Background Most research on SARS-CoV-2 variants focuses on initial symptomatology with limited data on longer-term sequelae. We sought to characterize the prevalence and differences in prolonged symptoms at three months post SARS-CoV-2-infection across the three major variant time-periods (pre-Delta, Delta, and Omicron). Methods This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, individual and organ system-based symptoms, and presence of ≥3 total symptoms across variants among COVID-positive and COVID-negative participants 3 months after their initial SARS-CoV-2 diagnosis. Variant periods were defined by dates with ≥50% dominant strain. We performed a sensitivity analysis using ≥90% dominance threshold and multivariable logistic regression modeling to estimate the independent effects of each variant adjusting for socio-demographic characteristics, baseline health, and vaccine status. Results The study included 3,223 participants (2,402 COVID-positive and 821 COVID-negative). Among the COVID-positive cohort, 463 (19.3%) were pre-Delta, 1,198 (49.9%) during Delta, and 741 (30.8%) during Omicron. Prolonged severe fatigue was highest in the pre-Delta COVID-positive cohort compared with Delta and Omicron cohorts (16.7% vs 11.5% vs 12.3%, respectively; p = 0.017), as was presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; p < 0.001). No difference was seen in the COVID-negative cohort between variant time-periods. In multivariable models, there was no difference in severe fatigue between variants. There was decreased odds of having ≥3 symptoms in Omicron compared with other variants; this was not significant after adjusting for vaccination status. Conclusions Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during the pre-Delta period compared with Delta and Omicron periods; however, these differences were no longer significant after adjusting for vaccination status. This suggests a potential beneficial effect of vaccination on the risk of developing long-term symptoms.

ImportanceLong-term sequelae after symptomatic SARS-CoV-2 infection may impact well-being, yet existing data primarily focus on discrete symptoms and/or health care use.ObjectiveTo compare patient-reported outcomes of physical, mental, and social well-being among adults with symptomatic illness who received a positive vs negative test result for SARS-CoV-2 infection.Design, Setting, and ParticipantsThis cohort study was a planned interim analysis of an ongoing multicenter prospective longitudinal registry study (the Innovative Support for Patients With SARS-CoV-2 Infections Registry [INSPIRE]). Participants were enrolled from December 11, 2020, to September 10, 2021, and comprised adults (aged ≥18 years) with acute symptoms suggestive of SARS-CoV-2 infection at the time of receipt of a SARS-CoV-2 test approved by the US Food and Drug Administration. The analysis included the first 1000 participants who completed baseline and 3-month follow-up surveys consisting of questions from the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29; 7 subscales, including physical function, anxiety, depression, fatigue, social participation, sleep disturbance, and pain interference) and the PROMIS Short Form–Cognitive Function 8a scale, for which population-normed T scores were reported.ExposuresSARS-CoV-2 status (positive or negative test result) at enrollment.Main Outcomes and MeasuresMean PROMIS scores for participants with positive COVID-19 tests vs negative COVID-19 tests were compared descriptively and using multivariable regression analysis.ResultsAmong 1000 participants, 722 (72.2%) received a positive COVID-19 result and 278 (27.8%) received a negative result; 406 of 998 participants (40.7%) were aged 18 to 34 years, 644 of 972 (66.3%) were female, 833 of 984 (84.7%) were non-Hispanic, and 685 of 974 (70.3%) were White. A total of 282 of 712 participants (39.6%) in the COVID-19–positive group and 147 of 275 participants (53.5%) in the COVID-19–negative group reported persistently poor physical, mental, or social well-being at 3-month follow-up. After adjustment, improvements in well-being were statistically and clinically greater for participants in the COVID-19–positive group vs the COVID-19–negative group only for social participation (β = 3.32; 95% CI, 1.84-4.80; P < .001); changes in other well-being domains were not clinically different between groups. Improvements in well-being in the COVID-19–positive group were concentrated among participants aged 18 to 34 years (eg, social participation: β = 3.90; 95% CI, 1.75-6.05; P < .001) and those who presented for COVID-19 testing in an ambulatory setting (eg, social participation: β = 4.16; 95% CI, 2.12-6.20; P < .001).Conclusions and RelevanceIn this study, participants in both the COVID-19–positive and COVID-19–negative groups reported persistently poor physical, mental, or social well-being at 3-month follow-up. Although some individuals had clinically meaningful improvements over time, many reported moderate to severe impairments in well-being 3 months later. These results highlight the importance of including a control group of participants with negative COVID-19 results for comparison when examining the sequelae of COVID-19.

Background The prevalence, incidence, and interrelationships of persistent symptoms after SARS-CoV-2 infection (Long COVID) vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present three months and six months after acute infection. Methods This was a multicenter, prospective study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to six-months post-diagnosis. Using LCA, we identified symptomatically homogenous groups among participants with COVID-19 (COVID-positive) and among others without COVID-19 (COVID-negative) at each time period for both general and fatigue-related symptoms. Results Among 5,963 baseline participants (4,504 COVID-positive and 1,459 COVID-negative), 4,056 had three-month and 2,856 had six-month data at the time of analysis. We identified four distinct phenotypes of post-COVID conditions at three- and six-months for both general and fatigue-related symptoms; minimal symptom groups represented 70% of participants at three and six months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste and smell, as well cognition problems. There was substantial class-switching over time; those in one symptom class at three months were equally likely to remain or enter a new phenotype at six months. Conclusions We identified distinct classes of post-COVID phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at three and six months follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that post-COVID conditions may have a more dynamic nature than previously recognized. Trial Registration NCT04610515

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Background While prior work examining SARS-CoV-2 variants of concern focused on hospitalization and death, less is known about differences in clinical presentation. We compared the prevalence of acute symptoms across pre-Delta, Delta, and Omicron. Methods We conducted an analysis of the INSPIRE Registry, a cohort study enrolling symptomatic SARS-CoV-2 positive participants. We determined the association between pre-Delta, Delta, and Omicron time periods and the prevalence of 21 COVID-19 acute symptoms. Results We enrolled 4,113 participants from December 2020 – June 2022. Pre-Delta vs Delta vs Omicron participants had increasing sore throat (40.9%, 54.6%, 70.6%; p < .001), cough (50.9%, 63.3%, 66.7%; p < .001), and runny noses (48.9%, 71.3%, 72.9%; p < .001). We observed reductions during Omicron in chest pain (31.1%, 24.2%, 20.9%; p < .001), shortness of breath (42.7%, 29.5%, 27.5%; p < .001), loss of taste (47.1%, 61.8%, 19.2%; p < .001), and loss of smell (47.5%, 55.6%, 20.0%; p < .001). After adjustment, those infected during Omicron had significantly higher odds of sore throat vs pre-Delta: OR 2.76 (95% CI: 2.26-3.35) and Delta, OR 1.96 (95% CI: 1.69-2.28). Conclusions Participants infected during Omicron were more likely to report symptoms of common respiratory viruses, such as sore throat, and less likely to report loss of smell and taste.