Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Background The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide However, little is known about the causes of death and the virus's pathologic features Objective To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests Design Prospective cohort study Setting Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19 Patients The first 12 consecutive COVID-19-positive deaths Measurements Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed Clinical data and medical course were evaluated Results Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2) Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively) Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart Limitation Limited sample size Conclusion The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it Primary funding source University Medical Center Hamburg-Eppendorf

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study.

COVID-19 pathophysiology: A review.

Little is known of the pathologic changes that lead to death in patients with COVID-19. This study reports the autopsy findings of consecutive patients who died with a diagnosis of COVID-19.

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19.

As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, self-limiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

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Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19.

Rationale: The global death toll from coronavirus disease (COVID-19) virus as of May 12, 2020, exceeds 286,000. The risk factors for death were attributed to advanced age and comorbidities but have not been accurately defined.Objectives: To report the clinical features of 85 fatal cases of COVID-19 in two hospitals in Wuhan.Methods: Medical records were collected of 85 fatal cases of COVID-19 between January 9, 2020, and February 15, 2020. Information recorded included medical history, exposure history, comorbidities, symptoms, signs, laboratory findings, computed tomographic scans, and clinical management.Measurements and Main Results: The median age of the patients was 65.8 years, and 72.9% were male. Common symptoms were fever (78 [91.8%]), shortness of breath (50 [58.8%]), fatigue (50 [58.8%]), and dyspnea (60 [70.6%]). Hypertension, diabetes, and coronary heart disease were the most common comorbidities. Notably, 81.2% of patients had very low eosinophil counts on admission. Complications included respiratory failure (80 [94.1%]), shock (69 [81.2%]), acute respiratory distress syndrome (63 [74.1%]), and arrhythmia (51 [60%]), among others. Most patients received antibiotic (77 [90.6%]), antiviral (78 [91.8%]), and glucocorticoid (65 [76.5%]) treatments. A total of 38 (44.7%) and 33 (38.8%) patients received intravenous immunoglobulin and IFN-α2b, respectively.Conclusions: In this depictive study of 85 fatal cases of COVID-19, most cases were males aged over 50 years with noncommunicable chronic diseases. The majority of the patients died of multiple organ failure. Early onset of shortness of breath may be used as an observational symptom for COVID-19 exacerbations. Eosinophilopenia may indicate a poor prognosis. A combination of antimicrobial drugs did not offer considerable benefit to the outcome of this group of patients.

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective Observational Study.

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study

Pirfenidone alleviates lipopolysaccharide-induced lung injury by accentuating BAP31 regulation of ER stress and mitochondrial injury.

disease), and 13 patients (16%) died from cardiac problems, namely cardiac arrest, acute coronary syndrome (ACS), and malignant arrhythmia (1). Cardiac involvement probably complicates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients, but the true incidence (considering specific echocardiographic findings) and the attributable mortality are aspects not yet well clarified. Very few reports have used echocardiographic criteria beyond biomarkers to diagnose cardiac injury, but none have differentiated between myocarditis, cardiomyopathy (stress or septic), ACS, and acute heart failure in the era of COVID-19. Acute cardiac injury was reported in 44.7% of the fatalities in the report by Du and colleagues, but the specific echocardiographic abnormalities are not presented (1). Did these “cardiac injuries” involve patients with myocarditis? Or were there features indicative of stress or even septic cardiomyopathy, mostly reversible entities? Considering biomarkers, troponin levels are markedly increased in myocarditis and ACS. On the contrary, in Takotsubo and septic cardiomyopathy, there is a disparity between biomarker levels and the extent of myocardial dysfunction. In addition, hypoakinesia usually does not correspond to a specific coronary artery territory (2). Therefore, a reference on the nature of cardiac injury would be worthy. A diagnosis of “cardiac injury” mainly relying on biomarker levels may be misleading. In a recent report involving 416 hospitalized patients from Wuhan, 19.7% presented with “acute myocardial injury.” The diagnosis relied on increased cardiac biomarker (hypersensitive troponin I) levels, regardless of the electrocardiographic and echocardiographic findings (3). Du and colleagues presented a high percentage of patients with “cardiac injury”; data on lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase are reported but not on cardiac-specific enzymes (1). On the other hand, cardiac-specific biomarkers alone may not be diagnostic of cardiac damage. TnI is elevated in septic shock, pulmonary embolism, and critically ill patients in ICU. In patients with “cardiac injury,” NTproBNP (N-terminal prohormone of brain natriuretic peptide) levels were found to be elevated (4). However, we have previously found that BNP is a biomarker that correlates with the severity of sepsis (5). BNP may be elevated when patients with SARS-CoV-2 present septic shock resulting from a superinfection, even with normal cardiac function. Additionally, the troponin and BNP levels were normal in a 64-year-old female patient from our ICU, who acutely established pericarditis on the 16th day after COVID-19 diagnosis. Moreover, in Figure 1C of Du and colleagues, they present a computed tomographic image of a 23-year-old female patient with COVID-19. The cardiac structure seems greatly enlarged; considering the young age of the patient, this finding could correspond to true myocarditis (therefore, ground glass opacities could depict hydrostatic pulmonary edema) (1). It would be informative if the authors provided data on this aspect (increased cardiac dimensions on computed tomographic imaging, a finding beyond the criteria used for “cardiac injury” diagnosis). Inciardi and colleagues reported a 53-yearold woman with COVID-19 who presented acute myopericarditis and cardiogenic shock with severe systolic dysfunction, confirmed with magnetic resonance imaging. Noteworthy, the patient never presented signs of respiratory involvement (6). Finally, data on the attributable to cardiac injury mortality are totally lacking (1). The proportion of the patients with “cardiac injury” who actually died because of cardiogenic shock is not mentioned. Markers of perfusion, such as low central venous oxygen saturation, would add information on the contribution of cardiac dysfunction to the fatal outcome. Furthermore, did the patients, dying of malignant arrythmia and cardiac arrest, suffer from cardiac comorbidities? Did the arrhythmia occur on a substrate of “myocardial injury,” or was this a complication of the prescribed medications (i.e., chloroquine)? All these issues need to be clarified to thoroughly understand the “myocardial damage” that COVID-19 induces. n

Xi Wang

Papers

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective Observational Study.

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study

Pirfenidone alleviates lipopolysaccharide-induced lung injury by accentuating BAP31 regulation of ER stress and mitochondrial injury.

Reply to Tsolaki and Zakynthinos: Are Patients with COVID-19 Dying of or with Cardiac Injury?