JMIR Publications

ABSTRACT

Background:

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), affects an estimated 10–30% of infected individuals and is characterized by persistent symptoms such as fatigue, dyspnea, cognitive dysfunction, and functional impairment. Despite rapid advances in understanding acute COVID-19 and its complications, the mechanisms underpinning symptom persistence remain unclear. Viral persistence, immune dysregulation, chronic inflammation, and autoimmunity have been implicated, but few studies have jointly integrated clinical, immunological, biological, and biopsychosocial domains within the same individuals.

Objective:

To identify clinical, biological, immunological, and sociodemographic factors associated with Long COVID by comparing individuals with persistent symptoms to carefully matched recovered controls, and to examine the influence of lifestyle and biopsychosocial variables on symptom persistence and functional outcomes over time

Methods:

RALongCOV is a dual-cohort (retrospective and prospective), longitudinal study conducted in Aragón, Spain, including adults (≥18 years) with confirmed SARS-CoV-2 infection. Approximately 400 participants will be recruited through the Long COVID Aragón Patient Association, the Aragón Health Service database, and primary care consultations. Long COVID and recovered participants will be matched by age (±3 years), sex/gender, and date of acute COVID-19 diagnosis (±30 days). Data collection includes standardized questionnaires on quality of life, physical activity, diet, sleep, mental health, functional status, cognitive performance, pain catastrophizing, and fatigue, alongside detailed clinical information and a broad panel of biochemical and immunological markers (including inflammatory and cytokine profiles, SARS-CoV-2 serology, and viral reactivation serologies). Statistical analyses will comprise descriptive and inferential methods, multivariable regression models, and machine-learning approaches (e.g. Random Forest) to identify predictors, derive risk profiles, and explore complex interactions.

Results:

We expect to identify distinct clinical and immunobiological profiles associated with persistent post-COVID symptoms, reduced quality of life and functional impairment, and to derive risk phenotypes that integrate clinical, biomarker and biopsychosocial variables, thereby informing more targeted follow-up and rehabilitation strategies.

Conclusions:

This protocol describes a comprehensive, multidimensional cohort study designed to clarify the determinants of Long COVID. By integrating clinical, functional, lifestyle, and immunobiological data in matched cohorts with longitudinal follow-up, ARALongCOV aims to generate robust evidence on risk factors, potential phenotypes, and prognostic markers, informing targeted preventive, diagnostic, and rehabilitative strategies for individuals with persistent post-COVID symptoms. Clinical Trial: This protocol was registered with the ISRCTN Registry before commencement (ISRCTN27312680).