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    9 Comments for this article
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    Analysis may be confounded, mis-specified
    Jesse Heitner, ScD, Global Health | Aceso Global
    This study is very important because it  investigates what treatments are effective for COVID-19. It concludes that methylprednisolone may be beneficial; however it also states that patients who died were less likely to be treated with antiviral therapy (P<.001). All analyses are bivariate, which makes treatment effects un-interpretable, because bivariate analysis allows for high levels of confounding by age, comorbidity, and presenting disease severity. Worse, it does not account for which patients received both steroids and antivirals to investigate which, if either, was having a beneficial effect. The question of treatment efficacy is of extreme importance at this stage of the pandemic, and it must be analyzed in a multivariable mode.

    Further, a logit or probit model would be more appropriate for a dichotomous outcome such as died vs. recovered; a cox model (which is a time-to-event) model assumes all patients will reach the same outcome, with the differences being when, not if, a patient will die/reach ARDS.

    In sum, this study is timely and of potentially great use in treatment decisions, but only if a better (multivariable) analysis is done of the association between treatment methods and survival.
    CONFLICT OF INTEREST: None Reported
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    Mode of transmission
    Raouf Allim, MB BCh DA DRCOG | General Practitioner, UK
    Do we know anything about the effect of mode of transmission on the severity of illness? For example, presuming that the virus can spread by aerosol (5-10 micrometre droplets) as well as large droplets and surface contamination, is there a difference in disease severity with different modes of transmission?
    CONFLICT OF INTEREST: None Reported
    Risk Factors for COVID-19 and Conditioning Sets
    Michael McAleer, PhD(Econometrics),Queen's | Asia University, Taiwan
    The detailed diagnostic and empirical analysis of the effects of acute respiratory distress syndrome (ARDS) and 84 deaths from confirmed COVID-19 pneumonia, for a sample of 201 older age men and women from a single hospital in Wuhan with compromised immune systems, is highly informative.

    Not surprisingly, older age was found to be a leading risk factor leading to death.

    It would be instructive for healthcare workers if the sample were extended to a larger number of patients, according to differences in ages, stages and severity of pneumonia, types and levels of chronic underlying conditions, comorbidities,
    tobacco and alcohol history, types of coinfections, including influenza, follow-up of recovered patients for reinfection, discharge rates, and alternative model specifications.

    There are at least three possible categorical outcomes, namely full recovery, partial recovery (after follow-up), and death, and numerous deterministic factors, which affect the model specifications that can be used.

    Issues of how to deal with missing data, which reduces the sample size, a larger number of statistical tests, and diagnostic checks regarding the underlying assumptions of the models to provide more robust empirical analysis, would be useful in future research.

    Overall, the list of variables in the conditioning set is more extensive than has been incorporated in the invaluable empirical study.
    CONFLICT OF INTEREST: None Reported
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    Additional COVID-19 Information about Italy
    Stefano Olgiati, PhD (Epidemiology) | University of Bergamo, Bergamo 24129, Italy

    Wu et at (2020) report in the Introduction to their study that the coronavirus: "... has subsequently spread to other regions of China and 37 countries, including the United States, Japan, Australia, and France.

    The WHO (2020) Situation Report 37 has reported that  Italy is the country with the highest number of positive confirmed cases and deaths after China. This information is important with regard to the early chain of transmission of the virus.

    As of March 13, 2020, Italy still had the highest number of confirmed cases (24747) and of deaths (1809) after China (Dong et
    al, 2020). This is important because with regard to the chain and magnitude of transmission of the virus.

    Stefano Olgiati
    stefano.olgiati@unibg.it
    s.a.olgiati@gmail.com

    REFERENCES

    Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994

    World Health Organization. Coronavirus disease 2019 (COVID-19): situation report—37. February 25, 2020. Accessed February 26, 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200226-sitrep-37-covid-19.pdf?sfvrsn=6126c0a4_2

    Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis; published online Feb 19. https://doi.org/10.1016/S1473-3099(20)30120-1.
    CONFLICT OF INTEREST: None Reported
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    Application of methylprednisolone in COVID-19 pneumonia
    Yin Wang, M.D.,Ph.D. | Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
    We read with interest in the original research article by  Wu et al. describing the clinical characteristics and factors associated with developing ARDS and progression from ARDS to death in patients with COVID-19 pneumonia. This is a very informative and timely study published in the context of COVID-19 pandemic and challenge worldwide. We have several concerns about the application of methylprednisolone in patients with COVID-19 pneumonia. Did the authors have any additional information regard to the dose and duration of methylprednisolone treatment, and were there any corticosteroid-induced complications observed in the patients who received methylprednisolone?

    The authors found administration
    of methylprednisolone appeared to reduce the risk of death in COVID-19 pneumonia patients with ARDS; however, of those who received methylprednisolone treatment, 23 of 50 patients died. This is rather high morality of approximate 50%; therefore, we are concerned that the evidence is not sufficient to declare the benefit of methylprednisolone treatment in the ‘real-world’ practice. Cytokine storm and viral evasion of cellular immune responses are thought to play important roles in the development of COVID-19 pneumonia, and histologic examination has shown diffuse alveolar damage and mucinous exudate similar to acute respiratory distress syndrome. Given corticosteroids as the conventional treatment for ARDS, it should be reasonable to consider the application of methylprednisolone in the treatment of severe COVID-19 pneumonia, but the issues of crucial importance are timing, dosage and duration.

    The study by Wu et al. highlights an important issue regard to the challenges in treatment of COVID-19 pneumonia. We agree with the authors that methylprednisolone should be applied in the treatment of severe cases, however, in terms of the indication, timing, dosage and duration, the application of methylprednisolone warrants further investigation. Therefore, the clinical applicability of the findings needs to be tempered owing to the unanswered questions that remain.
    CONFLICT OF INTEREST: None Reported
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    Conclusions on Methylprednisolone
    Hans-Joachim Kremer, Dr. rer. nat. | Medical Writing Service
    The authors’ conclusions on methylprednisolone and risk of deaths are unfounded and misleading. They wrote that methylprednisolone „decreased the risk of death” and based this statement on a Kaplan-Meier analysis with an impressively low p-value of 0.003. However, such an analysis is related to median time of survival rather than risk. In fact the median time in this selected subset differed by 15 days. But, are these 15 days really of any clinical relevance? Are these 15 days of benefit for the patients, considering that they spent this time not in freedom and good health condition but in the ICU and most likely under mechanical ventilation?
    Even these concerns are only lightly touching the crucial problem. In fact, 23 of the 50 (46%) with ARDS who received methylprednisolone died, compared with 21 of the other 34 (62%) with ARDS who did not receive this drug. At least for testing robustness of the conclusions, the authors should have performed an analysis of this difference by the Fisher’s Exact test; the 2-tailed version yields a p-value of 0.1856. This level cannot be considered as significant by any rule, thus, it cannot support the conclusions.
    The basic facts are even topping this concern, however. The data of this paper indicate that 23 of 62 (37%) who received methylprednisolone died, to be compared with 21 of the 139 (15%) who did not receive this drug, yielding a p-value of 0.000815 (Fisher’s Exact as above). Remember that all 201 patients reported here were selected because they were hospitalized and had pneumonia and evidence for COVID-19.
    The estimates of 37% vs. 15% are well in line with other reports from China [1, 2, 3].


    1. Wang D, Hu B, Hu C,et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585.
    2. Guan WJ, Ni ZY, Hu Y, Liang WH et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. doi: 10.1056/NEJMoa2002032.
    3. Zhou F, Yu T, Du R, Fan G, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 11. pii: S0140-6736(20)30566-3. doi: 10.1016/S0140-6736(20)30566-3.
    CONFLICT OF INTEREST: None Reported
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    Disseminated pulmonary microvascular thromboembolism in COVID-19: a mechanistic link between coagulopathy and respiratory failure?
    anne sofie andreasen, MD, PhD, EDIC | Department of Anesthesiology and Intensive Care, Herlev and Gentofte Hospital, Denmark
    In this article, Wu and colleagues report that the marked COVID-19-associated coagulopathy is associated with a higher risk of developing acute respiratory distress syndrome (ARDS). This finding may suggest a causative link between deranged coagulation and the pulmonary pathophysiology of COVID-19. I posit that pulmonary thromboembolism, particularly disseminated pulmonary microvascular thromboembolism, is a major contributor to respiratory failure in these patients.

    Our preliminary clinical experience in Denmark is consistent with recently published data that COVID-19-associated respiratory distress differs from the usual ARDS presentation. Hence, despite severe hypoxemia, static pulmonary compliance is typically only mildly affected, and relatively low
    peak end-expiratory pressure levels during mechanical ventilation (i.e. often less than 10 cm H2O) are required to achieve sufficient oxygenation (1,2). Furthermore, chest CT findings of ground glass opacities, septal thickening, and linear opacities (3,4) are quite consistent with the lung parenchymal changes of diseases in the pulmonary vasculature, such as chronic embolic disease or chronic sickle cell disease (5). Finally, a retrospective study based on 449 COVID-19 patients found that anticoagulant therapy is associated with a lower mortality in patients with D-dimer levels > 6 fold of upper limit of normal (1). This study furthermore refers to a yet unpublished lung dissection that shows evidence of pulmonary microvascular thrombi and occlusion in a critically ill COVID-19 patient (1). Like the study by Wu and colleagues, the abovementioned findings are all consistent with pulmonary thromboembolism, notably disseminated pulmonary microvascular thromboembolism, as an important contributing factor to respiratory failure in critically ill COVID-19 patients.

    Regrettably, and although many of the patients did exhibit cardiovascular risk factors, Wu and colleagues do not report whether anticoagulant therapy, as it is noted for methylprednisolone treatment, is associated with a reduced risk of ARDS and/or mortality. Furthermore, it would be relevant to know whether any relevant chest imaging or autopsies were performed, and if so, whether any signs of pulmonary thromboembolic disease were noted. If so, I believe that prospective clinical trials on anticoagulant therapy for critically ill COVID-19 patients should be considered in the very near future.

    References
    1. Liu X, Liu X, Xu Y, et al. Ventilatory ratio in hypercapnic mechanically ventilated patients with COVID-19 associated ARDS. American Journal of Respiratory and Critical Care Medicine. 2020;In press. doi:10.1164/rccm.202002-0373LE
    2. Meng L, Qiu H, Wan L, et al. Intubation and ventilation amid the COVID-19 outbreak: Wuhan’s experience. Anesthesiology. 2020;In press. doi:10.1097/ALN.0000000000003296
    3. Liu KC, Xu P, Lv WF, et al. CT manifestations of coronavirus disease-2019: a retrospective analysis of 73 cases by disease severity. European Journal of Radiology. 2020;126. doi:10.1016/j.ejrad.2020.108941
    4. Li Y, Xia L. Coronavirus disease 2019 (COVID-19): role of chest CT in diagnosis and management. American Journal of Roentgenology. 2020;In press:1-7. doi:10.2214/AJR.20.22954
    5. Montani D, Achouh L, Dorfmüller P, et al. Pulmonary veno-occlusive disease: Clinical, functional, radiologic, and hemodynamic char
    CONFLICT OF INTEREST: None Reported
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    Questions about Generalizability of Findings
    Stephen Mchugh, M.D. | University of Pittsburgh School of Medicine
    Dr. Wu and colleagues performed a study to describe demographic, laboratory, and treatment factors associated with the development of ARDS and death in patients with COVID-19 pneumonia.(1) However, specific details from this single-center study raise questions about widespread generalizability of the results.

    Treatment of ARDS frequently requires intubation and invasive mechanical ventilation. In their study, Wu et al report that 41.8% of patients developed ARDS and 21.9% died, but only 3% received invasive mechanical ventilation. Previous studies have suggested that greater than 85% of critically ill patients with ARDS will eventually need intubation and mechanical ventilation.(2,3) The reason for
    the limited use of this therapy was not discussed in the article. Did it represent a systematic difference in patterns of care or perhaps a scarcity of resources during a pandemic? This uncertainty makes it difficult to generalize their results, especially in regions where invasive mechanical ventilation is regularly used to treat ARDS.

    Furthermore, only 32.8% of patients in the study had pre-existing comorbidities. This is surprising in a population with a median age of 51 years. Additional discussion of this seemingly low degree of comorbidities is not provided. Given the ongoing COVID-19 pandemic, rapid publication of information like that in this study is important. However, more details on the patients and especially the treatment decisions for ARDS in the study would be helpful in guiding other clinicians’ decisions.

    Yin Wu, MD, MBA
    Julian H. Broad, MD
    Stephen M. McHugh, MD
    Department of Anesthesiology and Perioperative Medicine
    University of Pittsburgh School of Medicine


    References:
    1. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China [published online ahead of print, 2020 Mar 13]. JAMA Intern Med. 2020;e200994.
    2. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries [published correction appears in JAMA. 2016 Jul 19;316(3):350]. JAMA. 2016;315(8):788–800.
    3. Kangelaris KN, Ware LB, Wang CY, et al. Timing of Intubation and Clinical Outcomes in Adults with Acute Respiratory Distress Syndrome. Crit Care Med. 2016;44(1):120–129.
    CONFLICT OF INTEREST: None Reported
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    Misleading language used to describe methylprednisolone results
    Kyle Koster, MD, MS | Weill Cornell Medicine, New York, New York
    Wu and colleagues reported that methylprednisolone administration "reduced the risk of death" in patients with acute respiratory distress syndrome (ARDS) associated with coronavirus disease 19 (COVID-19). We caution against this implication of causation, given the observational study design and lack of statistical adjustment for potential confounders. Furthermore, we contend that the data do not in fact demonstrate that methylprednisolone was associated with a reduced risk of death.

    The authors reached their conclusion based on a hazard ratio of 0.38 (95% CI, 0.20-0.72; P = .003), which they derived from the Kaplan-Meier method with log-rank test [1]. The hazard ratio
    estimates the odds that an individual in the group in the numerator reached the endpoint first [2]. Thus, the hazard ratio reported by Wu et al. tells us that a randomly selected patient who received methylprednisolone had an odds of 0.38 of dying sooner than a randomly selected patient who did not receive methylprednisolone. Converting odds to probability, it can be stated that patients receiving methylprednisolone had a 28% probability of dying sooner (or inversely, a 72% probability of living longer). However, the hazard ratio does not tell us whether the risk of death was different at the end of the study period, which may be a more important comparison, particularly when the duration of follow-up is short.

    Wu et al. reported that, among patients with ARDS, 23 of 50 (46%) of those treated with methylprednisolone died versus 21 of 34 (62%) of those not treated with methylprednisolone. Based on these data, the risk ratio of death at the end of the study period was 0.74 (95% CI, 0.50-1.11). The confidence interval includes the possibility of a substantial amount of harm, and, as pointed out by Dr. Kremer in an earlier comment, the result does not reach statistical significance (P = 0.19 using 2-sided Fisher exact test). Therefore, we should not infer that methylprednisolone was associated with a reduced risk of death.

    Understanding the difference between hazard ratio and risk ratio is important, as is the language we use to describe these different methods of analysis. We submit that a more accurately stated conclusion might be as follows: Among COVID-19 patients with ARDS, methylprednisolone administration was associated with a delay in time to death, but by the end of the study period, probability of death was similar in both groups.

    Kyle M. Koster, MD, MS
    Brett G. Fischer, MD
    Weill Department of Medicine
    Weill Cornell Medicine
    New York, New York

    References:

    1. Bland JM, Altman DG. The logrank test. BMJ 2004;328(7447):1073. doi:10.1136/bmj.328.7447.1073

    2. Spruance SL, Reid JE, Grace M, Samore M. Hazard ratio in clinical trials. Antimicrob Agents Chemother. 2004;48(8):2787–2792. doi:10.1128/AAC.48.8.2787-2792.2004
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    March 13, 2020

    Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China

    Author Affiliations
    • 1Department of Pulmonary Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
    • 2Infection Division, Wuhan Jinyintan Hospital, Wuhan, China
    • 3Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
    • 4Tuberculosis and Respiratory Department, Wuhan Jinyintan Hospital, Wuhan, China
    • 5Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 6Department of Infectious Diseases, Fengxian Guhua Hospital, Shanghai, China
    • 7Department of Pulmonary Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 8Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 9Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 10Department of Emergency Medicine, Shanghai Pudong New Area Gongli Hospital, Shanghai, China
    • 11Shanghai Respiratory Research Institute, Shanghai, China
    • 12Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 13National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
    JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994
    Key Points

    Question  What clinical characteristics are associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death among patients with coronavirus disease 2019 (COVID-19) pneumonia?

    Findings  In this cohort study involving 201 patients with confirmed COVID-19 pneumonia, risk factors associated with the development of ARDS and progression from ARDS to death included older age, neutrophilia, and organ and coagulation dysfunction. Treatment with methylprednisolone may be beneficial for patients who develop ARDS.

    Meaning  Risk for developing ARDS included factors consistent with immune activation; older age was associated with both ARDS development and death, likely owing to less robust immune responses.

    Abstract

    Importance  Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.

    Objective  To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.

    Design, Setting, and Participants  Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020.

    Exposures  Confirmed COVID-19 pneumonia.

    Main Outcomes and Measures  The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.

    Results  Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).

    Conclusions and Relevance  Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

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