OBJECTIVE: To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.

DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.

EXPOSURE: SARS-CoV-2 infection.

MAIN OUTCOMES AND MEASURES: Presence of LC and participant-reported symptoms.

RESULTS: A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.

OBJECTIVE: To evaluate the likelihood of improvement among persons with likely LC.

DESIGN: Prospective, multisite cohort study (RECOVER-Adult [Researching COVID to Enhance Recovery]).

SETTING: 83 U.S.-based sites across 33 states; Washington, DC; and Puerto Rico.

PARTICIPANTS: 1019 persons in RECOVER-Adult with likely LC (LC Research Index [LCRI] ≥11) 12 months after first SARS-CoV-2 infection.

MEASUREMENTS: The primary outcome was time until 2 consecutive study visits with LCRI less than 11. Secondary outcomes were time until LCRI measure reduced 50% or more and quality of life was good or better, and LCRI decreased to 0. Unadjusted estimates of cumulative incidence and adjusted marginal cumulative incidence by age, sex, SARS-CoV-2 wave, and LC subtype were reported across all follow-up time points.

RESULTS: An estimated 36.2% (95% CI, 33.0% to 39.5%) met the primary outcome by 24 months after infection, and 50.1% (CI, 46.1% to 54.0%) met the primary outcome by 36 months. An estimated 56.4% (CI, 52.2% to 60.4%) and 26.9% (CI, 23.3% to 30.5%), respectively, met the 2 secondary outcomes by 36 months. Among persons who still reported likely LC at 18 months and 24 months after first infection, relative timing of subsequent symptom improvement was similar.

LIMITATION: Findings in this observational cohort are interpretable in a population with prevalent likely LC and do not address causal relationships between individual characteristics and symptom improvement.

CONCLUSION: Among persons with likely LC 12 months after initial SARS-CoV-2 infection, one half experience meaningful reductions in symptoms by 36 months, whereas a quarter experience complete remission of symptoms. These findings underscore both the potential for natural recovery and the urgent need for placebo-controlled therapeutic intervention trials.