or sneezing. 4 using the same size airway model, the authors observed that the dispersion distance decreased from 71 cm to 25 cm by changing the nasal cannula size from small to large when hfnc flow was set at 30 l/min, however, when hfnc flow was set at 60 l/min, the medium size nasal cannula generated shorter distance than both small and large nasal cannulas. this raises the role of proper fit of prong to nares and highlights the limitations of modelization. regardless of the sizes of nasal cannula, the dispersion distance was higher with 60 l/min than 30 l/min, which is inline with hui et al results 3 and may be expected, as higher velocity of the gas may carry exhaled smoke to a further distance. however, this effect of total flow did not occure when testing the the venturi mask. strangely, the venturi mask with large open holes and total gas flow of 40 l/min generated shorter dispersion distance than normal breathing. these inconsistencies are difficult to interpret without comprehensive peer reviewe of extensive methods and results. whether smoke imaging models truly reflect the natural features of the transportation and dispersion of bioaerosols generated by patients has not been established and results from these studies should be interpreted cautiously. in a recent clinical study of aerosol particle concentrations and sars-cov-2 virus detection in the vicinity of patients with covid-19, aerosol particle size and concentrations was measured before and after hfnc was applied to patients. no difference was observed between conventional nasal cannula applied prior to hfnc and hfnc. more importantly, no sars-cov-2 virus was detected in the room air with sampling cassette placed at 30 cm away from patients" airway for an hour. 5 it should also be noted that oxygen masks including venturi mask, nonbreather mask, simple mask, and aerosol mask, do not enable placement of a filter, except for some oxygen masks with special design. 6 bioaerosols generated by patients might be exhaled via the holes or the one-way valve on the masks and the high gas flow from the masks help carry those bioaerosols to a further distance. in contrast, patients using hfnc can wear a surgical mask over hfnc, in order to reduce the dispersion of bioaerosols generated by patients. 6, 7 in all, compared to conventional oxygen devices, hfnc has been proven to improve oxygenation and reduce intubation rate in hypoxemic patients. 8 abandoning hfnc to use other oxygen devices for the uncertain risks of virus transmission is unnecessary and ill advised. special caution taken to protect personnel during "aerosol generating procedures" is more important than avoidance of "aerosol dispersing procedures". 4 studying the production of aerosols by breathing support devices using lab models (e.g. smoke dispersion) is interesting but has important limitations because they are just simulations. what is really important, and still lacking in the literature, is a real life study assessing the actual virus cargo within the patient"s generated aerosols and, more important, how infective is such a viral cargo, which would probably depend on the physical and chemical characteristics of the aerosol particles. high-flow nasal cannula for covid-19 patients: low risk of bio-aerosol dispersion high-flow nasal cannula for covid-19 patients: low risk of bio-aerosol dispersion exhaled air dispersion during high-flow nasal cannula therapy versus cpap via different masks coughs and sneezes: their role in transmission of respiratory viral infections, including sars-cov-2 placing mask on covid-19 patients during highflow nasal cannula therapy reduces aerosol particle dispersion practical strategies to reduce nosocomial transmission to healthcare professionals providing respiratory care to patients with covid-19 preliminary findings on control of dispersion of aerosols and droplets during high-velocity nasal insufflation therapy using a simple surgical mask: implications for the high-flow nasal cannula year in review 2019: high-flow nasal cannula (hfnc) oxygen therapy for adult patients jl conceived of the idea and drafted the manuscript. jbf and se provided critical revision on the manuscript. all authors reviewed and revised the manuscript and approved the final draft. not applicable. not applicable. not applicable. not applicable. key: cord-355753-muefay2n authors: garner, justin l.; shah, pallav l. title: challenges of evaluating lung function as part of cancer care during the covid-19 pandemic date: 2020-07-02 journal: eur respir j doi: 10.1183/13993003.01621-2020 sha: doc_id: 355753 cord_uid: muefay2n severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is a newly identified agent foisted upon humanity and responsible for the contagious affliction, coronavirus disease 2019 (covid-19) [1] that has rapidly evolved into a pandemic testing to their limits, and sometimes beyond, the capacity to respond of healthcare systems across the world [2]. management is purely supportive and social isolation crucial to containment [3]. enforced reallocation of hospital resources and personnel to cope with the increasing numbers requiring hospital admission and intensive care [4] in the most trying of conditions has been at the expense of many hospital departments, among them those offering diagnostic and support services for lung cancer [5–7]. to the editor, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is a newly identified agent foisted upon humanity and responsible for the contagious affliction, coronavirus disease 2019 (covid-19)(1)that has rapidly evolved into a pandemic testing to their limits, and sometimes beyond, the capacity to respond of healthcare systems across the world (2) . management is purely supportive and social isolation crucial to containment (3) . enforced reallocation of hospital resources and personnel to cope with the increasing numbers requiring hospital admission and intensive care (4) in the most trying of conditions has been at the expense of many hospital departments, among them those offering diagnostic and support services for lung cancer (5) (6) (7) . evaluation of lung physiology is an essential preliminary to potentially curative treatments, surgical resection, chemotherapy and radiotherapy (8) . the risks to patients and staff associated with exposure to aerosols generated by forced expiratory manoeuvres in conventional testing has led to several societies issuing advice against their use(9, 10): formal evidence-based guidance has yet to be published. our institution is however adapting to less hazardous procedures and technologies for example, virtual clinical assessments. spirometry is the most feared aerosol generating procedure (agp) and we are looking into provision of peak expiratory flow meters to be used as an alternative in the home environment (11) . remote monitoring of cystic fibrosis patients with portable wireless transmission spirometers such as nuvoair has revolutionised their outpatient management, and minimising interpersonal contact, has the potential for transforming the care of cancer patients during the current 'lockdown' period (12) . use of either device can be supervised via a secure telemedicine link to ensure optimal technique and valid measurements: convenient, operationally and financially advantageous continuing surveillance of these patients particularly post-operatively. a promising alternative approach to evaluating lung function is that of quantitative computed tomography (qct) imaging (13) , and whilst currently a research tool has the potential for transforming clinical practice. fractionation of conventional ct scans on a scale of attenuation has been used to determine the relative contributions of pathologies. shroeder et al in 2013, examining more than 4000 ct scans made in expiration of individuals who were smokers, with and without chronic obstructive pulmonary disease (copd), correlated air trapping (areas of low attenuation equal to or less than -856 hounsfield units, hu) (14) with physiological measures of airway obstruction. their estimations of fev1 compared favourably with those of spirometry. wu et al in 2002, categorizing the pre-operative scans of 44 of their lung cancer patients, applied dual thresholds of attenuation distinguishing the contributions of tumour and atelectasis (greater than -500 hu), emphysema (less than -910 hu), and normal functioning parenchyma (-500 to -910 hu) and making accurate predictions of post-operative fev1 (15) . the authors, observing the small sample size, exercised caution in those patients with a qct-predicted fev1 less than 40% who have a higher risk of post-operative morbidity and mortality, and advised the addition of perfusion scintigraphy and exercise testing for comprehensive evaluation. functional respiratory imaging (fri), combining high resolution ct (hrct) and post-processing computational fluid dynamics, can be used to assess airway volume and resistance at a lobar level and is more sensitive to pharmacologically-induced changes than routine lung function tests (16) . total lung capacity and residual volumes, estimated on ct scans respectively made in maximum inspiration and expiration have also been shown to correlate well with plethysmographic-derived measurements (17) . (figure 1 ). in the absence of a local qct software platform, a number of commercial companies offer such an imaging service simply requiring uploading of an anonymised ct scan to a secure cloud-based service for analysis: the report is emailed within 24 hours. dual-energy phase ct (dect) (18) and single photon emission tomography (spect) ct (19) imaging enable evaluation of lobar perfusion, necessary for example, prior to surgery. furthermore, ct chest images acquired without electrocardiographic gating for non-cardiac indications have nevertheless proved serviceable for detecting coronary artery calcification (20, 21) and quantifying epicardial and thoracic fat (22) . the covid-19 pandemic and the necessity for social isolation is ushering in a new era of remote clinical evaluation. modifications of ct imaging and processing in chest medicine yield both anatomical and functional information in a safe environment. they are not expected to appreciably add to the radiation exposure of current use nor are they likely to be especially time-consuming (23, 24) . this approach could be transferable to other fields of medicine. the advent of serological testing for sars-cov-2 should help to restore some functionality to the health services, but a rethinking of current infrastructure and adaptation to the demands of changing global circumstances confronting us is called for. the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2 world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) covid-19 diagnosis and management: a comprehensive review fair allocation of scarce medical resources in the time of covid-19 managing cancer care during the covid-19 pandemic: agility and collaboration toward a common goal challenges in lung cancer therapy during the covid-19 pandemic cancer guidelines during the covid-19 pandemic. the lancet oncology guidelines on the radical management of patients with lung cancer pulmonary function laboratories: advice regarding covid-19 peak-flow or portable spirometry as a replacement for spirometry in the diagnosis of copd and asthma the use of home spirometry in pediatric cystic fibrosis patients: results of a feasibility study development of quantitative computed tomography lung protocols relationships between airflow obstruction and quantitative ct measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease prediction of postoperative lung function in patients with lung cancer: comparison of quantitative ct with perfusion scintigraphy a randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using cosuspension delivery technology in patients with copd quantitative evaluation of lobar pulmonary function of emphysema patients with endobronchial coils. respiration; international review of thoracic diseases assessment of lobar perfusion in smokers according to the presence and severity of emphysema: preliminary experience with dual-energy ct angiography pre-surgical evaluation of lung function. seminars in nuclear medicine relationship of coronary calcium on standard chest ct scans with mortality scct/str guidelines for coronary artery calcium scoring of noncontrast noncardiac chest ct scans: a report of the society of cardiovascular computed tomography and society of thoracic radiology epicardial and thoracic fat -noninvasive measurement and clinical implications. cardiovascular diagnosis and therapy dual-energy ct: radiation dose aspects comparison of the effect of radiation exposure from dual-energy ct versus single-energy ct on double-strand breaks at ct pulmonary angiography key: cord-349958-126yb5se authors: raskin, jo; lebeer, marnix; de bondt, charlotte; wener, reinier; janssens, annelies; van meerbeeck, jan p. title: cancer in the time of covid: expert opinion on how to adapt current practice date: 2020-04-16 journal: eur respir j doi: 10.1183/13993003.00959-2020 sha: doc_id: 349958 cord_uid: 126yb5se the susceptibility of cancer patients to adverse outcome of viral infections is well known from past experiences, e.g. influenza increasing the risk of hospital admission with respiratory distress four times, and the risk of death ten times, compared to patients without cancer [1]. to the editor: the susceptibility of cancer patients to adverse outcome of viral infections is well known from past experiences, e.g. influenza increasing the risk of hospital admission with respiratory distress four times, and the risk of death ten times, compared to patients without cancer [1] . this risk is particularly elevated in patients with neutropenia or lymphopenia, which is often the case in patients treated with chemotherapy. in wuhan, 1% of patients with sars-cov-2 were reported to suffer from cancer, which is more than three times the incidence of cancer in the chinese population [2] . in addition, in 39% of cancer patients (compared to 8% of patients without cancer) transfer to the intensive care unit was necessary, with their illness deteriorating more rapidly (13 vs 43 days to severe event) [2] . chemotherapy or surgery <1 month before was an important risk factor (or 5.34, p=0.0026). there is no doubt that patients with lung cancer or mesothelioma, who are often older and with concurrent obstructive or restrictive lung disease, are even more at risk for unfavourable outcomes in case of infection with sars-cov-2. therefore, we have to reconsider our current clinical practice, in order to limit time-in-hospital, promote telemedicine, avoid unnecessary contact with medical personnel, and reduce severe neutropenia. the british thoracic society (bts) recently published recommendations on covid and lung cancer/mesothelioma [3] ; the french haut conseil de la santé publique (hcsp) on cancer in general [4] [5] . this letter describes the viewpoint of the authors on these general recommendations (not always agreeing!) and tries to translate them into practical advice for clinicians (note: may not be feasible due to reimbursement issues), starting from the current standard of care. in all patients we propose to use video consultation as much as possible instead of face to face consultation [3, 5] . stages i-iii:  standard of care in most patients is chemoradiotherapy with 4 cycles of cisplatin/etoposide as preferred chemotherapy regimen.  replacing intravenous with oral etoposide to reduce time-in-hospital should be weighed against its lower biological availability and variable pharmacodynamics in a curative setting [6]  in patients with stage i sclc surgical resection of the tumour, followed by adjuvant chemotherapy (4 cycles of cisplatin/etoposide) is indicated.  in selected patients, accelerated hyperfractionation of radiotherapy (twice-daily) remains an option to decrease the number of hospital visits. stage iv or not eligible for chemoradiotherapy:  palliative chemotherapy with platinum/etoposide is recommended.  replacing intravenous with oral etoposide to reduce time-in-hospital may be considered, providing attention is given to its lower biological availability and variable pharmacodynamics [6] .  in patients with increased risk of febrile neutropenia (fn) dose reduction might be an alternative to primary prophylactic use of g-csf in all patients, given the palliative setting [7] .  given the limited improvement in overall survival and the need for triweekly clinic visits during the maintenance phase, the addition of a checkpoint inhibitor (atezolizumab or durvalumab) can be omitted.  the indication for second-line systemic therapy should be reviewed with extra care. in platinum-sensitive relapse, rechallenge with first-line chemotherapy is recommended. in platinum-refractory relapse, oral topotecan is the preferred regimen. cyclophosphamide/doxorubicin/vincristine is not recommended as an alternative to topotecan in view of the need to hospitalize the patient.  any third-line chemotherapy should be considered only in fit patients with low risk of complications. surgery  consider delaying surgery for up to 3 months in small tumours that appear not to grow fast; follow up of growth rate with chest ct is recommended [3] .  consider stereotactic radiotherapy as an alternative in patients who are marginally fit for surgery, due to comorbidity or limited pulmonary reserve [3] .  minimal invasive approaches are preferred over thoracotomy to limit time-inhospital [3] . adjuvant chemotherapy:  adjuvant chemotherapy in stage ii and iii and in some patients with high-risk stage ib leads to 5% improvement in 5-year survival and is therefore recommended.  in elderly patients, patients with significant comorbidity or decreased performance (ps ≥ 2), the possible benefits of adjuvant chemotherapy may be outweighed by the increased risk of complications. consider omitting adjuvant chemotherapy or stopping early (e.g. after 3 cycles) [3] .  consider giving cisplatin/docetaxel to limit time-in-hospital, as it avoids day 8 administration of gemcitabine or vinorelbine, and has equivalent efficacy. in nonsquamous nsclc, cisplatin/pemetrexed is an equally efficacious alternative [8] .  in patients with an activating egfr mutation, consider a 1 year course of daily oral egfr-tki as an alternative to adjuvant chemotherapy (currently no phase 3 evidence of superiority available).  consider delaying curative radiotherapy for small tumours that appear not to grow fast; follow up of growth rate with chest ct is recommended [3] .  consider giving cisplatin/pemetrexed instead of cisplatin/etoposide, or weekly carboplatin/paclitaxel in non-squamous nsclc to limit time-in-hospital [9] .  consider giving adjuvant durvalumab at a dose of 20 mg/kg every 4 weeks instead of 10 mg/kg every 2 weeks to limit time-in-hospital. phase 1b data have not shown an increase in adverse events [3, 10] systemic therapy:  evaluate the indication for palliative chemotherapy, immunotherapy or both with extra care in elderly patients or patients with significant comorbidity, decreased performance (ps ≥2), social isolation, decubitus, urinary catheters, … especially in second or further lines [3] .  consider delaying chemotherapy or immunotherapy in patients who are asymptomatic and have indolent disease [3] .  usual recommendations for chemotherapy, immunotherapy and targeted therapy apply.  in patients with increased risk of febrile neutropenia (fn) dose reduction might be an alternative to primary prophylactic use of g-csf in all patients, given the palliative setting [7] .  keep in mind that pneumonitis may also be drug-induced (e.g. chemotherapy, tki's) or immune-mediated (checkpoint inhibitors).  triweekly chemotherapy is preferred over weekly regimens (e.g. docetaxel) to limit time-in-hospital [4] .  consider limiting palliative chemotherapy to 4 cycles and omitting pemetrexed maintenance therapy [3] .  in patients who are pd-l1 >50%, first-line pembrolizumab monotherapy is preferred over pembrolizumab plus chemotherapy [3] .  consider giving nivolumab at a dose of 480 mg every 4 weeks instead of 240 mg every 2 weeks to limit time-in-hospital [3, 11] .  immunotherapy in second-line is preferred over chemotherapy in patients who did not receive immunotherapy in first line.  in case of lack of response to immunotherapy or significant toxicity, early discontinuation should be considered.  third-line chemotherapy is not advisable [3] .  consider evaluating the response to immunotherapy or tki less often in clinically stable patients. supportive therapy/other:  advance care planning should be discussed with all patients in order to avoid admission to hospital [3] .  do not resuscitate (dnr) status should be available for all stage 4 patients.  patients receiving denosumab or low-molecular-weight heparin should be taught to self-administer [3] .  patients receiving denosumab should not routinely consult a dentist before starting.  avoid transfusion of blood or platelets by using dose reduction or early discontinuation of chemotherapy in palliative patients.  in case of early-stage disease in a fit patient, evaluate for multimodality treatment including surgery (preferably extended pleurectomy/decortication) and chemotherapy.  palliative chemotherapy with 4 cycles of platinum/pemetrexed is recommended in all other cases of ps 0-1 patients.  evaluate the indication for palliative chemotherapy with extra care in elderly patients, patients with significant comorbidity or poorer performance (ps ≥2),  consider delaying chemotherapy in patients who are asymptomatic [3] .  pemetrexed maintenance therapy is not recommended due to lack of efficiency data.  be reluctant with second-line chemotherapy with either vinorelbine, gemcitabine or doxorubicin.  a home-managed indwelling pleural catheter is preferred over procedures that require a clinic visit [3] .  platinum/etoposide is preferred over more haematotoxic regimens such as adoc, cap or vip. influenza vaccines in immunosuppressed adults with cancer cancer patients in sars-cov-2 infection: a nationwide analysis in china lung cancer and mesothelioma service guidance during the covid-19 pandemic haut conseil de la santé publique. covid-19 et cancers solides: recommandations the official french guidelines to protect patients with cancer against sars-cov-2 infection the clinical pharmacology of etoposide and teniposide management of febrile neutropaenia: esmo clinical practice guidelines adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (e1505): an openlabel, multicentre, randomised, phase 3 trial proclaim: randomized phase iii trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study checkmate 384: phase iiib/iv trial of nivolumab (nivo) 480 mg q4w versus 240 mg q2w after ≤ 12 months of nivo in previously treated advanced nsclc key: cord-344641-rog2h4g7 authors: franco, cosimo; facciolongo, nicola; tonelli, roberto; dongilli, roberto; vianello, andrea; pisani, lara; scala, raffaele; malerba, mario; carlucci, annalisa; negri, emanuele alberto; spoladore, greta; arcaro, giovanna; tillio, paolo amedeo; lastoria, cinzia; schifino, gioachino; tabbi’, luca; guidelli, luca; guaraldi, giovanni; ranieri, v. marco; clini, enrico; nava, stefano title: feasibility and clinical impact of out-of-icu non-invasive respiratory support in patients with covid-19 related pneumonia date: 2020-08-03 journal: eur respir j doi: 10.1183/13993003.02130-2020 sha: doc_id: 344641 cord_uid: rog2h4g7 introduction: the coronavirus 2(sars-cov-2) outbreak spread rapidly in italy and the lack of intensive care unit(icu) beds soon became evident, forcing the application of noninvasive respiratory support(nrs) outside the icu, raising concerns over staff contamination. we aimed to analyse the safety of the hospital staff, the feasibility, and outcomes of nrs applied to patients outside the icu. methods: in this observational study, data from 670 consecutive patients with confirmed covid-19 referred to the pulmonology units in nine hospitals between march 1st and may 10th,2020 were analysed. data were collected including medication, mode and usage of the nrs (i.e. high-flow nasal cannula (hfnc), continuous positive airway pressure (cpap), noninvasive ventilation(niv)), length of stay in hospital, endotracheal intubation(eti) and deaths. results: forty-two health-care workers (11.4%) tested positive for infection, but only three of them required hospitalisation. data are reported for all patients (69.3% male), whose mean age was 68 (sd 13) years. the pao(2)/fio(2) ratio at baseline was 152±79, and the majority of patients (49.3%) were treated with cpap. the overall unadjusted 30-day mortality rate was 26.9% with 16%, 30%, and 30%, while the total eti rate was 27% with 29%, 25% and 28%, for hfnc, cpap, and niv, respectively, and the relative probability to die was not related to the nrs used after adjustment for confounders. eti and length of stay were not different among the groups. mortality rate increased with age and comorbidity class progression. conclusions: the application of nrs outside the icu is feasible and associated with favourable outcomes. nonetheless, it was associated with a risk of staff contamination. on february 20 th 2020, coronavirus disease 19 severely hit the northern part of italy. it was reported that, in lombardy, the most populated region of the country, more than 1500 patients required intensive care unit (icu) admission over only 4 weeks, largely exceeding the actual capacity (1) . in the same period, the number of hospital admissions was 7285 (2) . approximately 35% of these patients experienced acute respiratory failure (arf) requiring any form of respiratory support. a mathematical model of the occupation of intensive care resources in italy predicted saturation of the theoretically available beds in the national territory by mid-april 2020 (3) . under these circumstances, despite extraordinary efforts aimed at increasing the availability of icu resources, the italian societies of respiratory medicine proposed a protocol to provide ventilatory support outside the icu in dedicated respiratory covid units, reinforced by a higher number of nurses and noninvasive monitoring (4) . this recommendation was somehow in contrast to most of the available guidelines that contraindicated using noninvasive respiratory support (nrs) in these patients due to the major concerns over using bio-aerosol producing techniques, because of possible contamination of the hospital staff (5) . this "emergency" situation gave us the unique opportunity to challenge the hypothesis that nrs should not be used outside the icu during pandemics. we have therefore analyzed the feasibility and safety, in terms of staff contamination, of nrs applied to severely ill patients outside the icu. patients' characteristics and clinical outcomes were also analyzed. the study was conducted in four out of five hospitals in the area vasta emilia network and in five hospitals in the neighbouring regions, serving a population of approximately 8 million people. institutional review boards reviewed the protocol and authorized prospective data collection. informed consent was waived. a confirmed case of covid-19 was defined as a patient with a positive result on high throughput sequencing or real-time reverse transcriptase-polymerase chain reaction assay of nasal and pharyngeal swab specimens. data were collected from registries of the respiratory disease units coordinators at the nine hospitals identifying all of the patients receiving nrs outside the icu. excluding standard oxygen administration, patients were treated with three different types of nrs, namely high-flow nasal cannula (hfnc), continuous positive airway pressure (cpap), or noninvasive ventilation (niv), which also represented the three different groups in the analysis. the triage of patients was performed according to the italian respiratory societies joint guidelines based on severity. in particular, the following categories were proposed: a) green (sao 2 >94%, respiratory rate (rr)<20 breaths/min); b) yellow (sao 2 <94%, rr>20 but responds to 10-15 l/min oxygen); c) orange (sao 2 <94%, rr>20 but poor response to 10-15 l/min oxygen and requiring cpap/niv with very high fio 2 ); d) red (sao 2 <94%, rr>20 but poor response to 10-15 l/min oxygen, cpap/niv with very high fio 2 or presenting respiratory distress with pao 2 /fio 2 <200 and requiring eti and intensive care). patients belonging to these latter two categories were therefore considered eligible for nrs in dedicated respiratory covid areas (see below) set up for the isolation of confirmed cases and arf treatment. these patients were not "usually" treated outside the icu but, given the "emergency" situation, the lack of icu beds and only once multiorgan disfunction was excluded, they still resulted eligible for an nrs trial. the transfer of severely ill patients to the icu for intubation, with compromised haemodynamic parameters, low pao 2 /fio 2 or 'not responding to nrs', was discussed with the intensivists, based on prognosis, and obviously was only possible if beds were available. although not specifically mentioned in the guidelines, hfnc was also used in these two categories, during breaks in ventilation or as a stand-alone support. the use of helmet cpap devices was suggested as first-line treatment, mainly for safety reasons. clearly, this technique requires a sufficient supply of helmet interfaces (which ran out quite rapidly) and a high flow of o 2 (which exceeded the o 2 capacity in some hospitals), so that niv and hfnc were used as alternatives, the first when it was necessary to "save" oxygen, and the second when cpap availability finished. the respiratory covid areas consisted mainly of two different units, both present in all of the hospitals. the first one, formerly a respiratory ward, was an ad-hoc dedicated respiratory monitoring unit consisting of specialized monitored areas with an active full-day shift run by a fixed group of pulmonologists and with a "reinforced" nurse-patient ratio varying from 1:4 to 1:6 depending on the hospital. the second unit, called respiratory intermediate care units, consisted of a fixed medical team. these had a monitoring system similar to that of the respiratory monitoring units, together with the availability of icu ventilators and a nurse-patient ratio from 1:2 to 1:4, where more severely affected patients were usually treated. patients were continuously monitored with electrocardiogram trace, noninvasive blood pressure, arterial oxygen saturation, and respiratory rate (rr). intensive care medicine doctors were eventually available around the clock at the request of the ward teams. great care was taken to keep a distance of >1.5 metres between each bed and to provide natural ventilation and airflow of at least 160 l·s -1 per patient. concerning staff protection, first of all, courses were quickly organized for staff in the correct use of personal protective equipment (ppe), dressing and undressing. filtering facepiece class 3 (ffp3) or ffp2 masks, double non-sterile gloves, long-sleeved water-resistant gowns, goggles or face shields were mandatory in the presence of aerosol producing procedures. niv was delivered mainly by dedicated single circuit niv platforms provided with an oxygen blender and ad-hoc filters placed in the single tube circuit before the non-rebreathing devices to minimize bio-aerosol dispersion, or by icu ventilators. hfnc was delivered using standard devices (nasal high flow therapy, fisher and paykel healthcare ltd, new zealand), while helmet cpap dedicated devices, designed for pandemics, were simply activated by connecting them to the o 2 source available in the hospital with blender systems applied to obtain adequate values of delivered fio 2 (intersurgical spa, mirandola, italy and dimar srl, medolla, italy). data were collected prospectively from registries of the respiratory disease units identifying all of the patients receiving nrs outside the icu. variables recorded for each patient were obtained for the period from march 1 st until may 10 th 2020 and included the following: demographics (age, sex), comorbidities (type and number), respiratory condition at admission (respiratory rate (rr), pao 2 /fio 2 ratio), medications (type of drugs prescribed), mode and usage of the nrs (ventilatory settings for niv and cpap, and flow rate for hfnc), and stay in hospital (days). the number of patients who died, either in the respiratory unit or in the hospital, and the patients who received endotracheal intubation (eti) within the same time frame were recorded. patients who were still hospitalized at the time of data analysis were excluded. the health status of the staff working in the respiratory unit was closely monitored. all staff with fever or respiratory symptoms underwent chest radiography, and nasal and pharyngeal swab specimens were taken. serology for sars-cov-2 antibodies and pharyngeal swab was also periodically performed for all staff. no statistical sample size assessment was performed a priori, and sample size was the number of patients treated during the study period in the participant centres. baseline characteristics of patients treated with hfnc, cpap and niv were compared. across the treatment subgroups, continuous variables were expressed as means and standard deviation (sd) and were compared with the kruskal-wallis test and one-way anova test, while categorical variables were expressed as numbers and percentages (%) and were compared using the χ2 test or fisher's exact test. percentages of available data for the overall study population were based on the total number of patients included in the study, while the distribution of available data over the treatment subgroups was based on the available data for that variable, and the percentages were calculated using the number of available data for that subgroup. the fraction of infected professional health care workers was presented as numerical and percentage values. the association between ventilatory treatment and clinical outcomes was calculated using a logistic regression model. the 30day mortality rate was calculated adjusted for baseline confounders (age, p/f ratio, steroid usage and number of comorbidities). a total of 704 patients were considered and of these, 670 patients were included and their data analyzed. table 1 lists the patients' characteristics. cpap, as applied by helmet, was used on the majority of patients (supplementary table 1 ). twenty-eight out of 670 (4.2%) had a do not intubate (dni) order. figure 1 illustrates the patients' allocation to nrs and clinical outcome. a total amount of 180 patients died at 30 days. twenty of the 28 dni patients died (9% of the total number of deaths). in total, 114 patients died on spontaneous breathing without an expressed written dni order. most of the study patients were male (69.3%). hypertension, diabetes, dyslipidemia, obesity and chronic cardiovascular disorders were the comorbidities most represented, evenly distributed among the groups with the exception of obesity, which was more prevalent in the niv group. hydroxychloroquine, methylprednisolone, low molecular weight heparin and tocilizumab were the drugs most used for treatment. the frequency distribution of age and pao 2 /fio 2 ratio in the whole study population are shown in supplementary figure 1 . table 2 , 353 health care workers, including doctors, nurses, and health-care assistants, had been taking care of patients receiving nrs. forty-two of them (12%) tested positive for sars-cov-2 infection showing symptoms of mild (n=9) or moderate disease requiring hospitalization (n=3). all infected workers recovered well. the overall rate of workers infected, in personnel not specifically involved in the care of covid-19 patients, in the nine hospitals was 3.8±1.9%. outcome measures stratified by pao 2 /fio 2 ratio classes and according to nrs are reported in table 5 . patients with a pao 2 /fio 2 ratio below 50 mmhg presented a higher 30-day mortality rate and a higher rate of eti (p<0.001 and p<0.001, respectively). supplementary table 1 . niv was used as much as the patients could tolerate and in a small percentage of cases (43/177=24%), hfnc was applied during the intervals. patients with bilateral posterior infiltrates were also usually placed in the prone position for few hours a day, in all three nrs groups, with a schedule dependent on their tolerance. this study showed that using nrs devices is feasible in patients with arf due to sars-cov-2 infection treated outside icus, in newly developed dedicated covid respiratory monitoring units, formerly respiratory wards, and in respiratory intermediate care units. despite using the recommended ppe, a 11.4% contamination rate was observed among healthcare workers treating the infected patients. after adjusting for potential confounders, 30-day mortality rates using hfnc, cpap and niv were not significantly different. one of the major concerns of using bio-aerosol generating devices is that healthcare workers are at high risk of contracting the infection and therefore most international guidelines recommend being cautious or even contraindicate their use (6) (7) (8) . nevertheless, who advocate using cpap or niv for the management of respiratory failure in covid-19 patients, provided that appropriate ppe is worn by the personnel (9) . several studies have found that the maximum exhaled air dispersion via different oxygen administration and ventilatory support strategies is minimal for cpap through an oronasal mask or niv through a helmet equipped with an inflatable neck cushion, and is much less when compared with any kind of oxygen delivery system (10). interestingly enough, so far, studies have been conducted in negative pressure hospital rooms with at least six air changes per hour (minimum number of air changes recommended by who is 12 per hour). when these rooms were not available, as was the case for most of our patients, alternative hospital areas including rooms with natural ventilation (expressed as the product of room volume and air change rate) of at least 160 l·s -1 per patient were routinely employed, in keeping with the who statement (11) . indeed, according to the italian recommendations (4), the large majority of our study population received cpap (by helmet or face mask), mask-niv, and hfnc with a medical mask over the nasal prongs. taking all these precautions into account and using all of the appropriate protection, the number of health workers who tested positive at serology or pharyngeal swab was still quite high (11.4%); however, those who became ill (12/369, i.e. 3.3% of the staff involved) were in line with the 3.5% of health care workers requiring hospital admission in china (12) , the only study so far that has reported this outcome during the covid-19 outbreak. one may claim that our staff could have been infected in the community rather than by exposure to nrss; however, in the nine hospitals in this study, the overall rate of infection of health workers, in personnel not specifically involved in the care of covid-19 patients. the dramatic and rapidly increasing wave of the pandemic obliged us to treat a high number of severely hypoxic patients with nrs outside the icu. these patients are usually admitted to "protected" environments. the ats/ers guidelines (13) for example suggested using niv in de-novo respiratory failure only when managed by an experienced clinical team, and closely monitored in the icu. concerning the first point, all of the units involved had extensive experience in nrs use over a long period, and the nurse-patient ratio was "unusually" high for a ward, since during the outbreak, the nursing staff was reinforced in the locations where the acutely ill patients were admitted. in addition, fully equipped noninvasive monitoring systems were available. this is by far the largest report on the use of nrs outside the icu; however, our covid dedicated respiratory units cannot be considered equivalent to the "usual" respiratory wards. previous studies conducted in icus where nrs use was reported (1,15-21) account for 188 patients treated with niv and 61 by hfnc, without showing their characteristics and severity or the outcomes (in all but one study). interestingly, this latter study (19) showed a very high mortality rate both with niv and hfnc (80% and 52%, respectively). indeed, only a few patients were treated in the respiratory ward or unit, namely 80 and 33 patients using niv and hfnc respectively, with a poor survival rate (22, 23) . despite the fact that comparison among studies is extremely difficult due to the potential heterogeneity of patients included and/or to differing local hospital organization, the failure rate (i.e. mortality and/or eti) was much lower in our population, even when adjusted for potential confounders (see table 3 ), and it was comparable to what was observed (26%) in a large italian study performed in the icu in patients mostly intubated and with a pao 2 /fio 2 ratio similar to ours (1). in addition, in a recent two-period retrospective case-control study, oranger et al. (24) demonstrated that cpap could avoid intubation at 7 days and at 14 days, particularly in covid patients with a previous dni decision. the mortality rate was similar with all of the nrs modes used after adjustment for confounders; however, it has to be noted that hfnc was usually applied in less sick patients compared with niv and cpap, and this may reflect the attitude of the clinicians to start these latter two modes in patients where they judged that applying a relatively high level of external positive end expiratory pressure (peep) was more appropriate. it has been suggested that using any form of nrs might unduly delay the start of eti; however, it should be noted that 28 patients received a dni order (20 of them died), and that an icu bed was not promptly available at the time of deterioration, as reported in a specific small subset of the patient population. it may also be argued that "only" less than 5% of patients signed a dni order. in italy, the very large majority of the population are not sufficiently aware of the new advanced directive law (25), or they do not want to complete in advance any document in this respect. therefore, most of our patients arrived at hospital without any dni or do not resuscitate directives. the reasons for not proceeding to eti in the absence of a written dni order might be explained by: presumed lack of benefit from eti or mechanical ventilation (mv) based on clinical judgement, sudden death, or verbal refusal from the patient at the time of clinical deterioration. however, the majority of patients received "full treatment" when needed. despite the fact that this retrospective analysis in a large population indicates that nrs may help to treat severely affected covid-19 patients outside the icu, in newly dedicated respiratory areas with experienced staff, it also presents three main limitations. first, the design was retrospective, like most of the studies published during this terrible period. second, the decision to start one of the nrs modes was left to the attending physicians and mainly relied on the actual availability of equipment, so that the proportion of devices used was not evenly distributed. third, as in most reallife studies dealing with the covid-19 pandemic (1), missing data may be quite relevant; however, the critical nature of the situation did not always allow detailed information to be collected. to conclude, this is the first observational, large multicentre study showing that the application of noninvasive respiratory devices outside the icu is feasible but is associated with a risk of staff contamination; however, the retrospective study design precludes drawing firm conclusions about its effectiveness despite the fact that the mortality and intubation rates compare favourably with those of previous reports. baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region, italy official bulletin of lombardy region, date march 18 th covid-19 and italy: what next? managing the respiratory care of patients with covid-19. available at www.aiponet.it and www.sipirs.it date last accessed nosocomial outbreak of 2019 novel coronavirus pneumonia in wuhan, china intensive care society, association of anaesthetists and royal college of anaesthetists. critical care preparation and management in the covid-19 pandemic. available at: www.icmanaesthesiacovid-19.org date last accessed the australian and new zealand intensive care society covid-19 guidelines (version 1 surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) clinical management of severe acute respiratory infection (sari) when covid-19 disease is suspected. interim guidance -13 protecting healthcare workers from sars-cov-2 infection: practical indications infection prevention and control during health care when covid-19 is suspected: interim guidance. available at www.who.int. date last accessed death from covid-19 of 23 health care workers in china official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure characteristics and outcomes of 21 critically ill patients with covid-19 in washington state clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china clinical course and outcomes of 344 intensive care patients with covid-19 clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china covid-19 in critically ill patients in the seattle region -case series clinical features of patients infected with 2019 novel coronavirus in wuhan, china 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 china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china continuous positive airway pressure to avoid intubation in sars-cov-2 pneumonia: a two-period retrospective case-control study the italian law on informed consent and advance directives: new rules of conduct for the autonomy of doctors and patients in end-of-life care key: cord-350166-loxe11d6 authors: garmendia, onintza; rodríguez-lazaro, miguel a.; otero, jorge; phan, phuong; stoyanova, alexandrina; dinh-xuan, anh tuan; gozal, david; navajas, daniel; montserrat, josep m.; farré, ramon title: low-cost, easy-to-build non-invasive pressure support ventilator for under-resourced regions: open source hardware description, performance and feasibility testing date: 2020-04-20 journal: eur respir j doi: 10.1183/13993003.00846-2020 sha: doc_id: 350166 cord_uid: loxe11d6 aim: current pricing of commercial mechanical ventilators in low/middle-income countries (lmics) markedly restricts their availability, and consequently a considerable number of patients with acute/chronic respiratory failure cannot be adequately treated. our aim was to design and test an affordable and easy-to-build non-invasive bilevel pressure ventilator to allow reducing the serious shortage of ventilators in lmics. methods: the ventilator was built using off-the-shelf materials available via e-commerce and was based on a high-pressure blower, two pressure transducers and an arduino nano controller with a digital display (total retail cost <75 us$), with construction details open source provided for free replication. the ventilator was evaluated (and compared with a commercially available device (lumis-150, resmed): a) in the bench using an actively breathing patient simulator mimicking a range of obstructive/restrictive disease and b) in 12 healthy volunteers wearing a high airway resistance and thoracic/abdominal bands to mimic obstructive/restrictive patients. results: the designed ventilator provided inspiratory/expiratory pressures up to 20/10 cmh(2)o, respectively, with no faulty triggering or cycling both in the bench test and in volunteers. breathing difficulty score rated (1–10 scale) by the loaded breathing subjects was significantly (p<0.005) decreased from 5.45±1.68 without support to 2.83±1.66 when using the prototype ventilator, which showed no difference with the commercial device (2.80±1.48; p=1.000). conclusion: the low-cost, easy-to-build non-invasive ventilator performs similarly as a high-quality commercial device, with its open-source hardware description, will allow for free replication and use in lmics, facilitating application of this life-saving therapy to patients who otherwise could not be treated. non-invasive mechanical ventilation (niv) is a widely used and accepted treatment for chronic respiratory diseases and, in some cases, it is also an alternative to invasive ventilation options for patients with acute respiratory failure caused by a variety of aetiologies (1) . although positive pressure ventilation in low-and middleincome countries (lmic) is most frequently provided invasively, the benefits of niv are being increasingly recognised. indeed, for obvious reasons of cost and ease of use, niv appears to be not only an effective, but also a particularly suitable approach to provide respiratory support in patients living in developing low-income economies (2) . this is especially relevant since in these regions the burden of critical illness is large, and is expected to increase with growing urbanization, emerging epidemics and expanding access to hospitals (2) . furthermore, the elevated cost of healthcare staffing, infrastructure needs, and onerous access to supplies have hampered the development of fully equipped intensive care units (icu) in lmics (3) . as a consequence, the demand for cost-effective medical equipment, such as mechanical ventilators, is likely to greatly increase in those countries. moreover, mechanical ventilators are costly, which markedly restricts their availability, and consequently the ability to adequately treat a significant number of patients with both acute and chronic respiratory failure in lmics. these issues are all the more evident in light of the ongoing corona virus pandemic, where even industrialized economies are encountering significant shortages in the number of available ventilators to meet the demands imposed by this disease, such that availability of non-invasive respiratory support may be valuable for certain patients or as a temporary bridge (4, 5) . philanthropic donation of medical devices may help in providing mechanical ventilators to un-resourced regions in lmics, but these initiatives are fraught with considerable limitations. indeed, donation of commercially available equipment is expensive and is only partially effective since it has been reported that up to 50% of donated devices become unusable due to lack of adequate maintenance and inability to obtain spare parts (6) . in addition, donations are hardly sustainable because they require long-term commitments such as to provide device servicing. in this context, alternative solutions that are based on in-house manufacturing of pressure support devices (7, 8) could reduce the serious shortage of ventilators in lmics. accordingly, the aim of this study was to design and test a novel low-cost bilevel pressure support ventilator, and provide open access to the detailed technical information, thereby allowing for free and unrestricted replication and implementation. to ascertain adequate performance of the device, bench testing was carried out based on simulated patients with obstructive/restrictive diseases under well-controlled conditions, a common widely accepted approach to test therapeutic devices for respiratory support (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) . then, and following the existent literature (19) (20) (21) , the prototype ventilator was tested in healthy volunteers subjected to obstructive-restrictive loaded breathing to mimic patients with respiratory diseases requiring niv. the ventilator was designed to be affordable and easy-to-build, providing an open-source hardware description to allow free replication. the prototype was built using off-the-shelf materials available via e-commerce: a high-pressure blower and its driver (wm7040, ning bo feng hua wei cheng motor factory, zhejiang, china), two pressure transducers (xgzp6847005kpg, cfsensor, wuhu, anhui, china) and an arduino nano controller with a digital display. pressure and flow were continuously measured at the outlet of the ventilator and fed into the controller which was provided with a custom-made code to detect inspirations and expirations and to accordingly trigger the inspiratory and expiratory pressures generated by the blower. the ventilator can operate in timed or spontaneous timed (st) mode (spontaneous breaths of patients are assisted and if the patient's effort is not detected a timed breath is triggered according to a rescue frequency). the retail cost of this ventilator prototype was below 75 us$, and includes all required electronic circuits and power source. noteworthy, this cost could be considerably reduced by wholesale purchasing. all the technical information and detailed circuit schematics and controller code required to build this ventilator (including optional enclosure by conventional 3d printer) is available for release under free terms following the open-source hardware approach in the online supplement (technical_description.zip) . figure 1 shows external and internal images of the prototype. to assess the performance of the novel bilevel pressure ventilator under wellcontrolled conditions, the prototype was evaluated in a bench test using an active patient simulator modelling the respiratory mechanics of patients with different levels of obstructive/restrictive diseases ( figure 2 ). the passive component of the respiratory system model was a variable resistance-compliance (r-c) lung model (adult smartlung, imt analytics, switzerland). to implement an active breathing model, the passive r-c system simulating the lungs was enclosed in a cylindrical box connected to a negative pressure source (figure 2 ), as explained in detail in the online supplement (supplementary_methods&results.pdf). figure 3 shows examples of the simulated pleural pressures applied to the passive model to implement active patient models, which combined 2 breathing frequencies (15 and 20 breaths/min) and 3 negative peak pressure amplitudes (-6, -9, -12 cm h 2 o). four respiratory r-c systems were set for testing the ventilator, mimicking a patient with mild disease, a purely obstructive patient (increased r), a purely restrictive patient (reduced compliance) and a patient with both obstruction and restriction (table 1) . two breathing frequencies were used and different inspiratory efforts were set according to the level of disease ( table 1 ). as shown in the ventilator prototype was tested in 12 healthy volunteers (5 of them women) recruited from the university environment. their mean age was 32.4±5.8 years and their body mass index was 23.3±2.0 kg/m 2 (mean±se). to mimic the respiratory load corresponding to a patient requiring niv the volunteers were instrumented to increase their airway resistance and to decrease their respiratory compliance, as explained in detail in the online supplement (supplementary_methods&results.pdf). the protocol was carried out by one respiratory physiotherapist expert in niv. the volunteer subject was sitting in a comfortable armchair and was equipped with a finger pulse oximeter for monitoring oxygen saturation (wristox 2 , model 3150, nonin medical, plymouth). first, he/she was allowed to get familiar with the use of a nasal mask and niv for 3 minutes. to this end, he/she was connected to a non-invasive ventilator (lumis 150, vpap st, resmed) through conventional nasal mask and tubing, with inspiratory and expiratory pressures set to 8 and 4 cmh 2 o, respectively. subsequently, the subject was equipped with the resistive and restrictive loads and breathed spontaneously (unsupported) for 2 min. after that period of loaded breathing, the volunteer was asked to score his/her breathing discomfort sensation on a visual analog scale where 1 would correspond to spontaneous normal breathing and 10 to the maximum breathing discomfort he/she could consider unbearable. then, he/she was connected to a mechanical ventilator with inspiratory and expiratory pressures set to 16 and 6 cmh 2 o, respectively, in spontaneous trigger (st) mode with a backup frequency of 12 breaths/min. this ventilator was either the prototype under test or a commercially available highperformance device (lumis 150, vpap st, resmed; default settings), determined at random. at the end of a 2 min period, the subject was again asked to score his/her breathing discomfort and, without interruption nor notice to the subject, the ventilator was shifted to the other device for 2 min and then the volunteer was asked again for scoring discomfort. this process of alternating the ventilator (prototype or commercial) was repeated twice more. the discomfort scoring finally assigned to each ventilator was the mean score of the 3 periods corresponding to each device. any faulty triggering or cycling, as observed through inspection of the real time nasal pressure signal and subject's breathing activity, was registered by the physiotherapist. in the bench test, the different investigated variables were assessed by comparing the data obtained with the prototype and the commercial ventilator by means of a paired t-test. in the test with voluntary subjects, discomfort scores when the individual was not mechanically supported and when supported by the two ventilators were compared by paired t-test for normally distributed variables and by wilcoxon signed rank test for non-normally distributed variables. a value of p<0.05 was considered statistically significant. testing in volunteers with resistive and restrictive loads provided positive results on the feasibility of the ventilator prototype for application in humans. as expected from healthy subjects, no decrease in oxygen saturation was observed throughout the whole test period when compared with the unsupported baseline (97.0±1.3%): 96.8±1.0% (p=0.51) and 96.8±0.9% (p=0.23) when supported with the prototype and commercial ventilator, respectively. as shown in figure 6 , discomfort scoring when the 12 subjects were subjected to respiratory loading was 5.45±1.68. these values significantly decreased to 2.83±1.66 (p<0.005) when the loaded patient's breathing was supported by the prototype ventilator. interestingly, the relief in breathing difficulty was virtually the same as the one achieved with the high-performance commercial ventilator (2.80±1.48; p=1.000). no significant differences were observed in the variability across the 3 measurements of breathing discomfort (p=0.208; average standard deviation of 0.61). figure 7 presents an example of the nasal pressure and flow signals when the prototype ventilator, set to considerable values of niv inspiratory and expiratory pressures, was applied to a loaded-breathing volunteer, illustrating that the pressure waveform was suitable, and that the ventilator smoothly followed the breathing pattern of the subjects since no faulty triggering of cycling was detected. figure 2 .suppl (in the supplementary_-methods&results.pdf) shows that the prototype ventilator was able to trigger mandatory ventilation cycles in case of absence of subject's inspiratory effort. here we describe a very low cost bilevel pressure support ventilator which is furthermore, the ventilator control can be adapted to take into account the pressure drop induced by a humidifier in case this component is connected between the ventilator output and the tube connecting to the patient's mask. noteworthy, the proposed approach for ventilator construction empowers the final users in lmics to fully control the procedure, to adapt it to the local conditions, and to update the used components in response to market availability. moreover, continued support from and collaboration with experienced teams abroad is easy and readily feasible. in a time when the most complex devices appear to be needed and can only be provided by a very competitive and specialized industry, the simplicity and performance of this designed low cost device reminds us of the need to go back to the basics, inasmuch as the rationale and implementation of niv has not changed substantially from the pioneering times when this therapy was developed (24) . the bench test was carried out using a commonly used type of actively breathing patient simulator (9) (10) (11) 16, 18) , mimicking a wide spectrum of patient's respiratory mechanical alterations (obstruction and/or restriction), and including normal and high breathing frequencies. moreover, the ventilator was tested under conditions reproducing an unintended leak, a circumstance frequently encountered during clinical niv practice. the 16 different bench test settings (table 1) used to test the ventilator covered the wide range of conditions that non-invasive ventilators are exposed to in real-life clinical applications. the bench test showed that, regardless of the stressing test conditions, the prototype ventilator provided the target bilevel pressures (figure 5 .a) with no faulty triggering or cycling, and with a suitable triggering delay ( figure 5 .b), thereby enabling good synchronization with the inspiratory effort of the simulated patient. the relative simplicity of the feedback control system in the prototype ventilator explains the slightly different shape of pressure waveform observed over the wide range of test conditions ( figure 5 .a), and also facilitates interpretation of the determinants of the small increases in peak inspiratory pressures. whereas the commercial device applied an almost square pressure signal, the pressure waveform generated by the prototype exhibited progressive increase and decrease in inspiratory pressures (figure 4 ). this is consistent with the fact that the commercial device used as a comparator was probably equipped with a more powerful (and hence expensive) feedback system to control its blower. however, several other commercially available ventilators exhibit patterns of inspiratory pressures similar to those observed in the prototype (figure 4 .a) (24) . in fact, the slope of the ramp of increasing inspiratory pressure is one of the parameters that can be set by the user in some commercially available devices, since excessively rapid increases in early onset of inspiratory pressures may lead to patient discomfort ( figure 4 .b) by not mimicking the physiological inspiratory patterns characterized by progressive increases in flow. although tidal volume was not a direct outcome variable controlled by pressure support ventilators, it is interesting to note that the prototype ventilator resulted in tidal volumes that were similar to the ones generated by the commercial device ( figure 5.b) , adding further support to the suitability of the prototype ventilator for generating inspiratory pressure waveforms and adequate tidal volumes in a wide spectrum of simulated patients ( table 1 ). the applicability pilot study was carried out in healthy volunteers subjected to obstructive and restrictive breathing loads. this model is widely used in the literature to simulate the mechanical load of the respiratory system for investigating ventilation (19) (20) (21) and for simulating dyspnoea (26, 27) . in fact, the level of obstruction-restriction we applied to our volunteers resulted in a breathing discomfort score (figure 7 ) similar to the ones set in recent reports to mimic dyspnoea by loaded breathing (26, 27) . the results obtained when testing the applicability of the prototype ventilator in humans showed that, similar to the bench test, there were no faulty triggering or cycling events, that the pressure waveform was similar to those typically observed in commercial ventilators (figures 7 and 2.suppl) , and that the relief of breathing discomfort was virtually the same as the one achieved by the commercial ventilator ( figure 6 ). in addition to methodological and technical issues discussed above, the work presented here requires that we specifically address two aspects that are usually lacking in medical device studies: a) industrial/commercial model and b) safety/ethical issues. indeed, in this work we propose an alternative procedure for building ventilators inhouse and locally, i.e., outside the conventional medical device industrial market. there is little doubt that industry-based conventional production chains, including design, manufacturing and commercialization, play a key role in the healthcare system. accordingly, industry heavily invests in r&d and translates new knowledge from the laboratory bench to patient bedside. in other words, the medical device industry searches and delivers life-enhancing innovative solutions. unfortunately, such industrially-based model is hardly suitable to low-income settings that are usually resource scarce, and where the provision of even adequate basic services to the population is challenging. the main reason why the conventional industrial model does not work in lmics is that the standard industrial production scheme, which also applies to entirely non-for-profit companies, entails significant costs beyond those strictly required for device manufacturing. the vast majority of medical device companies are small and medium-sized, employing less than 50 people, both in europe (95% of all medical technology firms) and in the usa (80%) (28) . moreover, those companies, mainly based in usa and canada (49% of the world market), europe (27%), japan (7%) and china (6%), are highly and globally regulated to guarantee the safety and performance of their innovative and high technology products throughout their life-cycle, as well as pre-and post-marketing (28) . unlike many other industries, r&d expenditures represent a significant cost component for medical device companies. these companies spend on average between 6% and 12% of revenues towards r&d investment (29) , with some niche firms or start-ups incurring even higher r&d costs (> 20%). average selling, general and administrative expenses (sg&a), which include marketing, advertising and promotion costs and general and administrative costs, account for about one-third of total revenues (30) . importantly, the cost of goods sold (cogs), which measures the total cost that it takes for a medical device company to manufacture its products including labour, material costs, rental and utility costs, represent between 35% and 40% of revenues (30) , with the remaining costs going to taxes, interests and depreciation. thus, a disproportionately large share of medical device companies' revenues is slated for expenses beyond those needed to manufacture their products. in contrast, in the approach we describe in this work, as ventilator assembly is performed locally or directly linked local technical partners, the only costs incurred are those associated with purchasing of the components and the actual labor costs of assembling the device, both of which are low thanks to e-commerce and labor costs in lmics, respectively. noteworthy, the approach proposed here may not only allow for adequate availability of ventilators to patients (31) (32) (33) (34) , but may also contribute to the development of the local industry network in lmics (35) (36) (37) . regarding safety and ethical issues, it is important to emphasize that the development and testing of the niv devices that are available in market nowadays, was made possible by development of devices built in-house by physicians and researchers in developed countries, and that these innovations were designed, tested and improved in patients before the corresponding labeling was obtained (24) . notwithstanding, the in-house ventilator proposed here does not have the conventional fda/ce approvals. obviously, such approval procedures are tremendously important for ensuring that medical devices placed into the market are safe and reliable and, as such, have contributed to the progress currently achieved in health care. however, obtaining fda/ce labels is a process devised mainly for the industry in developed countries and is extremely expensive in terms of lmics financial resources. although these countries do not have the complex infrastructure required for such costly processes, simplified or ad-hoc approval procedures could be provided by local authorities or hospital ethical boards. however, particularly in light of the non-existent alternative of using industrial ventilators, i.e., leaving the patient untreated with the attendant consequences. under such difficult circumstances, the ethical trade-off towards compassionate use of medical devices, a mechanism already in place for non-labelled therapies in developed countries, may be considered. in conclusion, we have designed a low-cost easy-assembly ventilator with excellent performance characteristics in both the bench and in voluntary subjects. if as anticipated from these preliminary results, clinical field tests are favourable, this low-cost device may enable provision of respiratory support to patients in lmics who otherwise would have no access to this potentially life saving therapy, as well as escalation of ventilatory support availability in strenuous circumstances such as those imposed by respiratory virus pandemics. table 1 for conditions definition). to implement an active breathing model, the passive r-c system simulating the lungs was enclosed in a cylindrical box (20 cm diameter, 30 cm height), leaving the r-c inlet (airway opening) outside the box (figure 2 ). the air in this box a half-cycle sinusoidal voltage signal driving the blower allowed to generate simulated pleural pressures realistically mimicking those induced by inspiratory muscles in terms of amplitude, frequency and time course. the volunteers were naïve to the pathophysiology of respiratory diseases and had never received mechanical ventilation. they were provided with detailed explanations of the procedure in a specific meeting, and signed a written consent to participate in the protocol. each volunteer was told, in lay language, that: a) his/her respiration would be partially hindered to simulate the breathing difficulty perceived during a heavy physical work or sport practice, b) that a device to facilitate his/her breathing would then be connected through a nasal mask and c) that he/she would be asked to score the 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