Fatal COVID-19 Research Articles

The effect of cardiovascular disease and acute cardiac injury on fatal COVID-19: a meta-analysis.

BackgroundWith the continuance of the global COVID-19 pandemic, cardiovascular disease (CVD) and cardiac injury have been suggested to be risk factors for severe COVID-19.ObjectiveThe aim is to evaluate the mortality risks associated with CVD and cardiac injury among hospitalized COVID-19 patients, especially in subgroups of populations in different countries.MethodsA comprehensive systematic literature search was performed using 9 databases from November 1, 2019 to November 9, 2020. Meta-analyses were performed for CVD and cardiac injury between non-survivors and survivors of COVID-19.ResultsAlthough the prevalence of CVD in different populations was different, hospitalized COVID-19 patients with CVD were at a higher risk of fatal outcomes (OR = 2.72; 95% CI 2.35–3.16) than those without CVD. Separate meta-analyses of populations in four different countries also reached a similar conclusion that CVD was associated with an increase in mortality. Cardiac injury was common among hospitalized COVID-19 patients. Patients with cardiac injury had a significantly higher mortality risk than those without cardiac injury (OR = 13.25; 95% CI: 8.56–20.52).ConclusionsPatients' CVD history and biomarkers of cardiac injury should be taken into consideration during the hospital stay and incorporated into the routine laboratory panel for COVID-19.

Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

BackgroundKnowledge of the pathophysiology of COVID-19 is almost exclusively derived from studies that examined the immune response in blood. We here aimed to analyse the pulmonary immune response during severe...

Broad Severe Acute Respiratory Syndrome Coronavirus 2 Cell Tropism and Immunopathology in Lung Tissues From Fatal Coronavirus Disease 2019.

BackgroundCOVID-19 patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear.MethodsWe performed multicolor staining for SARS-CoV-2 proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases.ResultsLung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like and endothelial cells. Over 90% infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, and natural killer (NK), B and T cells. Most but not all infected cells were ACE2-positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high inflammatory cells including macrophages, monocytes, neutrophils and NK cells, and low B- but abundant T-cells consisting of mainly T helper cells, few cytotoxic T cells, and no T regulatory cell. Robust interleukin-6 expression was present in most cells, with or without infection.ConclusionsIn fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation and compromised immune responses.

Immunopathogenic Overlap and Shared Therapeutic Targets for Covid-19 and Tuberculosis Predicted from Transcriptomic Meta-Analysis

Current and previous tuberculosis (TB) increase the risk for severe and fatal COVID-19. To identify mechanisms of immunopathogenic interaction which may increase severity of COVID-19 and determine the impact of co-infection on subsequent TB progression, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning mild-critical disease, from whole blood, PBMCs and BALF. Thirty-five eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals, across the spectrum of TB infection. Twenty COVID-19 gene-signatures had significantly higher “COVID-19 risk scores” in active and progressive TB compared with non-progressing latent infection and uninfected controls (pFCN1- and SPP1-expressing macrophages enriched in BALF during severe COVID-19 in blood during active TB. Transcriptomic comparisons for shared gene ontologies and protein-protein interaction networks identified 12-gene disease exacerbation hot-spots between COVID-19 and TB which offer opportunity for therapeutic amelioration targeted at synergistic immunopathogenesis.Funding Information: D.S. is supported by the Walter and Eliza Hall Institute of Medical Research (WEHI). A. is supported by AXA research Fund (25776); National Research Foundation, South Africa (NRF; UID8829) and the Medical Research Council of South Africa (SAMRC; SHIP-02-013). X.W. is supported by the National Institutes of Health (NIH; R21AI154387). W.E.J. is funded by CRDF Global (DAA3-19-65672-1) and the NIH (U19AI111276, U01CA220413, R01GM127430, R21AI154387). A.C. is supported by WEHI, SAMRC (SHIP-02-2013), NIH (U19AI111276) and NRF (UID109040).Declaration of Interests: The authors declare no competing interests.

Clinical Features and Risk Factors for In-Hospital Mortality From COVID-19 Infection at a Tertiary Care Medical Center, at the Onset of the US COVID-19 Pandemic.

Background:Mortality from COVID-19 has been associated with older age, black race, and comorbidities including obesity, Understanding the clinical risk factors and laboratory biomarkers associated with severe and fatal COVID-19 will allow early interventions to help mitigate adverse outcomes. Our study identified risk factors for in-hospital mortality among patients with COVID-19 infection at a tertiary care center, in Detroit, Michigan.Methods:We conducted a single-center, retrospective cohort study at a 776-bed tertiary care urban academic medical center. Adult inpatients with confirmed COVID-19 (nasopharyngeal swab testing positive by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay) from March 8, 2020, to June 14, 2020, were included. Clinical information including the presence of comorbid conditions (according to the Charlson Weighted Index of Comorbidity (CWIC)), initial vital signs, admission laboratory markers and management data were collected. The primary outcome was in-hospital mortality.Results:Among 565 hospitalized patients, 172 patients died for a case fatality rate of 30.4%. The mean (SD) age of the cohort was 64.4 (16.2) years, and 294 (52.0%) were male. The patients who died were significantly older (mean [SD] age, 70.4 [14.1] years vs 61.7 [16.1] years; P < 0.0001), more likely to have congestive heart failure (35 [20.3%] vs 47 [12.0%]; P = 0.009), dementia (47 [27.3%] vs 48 [12.2%]; P < 0.0001), hemiplegia (18 [10.5%] vs 18 [4.8%]; P = 0.01) and a diagnosis of malignancy (16 [9.3%] vs 18 [4.6%]; P = 0.03).From multivariable analysis, factors associated with an increased odds of death were age greater than 60 years (OR = 2.2, P = 0.003), CWIC score (OR = 1.1, P = 0.023), qSOFA (OR = 1.7, P < 0.0001), WBC counts (OR = 1.1, P = 0.002), lymphocytopenia (OR = 2.0, P = 0.003), thrombocytopenia (OR = 1.9, P = 0.019), albumin (OR = 0.6, P = 0.014), and AST levels (OR = 2.0, P = 0.004) on admission.Conclusions:This study identified risk factor for in-hospital mortality among patients admitted with COVID-19 in a tertiary care hospital at the onset of U.S. Covid-19 pandemic. After adjusting for age, CWIC score, and laboratory data, qSOFA remained an independent predictor of mortality. Knowing these risk factors may help identify patients who would benefit from close observations and early interventions.

Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19.

COVID-19 has been associated with cardiac injury and dysfunction. While both myocardial inflammatory cell infiltration and myocarditis with myocyte injury have been reported in patients with fatal COVID-19, clinical-pathologic correlations remain limited. The objective was to determine the relationships between cardiac pathological changes in patients dying from COVID-19 and cardiac infection by SARS-CoV-2, laboratory measurements, clinical features, and treatments. In a retrospective study, 41 consecutive autopsies of patients with fatal COVID-19 were analyzed for the associations between cardiac inflammation, myocarditis, cardiac infection by SARS-CoV-2, clinical features, laboratory measurements, and treatments. Cardiac infection was assessed by in situ hybridization and NanoString transcriptomic profiling. Cardiac infection by SARS-CoV-2 was present in 30/41 cases: virus+ with myocarditis (n = 4), virus+ without myocarditis (n = 26), and virus- without myocarditis (n = 11). In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2. Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01). Myocarditis was more prevalent with IL-6 blockade than with nonbiologic immunosuppression, primarily glucocorticoids (2/3 vs 0/14; P = 0.02). Overall, SARS-CoV-2 cardiac infection was less prevalent in patients treated with nonbiologic immunosuppression (7/14 vs 21/24; P = 0.02). Myocardial macrophage and lymphocyte densities overall were positively correlated with the duration of symptoms but not with underlying comorbidities. In summary, cardiac infection with SARS-CoV-2 is common among patients dying from COVID-19 but often with only rare infected cells. Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes. Nonbiologic immunosuppression is associated with lower incidences of myocarditis and cardiac infection by SARS-CoV-2.

Postmortem radiologic and pathologic findings in COVID-19: The Toronto experience with pre-hospitalization deaths in the community

Over a year after the initial emergence of the disease, the COVID-19 pandemic continues to strain healthcare systems worldwide. The value of feedback and connection between clinical care, public health, and death investigation systems has never been more clear. To this end, knowledge of the radiologic and histopathologic features of fatal COVID-19 is critical for those working with the living and the dead. Most of the medical descriptions of COVID-19 are either focused on clinical in vivo medical imaging or autopsies performed following an intensive course of treatment over days to weeks prior to death, rather than deaths in the community prior to hospitalization. Here we report the postmortem computed tomography (PMCT) and lung histopathology in five fatal cases of COVID-19 that were subject to medicolegal death investigation. All individuals died in the community without medical treatment, or after a brief terminal admission to hospital. In these cases, the main PMCT findings included: diffuse lung changes including ground glass-type opacifications, a “crazy paving” appearance, variable areas of more dense consolidation, and relatively few areas of spared/less involved lung parenchyma. The unifying histopathology was diffuse alveolar damage in various stages of cellular evolution. In all cases, the pattern of PMCT and the lung histopathology corroborated the diagnosis of COVID-19. We propose the routine use of PMCT as a potential screening tool for the identification of COVID-19 related fatalities in the medicolegal setting where a paucity of historical information may not otherwise permit the identification of this disease prior to autopsy.

Deciphering the state of immune silence in fatal COVID-19 patients

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of ‘immune silence’ in patients with critical COVID-19.

Clinical risk factors for mortality of hospitalized patients with COVID-19: systematic review and meta-analysis.

New evidence from retrospective cohort studies on risk of death from COVID-19 infection became available. We aimed to systematically review the clinical risk factors for fatal outcome of COVID-19. We performed meta-analysis, using PubMed, EMBASE and Cochrane databases from December 1 2019 to June 10 2020. The meta-analysis summarized clinical, laboratory, radiological features, and complications of non-survivors with confirmed COVID-19. In addition, a fixed- or random-effects model was adopted based on the heterogeneity among studies. We also used funnel-plot with Egger's tests to screen potential publication bias. In total, twenty studies with 15,408 COVID-19 cases were included in our meta-analysis. Male, current smoking, and older age were associated with in-hospital death. Patients aged 60 years or over had the highest pooled ORs [OR 4.94 (2.89, 8.44)]. Non-survivors were more likely to have diabetes, hypertension, cardiovascular disease (CVD), respiratory disease, or chronic kidney disease (CKD). Respiratory disease had the highest pooled ORs [OR 2.55 (2.14, 3.05)]. Dyspnea [OR 3.31 (1.78, 6.16); I2 : 83%] and fatigue [OR 1.36 (1.07, 1.73); I2 : 0%] were associated with increased risk of death. Increased white blood cell count, decreased lymphocyte and platelet counts, were also associated with increased risk of death. Biomarkers of coagulation function, inflammation, liver and kidney function, cardiac and muscle injury were also elevated in nonsurvivors. Male, current smoking patients aged 60 years or over might face a greater risk of in-hospital death and the comorbidities such as diabetes, hypertension, CVD, respiratory disease, and CKD could also influence the prognosis of the COVID-19. Clinical feature such as dyspnea and fatigue could imply the exacerbation and even death. Our findings highlighted early markers of mortality which were beneficial to identify fatal COVID-19.

Histopathological features in fatal COVID-19 acute respiratory distress syndrome.

BackgroundCOVID-19 acute respiratory distress syndrome (ARDS) shares the common histological hallmarks with other forms of ARDS. However, the chronology of the histological lesions has not been well established.ObjectiveTo describe the chronological histopathological alterations in the lungs of patients with COVID-19 related ARDS.DesignA prospective cohort study was carried out.SettingIntensive Care Unit of a tertiary hospital.PatientsThe first 22 consecutive COVID-19 deaths.MeasurementsLung biopsies and histopathological analyses were performed in deceased patients with COVID-19 related ARDS. Clinical data and patient course were evaluated.ResultsThe median patient age was 66 [63–74] years; 73% were males. The median duration of mechanical ventilation was 17 [8–24] days. COVID-19 induced pulmonary injury was characterized by an exudative phase in the first week of the disease, followed by a proliferative/organizing phase in the second and third weeks, and finally an end-stage fibrosis phase after the third week. Viral RNA and proteins were detected in pneumocytes and macrophages in a very early stage of the disease, and were no longer detected after the second week.LimitationLimited sample size.ConclusionsThe chronological evolution of COVID-19 lung histopathological lesions seems to be similar to that seen in other forms of ARDS. In particular, lung lesions consistent with potentially corticosteroid-sensitive lesions are seen.

Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17–23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

Molecular Evolution of Human Coronavirus 229E in Hong Kong and a Fatal COVID-19 Case Involving Coinfection with a Novel Human Coronavirus 229E Genogroup

ABSTRACTCompared to other human coronaviruses, the genetic diversity and evolution of human coronavirus 229E (HCoV-229E) are relatively understudied. We report a fatal case of COVID-19 pneumonia coinfected with HCoV-229E in Hong Kong. Genome sequencing of SARS-CoV-2 and HCoV-229E from a nasopharyngeal sample of the patient showed that the SARS-CoV-2 strain HK13 was most closely related to SARS-CoV-2 type strain Wuhan-Hu-1 (99.99% nucleotide identity), compatible with his recent history of travel to Wuhan. The HCoV-229E strain HK20-42 was most closely related to HCoV-229E strain SC0865 from the United States (99.86% nucleotide identity). To investigate if it may represent a newly emerged HCoV-229E genotype in Hong Kong, we retrieved 41 archived respiratory samples that tested positive for HCoV-229E from 2004 to 2019. Pneumonia and exacerbations of chronic airway diseases were common among infected patients. Complete RdRp, S, and N gene sequencing of the 41 HCoV-229E strains revealed that our contemporary HCoV-229E strains have undergone significant genetic drift with clustering of strains in chronological order. Two novel genogroups were identified, in addition to previously described genogroups 1 to 4, with recent circulating strains including strain HK20-42 belonging to novel genogroup 6. Positive selection was detected in the spike protein and receptor-binding domain, which may be important for viral evolution at the receptor-binding interphase. Molecular dating analysis showed that HCoV-229E shared the most recent common ancestor with bat and camel/alpaca 229E-related viruses at ∼1884, while camel/alpaca viruses had a relatively recent common ancestor at ∼1999. Further studies are required to ascertain the evolutionary origin and path of HCoV-229E.IMPORTANCE Since its first appearance in the 1960s, the genetic diversity and evolution of human coronavirus 229E (HCoV-229E) have been relatively understudied. In this study, we report a fatal case of COVID-19 coinfected with HCoV-229E in Hong Kong. Genome sequencing revealed that our SARS-CoV-2 strain is highly identical to the SARS-CoV-2 strain from Wuhan, compatible with the patient’s recent travel history, whereas our HCoV-229E strain in this study is highly identical to a recent strain in the United States. We also retrieved 41 archived HCoV-229E strains from 2004 to 2019 in Hong Kong for sequence analysis. Pneumonia and exacerbations of chronic airway diseases were common diagnoses among the 41 patients. The results showed that HCoV-229E was evolving in chronological order. Two novel genogroups were identified in addition to the four preexisting HCoV-229E genogroups, with recent circulating strains belonging to novel genogroup 6. Molecular clock analysis dated bat-to-human and bat-to-camelid transmission to as early as 1884.

COVID-19 and male reproduction: Current research and unknown factors.

BackgroundThe testes are suspected target organs of SARS‐CoV‐2. However, the results of studies on the effect of COVID‐19 on male reproduction are controversial.ObjectiveTo summarize current research on the effects of COVID‐19 on male reproduction.MethodsA systematic review of English literature was performed using PubMed and Ovid Embase up to 18 August 2020. Research articles on the presence of SARS‐CoV‐2 in semen, the effects of the virus on semen parameters and any pathological changes in the testes were evaluated.ResultsFourteen studies were included in this review. Six of 176 survivors (3.4%) and 1 of 13 decedents (7.7%) in 2 of 12 studies were positive for viral RNA in semen and testicular tissue, respectively. After stratification of patient groups, we found that the virus was detected in the relatively early stage of infection, 6–16 days after disease onset, in semen from survivors. Two of 3 studies reported that some participants had substandard semen quality after COVID‐19, and 1 study found that COVID‐19 may impair semen quality in a severity‐related manner. Pathological analyses showed that injuries to the seminiferous tubule occurred in all decedents (N = 11). Another study found that orchitic and testis fibrin microthrombi occurred in patients with fatal disease (100%, N = 2). Scrotal discomfort of orchiepididymitis or spermatic cord inflammation has also been reported in COVID‐19 patients.ConclusionCurrent studies suggest that semen is rarely considered a carrier of SARS‐CoV‐2 genetic material during the infection period but not in the semen of recovered patients. Fatal COVID‐19 may cause testicular structure damage without the presence of virus.

Tissue-Specific Immunopathology in Fatal COVID-19.

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.

Ultrasound assessment of pulmonary fibroproliferative changes in severe COVID-19: a quantitative correlation study with histopathological findings.

PurposeThis study was designed to evaluate the usefulness of lung ultrasound (LUS) imaging to characterize the progression and severity of lung damage in cases of COVID-19.MethodsWe employed a set of combined ultrasound parameters and histopathological images obtained simultaneously in 28 patients (15 women, 0.6–83 years) with fatal COVID-19 submitted to minimally invasive autopsies, with different times of disease evolution from initial symptoms to death (3–37 days, median 18 days). For each patient, we analysed eight post-mortem LUS parameters and the proportion of three histological patterns (normal lung, exudative diffuse alveolar damage [DAD] and fibroproliferative DAD) in eight different lung regions. The relationship between histopathological and post-mortem ultrasonographic findings was assessed using various statistical approaches.ResultsStatistically significant positive correlations were observed between fibroproliferative DAD and peripheral consolidation (coefficient 0.43, p = 0.02) and pulmonary consolidation (coefficient 0.51, p = 0.005). A model combining age, time of evolution, sex and ultrasound score predicted reasonably well (r = 0.66) the proportion of pulmonary parenchyma with fibroproliferative DAD.ConclusionThe present study adds information to previous studies related to the use of LUS as a tool to assess the severity of acute pulmonary damage. We provide a histological background that supports the concept that LUS can be used to characterize the progression and severity of lung damage in severe COVID-19.

Effectiveness of the CoronaVac Vaccine in Prevention of Symptomatic and Progression to Severe COVID-19 in Pregnant Women in Brazil

Background: The effectiveness of Covid-19 inactivated vaccines in pregnant women is unknown. We estimated vaccine effectiveness (VE) of CoronaVac against symptomatic and severe Covid-19 and in preventing progression from symptomatic to severe Covid-19 in pregnant women in Brazil. Methods: We conducted a test-negative design study in all pregnant women aged 18 to 49 years in Brazil, linking records of negative and positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) tests to national vaccination records. We also linked records of test positive cases with notification of severe, hospitalized or fatal Covid-19. Using logistic regression, we estimated adjusted odds and VE against symptomatic Covid-19 by comparing vaccine status in test positive (confirmed cases) to that in subjects with a negative test result. We also calculated the odds/VE against progression by comparing vaccine status in symptomatic cases to that in severe Covid-19 cases. Results: Of 19838 tested pregnant women, 7424 (37.4%) tested positive for Covid-19 and 588 (7.9%) had severe disease. Only 83% of pregnant women who received a first dose of CoronaVac completed the vaccination scheme. A single dose of the CoronaVac vaccine was not effective at preventing symptomatic Covid-19. Effectiveness of two doses of CoronaVac was 41% (95% CI 27.1- 52.2) against symptomatic Covid-19, 85% (95% CI 59.5-94.8) against severe Covid-19 and (75%; 95% CI 27.9- 91.2) in preventing progression to severe Covid-19 among those infected. Conclusion: A complete regimen of CoronaVac in pregnant women was effective in preventing symptomatic Covid-19, and highly effective against severe illness in a setting that combines high disease burden and elevated Covid-19 related maternal deaths.Funding Information: This study is part of the VigiVac Fiocruz program, partially supported by a donation from the "Fazer o bem faz bem" program. EPS is funded by the Wellcome Trust [Grant number 213589/Z/18/Z]. Declaration of Interests: We declare no competing interests. VO, VB, MB, and MB-N are employees from Fiocruz, a federal public institution, which manufactures Vaxzevria in Brazil, through a full technology transfer agreement with AstraZenecaEthics Approval Statement: This study analysed de-identified data and was approved by the National Ethics committee (CONEP) (CAAE registration no. 50199321.9.0000.0040).

Pre-Existing Health Conditions and Severe COVID-19 Outcomes: Umbrella Review and Meta-Analysis of Global Evidence

Background: This umbrella review summarises the global evidence on the risk of severe COVID-19 outcomes in patients with pre-existing health conditions. Methods: Systematic reviews (SRs) were identified in PubMed, Embase/Medline, and seven pre-print servers until December 11, 2020. Risk estimates (odds ratio (OR), hazard ratio (HR), relative risk (RR)) for hospitalisation, intensive care unit admission, intubation, and death were extracted from primary studies. Meta-analyses were performed stratified by regions of the World Health Organisation. The evidence certainty was assessed using GRADE. Registration number CRD42020215846.Findings: 160 primary studies from 120 SRs contributed 464 estimates for 42 pre-existing conditions. Most studies were conducted in North America, European, and Western Pacific regions. Evidence from Africa, South/Latin America, and Eastern Mediterranean region was scarce. No evidence was available from South-East Asia region. Diabetes (HR 1∙2-2∙0 (1∙1-2∙8)), obesity (OR 1∙5-1∙75 (1∙1-2∙3)), heart failure (HR 1∙3-3∙3(0∙9-8∙2)), COPD (HR 1∙12-2∙2 (1∙1-3∙2)), and dementia (HR 1∙4-7.7 (1∙2-39∙6)) were associated with fatal COVID-19 in different regions, although the estimates varied. Evidence from Europe and North America showed that liver cirrhosis (OR 3∙2-5∙9 (0∙9-27∙7)) and active cancer (OR 1∙6-4∙7 (0∙5-14∙9)) were also associated with increased risk of death. Association between HIV and severe COVID-19 showed regional heterogeneity, with an increased risk of death in Africa (HR 1∙7 (1∙3-2∙2)). GRADE certainty was moderate to high for most associations.Interpretation: Risk of severe COVID-19 is consistently increased in certain patient subgroups across geographical regions, showing high variability in others. The results can be used to inform COVID-19 vaccine prioritisation or other intervention strategies.Funding Statement: Project ImVaCov – German Federal Ministry of HealthDeclaration of Interests: Authors declare no conflicts of interest.

The Blood-Brain Barrier is Dysregulated in COVID-19 and Serves as a CNS Entry Route for SARS-CoV-2

Neurological complications are common in COVID-19 patients. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected in patients’ brain tissues, its entry routes and resulting consequences are not well understood. Here, we report that the blood-brain barrier (BBB) and its microenvironment show pronounced upregulation of interferon signaling pathways in fatal COVID-19. Moreover, human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) were susceptible to SARS-CoV-2 infection and recapitulated the transcriptional changes detected in vivo . While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active transcytosis of the virus across the BBB in vitro . SARS-CoV-2 entry into BCECs could be reduced by anti-spike-, anti-ACE2- and anti-NRP1-specific antibodies or the TMPRSS2 inhibitor nafamostat. Together, our data provide direct evidence for SARS-CoV-2 brain entry across the BBB resulting in an increase in interferon signaling.

Fatal COVID-19 Outcomes are Associated with an Antibody Response Targeting Epitopes Shared with Endemic Coronaviruses

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.Funding: This work was supported by the Georg and Emily von Opel Foundation, the National Institute for Health Research (NIHR) [award CO-­‐CIN-­‐01], the Medical Research Council [grant MC_PC_19059], ME was supported by The Leona M. and Harry B. Helmsley Charitable Trust on May 31, 2021 for the project titled, "ICARUS –IBD: International study of COVID-­‐19 Antibody Response Under Sustained immune suppression in Inflammatory Bowel Disease. RP also supported by funds provided under Professor RW Snow’s Wellcome Trust Principal Fellowship (# 212176). Meso Scale Diagnostics (USA) provided loan of equipment, reagents and technical support. JSB was supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M011224/1]. CPT was funded by an ERC research grant UNIFLUVAC’ and two MRC CiC grants (Ref: BR00140). ALM is funded by a NIHR Research Capability Funding grant. HJK is supported by The Future of Humanity Institute at the University of Oxford DPhil Scholarship program. DE is funded by the Robertson Foundation. The funders played no role in the design, execution or reporting of the study.Declaration of Interest: DE declares lecture fees from Gilead. CPT and SG hold funding from Blue Water Vaccines. All others have nothing to disclose. Ethical Approval: Ethical approval was obtained for the Scottish National Blood Transfusion Service (SNBTS) anonymous archive -­‐ IRAS project number 18005. SNBTS blood donors gave fully informed consent to virological testing, donation was made under the SNBTS Blood Establishment Authorisation and the study was approved by the SNBTS Research and Sample Governance Committee.