Persistent COVID-19 symptoms at 6 months after onset and the role of vaccination before or after SARS-CoV-2 infection

This supplementary content accompanies a study investigating the persistence of COVID-19–related symptoms and organ-specific diagnoses up to 6 months after symptom onset, and the association of vaccination status (before or after SARS-CoV-2 infection) with these outcomes within the EPICC cohort.

Study design and cohort: EPICC (Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential) COVID-19 cohort including hospitalized Military Treatment Facility (H) participants, outpatient MTF (O) participants, and internet-based (I) participants, with linkage to Military Health System Data Repository records. Specimen and data collection schedule: Day 0, Day 3, Day 7, weekly to Day 14, Day 28, and at 3, 6, 9, and 12 months. Virology: nasal–throat and/or oral swab (H+O at baseline; H at interim points; H+O at follow-up; outpatient or post-discharge swabs could be self-collected or staff-collected NP/OP). Immunology: blood collection at multiple time points (H+O+I at baseline, Day 28, and 3/6/9/12 months), with at-home volumetric absorptive microsampling (VAMS) permitted for outpatients/post-discharge. Clinical characteristics: FLU-PRO Plus symptom diary collected daily for 14 days; surveys administered repeatedly (H+O+I). Outcomes and coding: Organ-system–specific diagnoses identified from health records using ICD-10 groupings defined in the supplement for cardiovascular (hypertension; ischemic heart disease; PE/DVT; myocarditis; cardiomyopathy; atrial fibrillation/flutter; cardiac arrest/VT; heart failure; cerebrovascular disease), pulmonary (viral/bacterial/unspecified pneumonia; asthma; obstructive and restrictive lung disease; pneumothorax; ARDS), neurology (meningitis/encephalitis; seizure disorder; headache disorders; sleep disorders excluding G47.3; pain NOS; acute CNS signs/symptoms; postviral fatigue/encephalopathy; dementia; movement disorders; neuropathies), mental health (depression/mood disorders; anxiety/somatoform/dissociative/stress-related disorders), endocrine (diabetes E08–E13), liver (chronic liver disease K70–K77; transplant status Z94.4), renal (acute kidney failure; chronic kidney disease/dialysis/transplant), and other (bacteremia; coagulopathy/DIC). Statistical analysis: Generalized linear models were run with each organ-system category as the outcome. Models included time windows in 30-day periods around symptom onset (pre- and post-onset), covariates listed in the tables (e.g., age group, sex, BMI category, hospitalization status, vaccination status prior to infection, variant period), and a random effect for participant. Inclusion analysis: eTable 4 compares participants included versus not included in the analysis based on availability of survey and Military Health System data.

Time since symptom onset (reference: 61–90 days pre-onset): - 0–30 days post-onset: Marked increases across systems: Pulmonary RR 11.33 (8.42–15.26, p=0.00); Renal 6.96 (3.56–13.62, p=0.00); Liver 3.95 (1.80–8.66, p=0.00); Cardiovascular 2.89 (2.20–3.79, p=0.00); Diabetes 2.69 (1.91–3.79, p=0.00); Neurology 2.24 (1.81–2.78, p=0.00); Mental health 1.40 (1.11–1.77, p=0.00). - 31–60 days post-onset: Pulmonary 3.84 (2.78–5.29, p=0.00); Cardiovascular 1.48 (1.09–2.00, p=0.01); Neurology 1.35 (1.07–1.71, p=0.01); others largely not significant. - 61–90 days post-onset: Pulmonary 2.76 (1.97–3.86, p=0.00); Cardiovascular 1.48 (1.09–2.00, p=0.01); Diabetes 1.70 (1.18–2.45, p=0.00); Neurology 1.50 (1.19–1.90, p=0.00). - 91–120 days post-onset: Pulmonary 2.49 (1.77–3.50, p=0.00); Cardiovascular 1.38 (1.02–1.88, p=0.04); Diabetes 1.46 (1.00–2.13, p=0.05); Neurology 1.27 (1.00–1.61, p=0.05). - 121–150 days post-onset: Pulmonary 1.86 (1.30–2.66, p=0.00); Neurology 1.34 (1.06–1.70, p=0.02); other categories generally NS. - 151–180 days post-onset: Pulmonary 2.00 (1.40–2.84, p=0.00); Diabetes 1.46 (1.00–2.13, p=0.05); Neurology 1.29 (1.02–1.64, p=0.04); Mental health 1.28 (1.01–1.62, p=0.04). Vaccination status and variant period: - Unvaccinated prior to infection: Pulmonary 1.72 (1.32–2.27, p=0.00); Neurology 1.27 (1.00–1.59, p=0.05); other systems mostly NS. - Delta variant period (Jul 1–Dec 31, 2021): Pulmonary 1.28 (1.01–1.61, p=0.04); Neurology 1.36 (1.06–1.73, p=0.02); Mental health 1.53 (1.07–2.19, p=0.02). Severity and demographics: - Hospitalized for COVID-19: Elevated risk across systems, e.g., Pulmonary 3.26 (2.67–3.97, p=0.00); Renal 9.60 (4.76–19.34, p=0.00); Liver 4.31 (2.21–8.41, p=0.00); Cardiovascular 3.38 (2.53–4.51, p=0.00); Diabetes 4.08 (2.53–6.57, p=0.00); Neurology 1.62 (1.21–2.16, p=0.00); Mental health 1.71 (1.07–2.72, p=0.03). - Age vs 18–44 (Ref): 45–64 increased risks (e.g., Pulmonary 1.39, p=0.00; Renal 5.03, p=0.00; Liver 3.67, p=0.00; Cardiovascular 5.30, p=0.00; Diabetes 5.21, p=0.00). Age 65+ showed larger effects (Pulmonary 2.61, p=0.00; Renal 30.15, p=0.00; Cardiovascular 14.70, p=0.00; Diabetes 20.49, p=0.00). - Sex: Female associated with higher Pulmonary 1.26 (p=0.00); Diabetes 3.40 (p=0.00); Neurology 1.43 (p=0.00); Mental health 2.90 (p=0.00). - BMI vs under/normal (Ref): Overweight/Obese/Severely obese associated with higher risks in multiple systems (e.g., Pulmonary overweight 1.13 [NS], obese 1.52 [p=0.00], severely obese 1.61 [p=0.00]; Cardiovascular obese 2.06 [p=0.00], severely obese 3.02 [p=0.00]; Diabetes obese 2.97 [p=0.00], severely obese 3.99 [p=0.00]; Mental health overweight 1.89 [p=0.00], obese 2.61 [p=0.00], severely obese 2.41 [p=0.00]). Inclusion comparison (eTable 4): Included (N=1832) vs not included (N=657) differed by age group (p<0.001), sex (p=0.010), and race/ethnicity (p=0.003).

Across the EPICC cohort, the risk of new organ-system–specific diagnoses was substantially elevated in the first 30 days after COVID-19 onset and remained above pre-onset reference levels for several systems up to 6 months, particularly for pulmonary, diabetes, and neurologic outcomes. Greater clinical severity (hospitalization), older age, female sex, and higher BMI were associated with higher risks in multiple domains. Unvaccinated status prior to infection was associated with higher pulmonary and borderline higher neurologic risks, and infections during the Delta period were associated with increased pulmonary, neurologic, and mental health diagnoses. These findings align with the study objective by characterizing persistent post-acute sequelae and illustrating how vaccination status, variant period, and patient factors relate to post-COVID outcomes.

This supplement details the EPICC cohort’s data/sampling schedule, ICD-10 outcome definitions, and GLM-based analyses demonstrating time-dependent increases in organ-specific diagnoses after COVID-19 that persist to 6 months for several systems, with strong associations for hospitalization, older age, female sex, and higher BMI. The results support the persistence of post-acute sequelae and highlight subgroups at elevated risk. Future research could extend follow-up beyond 12 months, examine dose/timing of vaccination (including boosters), evaluate variant-specific effects beyond Delta, and assess mechanisms underlying organ-specific risks.

Analyses were limited to participants with available survey and Military Health System data; included versus not included participants differed significantly by age, sex, and race/ethnicity (eTable 4). The cohort comprises MTF and Military Health System participants, and findings are based on diagnoses identified from health records using predefined ICD-10 groupings.