Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19) 1 – 4 . However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.

CLIA-certified laboratories were enrolled through the IMPACT biorepository study 15. In the IMPACT study, biospecimens including blood, nasopharyngeal swabs, saliva, urine and stool samples were collected at study enrolment (baseline denotes the first time point) and longitudinally on average every 3 to 7 days (serial time points). The detailed demographics and clinical characteristics of these 98 participants are shown in Extended Data Table 1. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood, and plasma was used for titre measurements of SARS-CoV-2 spike S1 protein-specific IgG and IgM antibodies (anti-S1-IgG and-IgM) and cytokine or chemokine measurements. Freshly isolated PBMCs were stained and analysed by flow cytometry 15. We obtained longitudinal serial time-point samples from a subset of these 98 study participants (n = 48; information in Extended Data Table 1). To compare the immune phenotypes between sexes, two sets of data analyses were performed in parallel-baseline and longitudinal, as described below. As a control group, healthcare workers (HCWs) from Yale-New Haven Hospital were enrolled who were uninfected with COVID-19. Demographics and background information for the HCW group and the demographics of HCWs for cytokine assays and flow cytometry assays for the primary analyses are in Extended Data Table 1. Demographic data, time-point information of the samples defined by the days from the symptom onset (DFSO) in each patient, treatment information, and raw data used to generate figures and tables is in Supplementary Table 1. Baseline analysis The baseline analysis was performed on samples from the first time point of patients who met the following criteria: not in intensive care unit (ICU), had not received tocilizumab, and had not received high doses of corticosteroids (prednisone equivalent of more than 40 mg) before the first sample collection date. This patient group, cohort A, consisted of 39 patients (17 male and 22 female) (Extended Data Tables 1, 2). Intersex and transgender individuals were not represented in this study. Figures 1-4 represent analyses of baseline raw values obtained from patients in cohort A. In cohort A patients, male and female patients were matched in terms of age, body mass index (BMI), and DFSO at the first time point sample collection (Extended Data Fig. 1a). However, there were significant differences in age and BMI between HCW controls and patients (patients had higher age and BMI values) (Extended Data Table 1), and therefore an age-and BMI-adjusted difference-indifferences analysis was also performed in parallel (Extended Data Table 3). Longitudinal analysis As parallel secondary analyses, we performed longitudinal analysis on a total patient cohort (cohort B) to evaluate the difference in immune response over the course of the disease between male and female patients. Cohort B included all patient samples from cohort A (including several time-point samples from the cohort A patients) as well as an additional 59 patients who d...

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BACKGROUND. The effects of the novel coronavirus disease 2019 in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption. METHODS.We analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTS. SARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSION. This case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19. FUNDING.Beatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.

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Background. The effects of Covid-19 in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic Covid-19 complicated by severe preeclampsia and placental abruption.Methods. We analyzed placenta for the presence of SARS-CoV-2 through molecular and immunohistochemical assays and by and electron microscopy, and we measured the maternal antibody response in blood to this infection.Results. SARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the maternal-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for vasculopathy typically associated with preeclampsia.Conclusion. This case demonstrates, for the first time, SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with Covid-19.

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