Differential Factors Associated With the Presence of Persistent Symptoms in Individuals Diagnosed With Long COVID:...

Long COVID (postacute sequelae of SARS-CoV-2 infection) is a heterogeneous condition with persistent multisystem symptoms and substantial functional burden. Integrative longitudinal studies combining clinical phenotyping, lifestyle factors, and immunobiological markers are needed to clarify determinants of symptom persistence and inform risk stratification and targeted interventions.

This study aims to identify clinical, biological/immunological, and sociodemographic factors associated with Long COVID status by comparing individuals with persistent symptoms to matched recovered controls, and to evaluate longitudinal changes in symptoms and secondary outcomes over follow-up.

ARALongCOV is a longitudinal matched case-control observational study conducted in Aragón, Spain, including adults (≥18 years of age) with confirmed SARS-CoV-2 infection. Participants are recruited through 3 sources: the Long COVID Aragón Patient Association, the Aragón Health Service database, and primary care consultations. Long COVID and recovered participants are individually matched 1:1 (without replacement) on sex/gender (exact), age (±3 years), and date of acute COVID-19 diagnosis (±30 days). Outcomes include persistent symptoms and functioning and patient-reported outcomes (quality of life, physical activity, diet, sleep, mental health, functional status, cognitive performance, pain catastrophizing, and fatigue), alongside clinical variables and biochemical/immunological markers (including inflammatory and cytokine profiles, SARS-CoV-2 antispike immunoglobulin G serology, and viral reactivation serologies). Measurements are obtained at baseline (T0) and repeated at follow-up (T1) using standardized procedures.

The study received ethics approval from the Clinical Research Ethics Committee of Aragón (PI21/278). Funding was provided by Instituto de Salud Carlos III through project PI22/01070 (cofunded by the European Union) for the period 2023-2027. Baseline assessments (T0) were initiated in late 2022/early 2023. As of February 2026, a total of 200 participants have been enrolled (n=100 Long COVID; n=100 recovered controls) and have completed T0; T1 assessments are scheduled for late 2025/early 2026 (~3-year follow-up for the earliest enrolled participants). Primary analyses will be conducted after completion of T1 assessments, with dissemination planned from the second half of 2026 and continuing through 2027.

This protocol describes a comprehensive, multidimensional longitudinal study designed to clarify determinants of Long COVID by integrating clinical, functional, lifestyle, and immunobiological data in matched cohorts. Findings are expected to support risk stratification, phenotype discovery, and identification of prognostic markers to inform preventive, diagnostic, and rehabilitative strategies.

ISRCTN Registry ISRCTN27312680; https://tinyurl.com/33cbysrk.

DERR1-10.2196/67133.