Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.

Summary

In a nested population-based study (982 PCS, 576 controls), 67.6% of adults with PCS remained symptomatic into the second year. Objective deficits included reduced handgrip strength, lower peak VO2 (27.9 vs 31.0 ml/min/kg), and higher VE/VCO2 slope. No evidence supported viral persistence, EBV reactivation, adrenal insufficiency, or elevated complement as drivers; post-exertional malaise identified a more severe phenotype.

Key Findings

• 67.6% of PCS cases remained symptomatic >1 year; predominant clusters were fatigue, cognitive issues, breathlessness, and sleep/anxiety.
• Objective impairments vs recovered controls: lower handgrip strength (40.2 vs 42.5 kg), reduced peak VO2 (27.9 vs 31.0 ml/min/kg), and higher VE/VCO2 slope (28.8 vs 27.1).
• No biomarker evidence for viral persistence (stool PCR, plasma spike antigen negative), EBV reactivation, adrenal insufficiency, or increased complement turnover.
• Post-exertional malaise associated with more severe symptoms and broader objective deficits.

Clinical Implications

Emphasizes rehabilitation and symptom-targeted care (e.g., pacing for post-exertional malaise), risk-factor modification (obesity, smoking), and deprioritizes antiviral or endocrine testing in persistent PCS absent specific indications.

Limitations

• No pre-infection baseline for cognition/exercise capacity; changes inferred relative to controls.
• Clinic-based reassessment excluded individuals unable to attend (potential selection bias).

Future Directions

Define longitudinal phenotypes and response to targeted rehabilitation; test pacing strategies in PEM-positive PCS; mechanistic work on dysautonomia and ventilatory inefficiency.