Wuhan Union Hospital

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak is evolving rapidly worldwide. OBJECTIVE: To evaluate the risk of serious adverse outcomes in patients with COVID-19 by stratifying the comorbidity status. METHODS: We analysed data from 1590 laboratory confirmed hospitalised patients from 575 hospitals in 31 provinces/autonomous regions/provincial municipalities across mainland China between 11 December 2019 and 31 January 2020. We analysed the composite end-points, which consisted of admission to an intensive care unit, invasive ventilation or death. The risk of reaching the composite end-points was compared according to the presence and number of comorbidities. RESULTS: The mean age was 48.9 years and 686 (42.7%) patients were female. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached the composite end-points. 399 (25.1%) reported having at least one comorbidity. The most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. After adjusting for age and smoking status, COPD (HR (95% CI) 2.681 (1.424-5.048)), diabetes (1.59 (1.03-2.45)), hypertension (1.58 (1.07-2.32)) and malignancy (3.50 (1.60-7.64)) were risk factors of reaching the composite end-points. The hazard ratio (95% CI) was 1.79 (1.16-2.77) among patients with at least one comorbidity and 2.59 (1.61-4.17) among patients with two or more comorbidities. CONCLUSION: Among laboratory confirmed cases of COVID-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A greater number of comorbidities also correlated with poorer clinical outcomes.

The outbreak of the novel coronavirus disease (COVID-19) quickly spread all over China and to more than 20 other countries. Although the virus (severe acute respiratory syndrome coronavirus [SARS-Cov-2]) nucleic acid real-time polymerase chain reaction (PCR) test has become the standard method for diagnosis of SARS-CoV-2 infection, these real-time PCR test kits have many limitations. In addition, high false-negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify a large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point-of-care lateral flow immunoassay that can detect immunoglobulin M (IgM) and IgG antibodies simultaneously against SARS-CoV-2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID-19 patients and 128 negative patients at eight different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM-IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS-CoV-2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.

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. Ig or mannitol spherical particles characteristic of coronavirus in proximal tubular The of the particles and the of spikes were to identified and Middle East respiratory Y. et findings of COVID-19 associated with acute respiratory Med. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar Furthermore, coronavirus-like particles were identified in associated with and occasional vacuolation and detachment of from the glomerular basement was by an antibody SARS-CoV nucleoprotein These findings that SARS-CoV-2 virus can the renal tubular epithelium and which was associated with and proteinuria in these patients with COVID-19. morphologic was erythrocyte in the lumen of glomerular and peritubular capillaries without blood cell fibrin or fibrinoid in cases with glomerular less blood cell aggregation was present in peritubular which is associated with a relatively of casts were present in patients and were associated with rhabdomyolysis with high serum levels of creatine or hyperventilation-relevant rhabdomyolysis a direct viral on is also was interstitial hemorrhage as is characteristic for by hantavirus J. et the of hantavirus Full Text Full Text PDF PubMed Scopus Google Scholar Furthermore, vasculitis, of the morphologic of syndrome caused by cytoplasmic PubMed Google Scholar was not identified in these patients with COVID-19. 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Background The 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. Methods Peripheral 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. Findings Of 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. Interpretation The 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. Funding The 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 The novel COVID-19 outbreak has affected more than 200 countries and territories as of March 2020. Given that patients with cancer are generally more vulnerable to infections, systematic analysis of diverse cohorts of patients with cancer affected by COVID-19 is needed. We performed a multicenter study including 105 patients with cancer and 536 age-matched noncancer patients confirmed with COVID-19. Our results showed COVID-19 patients with cancer had higher risks in all severe outcomes. Patients with hematologic cancer, lung cancer, or with metastatic cancer (stage IV) had the highest frequency of severe events. Patients with nonmetastatic cancer experienced similar frequencies of severe conditions to those observed in patients without cancer. Patients who received surgery had higher risks of having severe events, whereas patients who underwent only radiotherapy did not demonstrate significant differences in severe events when compared with patients without cancer. These findings indicate that patients with cancer appear more vulnerable to SARS-CoV-2 outbreak. Significance: Because this is the first large cohort study on this topic, our report will provide much-needed information that will benefit patients with cancer globally. As such, we believe it is extremely important that our study be disseminated widely to alert clinicians and patients. This article is highlighted in the In This Issue feature, p. 747

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.

Importance: Early identification of patients with novel coronavirus disease 2019 (COVID-19) who may develop critical illness is of great importance and may aid in delivering proper treatment and optimizing use of resources. Objective: To develop and validate a clinical score at hospital admission for predicting which patients with COVID-19 will develop critical illness based on a nationwide cohort in China. Design, Setting, and Participants: Collaborating with the National Health Commission of China, we established a retrospective cohort of patients with COVID-19 from 575 hospitals in 31 provincial administrative regions as of January 31, 2020. Epidemiological, clinical, laboratory, and imaging variables ascertained at hospital admission were screened using Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression to construct a predictive risk score (COVID-GRAM). The score provides an estimate of the risk that a hospitalized patient with COVID-19 will develop critical illness. Accuracy of the score was measured by the area under the receiver operating characteristic curve (AUC). Data from 4 additional cohorts in China hospitalized with COVID-19 were used to validate the score. Data were analyzed between February 20, 2020 and March 17, 2020. Main Outcomes and Measures: Among patients with COVID-19 admitted to the hospital, critical illness was defined as the composite measure of admission to the intensive care unit, invasive ventilation, or death. Results: The development cohort included 1590 patients. the mean (SD) age of patients in the cohort was 48.9 (15.7) years; 904 (57.3%) were men. The validation cohort included 710 patients with a mean (SD) age of 48.2 (15.2) years, and 382 (53.8%) were men and 172 (24.2%). From 72 potential predictors, 10 variables were independent predictive factors and were included in the risk score: chest radiographic abnormality (OR, 3.39; 95% CI, 2.14-5.38), age (OR, 1.03; 95% CI, 1.01-1.05), hemoptysis (OR, 4.53; 95% CI, 1.36-15.15), dyspnea (OR, 1.88; 95% CI, 1.18-3.01), unconsciousness (OR, 4.71; 95% CI, 1.39-15.98), number of comorbidities (OR, 1.60; 95% CI, 1.27-2.00), cancer history (OR, 4.07; 95% CI, 1.23-13.43), neutrophil-to-lymphocyte ratio (OR, 1.06; 95% CI, 1.02-1.10), lactate dehydrogenase (OR, 1.002; 95% CI, 1.001-1.004) and direct bilirubin (OR, 1.15; 95% CI, 1.06-1.24). The mean AUC in the development cohort was 0.88 (95% CI, 0.85-0.91) and the AUC in the validation cohort was 0.88 (95% CI, 0.84-0.93). The score has been translated into an online risk calculator that is freely available to the public (http://118.126.104.170/). Conclusions and Relevance: In this study, a risk score based on characteristics of COVID-19 patients at the time of admission to the hospital was developed that may help predict a patient's risk of developing critical illness.

Abstract Background Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical characteristics of these cases. Methods We extracted the data on 1,099 patients with laboratory-confirmed 2019-nCoV ARD from 552 hospitals in 31 provinces/provincial municipalities through January 29 th , 2020. Results The median age was 47.0 years, and 41.90% were females. Only 1.18% of patients had a direct contact with wildlife, whereas 31.30% had been to Wuhan and 71.80% had contacted with people from Wuhan. Fever (87.9%) and cough (67.7%) were the most common symptoms. Diarrhea is uncommon. The median incubation period was 3.0 days (range, 0 to 24.0 days). On admission, ground-glass opacity was the typical radiological finding on chest computed tomography (50.00%). Significantly more severe cases were diagnosed by symptoms plus reverse-transcriptase polymerase-chain-reaction without abnormal radiological findings than non-severe cases (23.87% vs. 5.20%, P <0.001). Lymphopenia was observed in 82.1% of patients. 55 patients (5.00%) were admitted to intensive care unit and 15 (1.36%) succumbed. Severe pneumonia was independently associated with either the admission to intensive care unit, mechanical ventilation, or death in multivariate competing-risk model (sub-distribution hazards ratio, 9.80; 95% confidence interval, 4.06 to 23.67). Conclusions The 2019-nCoV epidemic spreads rapidly by human-to-human transmission. Normal radiologic findings are present among some patients with 2019-nCoV infection. The disease severity (including oxygen saturation, respiratory rate, blood leukocyte/lymphocyte count and chest X-ray/CT manifestations) predict poor clinical outcomes.

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.

Abstract 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.

Many noninvasive methods for diagnosing liver fibrosis (LF) have been proposed. To determine the best method for diagnosing LF in nonalcoholic fatty liver disease (NAFLD), we conducted a systemic review and meta-analysis to compare the performance of aspartate aminotransferase to platelets ratio index (APRI), fibrosis-4 index (FIB-4), BARD score, NAFLD fibrosis score (NFS), FibroScan, shear wave elastography (SWE), and magnetic resonance elastography (MRE) for diagnosing LF in NAFLD. We compared the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC) of these noninvasive methods for detecting significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis. Heterogeneity was explored using meta-regression. Sixty-four articles with a total of 13,046 NAFLD subjects were included. The overall mean prevalence of SF, AF, and cirrhosis was 45.0%, 24.0%, and 9.4% in NAFLD patients, respectively. With an APRI threshold of 1.0 and 1.5, the sensitivities and specificities were 50.0% and 84.0% and 18.3% and 96.1%, respectively, for AF. With a FIB-4 threshold of 2.67 and 3.25, the sensitivities and specificities were 26.6% and 96.5% and 31.8% and 96.0%, respectively, for AF. The summary sensitivities and specificities of BARD score (threshold of 2), NFS (threshold of -1.455), FibroScan M (threshold of 8.7-9), SWE, and MRE for detecting AF were 0.76 and 0.61, 0.72 and 0.70, 0.87 and 0.79, 0.90 and 0.93, and 0.84 and 0.90, respectively. The summary AUROC values using APRI, FIB-4, BARD score, NFS, FibroScan M probe, XL probe, SWE, and MRE for diagnosing AF were 0.77, 0.84, 0.76, 0.84, 0.88, 0.85, 0.95, and 0.96, respectively. CONCLUSION: MRE and SWE may have the highest diagnostic accuracy for staging fibrosis in NAFLD patients. Among the four noninvasive simple indexes, NFS and FIB-4 probably offer the best diagnostic performance for detecting AF. (Hepatology 2017;66:1486-1501).

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.

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

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.

With the development of information technology, the concept of smart healthcare has gradually come to the fore. Smart healthcare uses a new generation of information technologies, such as the internet of things (loT), big data, cloud computing, and artificial intelligence, to transform the traditional medical system in an all-round way, making healthcare more efficient, more convenient, and more personalized. With the aim of introducing the concept of smart healthcare, in this review, we first list the key technologies that support smart healthcare and introduce the current status of smart healthcare in several important fields. Then we expound the existing problems with smart healthcare and try to propose solutions to them. Finally, we look ahead and evaluate the future prospects of smart healthcare.

Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil-derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse.

Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc.

Abstract Objective To evaluate the spectrum of comorbidities and its impact on the clinical outcome in patients with coronavirus disease 2019 (COVID-19). Design Retrospective case studies Setting 575 hospitals in 31 province/autonomous regions/provincial municipalities across China Participants 1,590 laboratory-confirmed hospitalized patients. Data were collected from November 21 st , 2019 to January 31 st , 2020. Main outcomes and measures Epidemiological and clinical variables (in particular, comorbidities) were extracted from medical charts. The disease severity was categorized based on the American Thoracic Society guidelines for community-acquired pneumonia. The primary endpoint was the composite endpoints, which consisted of the admission to intensive care unit (ICU), or invasive ventilation, or death. The risk of reaching to the composite endpoints was compared among patients with COVID-19 according to the presence and number of comorbidities. Results Of the 1,590 cases, the mean age was 48.9 years. 686 patients (42.7%) were females. 647 (40.7%) patients were managed inside Hubei province, and 1,334 (83.9%) patients had a contact history of Wuhan city. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. 269 (16.9%), 59 (3.7%), 30 (1.9%), 130 (8.2%), 28 (1.8%), 24 (1.5%), 21 (1.3%), 18 (1.1%) and 3 (0.2%) patients reported having hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency, respectively. 130 (8.2%) patients reported having two or more comorbidities. Patients with two or more comorbidities had significantly escalated risks of reaching to the composite endpoint compared with those who had a single comorbidity, and even more so as compared with those without (all P &lt;0.05). After adjusting for age and smoking status, patients with COPD (HR 2.681, 95%CI 1.424-5.048), diabetes (HR 1.59, 95%CI 1.03-2.45), hypertension (HR 1.58, 95%CI 1.07-2.32) and malignancy (HR 3.50, 95%CI 1.60-7.64) were more likely to reach to the composite endpoints than those without. As compared with patients without comorbidity, the HR (95%CI) was 1.79 (95%CI 1.16-2.77) among patients with at least one comorbidity and 2.59 (95%CI 1.61-4.17) among patients with two or more comorbidities. Conclusion Comorbidities are present in around one fourth of patients with COVID-19 in China, and predispose to poorer clinical outcomes. Highlights What is already known on this topic - Since November 2019, the rapid outbreak of coronavirus disease 2019 (COVID-19) has recently become a public health emergency of international concern. There have been 79,331 laboratory-confirmed cases and 2,595 deaths globally as of February 25 th , 2020 - Previous studies have demonstrated the association between comorbidities and other severe acute respiratory diseases including SARS and MERS. - No study with a nationwide representative cohort has demonstrated the spectrum of comorbidities and the impact of comorbidities on the clinical outcomes in patients with COVID-19. What this study adds - In this nationwide study with 1,590 patients with COVID-19, comorbidities were identified in 399 patients. Comorbidities of COVID-19 mainly included hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency. - The presence of as well as the number of comorbidities predicted the poor clinical outcomes (admission to intensive care unit, invasive ventilation, or death) of COVID-19. - Comorbidities should be taken into account when estimating the clinical outcomes of patients with COVID-19 on hospital admission.

Pregnant Women with Covid-19 in Wuhan, China Among 118 pregnant women with Covid-19 in Wuhan, China, the vast majority had a mild course of disease.