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

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications

The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

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Mechanisms of SARS-CoV-2 entry into cells.

A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan, China, in December 2019. Since then, the virus has made its way across the globe to affect over 180 countries. SARS-CoV-2 has infected humans in all age groups, of all ethnicities, both males and females while spreading through communities at an alarming rate. Given the nature of this virus, there is much still to be learned; however, we know that the clinical manifestations range from a common cold to more severe diseases such as bronchitis, pneumonia, severe acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. It is believed that COVID-19, in those with underlying health conditions or comorbidities, has an increasingly rapid and severe progression, often leading to death. This paper examined the comorbid conditions, the progression of the disease, and mortality rates in patients of all ages, infected with the ongoing COVID-19 disease. An electronic literature review search was performed, and applicable data was then collected from peer-reviewed articles published from January to April 20, 2020. From what is known at the moment, patients with COVID-19 disease who have comorbidities, such as hypertension or diabetes mellitus, are more likely to develop a more severe course and progression of the disease. Furthermore, older patients, especially those 65 years old and above who have comorbidities and are infected, have an increased admission rate into the intensive care unit (ICU) and mortality from the COVID-19 disease. Patients with comorbidities should take all necessary precautions to avoid getting infected with SARS CoV-2, as they usually have the worst prognosis.

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Comorbidity and its Impact on Patients with COVID-19.

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Comorbidities are associated with the severity of coronavirus disease 2019 (COVID-19). This meta-analysis aimed to explore the risk of severe COVID-19 in patients with pre-existing chronic obstructive pulmonary disease (COPD) and ongoing smoking history. A comprehensive systematic literature search was carried out to find studies published from December 2019 to 22 March 2020 from five databases. The languages of literature included English and Chinese. The point prevalence of severe COVID-19 in patients with pre-existing COPD and those with ongoing smoking was evaluated with this meta-analysis. Overall 11 case series, published either in Chinese or English language with a total of 2002 cases, were included in this study. The pooled OR of COPD and the development of severe COVID-19 was 4.38 (fixed-effects model; 95% CI: 2.34-8.20), while the OR of ongoing smoking was 1.98 (fixed-effects model; 95% CI: 1.29-3.05). There was no publication bias as examined by the funnel plot and Egger's test (P = not significant). The heterogeneity of included studies was moderate for both COPD and ongoing smoking history on the severity of COVID-19. COPD and ongoing smoking history attribute to the worse progression and outcome of COVID-19.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.25889

The impact of COPD and smoking history on the severity of COVID-19: A systemic review and meta-analysis.

Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis.

We examined the effects of coronary heart disease (CHD), hypertension and diabetes on the development of severe COVID-19. We performed a comprehensive, systematic literature search for studies published between December 2019 and July 5, 2020 in five databases. The prevalence of severe COVID-19 in patients with CHD, hypertension and diabetes was evaluated through a meta-analysis. Thirty-five articles with 8,170 patients were included, and all the available studies were case series. The pooled odds ratio for the development of severe COVID-19 was 3.21 for patients with CHD (fixed-effects model, 95% CI: 2.58-3.99), 2.27 for patients with hypertension (random-effects model, 95% CI: 1.79-2.90) and 2.34 for patients with diabetes (random-effects model, 95% CI: 1.79-3.05). The heterogeneity of the studies was moderate for the effect of CHD on COVID-19 severity, but was high for the effects of diabetes and hypertension. Funnel plots and Egger's tests revealed no publication bias in the CHD and hypertension analyses, but suggested publication bias in the diabetes analysis. This bias was corrected using the trim-and-fill method, and was ultimately found to have no effect on the results. Our findings suggest patients with CHD, hypertension and diabetes are at greater risk for developing severe COVID-19 than those without these conditions.

Impact of cardiovascular and metabolic diseases on the severity of COVID-19: a systematic review and meta-analysis.

This study aimed to explore the clinical practice of phospholipid metabolic pathways in COVID-19. In this study, 48 COVID-19 patients and 17 healthy controls were included. Patients were divided into mild (n=40) and severe (n=8) according to their severity. Phospholipid metabolites, TCA circulating metabolites, eicosanoid metabolites, and closely associated enzymes and transfer proteins were detected in the plasma of all individuals using metabolomics and proteomics assays, respectively. 30 of the 33 metabolites found differed significantly (P<0.05) between patients and healthy controls (P<0.05), with D-dimmer significantly correlated with all of the lysophospholipid metabolites (LysoPE, LysoPC, LysoPI and LPA). In particular, we found that phosphatidylinositol (PI) and phosphatidylcholine (PC) could identify patients from healthy controls (AUC 0.771 and 0.745, respectively) and that the severity of the patients could be determined (AUC 0.663 and 0.809, respectively). The last measurement before discharge also revealed significant changes in both PI and PC. For the first time, our study explores the significance of the phospholipid metabolic system in COVID-19 patients. Based on molecular pathway mechanisms, three important phospholipid pathways related to Ceramide-Malate acid (Cer-SM), Lysophospholipid (LPs), and membrane function were established. Clinical values discovered included the role of Cer in maintaining the inflammatory internal environment, the modulation of procoagulant LPA by upstream fibrinolytic metabolites, and the role of PI and PC in predicting disease aggravation.

Effect of a Functional Phospholipid Metabolome-Protein Association Pathway on the Mechanism of COVID-19 Disease Progression

Editors, We read with great interest the study by Attia et al comparing the prevalence and characteristics of metabolic profiles among metabolicassociated fatty liver disease (MAFLD) patients with chronic hepatitis C virus (HCV) infection.1 They concluded that MAFLD was highly prevalent in patients with chronic HCV infection and has risen from the period 2007– 2013 to 2014– 2020 in Egypt. This study had a large sample size and validated the association between MAFLD and HCV.1 Patients with HCV infection and coexisting MAFLD had more severe hepatic fibrosis evaluated by Fibrosis4 (FIB4) score and nonalcoholic fatty liver disease (NAFLD) fibrosis score. However, the prognosis of those patients is still unclear. To analyse whether MAFLD contributes to the mortality associated with HCV infection, we recruited 348 patients with HCV infection from the third National Health and Nutrition Examination Surveys 1988– 1994 (NHANES III), and conducted a longitudinal study to examine the longterm mortality of participants with HCV infection and MAFLD. In the fully adjusted model, MAFLD was significantly and independently associated with higher risk for allcause mortality (adjust hazard ratio [aHR], 1.66; 95% CI, 1.13– 2.44; p < 0.01) in the overall population (Table 1). Moreover, participants with MAFLD had higher othercause(noncardiovascular disease [CVD], noncancer) related mortality rates (aHR, 2.23; 95% CI, 1.19– 4.17; p < 0.02). However, we found no significant difference in CVD and cancerrelated mortality between groups (Table 1). Chronic hepatitis B or hepatitis C infection could increase the risk of development of hepatic steatosis, cirrhosis and carcinogenesis.2– 4 Recently, van Kleef et al concluded that chronic hepatitis B could increase the risk of liverrelated clinical events and death in patients with MAFLD.5 Similarly, our study shows for the first time that MAFLD is associated with an increased risk of allcause mortality among patients with HCV infection. In conclusion, our results provide evidence for the clinical usefulness of the novel MAFLD criteria in HCV and emphasise the significance of metabolic health assessment in these participants. Further prospective studies are required to validate the impact of MAFLD on patients with HCV infection.

Qianwen Zhao

Papers

The impact of COPD and smoking history on the severity of COVID-19: A systemic review and meta-analysis.

Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis.

Impact of cardiovascular and metabolic diseases on the severity of COVID-19: a systematic review and meta-analysis.

Effect of a Functional Phospholipid Metabolome-Protein Association Pathway on the Mechanism of COVID-19 Disease Progression

Letter: metabolic dysfunction‐associated fatty liver disease increases risk of all‐cause mortality in patients with chronic hepatitis C