COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy.

Severe neurological symptoms are associated with Coronavirus disease 2019 (COVID-19). However, the morphologic features, pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection. In this study, neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining, ultrastructural examination under electron microscopy, and an image threshold method, in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals. Differentially expressed proteins were identified by quantitative proteomic assays. Histopathological findings included neurophagocytosis, microglia nodules, satellite phenomena, extensive edema, focal hemorrhage, and infarction, as well as infiltrating mononuclear cells. Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes, severe damage of the blood-brain barrier (BBB) and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+ monocytes and occasionally CD4+/CD8+ T lymphocytes. Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses, autophagy and cellular metabolism in COVID-19 patient brains compared with control brains. Proteins involved in brain development, neuroprotection, and extracellular matrix proteins of the basement membrane were downregulated, potentially caused by the activation of transforming growth factor ß receptor and vascular endothelial growth factor signaling pathways. Thus, our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis (CAME) and suggest potential therapeutic targets.

Non-Ischemic, Non-Hypoxic Myocardial Injury, and Long-Term Mortality in Patients with Coronavirus Disease 2019: A Retrospective Cohort Study.

Objective: Cardiac damage is commonly reported in patients with coronavirus disease 2019 (COVID-19) but its prevalence and impact on the long-term survival of patients remain uncertain. This study aimed to explore the prevalence of myocardial injury and assess its prognostic value in patients with COVID-19. Methods: A single-center, retrospective cohort study was performed at the Affiliated Hospital of Jianghan University. Data from 766 patients with confirmed COVID-19 who were hospitalized from December 27, 2019 to April 25, 2020 were collected. Demographic, clinical, laboratory, electrocardiogram, treatment data and all-cause mortality during follow-up were collected and analyzed. Results: Of the 766 patients with moderate to critically ill COVID-19, 86 (11.2%) died after a mean follow-up of 72.8 days. Myocardial injury occurred in 94 (12.3%) patients. The mortality rate was 64.9% (61/94) and 3.7% (25/672) in patients with and without myocardial injury, respectively. Cox regression showed that myocardial injury was an independent risk factor for mortality (hazard ratio: 8.76, 95% confidence interval: 4.76-16.11, P < 0.001). Of the 90 patients with myocardial injury with electrocardiogram results, sinus tachycardia was present in 29, bundle branch block in 26, low voltage in 10, and abnormal T-wave in 53. Conclusions: COVID-19 not only involves pneumonia but also cardiac damage. Myocardial injury is a common complication and an independent risk factor for mortality in COVID-19 patients.

Risk for newly diagnosed diabetes after COVID-19: a systematic review and meta-analysis.

BACKGROUND: There is growing evidence that patients recovering after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have a variety of acute sequelae including newly diagnosed diabetes. However, the risk of diabetes in the post-acute phase is unclear. To solve this question, we aimed to determine if there was any association between status post-coronavirus disease (COVID-19) infection and a new diagnosis of diabetes. METHODS: We performed a systematic review and meta-analysis of cohort studies assessing new-onset diabetes after COVID-19. PubMed, Embase, Web of Science, and Cochrane databases were all searched from inception to June 10, 2022. Three evaluators independently extracted individual study data and assessed the risk of bias. Random-effects models estimated the pooled incidence and relative risk (RR) of diabetes compared to non-COVID-19 after COVID-19. RESULTS: Nine studies with nearly 40 million participants were included. Overall, the incidence of diabetes after COVID-19 was 15.53 (7.91-25.64) per 1000 person-years, and the relative risk of diabetes after COVID-19 infection was elevated (RR 1.62 [1.45-1.80]). The relative risk of type 1 diabetes was RR=1.48 (1.26-1.75) and type 2 diabetes was RR=1.70 (1.32-2.19), compared to non-COVID-19 patients. At all ages, there was a statistically significant positive association between infection with COVID-19 and the risk of diabetes: <18 years: RR=1.72 (1.19-2.49), ≥18 years: RR=1.63 (1.26-2.11), and >65 years: RR=1.68 (1.22-2.30). The relative risk of diabetes in different gender groups was about 2 (males: RR=2.08 [1.27-3.40]; females: RR=1.99 [1.47-2.80]). The risk of diabetes increased 1.17-fold (1.02-1.34) after COVID-19 infection compared to patients with general upper respiratory tract infections. Patients with severe COVID-19 were at higher risk (RR=1.67 [1.25-2.23]) of diabetes after COVID-19. The risk (RR=1.95 [1.85-2.06]) of diabetes was highest in the first 3 months after COVID-19. These results remained after taking confounding factors into account. CONCLUSIONS: After COVID-19, patients of all ages and genders had an elevated incidence and relative risk for a new diagnosis of diabetes. Particular attention should be paid during the first 3 months of follow-up after COVID-19 for new-onset diabetes.

Neutrophil infiltration and myocarditis in patients with severe COVID-19: A post-mortem study

Aims To investigate cardiac pathology in critically ill patients with coronavirus disease 2019 (COVID-19) and identify associations between pathological changes and clinical characteristics. Methods The present autopsy cohort study included hearts from 26 deceased patients hospitalized in intensive care units due to COVID-19, and was conducted at four sites in Wuhan, China. Cases were divided into a neutrophil infiltration group and a no-neutrophil group based on the presence or absence of histopathologically identified neutrophilic infiltrates. Results Among the 26 patients, histopathological examination identified active myocarditis in four patients. All patients with myocarditis exhibited extensive accompanying neutrophil infiltration, and all patients without myocarditis did not. The neutrophil infiltration group exhibited significantly higher rates of detection of interleukin-6 (100 vs. 4.6%) and tumor necrosis factor-alpha (100 vs. 31.8%) than the no-neutrophil group (both p < 0.05). On admission, four patients with neutrophil infiltration in myocardium had significantly higher baseline levels of aspartate aminotransferase, D dimer, and high-sensitivity C reactive protein than the other 22 patients (all p < 0.05). During hospitalization, patients with neutrophil infiltration had significantly higher maximum creatine kinase-MB (median 280.0 IU/L vs. 38.7 IU/L, p = 0.04) and higher troponin I (median 1.112 ng/ml vs. 0.220 ng/ml, p = 0.56) than patients without neutrophil infiltration. Conclusion Active myocarditis was frequently associated with neutrophil infiltration in the hearts of deceased patients with severe COVID-19. Patients with neutrophil-infiltrated myocarditis had a series of severely abnormal laboratory test results on admission, and high maximum creatine kinase-MB during hospitalization. The role of neutrophils in severe heart injury and systemic conditions in patients with COVID-19 should be emphasized.

Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein.

Nucleocapsid (N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the formation of ribonucleoprotein (RNP) complex with the viral RNA. Here we reported the crystal structures of the N-terminal domain (NTD) and C-terminal domain (CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

The Prediction Value of D-Dimer on Prognosis in Intensive Care Unit among Old Patients ( ≥65 Years): A 9-Year Single-Center Retrospective Study of 9261 Cases.

Background: D-dimer (DD) has been indicated as a potential indicator due to its connection with the prognosis of the COVID-19 pandemic. Aging is linked to elevated DD levels in coagulation activation. However, few studies have investigated the correlation of DD with prognosis, especially in the old population. Therefore, this study aims at investigating the correlation of DD with prognosis in shock and perioperative populations over 65 years of age. Methods: We analyzed 9261 old patients admitted to intensive care units (ICUs) with either confirmed shock or in perioperative period of high-risk surgery, with 8813 of them had DD levels determined on admission. In-hospital mortality, length of ICU stay and ventilation time (VT) associated variables were assessed using generalized linear models. Results: Although DD levels had no positive correlations with in-hospital mortality (RR, 1.006; 95% CI, 0.998-1.014) and length of ICU stay (RR, 1.012; 95% CI, 0.997-1.028) in Model 3, they were strongly correlated with VT (RR, 1.577; 95% CI, 1.024-2.064). Higher DD levels in females (RR, 1.804; 95% CI, 1.116-2.602), those who used antibiotics (RR, 1.736; 95% CI, 1.092-2.453), those with surgery (RR, 1.640; 95% CI, 1.273-2.114), and those with shock (RR, 1.740; 95% CI, 1.001-2.687) had stronger correlation with longer VT than the counterparts. While patients who were between 65 and 74 years old (RR, 1.023; 95% CI, 1.003-1.043), with no use of antibiotics (RR, 1.007; 95% CI, 1.001-1.013) nor shock (RR, 1.011; 95% CI, 1.002-1.021), but had undergone surgical procedures (RR, 1.030; 95% CI, 1.012-1.048) were correlated with a longer ICU length of stay. Conclusion: DD levels at ICU admission are highly related to increased VT and length of ICU stay in the old population with either confirmed shock or after high-risk surgery, indicating the strong potential of DD as a marker with prognostic utility for all ICU patients in the future.

Cardiac Involvement in COVID-19: A Global Bibliometric and Visualized Analysis.

Objective: Coronavirus disease 2019 (COVID-19), which was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), had already resulted in widespread epidemics worldwide and millions of people's deaths since its outbreak in 2019. COVID-19 had also been demonstrated to affect people's cardiac function. However, the specific mechanism and influence of this damage were not clear yet. The purpose of the present study was to provide a bibliometric analysis of the current studies related to cardiac involvement after SARS-CoV-2 infection. Methods: A bibliometric literature search was performed on the web of science. The number and type of publications, countries, institutional sources, journals, and citation patterns were analyzed. In addition, qualitative and quantitative evaluations were carried out to visualize the scientific achievements in this field by using the VOSviewer software. Results: Web of science had recorded 2,24,097 documents on COVID-19 at the time of data collection (May 12, 2022). A total of 2,025 documents related to cardiac involvement were recorded at last. The countries with the most published articles were the United States of America (USA) (n =747, 36.9%), Italy (n =324, 16%), and England (n =213, 10.5%). Although the countries and institutions that published the most articles were mainly from the USA, the top three authors were from Germany, England, and Poland. Frontiers in Cardiovascular Medicine was the journal with the most studies (65 3.2%), followed by ESC Heart Failure (59 2.9%) and Journal of Clinical Medicine (56 2.8%). We identified 13,739 authors, among which Karin Klingel and Amer Harky had the most articles, and Shaobo Shi was co-cited most often. There existed some cooperation between different authors, but the scope was limited. Myocarditis and heart failure (HF) were the main research hotspots of COVID-19 on cardiac dysfunction and may be crucial to the prognosis of patients. Conclusions: It was the first bibliometric analysis of publications related to COVID-19-associated cardiac disorder. This study provided academics and researchers with useful information on the most influential articles of COVID-19 and cardiac dysfunction. Cooperation between countries and institutions must be strengthened on myocarditis and HF during COVID-19 pandemic.

Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury.

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.

Manifestations and Mechanism of SARS-CoV2 Mediated Cardiac Injury.

Coronavirus disease 2019 (COVID-19), a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) had resulted in considerable morbidity and mortality. COVID-19 primarily posed a threat to the respiratory system and violated many different organs, including the heart, kidney, liver, and blood vessels with the development of the disease. Severe patients were often accompanied by cardiac injury, and once the heart gets damaged, the mortality of patients will significantly increase. The main clinical manifestations of cardiac injury range from myocarditis, heart failure (HF), arrhythmia, and Takotsubo cardiomyopathy (TCM). A high abundance of angiotensin-converting enzyme II (ACE2) on the membrane of cardiomyocytes makes it possible that the virus can directly attack cardiomyocytes as subsequently evidenced by the detection of spike protein and virus RNA in autopsy cardiac tissues. The secondary myocardial injury through systemic inflammatory and immune response also caused obvious cardiac damage. The pathological manifestations of heart tissue were diverse, varied from mild cardiomyocyte edema, myocardial hypertrophy, cardiomyocyte degeneration, and necrosis to severe myocarditis caused by lymphocyte and macrophage infiltration. However, the mechanism of heart injury was still unclear. Here, we summarized the clinical manifestations and mechanism of SARS-CoV2 mediated cardiac injury, providing a reference for cardiac treatment in critically ill patients.

Anti-inflammatory and immune therapy in severe coronavirus disease 2019 (COVID-19) patients: An update.

In March 2020, when coronavirus disease 2019 (COVID-19) was just beginning to spread around the world, we presented the potential benefits and controversies of anti-inflammatory therapy in COVID-19 patients based on the limited experience and proposed some types of anti-inflammatory drugs with potential therapeutic value, while without evidence-based data. In the past one more year, many clinical trials or real-world studies have been performed, either confirm or deny the efficacy of certain anti-inflammatory drugs in the treatment of COVID-19. In this review we summarize the progress of anti-inflammatory and immune therapy in COVID-19, including glucocorticoids, IL-6 antagonist, IL-1 inhibitor, kinase inhibitors, non-steroidal anti-inflammatory drugs and chloroquine/hydroxychloroquine.

Fighting COVID-19: a qualitative study into the lives of intensive care unit survivors in Wuhan, China.

OBJECTIVES: We aimed to provide an insight into the life of survivors of critical COVID-19 in China. METHODS: We conducted an online survey and qualitative interviews among intensive care unit survivors of critical COVID-19 between November and December 2020 in Wuhan, China. Eligible participants were asked to complete the EQ-5D-5L and the Short Form 36-Item Survey, and invited to participate in a semistructured face-to-face interview. Descriptive analyses and phenomenological approach were adopted to analyse quantitative and qualitative data, respectively. RESULTS: Of 10 survivors who completed the questionnaire, 8 participated in the interview. The mean scores±SD of EuroQol-5 Dimensions-5 Level utility and EuroQol-Visual Analogue Scale were 0.88±0.15 and 80.9±14.2, respectively. The qualitative interview identified four themes, namely poor physical health, post-traumatic stress, social stigma and family support. CONCLUSIONS: COVID-19 survivors continue fighting physical and psychological impacts. Despite strong family support, these patients are struggling with social stigma. It is a long, challenging journey to recovery for patients and society.

Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation.

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.

Establishment of Human Pluripotent Stem Cell-Derived Skin Organoids Enabled Pathophysiological Model of SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.