Union Hospital

Importance: The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. Objective: To study the neurologic manifestations of patients with COVID-19. Design, Setting, and Participants: This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. Main Outcomes and Measures: Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Results: Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). Conclusions and Relevance: Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases died of COVID-19 and 1019 survived patients in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men tend to be more serious than women (P=0.035). In the public data set, the number of men is 2.4 times that of women in the deceased group (70.3% vs. 29.7%, P=0.016). In SARS patients, the gender role in mortality was also observed. The percentage of male were higher in the deceased group than in the survived group (P=0.015). Conclusion: Male gender is a risk factor for worse outcomes independent of age and susceptibility in patients with COVID.

OBJECTIVE: Since the outbreak of Coronavirus Disease 2019 (COVID-19) in December 2019, various digestive symptoms have been frequently reported in patients infected with the virus. In this study, we aimed to further investigate the prevalence and outcomes of COVID-19 patients with digestive symptoms. METHODS: In this descriptive, cross-sectional, multicenter study, we enrolled confirmed patients with COVID-19 who presented to 3 hospitals from January 18, 2020, to February 28, 2020. All patients were confirmed by real-time polymerase chain reaction and were analyzed for clinical characteristics, laboratory data, and treatment. Data were followed up until March 18, 2020. RESULTS: In the present study, 204 patients with COVID-19 and full laboratory, imaging, and historical data were analyzed. The average age was 52.9 years (SD ± 16), including 107 men and 97 women. Although most patients presented to the hospital with fever or respiratory symptoms, we found that 103 patients (50.5%) reported a digestive symptom, including lack of appetite (81 [78.6%] cases), diarrhea (35 [34%] cases), vomiting (4 [3.9%] cases), and abdominal pain (2 [1.9%] cases). If lack of appetite is excluded from the analysis (because it is less specific for the gastrointestinal tract), there were 38 total cases (18.6%) where patients presented with a gastrointestinal-specific symptom, including diarrhea, vomiting, or abdominal pain. Patients with digestive symptoms had a significantly longer time from onset to admission than patients without digestive symptoms (9.0 days vs 7.3 days). In 6 cases, there were digestive symptoms, but no respiratory symptoms. As the severity of the disease increased, digestive symptoms became more pronounced. Patients with digestive symptoms had higher mean liver enzyme levels, lower monocyte count, longer prothrombin time, and received more antimicrobial treatment than those without digestive symptoms. DISCUSSION: We found that digestive symptoms are common in patients with COVID-19. Moreover, these patients have a longer time from onset to admission, evidence of longer coagulation, and higher liver enzyme levels. Clinicians should recognize that digestive symptoms, such as diarrhea, are commonly among the presenting features of COVID-19 and that the index of suspicion may need to be raised earlier in at-risk patients presenting with digestive symptoms. However, further large sample studies are needed to confirm these findings.

Although the respiratory and immune systems are the major targets of Coronavirus Disease 2019 (COVID-19), acute kidney injury and proteinuria have also been observed. Currently, detailed pathologic examination of kidney damage in critically ill patients with COVID-19 has been lacking. To help define this we analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 by light microscopy, ultrastructural observation and immunostaining. Patients were on average 69 years (19 male and 7 female) with respiratory failure associated with multiple organ dysfunction syndrome as the cause of death. Nine of the 26 showed clinical signs of kidney injury that included increased serum creatinine and/or new-onset proteinuria. By light microscopy, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, and even frank necrosis was observed. Occasional hemosiderin granules and pigmented casts were identified. There were prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material. Evidence of vasculitis, interstitial inflammation or hemorrhage was absent. Electron microscopic examination showed clusters of coronavirus-like particles with distinctive spikes in the tubular epithelium and podocytes. Furthermore, the receptor of SARS-CoV-2, ACE2 was found to be upregulated in patients with COVID-19, and immunostaining with SARS-CoV nucleoprotein antibody was positive in tubules. In addition to the direct virulence of SARS-CoV-2, factors contributing to acute kidney injury included systemic hypoxia, abnormal coagulation, and possible drug or hyperventilation-relevant rhabdomyolysis. Thus, our studies provide direct evidence of the invasion of SARSCoV-2 into kidney tissue. These findings will greatly add to the current understanding of SARS-CoV-2 infection. Although the respiratory and immune systems are the major targets of Coronavirus Disease 2019 (COVID-19), acute kidney injury and proteinuria have also been observed. Currently, detailed pathologic examination of kidney damage in critically ill patients with COVID-19 has been lacking. To help define this we analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 by light microscopy, ultrastructural observation and immunostaining. Patients were on average 69 years (19 male and 7 female) with respiratory failure associated with multiple organ dysfunction syndrome as the cause of death. Nine of the 26 showed clinical signs of kidney injury that included increased serum creatinine and/or new-onset proteinuria. By light microscopy, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, and even frank necrosis was observed. Occasional hemosiderin granules and pigmented casts were identified. There were prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material. Evidence of vasculitis, interstitial inflammation or hemorrhage was absent. Electron microscopic examination showed clusters of coronavirus-like particles with distinctive spikes in the tubular epithelium and podocytes. Furthermore, the receptor of SARS-CoV-2, ACE2 was found to be upregulated in patients with COVID-19, and immunostaining with SARS-CoV nucleoprotein antibody was positive in tubules. In addition to the direct virulence of SARS-CoV-2, factors contributing to acute kidney injury included systemic hypoxia, abnormal coagulation, and possible drug or hyperventilation-relevant rhabdomyolysis. Thus, our studies provide direct evidence of the invasion of SARSCoV-2 into kidney tissue. These findings will greatly add to the current understanding of SARS-CoV-2 infection. Editor’s NoteThe Editors recommend that the readers also view the letter to the editor by Kissling et al. (see page 228) reporting a case of COVID-19–associated collapsing glomerulopathy featuring cytoplasmic vacuoles containing numerous spherical particles. The nature of those intracellular organelles as viral particles is questioned in 2 letters to the editor, Nadasdy et al. (see page 233) and Miller and Brealey (see page 231), that provide important information when examining viral-like electron microscopy structures in the kidney. The Editors recommend that the readers also view the letter to the editor by Kissling et al. (see page 228) reporting a case of COVID-19–associated collapsing glomerulopathy featuring cytoplasmic vacuoles containing numerous spherical particles. The nature of those intracellular organelles as viral particles is questioned in 2 letters to the editor, Nadasdy et al. (see page 233) and Miller and Brealey (see page 231), that provide important information when examining viral-like electron microscopy structures in the kidney. In December 2019, a cluster of patients with pneumonia of unknown etiology was reported in Wuhan, Hubei Province, China. On January 9, 2020, the Chinese Center for Disease Control and Prevention identified the causative agent as a novel coronavirus, which now is officially termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1Lu R. Zhao X. Li J. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (7711) Google Scholar The illness caused by SARS-CoV-2, coronavirus disease 2019 (COVID-19), mainly manifests with fever, dry cough, dyspnea, myalgia, and diarrhea. However, COVID-19 presentations can range from asymptomatic infection, self-limited influenza-type symptoms, and acute pneumonia to severe respiratory failure with high mortality. Currently, the epidemic in China is being gradually controlled with major domestic efforts and international support. However, the global epidemic has now become a pandemic. Without knowing the detailed mechanisms of COVID-19, specific management is lacking. The reported mortality in different countries varies according to extent of testing performed, ranging from 0.3% to 10%. The respiratory, immune, and coagulation systems are the major targets of this pandemic disease.2Guan W.J. Ni Z.Y. Hu Y. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (19246) Google Scholar Kidney injury has appeared relatively less with COVID-19 than with Middle East respiratory syndrome or hantavirus infections, perhaps due to the different underlying mechanisms and ensuing pathologic manifestations. Clinically, the incidence of acute kidney injury (AKI) in COVID-19 varied from 0.9% to 29% in different centers. New onset proteinuria was also reported by several institutions.3Alsaad K.O. Hajeer A.H. Al Balwi M. et al.Histopathology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection—clinicopathological and ultrastructural study.Histopathology. 2018; 72: 516-524Crossref PubMed Scopus (215) Google Scholar Currently, the pathologic investigation has primarily focused on respiratory, hematopoietic, and immune systems, whereas morphologic data of kidney injury are lacking. In this study, we report on our experience of kidney findings at autopsy in patients with severe COVID-19. The 26 patients with COVID-19 included 19 males and 7 females, with an average age of 69 years (range, 39–87 years). All 26 cases had positive results for SARS-CoV-2 by nucleic acid testing and characteristic radiologic alterations in lungs. Eleven patients had history of hypertension or diabetes or both. Data on angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers for hypertension or diabetes or both before the terminal hospitalization were not available. Patients were treated with calcium-channel blockers if needed for hypertension during the terminal hospitalization, without ACE inhibitors or angiotensin-receptor blockers or both, due to uncertainty regarding possible effects. Six patients had history of tumor. The clinical information is summarized in Tables 1 and 2.Table 1Clinical information of 26 patients with COVID-19IDSexAge (y)History of HT, DM, CKD or tumorHypotension/vasopressorBUN (mmol/l)Cr (μmol/l)UrineHb (g/l)WBC (g/l)LY (g/l)LY%PLT (T/l)D-dimer (μg/ml)ALT (U/l)AST (U/l)TBIL (μmol/l)CK (U/l)PROBLDWBC1M77NY22.52239.8N/AN/AN/AN/A25.10.371.5033>8.006071N/AN/A2F60NNN/AN/A−2+1+11217.870.824.601032.35N/AN/AN/AN/A3M51Pancreas CaY18.9671.3Trace−−9631.870.752.40385.61102126110.23284M87DM, HT, CKDY42.45229.8N/AN/AN/A7013.630.261.902191.0813169.5995M39Gastric CaN7.1831N/AN/AN/A9811.40.443.902736.1151823.9876M66Liver CaY41.84161.4N/AN/AN/A8912.520.241.90570.918415049.110017M77Skin CaY24.14460.2N/AN/AN/A9323.590.813.401055.32214813.63128F87DM, HT, CKDYN/AN/A3+3+1+1018.980.485.40110>8.00N/AN/AN/AN/A9M70Lung CaN12.86207.3N/AN/AN/A1125.760.8114.102152.8536784014.9245910F84HTN14.28114.7N/AN/AN/A607.690.536.80752.86293016.15411F83HTY21.54108N/AN/AN/A692.280.177.30302.087179546.549512M63HTY7.345.9−±−10241.480.531.301791.02107448.515813M52NY7.5158.72+−±7311.190.665.903422.69975218.919414M61HTY13.9994.21+1+±8015.670.644.10802.3887741.325915F70HT, Lung CaY5.7944.1N/AN/AN/A10218.891.216.40106>8.00543526.13716M64HTY20.42137.3N/AN/AN/A933.350.5616.80237.69213818.96417M66HTY3.2457.92+3+1+810.260.0829.90154.953491573.2N/A18F62NY11.8661.8N/AN/AN/A889.140.697.60763.42191814.22319M55DM, HTY9.2443.72+1+3+781.280.086.20182.05599119957.73420M83N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A21F86N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A22M78N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A23M62N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A24M51N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A25M72N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A26M86HTY4.3663.61+−−9745.440.380.801553.77153524.5213ALT, alanine aminotransferase; AST, aspartate aminotransferase; BLD, blood; BUN, blood urea nitrogen; Ca, cancer; CK, creatine kinase; CKD, chronic kidney disease; Cr, creatinine; DM, diabetes; F, female; Hb, hemoglobin; HT, hypertension; ID, identification number; LY, lymphocytes; M, male; N, no; N/A, not available; PLT, platelet; PRO, proteinuria; TBIL, total bilirubin; WBC, white blood cell; Y, yes.The cause of death in all patients was respiratory failure. In addition, patients 1, 5, 14, 15, 16, 25, and 26 had multiorgan failure. Open table in a new tab Table 2Treatment historyIDExposure to nephrotoxic drugRenal replacement therapyAntiviralsSteroid1NNArbidolY2YCRRTArbidolY3NNRibavirinN4NNRibavirin, arbidolN5NNArbidolY6NNArbidolY7NCRRTArbidolY8NNArbidolN9NNNN10NCRRTArbidolY11NNArbidolY12NNArbidolY13YNLopinavir/ritonavirY14YNNY15NNLopinavir/ritonavirY16NNLopinavir/ritonavirY17YNNY18NCRRTNY19NCRRTLopinavir/ritonavirY20N/AN/AN/AN/A21N/AN/AN/AN/A22N/AN/AN/AN/A23N/AN/AN/AN/A24N/AN/AN/AN/A25N/AN/AN/AN/A26NNLopinavir/ritonavirYCRRT, continuous renal replacement therapy; ID, identification number; N, no; N/A, not available; Y, yes. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; BLD, blood; BUN, blood urea nitrogen; Ca, cancer; CK, creatine kinase; CKD, chronic kidney disease; Cr, creatinine; DM, diabetes; F, female; Hb, hemoglobin; HT, hypertension; ID, identification number; LY, lymphocytes; M, male; N, no; N/A, not available; PLT, platelet; PRO, proteinuria; TBIL, total bilirubin; WBC, white blood cell; Y, yes. The cause of death in all patients was respiratory failure. In addition, patients 1, 5, 14, 15, 16, 25, and 26 had multiorgan failure. CRRT, continuous renal replacement therapy; ID, identification number; N, no; N/A, not available; Y, yes. All tissue samples were well preserved without autolysis. There was prominent proximal acute tubule injury (ATI) manifested as the loss of brush border, vacuolar degeneration, dilatation of the tubular lumen with cellular debris, and occasionally even frank necrosis and detachment of epithelium with bare tubular basement membrane noted (the latter observed in 4 cases). The majority of the vacuoles in cytoplasm were variable in size; however, focal isometric fine vacuolization was uncommonly present and is associated with, for example, mannitol or i.v. Ig therapy (Figure 1a and b). In 2 patients, consistent with corresponding pathologic findings in their lungs, acute pyelonephritis was observed with multiple foci of bacteria and diffuse polymorphonuclear casts in the lumen of tubules. In 1 of these 2 patients, an arcuate artery was infiltrated with numerous inflammatory cells (Figure 1c and d), likely representing reaction to bacterial infection. Diffuse erythrocyte aggregation and obstruction were present in peritubular and glomerular capillary loops without distinct fragmentation of erythrocytes or platelets or fibrin thrombi. Occasional hemosiderin granules in tubular epithelium were identified in 4 patients with hematuria by dipstick (Figure 1e). In 3 cases, pigmented casts were found with high levels of creatine phosphokinase, possibly representing rhabdomyolysis (Figure 1f). Distal tubules and collecting ducts showed only occasional cellular swelling and edematous expansion of the interstitial space without significant inflammation. Lymphocytic infiltrates were present in areas of nonspecific fibrosis including subcapsular areas. Glomeruli showed varied degrees of underlying morphologic changes, such as nodular mesangial expanding and hyalinosis of arterioles, which constituted evidence of diabetic nephropathy in 2 of the patients with diabetes, and arteriosclerosis of medium-size arteries with ischemic glomeruli in 11 of the patients with hypertension. Focal obsolescent glomeruli were detected proportional to the age in this population. Endothelial cell swelling with variable foamy degeneration was present in 5 of the patients with COVID-19, and they were usually older and had hypertensive or diabetic histories. In 3 cases, a few areas of segmental fibrin thrombus in glomerular capillary loops were identified associated with severe injury of the endothelium (Figure 1g). Occasional podocyte vacuolation and even detachment from the glomerular basement membrane was noted. Focal segmental glomerulosclerosis was observed in 2 patients with overt proteinuria as well as history of diabetes. Ischemic changes with shrinkage of capillary loops with accumulation of plasma in Bowman’s space was present in 7 cases, occasionally with pseudocrescent appearance (Figure 1h). Crescents and hypercellular or inflammatory lesions of glomeruli were not present. The pathologic findings are summarized in Table 3.Table 3The pathologic abnormalities of kidney in 26 cases of deceased patients with COVID-19IDLMEMIFTubule interstitiumGlomeruliATIMultiple foci of bacteriaPigmented castsArteriosclerosisSegmental fibrin thrombusFSGSCoronavirus-like particlesDense depositsSubendothelial lucent expansionIgGIgASARS-CoV NP1SevereNNMild to moderateNNN/AN/AN/AN/AN/AN/A2ModerateNNMildNNYNNN/AN/AN/A3Mild to moderateNYMildNNYNYN/AN/AN/A4SevereNNSevereNYYNYN/AN/AN/A5MildNNMildNNN/AN/AN/AN/AN/AN/A6Mild to moderateNYMildNNN/AN/AN/AN/AN/AN/A7SevereNNMild to moderateNNN/AN/AN/AN/AN/AN/A8ModerateNNSevereFocalYN/AN/AN/AN/AN/AN/A9ModerateNYModerateNNN/AN/AN/AN/AN/AN/A10ModerateNNModerate to severeNNN/AN/AN/AN/AN/AN/A11Moderate to severeNNModerate to severeFocalNN/AN/AN/AN/AN/AN/A12Moderate to severeNNModerateNNYNYN/AN/AN/A13Mild to moderateNNMildNNN/AN/AN/AN/AN/AN/A14SevereMultiple focalNModerateDiffuseNN/AN/AN/AN/AN/AN/A15Mild to moderateNNModerate to severeNNN/AN/AN/AN/AN/AN/A16SevereMultiple focalNModerate to severeNNN/AN/AN/AN/AN/AN/A17ModerateNNModerateNNN/AN/AN/AN/AN/AN/A18ModerateNNMildNNN/AN/AN/AN/AN/AN/A19MildNNModerate to to to to to severeNNModerate to to acute tubular COVID-19, coronavirus disease electron focal segmental ID, identification number; light N, not N/A, not available; severe acute syndrome Y, Open table in a new tab acute tubular COVID-19, coronavirus disease electron focal segmental ID, identification number; light N, not N/A, not available; severe acute syndrome Y, particles were identified in the cytoplasm of renal proximal tubular epithelium as well as in the and less in tubules. The of particles varied from to with distinctive to in a of this coronavirus included membrane with to the viral and the of the particles (Figure In 1 and with segmental mesangial and increased were present (Figure and were noted in were These 2 patients not have evidence of bacterial at autopsy in or In 2 of 3 patients with diabetes, characteristic changes of diabetic nephropathy were present by electron microscopy including increased of the glomerular basement membrane without mesangial expansion and segmental and erythrocytes were observed obstructing peritubular capillary with of endothelium (Figure or fibrin were not detected in with this of erythrocytes in segmental glomerular capillary loops was without inflammation or In glomerular capillary a varied extent of injury was including lucent and without The ultrastructural findings are summarized in Table for inflammatory cells not specific accumulation of these with of and cells in areas of nonspecific with and present in the obstruction was of for showed in the significant platelet and for cells showed of peritubular capillary (Figure In an of a was and without COVID-19, for ACE of proximal tubules without glomerular was which is consistent with was observed in the kidney (Figure ACE2 was also in 5 of the patients ACE2 in 3 of these ACE2 was prominent in proximal tubular in areas with severe In addition, focal cells was as well as occasional podocyte (Figure or was from in cases, and nonspecific and were present. showed segmental capillary however, without the capillary with by case showed in mesangial as well as capillary associated with corresponding mesangial and by By an the of SARS-CoV nucleoprotein was analyzed in the cases, and 3 showed positive in a or cytoplasm in tubular epithelium (Figure and positive showed The immunostaining findings are summarized in Table In the present study, we report the kidney and immunostaining findings from autopsies of 26 patients from respiratory failure due to COVID-19. is the report of kidney pathologic presentations in patients with SARS-CoV-2 infection. autopsy the range of abnormalities present and the specific kidney cells likely with the and provide important information for studies in less ill patients with COVID-19 and kidney observed significant the of mainly by erythrocytes with ensuing as well as glomerular and changes of underlying diabetic or hypertensive of these findings are in with mechanisms for in kidney. also findings that distinct mechanisms of this novel coronavirus infection, direct kidney and likely Thus, these pathologic provide a for understanding of COVID-19. observed diffuse acute proximal tubular injury with loss of brush and which be caused by the direct virulence of SARS-CoV-2, by our ultrastructural and immunostaining The tubular cytoplasmic vacuoles were variable in However, in a few patients, focal isometric fine vacuolization was present and is likely to with or such as i.v. 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BackgroundThe dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear.MethodsPeripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays.FindingsOf the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0·6 (0·6-0·8)] but increases in neutrophil counts [4·7 (3·6-5·8)] than 27 mild cases [1.1 (0·8-1·4); 2·0 (1·5-2·9)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0·93) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0·94) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19.InterpretationThe degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases.FundingThe National Natural Science Foundation of China, the National Science and Technology Major Project, the Health Commission of Hubei Province, Huazhong University of Science and Technology, and the Medical Faculty of the University of Duisburg-Essen and Stiftung Universitaetsmedizin, Hospital Essen, Germany.

Abstract Objective To assess the prevalence of diabetes and its risk factors. Design Population based, cross sectional study. Setting 31 provinces in mainland China with nationally representative cross sectional data from 2015 to 2017. Participants 75 880 participants aged 18 and older—a nationally representative sample of the mainland Chinese population. Main outcome measures Prevalence of diabetes among adults living in China, and the prevalence by sex, regions, and ethnic groups, estimated by the 2018 American Diabetes Association (ADA) and the World Health Organization diagnostic criteria. Demographic characteristics, lifestyle, and history of disease were recorded by participants on a questionnaire. Anthropometric and clinical assessments were made of serum concentrations of fasting plasma glucose (one measurement), two hour plasma glucose, and glycated haemoglobin (HbA 1c ). Results The weighted prevalence of total diabetes (n=9772), self-reported diabetes (n=4464), newly diagnosed diabetes (n=5308), and prediabetes (n=27 230) diagnosed by the ADA criteria were 12.8% (95% confidence interval 12.0% to 13.6%), 6.0% (5.4% to 6.7%), 6.8% (6.1% to 7.4%), and 35.2% (33.5% to 37.0%), respectively, among adults living in China. The weighted prevalence of total diabetes was higher among adults aged 50 and older and among men. The prevalence of total diabetes in 31 provinces ranged from 6.2% in Guizhou to 19.9% in Inner Mongolia. Han ethnicity had the highest prevalence of diabetes (12.8%) and Hui ethnicity had the lowest (6.3%) among five investigated ethnicities. The weighted prevalence of total diabetes (n=8385) using the WHO criteria was 11.2% (95% confidence interval 10.5% to 11.9%). Conclusion The prevalence of diabetes has increased slightly from 2007 to 2017 among adults living in China. The findings indicate that diabetes is an important public health problem in China.

Abstract By 27 February 2020, the outbreak of coronavirus disease 2019 (COVID‐19) caused 82 623 confirmed cases and 2858 deaths globally, more than severe acute respiratory syndrome (SARS) (8273 cases, 775 deaths) and Middle East respiratory syndrome (MERS) (1139 cases, 431 deaths) caused in 2003 and 2013, respectively. COVID‐19 has spread to 46 countries internationally. Total fatality rate of COVID‐19 is estimated at 3.46% by far based on published data from the Chinese Center for Disease Control and Prevention (China CDC). Average incubation period of COVID‐19 is around 6.4 days, ranges from 0 to 24 days. The basic reproductive number ( R 0 ) of COVID‐19 ranges from 2 to 3.5 at the early phase regardless of different prediction models, which is higher than SARS and MERS. A study from China CDC showed majority of patients (80.9%) were considered asymptomatic or mild pneumonia but released large amounts of viruses at the early phase of infection, which posed enormous challenges for containing the spread of COVID‐19. Nosocomial transmission was another severe problem. A total of 3019 health workers were infected by 12 February 2020, which accounted for 3.83% of total number of infections, and extremely burdened the health system, especially in Wuhan. Limited epidemiological and clinical data suggest that the disease spectrum of COVID‐19 may differ from SARS or MERS. We summarize latest literatures on genetic, epidemiological, and clinical features of COVID‐19 in comparison to SARS and MERS and emphasize special measures on diagnosis and potential interventions. This review will improve our understanding of the unique features of COVID‐19 and enhance our control measures in the future.

Abstract Antibody–drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg ® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as “biological missiles”, is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs.

BACKGROUND: The newly identified 2019-nCoV, which appears to have originated in Wuhan, the capital city of Hubei province in central China, is spreading rapidly nationwide. A number of cases of neonates born to mothers with 2019-nCoV pneumonia have been recorded. However, the clinical features of these cases have not been reported, and there is no sufficient evidence for the proper prevention and control of 2019-nCoV infections in neonates. METHODS: The clinical features and outcomes of 10 neonates (including 2 twins) born to 9 mothers with confirmed 2019-nCoV infection in 5 hospitals from January 20 to February 5, 2020 were retrospectively analyzed. RESULTS: Among these 9 pregnant women with confirmed 2019-nCoV infection, onset of clinical symptoms occurred before delivery in 4 cases, on the day of delivery in 2 cases, and after delivery in 3 cases. In most cases, fever and a cough were the first symptoms experienced, and 1 patient also had diarrhea. Of the newborns born to these mothers, 8 were male and 2 were female; 4 were full-term infants and 6 were born premature; 2 were small-for-gestational-age (SGA) infants and 1 was a large-for-gestational-age (LGA) infant; there were 8 singletons and 2 twins. Of the neonates, 6 had a Pediatric Critical Illness Score (PCIS) score of less than 90. Clinically, the first symptom in the neonates was shortness of breath (n=6), but other initial symptoms such as fever (n=2), thrombocytopenia accompanied by abnormal liver function (n=2), rapid heart rate (n=1), vomiting (n=1), and pneumothorax (n=1) were observed. Up to now, 5 neonates have been cured and discharged, 1 has died, and 4 neonates remain in hospital in a stable condition. Pharyngeal swab specimens were collected from 9 of the 10 neonates 1 to 9 days after birth for nucleic acid amplification tests for 2019-nCoV, all of which showed negative results. CONCLUSIONS: Perinatal 2019-nCoV infection may have adverse effects on newborns, causing problems such as fetal distress, premature labor, respiratory distress, thrombocytopenia accompanied by abnormal liver function, and even death. However, vertical transmission of 2019-nCoV is yet to be confirmed.

BACKGOUND: To figure out whether diabetes is a risk factor influencing the progression and prognosis of 2019 novel coronavirus disease (COVID-19). METHODS: A total of 174 consecutive patients confirmed with COVID-19 were studied. Demographic data, medical history, symptoms and signs, laboratory findings, chest computed tomography (CT) as well the treatment measures were collected and analysed. RESULTS: We found that COVID-19 patients without other comorbidities but with diabetes (n = 24) were at higher risk of severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses and hypercoagulable state associated with dysregulation of glucose metabolism. Furthermore, serum levels of inflammation-related biomarkers such as IL-6, C-reactive protein, serum ferritin and coagulation index, D-dimer, were significantly higher (P < .01) in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of COVID-19. CONCLUSIONS: Our data support the notion that diabetes should be considered as a risk factor for a rapid progression and bad prognosis of COVID-19. More intensive attention should be paid to patients with diabetes, in case of rapid deterioration.

Importance: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective: To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants: Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention: Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures: Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results: Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.59 [95% CI, 0.22-1.59]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.95]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care. Conclusion and Relevance: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000029757.

BACKGROUND: From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. Related clinical features are needed. METHODS: We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between 16 January and 29 January 2020. All patients were confirmed to be infected with SARS-CoV-2, and the final date of follow-up was 4 February 2020. RESULTS: The median age of 69 enrolled patients was 42.0 years (interquartile range 35.0-62.0), and 32 patients (46%) were men. The most common symptoms were fever (60 [87%]), cough (38 [55%]), and fatigue (29 [42%]). Most patients received antiviral therapy (66 [98.5%] of 67 patients) and antibiotic therapy (66 [98.5%] of 67 patients). As of 4 February 2020, 18 (26.9%) of 67 patients had been discharged, and 5 patients had died, with a mortality rate of 7.5%. According to the lowest SpO2 during admission, cases were divided into the SpO2 ≥ 90% group (n = 55) and the SpO2 < 90% group (n = 14). All 5 deaths occurred in the SpO2 < 90% group. Compared with SpO2 ≥ 90% group, patients of the SpO2 < 90% group were older and showed more comorbidities and higher plasma levels of interleukin (IL) 6, IL10, lactate dehydrogenase, and C reactive protein. Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate. CONCLUSIONS: COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.

In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.

Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

BACKGROUND AND PURPOSE: COVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19. Therefore, we described the clinical characteristics, laboratory features, treatment and outcomes of CVD complicating SARS-CoV-2 infection. MATERIALS AND METHODS: Demographic and clinical characteristics, laboratory findings, treatments and clinical outcomes were collected and analysed. Clinical characteristics and laboratory findings of patients with COVID-19 with or without new-onset CVD were compared. RESULTS: Of 219 patients with COVID-19, 10 (4.6%) developed acute ischaemic stroke and 1 (0.5%) had intracerebral haemorrhage. COVID-19 with new onset of CVD were significantly older (75.7±10.8 years vs 52.1±15.3 years, p<0.001), more likely to present with severe COVID-19 (81.8% vs 39.9%, p<0.01) and were more likely to have cardiovascular risk factors, including hypertension, diabetes and medical history of CVD (all p<0.05). In addition, they were more likely to have increased inflammatory response and hypercoagulable state as reflected in C reactive protein (51.1 (1.3-127.9) vs 12.1 (0.1-212.0) mg/L, p<0.05) and D-dimer (6.9 (0.3-20.0) vs 0.5 (0.1-20.0) mg/L, p<0.001). Of 10 patients with ischemic stroke; 6 received antiplatelet treatment with aspirin or clopidogrel; and 3 of them died. The other four patients received anticoagulant treatment with enoxaparin and 2 of them died. As of 24 March 2020, six patients with CVD died (54.5%). CONCLUSION: Acute CVD is not uncommon in COVID-19. Our findings suggest that older patients with risk factors are more likely to develop CVD. The development of CVD is an important negative prognostic factor which requires further study to identify optimal management strategy to combat the COVID-19 outbreak.

Background CT may play a central role in the diagnosis and management of coronavirus disease 2019 (COVID-19) pneumonia. Purpose To perform a longitudinal study to analyze the serial CT findings over time in patients with COVID-19 pneumonia. Materials and Methods During January 16 to February 17, 2020, 90 patients (33 men, 57 women; mean age, 45 years) with COVID-19 pneumonia were prospectively enrolled and followed up until being discharged, death, or the end of the study. A total of 366 CT scans were acquired and reviewed by two groups of radiologists for the patterns and distribution of lung abnormalities, total CT scores, and number of zones involved. Those features were analyzed for temporal change. Results CT scores and number of zones involved progressed rapidly, peaked during illness days 6-11 (median CT score, 5; median number of zones involved, five), and were followed by persistence of high levels. The predominant pattern of abnormalities after symptom onset was ground-glass opacity (35 of 78 scans [45%] to 49 of 79 scans [62%] in different periods). The percentage of mixed pattern peaked on illness days 12-17 (30 of 78 scans [38%]) and became the second most predominant pattern thereafter. Pure ground-glass opacity was the most prevalent subtype of ground-glass opacity after symptom onset (20 of 50 scans [40%] to 20 of 28 scans [71%]). The percentage of ground-glass opacity with irregular linear opacity peaked on illness days 6-11 (14 of 50 scans [28%]) and became the second most prevalent subtype thereafter. The distribution of lesions was predominantly bilateral and subpleural. Sixty-six of the 70 patients discharged (94%) had residual disease on final CT scans (median CT score, 4; median number of zones involved, four), with ground-glass opacity (42 of 70 patients [60%]) and pure ground-glass opacity (31 of 42 patients [74%]) the most common pattern and subtype. Conclusion The extent of lung abnormalities at CT peaked during illness days 6-11. The temporal changes of the diverse CT manifestations followed a specific pattern, which might indicate the progression and recovery of the illness. © RSNA, 2020

Background: During the Coronavirus Disease 2019 (COVID-19) pandemic, frontline nurses face enormous mental health challenges. Epidemiological data on the mental health statuses of frontline nurses are still limited. The aim of this study was to examine mental health (burnout, anxiety, depression, and fear) and their associated factors among frontline nurses who were caring for COVID-19 patients in Wuhan, China. Methods: A large-scale cross-sectional, descriptive, correlational study design was used. A total of 2,014 eligible frontline nurses from two hospitals in Wuhan, China, participated in the study. Besides sociodemographic and background data, a set of valid and reliable instruments were used to measure outcomes of burnout, anxiety, depression, fear, skin lesion, self-efficacy, resilience, and social support via the online survey in February 2020. Findings: On average, the participants had a moderate level of burnout and a high level of fear. About half of the nurses reported moderate and high work burnout, as shown in emotional exhaustion (n = 1,218, 60.5%), depersonalization (n = 853, 42.3%), and personal accomplishment (n = 1,219, 60.6%). The findings showed that 288 (14.3%), 217 (10.7%), and 1,837 (91.2%) nurses reported moderate and high levels of anxiety, depression, and fear, respectively. The majority of the nurses (n = 1,910, 94.8%) had one or more skin lesions, and 1,950 (96.8%) nurses expressed their frontline work willingness. Mental health outcomes were statistically positively correlated with skin lesion and negatively correlated with self-efficacy, resilience, social support, and frontline work willingness. Interpretation: The frontline nurses experienced a variety of mental health challenges, especially burnout and fear, which warrant attention and support from policymakers. Future interventions at the national and organisational levels are needed to improve mental health during this pandemic by preventing and managing skin lesions, building self-efficacy and resilience, providing sufficient social support, and ensuring frontline work willingness.

The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), the pathogen of 2019 novel coronavirus disease (COVID-19), has posed a serious threat to global public health. The WHO has declared the outbreak of SARS-CoV-2 infection an international public health emergency. Lung lesions have been considered as the major damage caused by SARS-CoV-2 infection. However, liver injury has also been reported to occur during the course of the disease in severe cases. Similarly, previous studies have shown that liver damage was common in the patients infected by the other two highly pathogenic coronavirus - severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), and associated with the severity of diseases. In this review, the characteristics and mechanism of liver injury caused by SARS-CoV, MERS-CoV as well as SARS-CoV-2 infection were summarized, which may provide help for further studies on the liver injury of COVID-19.

PURPOSE: Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism. MATERIALS AND METHODS: Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell. RESULTS: Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity. CONCLUSION: Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.

Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.