Symptom Trajectories and Clinical Subtypes in Post-COVID-19 Condition: Systematic Review and Clustering Analysis

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.

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.

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.

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.

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.