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Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021–22 (n = 467). Respiratory viruses and/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children <5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1β and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1–2 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host–pathogen interactions drive nasal innate immune activation in children.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1–5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.

The goal of this study is to create a predictive, interpretable model of early hospital respiratory failure among emergency department (ED) patients admitted with coronavirus disease 2019 (COVID-19).

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.

Introduction:Guideline-recommended medical therapy (GDMT) for cardiovascular risk reduction remains sub-optimally prescribed in patients with peripheral artery disease (PAD). To begin addressing this issue, it is key as a health system to be able to monitor electronic health record (EHR)-based real-world data to assess GDMT usage rates and its association with long-term mortality and amputation.Methods:We included all patients with PAD who underwent peripheral vascular interventions (PVI) across the Yale New Haven Health System in 2016-2022. GDMT at PVI discharge was defined as having all 3 of: angiotensin converting enzyme inhibitor/angiotensin receptor blocker (if hypertensive), antiplatelet, and statin. Propensity scores were calculated based on age, sex, race, ethnicity, and Elixhauser comorbidities. Inverse probability weighted Cox regression models with a random effect for site and provider were constructed to evaluate the relationship between GDMT and 2-year mortality and major amputation.Results:A total of 3,741 patients with PAD underwent PVI. The average age was 72.3 (± 12.9) years, and 39% were female. GDMT rates at PVI discharge ranged from 24% to 40% during the study period. Lack of GDMT at discharge had a statistically insignificant association 2-year mortality risk (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.98-1.50, p=0.07; figure top) and a significant positive association with 2-year major amputation risk (HR: 2.73, 95% CI:1.51-4.94, p<0.001; figure bottom).Conclusions:This study leveraged system-wide EHR data to study GDMT use and its association with mortality and major amputation, which may serve as a metric for quality of PAD care.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Gamma, emerged in the city of Manaus in late 2020 during a large resurgence of coronavirus disease (COVID-19), and has spread throughout Brazil. The effectiveness of vaccines in settings with widespread Gamma variant transmission has not been reported.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.