Background

Incidence estimates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, also known as long COVID, have varied across studies and changed over time. We estimated long COVID incidence among adult and pediatric populations in 3 nationwide research networks of electronic health records (EHRs) participating in the RECOVER (Researching COVID to Enhance Recovery) Initiative using different classification algorithms (computable phenotypes).

Methods

This EHR-based retrospective cohort study included adult and pediatric patients with documented acute SARS-CoV-2 infection and 2 control groups: contemporary coronavirus disease 2019 (COVID-19)–negative and historical patients (2019). We examined the proportion of individuals identified as having symptoms or conditions consistent with probable long COVID within 30–180 days after COVID-19 infection (incidence proportion). Each network (the National COVID Cohort Collaborative [N3C], National Patient-Centered Clinical Research Network [PCORnet], and PEDSnet) implemented its own long COVID definition. We introduced a harmonized definition for adults in a supplementary analysis.

Results

Overall, 4% of children and 10%–26% of adults developed long COVID, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 1.5% in children and ranged from 5% to 6% among adults, representing a lower-bound incidence estimation based on our control groups. Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants.

Conclusions

Our findings indicate that preventing and mitigating long COVID remains a public health priority. Examining temporal patterns and risk factors for long COVID incidence informs our understanding of etiology and can improve prevention and management.

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“Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts.”

Ensitrelvir, an oral inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease, is approved in Japan for the treatment of mild-to-moderate coronavirus disease 2019 (Covid-19). Previously, no antiviral agents were approved for postexposure prophylaxis in household contacts of patients with Covid-19.

Methods

In this double-blind, randomized, placebo-controlled trial, we randomly assigned persons who were SARS-CoV-2–negative on local diagnostic testing but were household contacts of a patient with Covid-19 (the index patient) to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or placebo within 72 hours after symptom onset in the index patient. The primary end point was Covid-19 (defined by a central laboratory–confirmed positive reverse-transcriptase–polymerase-chain-reaction assay and the presence of ≥1 of 14 prespecified Covid-19 symptoms lasting ≥48 hours) by day 10 in a household contact in the modified intention-to-treat population (all the participants who underwent randomization, had a central laboratory–confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of the trial drug or placebo).

Research Summary

Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts

Results

The modified intention-to-treat population included 1030 participants in the ensitrelvir group and 1011 in the placebo group. The mean age of the participants was 42.4 years; 71.1% had undergone randomization within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. The incidence of Covid-19 was lower in the ensitrelvir group than in the placebo group (2.9% vs. 9.0%; risk ratio, 0.33; 95% confidence interval [CI], 0.22 to 0.49; P<0.001). The incidence of adverse events during the trial was similar in the two groups (15.1% in the ensitrelvir group and 15.5% in the placebo group), as was the incidence of serious adverse events (0.2% in each group). No Covid-19–related hospitalizations or deaths were reported.

Conclusions

Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts. (Funded by Shionogi; SCORPIO-PEP Japan Registry for Clinical Trials number, jRCT2031230124; ClinicalTrials.gov number, NCT05897541.)

Background:

Post–COVID-19 condition presents complex symptomatology involving multifaceted interactions, which has resulted in a current lack of comprehensive understanding of its disease trajectory. This knowledge gap significantly compromises the efficiency of symptom management and adversely affects patients’ quality of life.

Objective:

This study aims to comprehensively characterize the temporal evolution of post–COVID-19 condition by identifying core symptom clusters and clinical phenotypes, thereby enhancing understanding of the disease trajectory.

Methods:

The PubMed, Web of Science, and Embase databases were searched from December 1, 2019, to March 1, 2024. Observational studies related to the prevalence of symptoms in post–COVID-19 condition had been included. We conducted a meta-analysis to synthesize symptom prevalence across different follow-up intervals following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used a network to explore interrelationships and co-occurrence patterns among symptoms, enabling the identification of core symptoms and changes over time. Clustering analysis was used to classify included studies into distinct clinical subtypes.

Results:

This study analyzed 155 sets of macrolevel data from 108 clinical studies, encompassing 63,771 patients. Fatigue was the most prevalent symptom across all 4 follow-up points (52%, 48%, 46%, and 54%). Dyspnea peaked at the third and sixth follow-ups (36% and 31%) and then declined steadily (28% and 22%). Subgroup analysis revealed that Africa reported the fewest symptoms overall, yet showed high early incidences of fatigue (68%, 95% CI 50%‐85%) and dyspnea (56%, 95% CI 15%‐98%). The Americas placed greater emphasis on symptom evolution within the first postinfection year, with notably higher prevalence of anxiety (60%, 95% CI 54%‐66%) and depression (36%, 95% CI 16%‐55%). Asia and Europe documented the most comprehensive symptom profiles, with Asia reporting lower early dyspnea rates (29%, 95% CI 18%‐40%) and Europe exhibiting more complex multisystem involvement during long-term follow-up. Network analysis showed that core post–COVID-19 symptoms evolved from early respiratory-neurological manifestations to chronic multisystem symptoms dominated by dizziness. Clustering analysis further indicated a progressive convergence of 2 initially distinct post–COVID-19 subtypes, with the acute inflammatory type becoming less prominent and gradually transitioning into a more chronic, persistent pattern.

Conclusions:

This study provides a comprehensive characterization of the dynamic evolution of post–COVID-19 condition symptoms and clinical subtypes, highlighting their multisystem involvement. The results reveal a progressive decline in respiratory symptoms over time, while neurological manifestations emerge as the most persistent and systemically impactful core symptoms. Our findings emphasize the need for region-specific surveillance and early warning systems informed by symptom progression patterns. By continuously monitoring the trajectories of symptom clusters, this approach offers valuable insights for identifying early warning signals and targeted intervention points in the management of postinfectious sequelae arising from future large-scale epidemics.

Trial Registration:PROSPERO CRD42024537825; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024537825

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

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