ImportanceSARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.ObjectiveTo develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and ParticipantsProspective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.ExposureSARS-CoV-2 infection.Main Outcomes and MeasuresPASC and 44 participant-reported symptoms (with severity thresholds).ResultsA total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and RelevanceA definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms Graphical abstract Highlights d The magnitude of early CD4 + T cell responses correlates with severity of COVID-19 d Prior lung disease correlates with higher SARS-CoV-2specific CD8 + T cell responses d PASC is associated with a decline in N-specific interferon-gproducing CD8 + T cells d Neutralizing capacity correlates with SARS-CoV-2-specific CD4 + T cell responses

The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence suggesting recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with decreased odds of Long COVID.

Background Despite early antiretroviral therapy (ART), ART-suppressed people with HIV (PWH) remain at higher risk for infections and infection-related malignancies than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear. Methods ART-suppressed PWH and HIV-negative controls, all CMV-seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [Early ART] vs. later) and nadir CD4 count among later initiators. Between-group differences in kynurenine/tryptophan (KT) ratio, IP-10, sCD14, sCD163, sTNFR2, IL-6, and suPAR were assessed after adjustment for confounders. Results Most participants (92%) were male, reflecting demographics of early ART initiators in San Francisco. Most biomarkers were higher among later ART initiators. Early ART participants achieved near-normal sTNFR2, IL-6, and suPAR levels, but substantially higher KT ratio than those without HIV after adjustment for confounders (P=0.008). sCD14, sCD163, and IP-10 followed a similar trend. Conclusions While early ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. As this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this pathway may contribute to persistent risks of these complications in this setting.

Epstein-Barr virus (EBV) reactivation has been proposed as a driver of Long COVID (LC), but studies in well-characterized post-acute COVID-19 cohorts of individuals with and without Long COVID symptoms over a time course consistent with current case definitions of LC are limited. In a cohort of 294 hundred adults with a history of SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were associated with serological evidence of recent EBV reactivation (early antigen-D IgG positivity or nuclear antigen IgG levels >600 U/mL), but not with ongoing EBV viremia.. Importantly, Long COVID was also observed in the small proportion without evidence of prior or recent EBV infection, suggesting that EBV reactivation is not a prerequisite for this condition. Overall, these findings expand our knowledge of the relationships between EBV reactivation and LC and suggest that further assessment during the acute phase of COVID-19 is warranted.