Factors Associated with Long Covid Symptoms in an Online Cohort Study

ImportanceProlonged symptoms following SARS-CoV-2 infection, or Long COVID, is common, but few prospective studies of Long COVID risk factors have been conducted. ObjectiveTo determine whether sociodemographic factors, lifestyle, or medical history preceding COVID-19 or characteristics of acute SARS-CoV-2 infection are associated with Long COVID. DesignCohort study with longitudinal assessment of symptoms before, during, and after SARS-CoV-2 infection, and cross-sectional assessment of Long COVID symptoms using data from the COVID-19 Citizen Science (CCS) study. SettingCCS is an online cohort study that began enrolling March 26, 2020. We included data collected between March 26, 2020, and May 18, 2022. ParticipantsAdult CCS participants who reported a positive SARS-CoV-2 test result (PCR, Antigen, or Antibody) more than 30 days prior to May 4, 2022, were surveyed. ExposuresAge, sex, race/ethnicity, education, employment, socioeconomic status/financial insecurity, self-reported medical history, vaccination status, time of infection (variant wave), number of acute symptoms, pre-COVID depression, anxiety, alcohol and drug use, sleep, exercise. Main OutcomePresence of at least 1 Long COVID symptom greater than 1 month after acute infection. Sensitivity analyses were performed considering only symptoms beyond 3 months and only severe symptoms. Results13,305 participants reported a SARS-CoV-2 positive test more than 30 days prior, 1480 (11.1% of eligible) responded to a survey about Long COVID symptoms, and 476 (32.2% of respondents) reported Long COVID symptoms (median 360 days after infection). Respondents mean age was 53 and 1017 (69%) were female. Common Long COVID symptoms included fatigue, reported by 230/476 (48.3%), shortness of breath (109, 22.9%), confusion/brain fog (108, 22.7%), headache (103, 21.6%), and altered taste or smell (98, 20.6%). In multivariable models, number of acute COVID-19 symptoms (OR 1.30 per symptom, 95%CI 1.20-1.40), lower socioeconomic status/financial insecurity (OR 1.62, 95%CI 1.02-2.63), pre-infection depression (OR 1.08, 95%CI 1.01-1.16), and earlier variants (OR 0.37 for Omicron compared to ancestral strain, 95%CI 0.15-0.90) were associated with Long COVID symptoms. Conclusions and RelevanceVariant wave, severity of acute infection, lower socioeconomic status and pre-existing depression are associated with Long COVID symptoms. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the patterns of symptoms and risk factors for Long COVID among SARS-CoV-2 infected individuals? FindingsPersistent symptoms were highly prevalent, especially fatigue, shortness of breath, headache, brain fog/confusion, and altered taste/smell, which persisted beyond 1 year among 56% of participants with symptoms; a minority of participants reported severe Long COVID symptoms. Number of acute symptoms during acute SARS-CoV-2 infection, financial insecurity, pre-existing depression, and infection with earlier variants are associated with prevalent Long COVID symptoms independent of vaccination, medical history, and other factors. MeaningSeverity of acute infection, SARS-CoV-2 variant, and financial insecurity and depression are associated with Long COVID symptoms.

HLA-B*15:01 is associated with asymptomatic SARS-CoV-2 infection

Despite some inconsistent reporting of symptoms, studies have demonstrated that at least 20% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will remain asymptomatic. Although most global efforts have focused on understanding factors underlying severe illness in COVID-19 (coronavirus disease of 2019), the examination of asymptomatic infection provides a unique opportunity to consider early disease and immunologic features promoting rapid viral clearance. Owing to its critical role in the immune response, we postulated that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection. We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in the UCSF Citizen Science smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n=1428) was comprised of unvaccinated, self-identified subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci (HLA-A, -B, -C, -DRB1, -DQB1) with disease course and identified a strong association of HLA-B*15:01 with asymptomatic infection, and reproduced this association in two independent cohorts. Suggesting that this genetic association is due to pre-existing T-cell immunity, we show that T cells from pre-pandemic individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF, and 100% of the reactive cells displayed memory phenotype. Finally, we characterize the protein structure of HLA-B*15:01-peptide complexes, demonstrating that the NQKLIANQF peptide from SARS-CoV-2, and the highly homologous NQKLIANAF from seasonal coronaviruses OC43-CoV and HKU1-CoV, share similar ability to be stabilized and presented by HLA-B*15:01, providing the molecular basis for T-cell cross-reactivity and HLA-B*15:01-mediated pre-existing immunity.

Predictors of Incident Viral Symptoms Ascertained in the Era of Covid-19

BackgroundIn the absence of universal testing, effective therapies, or vaccines, identifying risk factors for viral infection, particularly readily modifiable exposures and behaviors, is required to identify effective strategies against viral infection and transmission. MethodsWe conducted a world-wide mobile application-based prospective cohort study available to English speaking adults with a smartphone. We collected self-reported characteristics, exposures, and behaviors, as well as smartphone-based geolocation data. Our main outcome was incident symptoms of viral infection, defined as fevers and chills plus one other symptom previously shown to occur with SARS-CoV-2 infection, determined by daily surveys. FindingsAmong 14, 335 participants residing in all 50 US states and 93 different countries followed for a median 21 days (IQR 10-26 days), 424 (3%) developed incident viral symptoms. In pooled multivariable logistic regression models, female biological sex (odds ration [OR] 1.75, 95% CI 1.39-2.20, p<0.001), anemia (OR 1.45, 95% CI 1.16-1.81, p=0.001), hypertension (OR 1.35, 95% CI 1.08-1.68, p=0.007), cigarette smoking in the last 30 days (OR 1.86, 95% CI 1.35-2.55, p<0.001), any viral symptoms among household members 6-12 days prior (OR 2.06, 95% CI 1.67-2.55, p<0.001), and the maximum number of individuals the participant interacted with within 6 feet in the past 6-12 days (OR 1.15, 95% CI 1.06-1.25, p<0.001) were each associated with a higher risk of developing viral symptoms. Conversely, a higher subjective social status (OR 0.87, 95% CI 0.83-0.93, p<0.001), at least weekly exercise (OR 0.57, 95% CI 0.47-0.70, p<0.001), and sanitizing ones phone (OR 0.79, 95% CI 0.63-0.99, p=0.037) were each associated with a lower risk of developing viral symptoms. InterpretationWhile several immutable characteristics were associated with the risk of developing viral symptoms, multiple immediately modifiable exposures and habits that influence risk were also observed, potentially identifying readily accessible strategies to mitigate risk in the Covid-19 era. FundingThis study was funded by IU2CEB021881-01 and 3U2CEB021881-05S1 from the NIH/ NIBIB to Drs. Marcus, Olgin, and Pletcher. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPredictors of incident viral infection have been determined largely from cross-sectional studies prone to recall bias among individuals representing geographically constrained regions, and most were conducted before the era of the current Covid-19 pandemic. Added value of this studyWe conducted a world-wide, mobile application-based, longitudinal cohort study utilizing time-updated predictors and outcomes, providing novel and current information regarding risk-factors for incident viral symptoms based on real-time information in the era of Covid-19. Implications of all the available evidenceThese data suggest that certain immutable characteristics influence the risk for incident viral symptoms, while smoking cessation, physical distancing to avoid contact with individuals outside the household, regular exercise, and sanitizing ones phone may each help mitigate the risk of viral infection.