Approximately 80% of hospitalized patients with COVID-19 report persistent symptoms several months after infection onset. 1,2 However, knowledge of long-term outcomes among individuals with mild COVID-19 is scarce, and prevalence data are hampered by selection bias and suboptimal control groups. 3,4 This cohort study investigated COVID-19-related long-term symptoms in health care professionals.Methods | The COMMUNITY (COVID-19 Biomarker and Immunity) study investigates long-term immunity after mild COVID-19 5 (eMethods in the Supplement). Between April 15, 2020, and May 8, 2020, health care professionals at Danderyd Hospital, Stockholm, Sweden, were invited to participate, with a limit of approximately 2000 participants because of testing restrictions. Participants had blood sampling performed every 4 months. Demographics, symptoms and severity (mild or severe), and chronic diseases were obtained through questionnaires at baseline. Participants who were seropositive for SARS-CoV-2 anti-spike IgG at baseline and who reported severe symptoms were excluded, as were initially seronegative participants who seroconverted during follow-up. At the 8-month follow-up (January 11-29, 2021), participants reported via smartphone app the presence, duration (<2 months, ≥2 months, ≥4 months, ≥8 months), and severity (mild, moderate, or severe) of 23 predefined symptoms. For participants reporting at least 1 symptom persistent for at least 2 months, the Sheehan Disability Scale 6 was used to score functional impairment from present or prior long-term symptoms (0, not at all; 1-3, mild; 4-6, moderate; and 7-10, marked) in 3 interrelated domains (work, social, and home life). Associations between categorical variables were assessed using the χ 2 test of independence. Risk ratios (RRs) and their corresponding 95% CIs were calculated comparing seropositive and seronegative participants for moderate to severe symptoms lasting 2 or more or 8 or more months and for moderate to marked disruption on the Sheehan Disability Scale, using the STATA command cs. Statistical analyses were performed using STATA, version 16.1 (StataCorp LP). A 2-sided P value <.05 was considered statistically significant. The study was approved by the Swedish Ethical Review Authority, and informed written consent was obtained from all participants.Results | Participant enrollment was closed after 2149 of 4375 health care professionals (49%) enrolled; 393 were

Objective: The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis. Approach and Results: One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that plasma levels of NET markers were all elevated in patients with COVID-19 relative to healthy controls, were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. Levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage. Conclusions: Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04402944, NCT04541979, NCT04445285, NCT04432987, NCT04402970.

Objective: Patients with coronavirus disease 2019 (COVID-19) have a high rate of thrombosis. We hypothesized that severe acute respiratory syndrome coronavirus 2 leads to induction of TF (tissue factor) expression and increased levels of circulating TF-positive extracellular vesicles (EV) that may drive thrombosis. Approach and Results: We measured levels of plasma EV TF activity in 100 patients with COVID-19 with moderate and severe disease and 28 healthy controls. Levels of EV TF activity were significantly higher in patients with COVID-19 compared with controls. In addition, levels of EV TF activity were associated with disease severity and mortality. Finally, levels of EV TF activity correlated with several plasma markers, including D-dimer, which has been shown to be associated with thrombosis in patients with COVID-19. Conclusions: Our results indicate that severe acute respiratory syndrome coronavirus 2 infection induces the release of TF-positive EVs into the circulation that are likely to contribute to thrombosis in patients with COVID-19. EV TF activity was also associated with severity and mortality.

Background Emerging data support detectable immune responses for months after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and vaccination, but it is not yet established to what degree and for how long protection against reinfection lasts. Methods We investigated SARS‐CoV‐2‐specific humoral and cellular immune responses more than 8 months post‐asymptomatic, mild and severe infection in a cohort of 1884 healthcare workers (HCW) and 51 hospitalized COVID‐19 patients. Possible protection against SARS‐CoV‐2 reinfection was analyzed by a weekly 3‐month polymerase chain reaction (PCR) screening of 252 HCW that had seroconverted 7 months prior to start of screening and 48 HCW that had remained seronegative at multiple time points. Results All COVID‐19 patients and 96% (355/370) of HCW who were anti‐spike IgG positive at inclusion remained anti‐spike IgG positive at the 8‐month follow‐up. Circulating SARS‐CoV‐2‐specific memory T cell responses were detected in 88% (45/51) of COVID‐19 patients and in 63% (233/370) of seropositive HCW. The cumulative incidence of PCR‐confirmed SARS‐CoV‐2 infection was 1% (3/252) among anti‐spike IgG positive HCW (0.13 cases per 100 weeks at risk) compared to 23% (11/48) among anti‐spike IgG negative HCW (2.78 cases per 100 weeks at risk), resulting in a protective effect of 95.2% (95% CI 81.9%–99.1%). Conclusions The vast majority of anti‐spike IgG positive individuals remain anti‐spike IgG positive for at least 8 months regardless of initial COVID‐19 disease severity. The presence of anti‐spike IgG antibodies is associated with a substantially reduced risk of reinfection up to 9 months following asymptomatic to mild COVID‐19.

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