Study Highlights

• The RECOVER prospective observational cohort study included adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) in 33 states plus Washington, DC, and Puerto Rico.
• Adults enrolled in RECOVER before April 10, 2023, completed a survey 6 or more months after acute symptom onset or test date regarding PASC and 44 participant-reported symptoms (with severity thresholds).
• Selection included population-based, volunteer, and convenience sampling.
• Of 9764 participants meeting selection criteria, 89% were SARS-CoV-2 infected, 71% were female, 16% were Hispanic/Latino, 15% were non-Hispanic Black, and 58% were fully vaccinated, and their median age was 47 years (interquartile range, 35-60 years).
• Adjusted odds ratios in infected vs uninfected participants were at least 1.5 for 37 symptoms.
• The optimal PASC score threshold used was 12 or higher.
• Twelve symptoms contributed most to PASC score, with corresponding scores ranging from 1 to 8.
• Ordered by decreasing frequencies among participants with a qualifying PASC score, the symptoms were 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.
• Symptoms correlated with the selected symptoms included dry mouth, weakness, headaches, tremor, muscle and abdominal pain, fever/sweats/chills, and sleep disturbance.
• Among participants with PASC, the most common symptoms were postexertional malaise (87%), fatigue (85%), brain fog (64%), dizziness (62%), gastrointestinal symptoms (59%), and palpitations (57%).
• Four PASC subgroups were identified: loss of or change in smell or taste (100%) in cluster 1 (n=477); postexertional malaise (99%) and fatigue (84%) in cluster 2 (n=405); brain fog (100%), postexertional malaise (99%), and fatigue (94%) in cluster 3 (n=587); and fatigue (94%), postexertional malaise (94%), dizziness (94%), brain fog (94%), gastrointestinal symptoms (88%), and palpitations (86%) in cluster 4 (n=562).
• “Among 2231 participants first infected on or after December 1, 2021 [when Omicron was the dominant variant], and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months,” the authors write.
• Participants who were unvaccinated or infected before Omicron became the dominant variant were more likely to have long COVID and to have more severe cases.
• "In the Omicron cohorts, the estimated proportion of PASC positivity was greater among reinfected participants compared with participants with 1 reported infection (acute Omicron: 20% vs 9.7%; postacute Omicron: 21% vs 16%),” the authors add.
• The investigators concluded that 37 symptoms across multiple pathophysiological domains were identified more often in SARS-CoV-2-infected vs uninfected participants at 6 or more months after infection.
• Long-term symptoms associated with SARS-CoV-2 infection spanned multiple organ systems; this diversity of symptoms may reflect persistent viral reservoirs, autoimmunity, or direct differential organ injury.
• The researchers derived a preliminary rule for identifying and defining PASC based on a composite symptom score.
• Using that definition, approximately 10% of people infected with Omicron reported having long COVID, a lower percentage than estimated for people infected with SARS CoV-2 strains circulating earlier.
• Modest reduction in PASC frequency among fully vaccinated participants is consistent with findings of recent systematic reviews.
• A framework to identify PASC cases based on symptoms is a first step to defining PASC as a new condition.
• To refine actionable definitions of PASC, additional clinical features should be incorporated, based on further research.
• Future studies should also address mechanisms underlying vulnerability to long COVID, how to prevent it, and potential treatments, as well as the relationships among age, sex, race and ethnicity, social determinants of health, vaccination status after index date, comorbidities, and pregnancy status during infection on the risk for PASC and the distribution of PASC subgroups.
• As PASC symptoms are heterogeneous, determining whether PASC represents 1 unified condition or a group of unique phenotypes has important implications for researching the pathophysiology underlying PASC and clinical trial design.
• Study limitations include likely selection bias among postacute cohort participants, failure to detect prior asymptomatic SARS-CoV-2 infections among uninfected participants, reliance on self-reported symptoms, possible confounding, and failure to analyze all of the more than 200 symptoms of PASC that have been reported.