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.

Supporting immigrant caregivers during the COVID-19 pandemic: Continuous adaptation and implementation of an early childhood digital engagement program.

Digital messaging programs have the potential to be a powerful, low-cost, technological tool to support multiple facets of caregivers' knowledge, and implementation of developmentally appropriate caregiver-child activities among diverse immigrant populations. However, involving caregivers and community stakeholders in the cultural and linguistic tailoring of interventions to optimize utilization and engagement may be critical to ensuring messaging programs' usability and acceptability. The purpose of this mixed-method study was to use the dynamic adaptation process (DAP) within an Exploration, Preparation, Implementation, Sustainment (EPIS) framework to examine the implementation of a digital messaging program, developed at the beginning of the COVID-19 pandemic, aimed at providing Spanish-, English-, and Mandarin-speaking immigrant caregivers with caregiver-child activities that supported children's development and caregivers' knowledge. Building upon the EPIS framework, using DAP, we assessed the feasibility and acceptability of a messaging program via short message service or multimedia message service, WeChat, and Remind and webinar program during the COVID-19 pandemic. The study illustrated how a digital messaging program is a feasible mechanism for sharing developmentally and culturally appropriate information with immigrant caregivers. In addition, the use of the DAP and the EPIS framework allowed us to continuously track the process of cultural adaptation, identify barriers and facilitators of the outreach program, and examine how implementation unfolded across all three groups of caregivers.

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.

Dynamic landscape mapping of humoral immunity to SARS-CoV-2 identifies non-structural protein antibodies associated with the survival of critical COVID-19 patients.

A comprehensive analysis of the humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential in understanding COVID-19 pathogenesis and developing antibody-based diagnostics and therapy. In this work, we performed a longitudinal analysis of antibody responses to SARS-CoV-2 proteins in 104 serum samples from 49 critical COVID-19 patients using a peptide-based SARS-CoV-2 proteome microarray. Our data show that the binding epitopes of IgM and IgG antibodies differ across SARS-CoV-2 proteins and even within the same protein. Moreover, most IgM and IgG epitopes are located within nonstructural proteins (nsps), which are critical in inactivating the host's innate immune response and enabling SARS-CoV-2 replication, transcription, and polyprotein processing. IgM antibodies are associated with a good prognosis and target nsp3 and nsp5 proteases, whereas IgG antibodies are associated with high mortality and target structural proteins (Nucleocapsid, Spike, ORF3a). The epitopes targeted by antibodies in patients with a high mortality rate were further validated using an independent serum cohort (n = 56) and using global correlation mapping analysis with the clinical variables that are associated with COVID-19 severity. Our data provide fundamental insight into humoral immunity during SARS-CoV-2 infection. SARS-CoV-2 immunogenic epitopes identified in this work could also help direct antibody-based COVID-19 treatment and triage patients.

Association between tachyarrhythmia and mortality in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19).

BACKGROUND: Cardiovascular involvement manifesting as arrhythmias has been confirmed in patients with coronavirus disease 2019 (COVID-19), so we aimed to explore the association between primary tachyarrhythmia and death in critically ill patients with COVID-19 in this retrospective study. METHODS: A total of 79 critically ill patients with COVID-19 were included. Demographic characteristics, clinical data (past history, vital signs, therapeutic management, and outcomes), and results of laboratory findings and cardiac investigations were collected. All statistical analyses were performed using SPSS 23.0 software (IBM, Armonk, NY, USA). RESULTS: The median age was 65±12 years, and 53 patients (67%) were male. A total of 57 (72%) patients died, and compared with survivors, these patients were older and had significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score and fewer lymphocytes as well as higher heart rate (P<0.05). Autopsy findings did not suggest severe myocarditis. A total of 19 (24%) patients had tachyarrhythmias, including 10 (13%) with atrial fibrillation (AF) and 9 (11%) with ventricular tachycardia or fibrillation. The incidence of tachyarrhythmias in non-survivor was much higher than in survivors (P=0.04). In a Cox regression model, older patients with ventricular tachyarrhythmias (VTAs) age were at a higher risk of death, with hazard ratio (HR) of 3.302 [95% confidence interval (CI), 1.524-7.154, P=0.002] and 1.045 (95% CI, 1.020-1.071, P=0.000), respectively. The use of beta-blockers [HR, 0.219 (95% CI, 0.066-0.722); P=0.013] was associated with a lower risk of death. CONCLUSIONS: Critically ill patients with COVID-19 had a poor prognosis. VTA and older age were independent prognostic factors of death. Beta-blockers might be an effective therapy to improve survival.

The Effect of Prior Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Treatment on Coronavirus Disease 2019 (COVID-19) Susceptibility and Outcome: A Systematic Review and Meta-analysis.

There have been arguments on whether angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) treatment alters the risk of coronavirus disease 2019 (COVID-19) susceptibility and disease severity. We identified a total of 102 eligible studies for systematic review, in which 49 studies adjusting for confounders were included in the meta-analysis. We found no association between prior ACEI/ARB use and risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the general population (adjusted odds ratio [aOR], 1.00; 95% confidence interval [CI], .94-1.05). The risk of mortality (aOR, .87; 95% CI, .66-1.04) and severe outcomes (aOR, .95; 95% CI, .73-1.24) were also unchanged among COVID-19 patients taking ACEIs/ARBs. These findings remained consistent in subgroup analyses stratified by populations, drug exposures, and other secondary outcomes. This systematic review provides evidence-based support to current medical guidelines and position statements that ACEIs/ARBs should not be discontinued. Additionally, there has been no evidence for initiating ACEI/ARB regimen as prevention or treatment of COVID-19.

Risk factors for mortality due to COVID-19 in intensive care units: a single-center study.

BACKGROUND: Many studies have revealed several risk factors associated with the prognosis of patients with coronavirus disease 2019 (COVID-19), but the risk factors associated with death in critically ill COVID-19 patients still needs to be fully elucidated. Therefore, we analyzed clinical characteristics and laboratory data of ICU patients to identify risk factors associated with COVID-19 death. METHODS: Patients with COVID-19 from the ICU in the Sino-French New City Branch of Tongji Hospital Wuhan, China, between February 4 and February 29, 2020, were enrolled in this study. The final date of follow-up was April 4, 2020. Clinical manifestations, laboratory tests, treatment, and outcome of participants before and during the ICU stay were retrospectively collected and analyzed. RESULTS: A total of 92 patients were admitted or transferred to the ICU from February 4 to February 29, 2020. Compared to survivors, the majority of non-survivors (73.8%) presented with dyspnea. A random forest classifier and ROC curve were used to develop a predictive model. IL-6, D-dimer, lymphocytes, and albumin achieved good performance with AUCs of 0.9476, 0.9165, 0.8994, and 0.9251, respectively, which were consistent with clinical observations, such as inflammation, lymphopenia, and coagulation dysfunction. Combining IL-6 and D-dimer improved the performance of this model with an excellent AUC (0.997). CONCLUSIONS: Mortality in COVID-19 was not rare in critically ill patients. The model that combined IL-6 and D-dimer was valuable for predicting the mortality of patients with COVID-19 with excellent performance. This model needs to be further optimized by adding more indicators and then evaluated with a multicenter study.

The Promise of Aggregation-Induced Emission Luminogens for Detecting COVID-19.

The long-term pandemic of coronavirus disease 2019 (COVID-19) requires sensitive and accurate diagnostic assays to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and SARS-CoV-2 antibodies in infected individuals. Currently, RNA of SARS-CoV-2 virus is mainly detected by reverse transcription-polymerase chain reaction (RT-PCR)-based nucleic acid assays, while SARS-CoV-2 antigen and antibody are identified by immunological assays. Both nucleic acid assays and immunological assays rely on the luminescence signals of specific luminescence probes for qualitative and quantitative detection. The exploration of novel luminescence probes will play a crucial role in improving the detection sensitivity of the assays. As innate probes, aggregation-induced emission (AIE) luminogens (AIEgens) exhibit negligible luminescence in the free state but enhanced luminescence in the aggregated or restricted states. Moreover, AIEgen-based nanoparticles (AIE dots) offer efficient luminescence, good biocompatibility and water solubility, and superior photostability. Both AIEgens and AIE dots have been widely used for high-performance detection of biomolecules and small molecules, chemical/biological imaging, and medical therapeutics. In this review, the availability of AIEgens and AIE dots in nucleic acid assays and immunological assays are enumerated and discussed. By building a bridge between AIE materials and COVID-19, we hope to inspire researchers to use AIE materials as a powerful weapon against COVID-19.

Myocardial Injury on Admission as a Risk in Critically Ill COVID-19 Patients: A Retrospective in-ICU Study.

OBJECTIVE: The aim of this study was to investigate the incidence, clinical presentation, cardiovascular (CV) complications, and mortality risk of myocardial injury on admission in critically ill intensive care unit (ICU) inpatients with COVID-19. DESIGN: A single-center, retrospective, observational study. SETTING: A newly built ICU in Tongji hospital (Sino-French new city campus), Huazhong University of Science and Technology, Wuhan, China. PARTICIPANTS: Seventy-seven critical COVID-19 patients. INTERVENTIONS: Patients were divided into a myocardial injury group and nonmyocardial injury group according to the on-admission levels of high-sensitivity cardiac troponin I. MEASUREMENTS AND MAIN RESULTS: Demographic data, clinical characteristics, laboratory tests, treatment, and clinical outcome were evaluated, stratified by the presence of myocardial injury on admission. Compared with nonmyocardial injury patients, patients with myocardial injury were older (68.4 ± 10.1 v 62.1 ± 13.5 years; p = 0.02), had higher prevalence of underlying CV disease (34.1% v 11.1%; p = 0.02), and in-ICU CV complications (41.5% v 13.9%; p = 0.008), higher Acute Physiology and Chronic Health Evaluation II scores (20.3 ± 7.3 v 14.4 ± 7.4; p = 0.001), and Sequential Organ Failure Assessment scores (7, interquartile range (IQR) 5-10 v 5, IQR 3-6; p < 0.001). Myocardial injury on admission increased the risk of 28-day mortality (hazard ratio [HR], 2.200; 95% confidence interval [CI] 1.29 to 3.74; p = 0.004). Age ≥75 years was another risk factor for mortality (HR, 2.882; 95% CI 1.51-5.50; p = 0.002). CONCLUSION: Critically ill patients with COVID-19 had a high risk of CV complications. Myocardial injury on admission may be a common comorbidity and is associated with severity and a high risk of mortality in this population.

Antiphospholipid Antibodies in Critically Ill Patients With COVID-19.

OBJECTIVE: Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID-19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 COVID-19 patients who were critically ill and 13 COVID-19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti-ß2 -glycoprotein I (anti-ß2 GPI) (IgG, IgM, and IgA), and IgG anti-ß2 GPI-domain 1 (anti-ß2 GPI-D1) and IgM and IgG anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies were detected in the serum by enzyme-linked immunosorbent assay. RESULTS: Of the 66 COVID-19 patients in critical condition, aPLs were detected in 31 (47% ). Antiphospholipid antibodies were not present among COVID-19 patients who were not in critical condition. The IgA anti-ß2 GPI antibody was the most commonly observed aPL in patients with COVID-19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti-ß2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti-ß2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti-ß2 GPI + IgA aCL + IgG anti-ß2 GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35-39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs (P = 0.023). CONCLUSION: Antiphospholipid antibodies were common in critically ill patients with COVID-19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as "COVID-19-induced APS-like syndrome." Long-term follow-up of COVID-19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus.

Clinical characteristics and survival analysis in critical and non-critical patients with COVID-19 in Wuhan, China: a single-center retrospective case control study.

Since the outbreak of COVID-19 in China at the end of 2019, the world has experienced a large-scale epidemic caused by the SARS-CoV-2. The epidemiological and clinical course of COVID-19 patients has been reported, but there have been few analyses about the characteristics, predictive risk factors, and outcomes of critical patients. In this single-center retrospective case-control study, 90 adult inpatients hospitalized at Tongji Hospital (Wuhan, China) were included. Demographic, clinical, laboratory tests, and treatment data were obtained and compared between critical and non-critical patients. We found that compared with non-critical patients, the critical patients had higher SOFA score and qSOFA scores. Critical patients had lower lymphocyte and platelet count, elevated D-dimer, decreased fibrinogen, and elevated high-sensitivity C-reactive protein (hsCRP), and interleukin-6(IL-6). More critical patients received treatment including antibiotics, anticoagulation, corticosteroid, and oxygen therapy than non-critical ones. Multivariable regression showed higher qSOFA score and elevation of IL-6 were related to critical patients. Antibiotic usage and anticoagulation were associated with decreased in-hospital mortality. And critical grouping contributed greatly to in-hospital death. Critical COVID-19 patients have a more severe clinical course. qSOFA score and elevation of IL-6 are risk factors for critical condition. Non-critical grouping, positive antibiotic application, and anticoagulation may be beneficial for patient survival.

Swollen heart in COVID-19 patients who progress to critical illness: a perspective from echo-cardiologists.

AIMS: Cardiac complications are common and associated with mortality in critically ill patients with COVID-19; however, the diagnostic and prognostic implications of critical care echocardiography (CCE) have not been studied. METHODS AND RESULTS: A cohort of 43 patients with COVID-19 who were in the intensive care unit (ICU) underwent bedside CCE during their disease course. Demographic, clinical, and survival data were collected. The echocardiographic analyses revealed high frequencies of pericardial effusion (90.7%), increased left ventricular mass index (60.5%), elevated relative wall thickness (76.7%), and reduced left ventricular stroke volume index (LVSVi; 53.5%) and cardiac index (51.2%). Twenty-two (51.2%) patients died in the ICU. In multivariate Cox regression, the strongest predictor of in-ICU death was decreased cardiac index [hazard ratio (HR), 0.67, 95% confidence interval (CI), 0.45-0.98; P = 0.041], after adjusting for male sex, shock status, high-sensitivity cardiac troponin I, and N-terminal pro-B-type natriuretic peptide. Negative associations with mortality were observed for LVSVi (HR, 0.91, 95% CI 0.85-0.96; P = 0.002), tricuspid annular plane systolic excursion (HR, 0.74, 95% CI 0.64-0.84; P < 0.001), and S' (HR, 0.78, 95% CI 0.69-0.88; P < 0.001). Kaplan-Meier analyses indicated that reductions in LVSVi, cardiac index, TAPSE, and S' were associated with a shorter survival time. CONCLUSIONS: Pericardial effusion and increased ventricular mass in COVID-19 might indicate a swollen heart. Both left and right heart dysfunction and a reduced cardiac index may lead to an increased risk of mortality. Clinicians should pay special attention to cardiac haemodynamic disorders in critical patients with COVID-19.

Neurological Manifestations in Critically Ill Patients With COVID-19: A Retrospective Study.

Background: The complications of coronavirus disease 2019 (COVID-19) involved multiple organs or systems, especially in critically ill patients. We aim to investigate the neurological complications in critically ill patients with COVID-19. Methods: This retrospective single-center case series analyzed critically ill patients with COVID-19 at the intensive care unit of Tongji Hospital, Wuhan, China from February 5 to April 2, 2020. Demographic data, clinical and laboratory findings, comorbidities and treatments were collected and analyzed. Results: Among 86 patients with confirmed COVID-19, 54 patients (62.8%) were male, and the mean (SD) age was 66.6 (11.1) years. Overall, 65% patients presented with at least one neurological symptom. Twenty patients (23.3%) had symptoms involving the central nervous system, including delirium, cerebrovascular diseases and hypoxic-ischemic brain injury, while 6 patients (7%) had neuromuscular involvement. Seven of 86 patients exhibited new stroke and 6 (7%) cases were ischemic. A significantly higher prevalence of antiphospholipid antibodies was observed in patients with ischemic stroke than in those without stroke (83.3 vs. 26.9%, p < 0.05). Patients with ischemic stroke were more likely to have a higher myoglobulin level, and a lower hemoglobin level. Conclusions: The clinical spectrum of neurological complications in critically ill patients with COVID-19 was broad. Stroke, delirium and neuromuscular diseases are common neurological complications of COVID-19. Physicians should pay close attention to neurological complications in critically ill patients with COVID-19.

Correlation between cytokines and coagulation-related parameters in patients with coronavirus disease 2019 admitted to ICU.

BACKGROUND: The novel SARS-CoV-2 caused a large number of infections and deaths worldwide. Thus, new ideas for an appropriated assessment of patients' condition and clinical treatment are of utmost importance. Therefore, in this study, the laboratory parameters of patients with coronavirus disease 2019 (COVID-19) were evaluated to identify the correlation between cytokine expression and other laboratory parameters. METHODS: A retrospective and single-center study was performed in Wuhan, involving 83 severe or critical COVID-19 patients admitted to the intensive care unit (ICU). Laboratory parameters in ICU patients with laboratory-confirmed infection of SARS-CoV2 were collected. The association between parameters was assessed by Spearman's rank correlation. RESULTS: Patients' median age was 66 years (IQR, 57-73), and 55 (66%) were men. Among the 83 patients, 61 (73%) had 1 or more coexisting medical condition. The median concentration of IL-2R, IL-6, IL8, IL10, and TNFα were above the normal range, without IL-1ß. A significant negative correlation between IL-6 and platelet count was discovered (r2 = -0.448, P < 0.001) as well as a significant correlation between IL-6 and other platelet parameters. Finally, a correlation between multiple cytokines and coagulation indicators was found, pro-inflammatory factors were found to be more associated to coagulation parameters, with the highest correlation between IL-6 and the International normalized ratio (INR) (r2 = 0.444, P < 0.001). CONCLUSIONS: Our results suggested that cytokines play an important role in the pathogenesis of COVID-19. In addition, IL-6 seems more relevant in the evaluation of the condition of COVID-19 patients.