Refinement of post-COVID condition core symptoms, subtypes, determinants, and health impacts: a cohort study integrating real-world data and patient-reported outcomes

Background: Post-COVID-19 condition (PCC) affects millions of people, and is an essential component of the long-term impact of COVID-19 during the post-pandemic era. Yet, consensus on clinical case definition and core components of PCC remains lacking, affecting our ability to inform research and evidence-based management. Our study aims 1) to identify the most specific symptoms for PCC, and identify clinical subtypes; 2) to evaluate both virus- and host-related determinants of PCC, and 3) assess the impact of PCC on physical and mental health. Methods: We studied participants from UK Biobank who completed a health and wellbeing survey between June and September 2022. Participants reported the current conditions of the presence, duration, and functional limitations of 45 symptoms, using an online questionnaire designed specifically for COVID-19 research. SARS-CoV-2 infection status and disease history were obtained through linkage to surveillance data and electronic medical records, respectively. Participants reporting symptoms within 30 days after infection (acute phase) were excluded. The most specific PCC symptoms were defined using two criteria: statistical significance (P < 0.05 after Bonferroni correction) and clinical relevance (absolute risk increase > 5%). Propensity score weighting was used to control for confounding. Subtypes of PCC were then defined based on the specific symptoms among the COVID-19 infected individuals. A multivariable regression was used to study pathogen- and host-related risk factors for PCC, and its impact on 13 physical and 4 mental health patient-reported functional outcomes. Findings: 172,303 participants (mean age 68.9, 57.4% female) were included in the analysis, of whom 43,395 had PCR-confirmed COVID-19. We identified 10 most specific symptoms and classified four PCC subtypes: ENT subtype (30.1%), characterized by alterations in smell, taste, and hearing loss; cardiopulmonary subtype (10.4%), characterized by shortness of breath, postural tachycardia, chest tightness, and chest pressure; neurological subtype (23.5%), characterized by brain fog and difficulty speaking; and general fatigue subtype (38.0%), characterized by mild fatigue. A higher PCC risk was observed for patients with Wild-type variant, multiple infections, and severe acute COVID-19 illness, consistently across the four PCC subtypes. In addition, a range of factors, including socioeconomic deprivation, higher BMI, unhealthy lifestyle, and multiple chronic health conditions, were associated with increased PCC risk, except for age and sex. Conversely, vaccination was associated with a largely reduced PCC risk, particularly for the cardiopulmonary subtypes. Individuals with PCC experienced a much worse physical and mental health. Specifically, the cardiopulmonary subtype had the most pronounced adverse impact on function impairments, followed by neurological, mild fatigue, and ENT subtype. The most affected functions included the ability to concentrate, participate in day-to-day work, and emotional vulnerability to health problems. Interpretation: PCC can be categorized into four distinct subtypes based on ten core symptoms. These subtypes appeared to share a majority of pathogen and host-related risk factors, but their impact on health varied markedly by subtype. Our findings could help refine current guidelines for precise PCC diagnosis and progression, enhance the identification of PCC subgroups for targeted research, and inform evidence-based policy making to tackle this new and debilitating condition.