Post-Acute Sequelae of COVID-19 Persist Over 3 Years in Acute Lung Injury/Acute Respiratory Distress Syndrome Survivors But Are Not Associated With Persistent Thromboinflammation or Endothelial Dysfunction

Abstract

Importance: Inflammation, endothelial dysfunction, and complement activation are associated with COVID-19 acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Objectives: We hypothesized that higher levels of inflammation, endothelial dysfunction, and complement activation implicated in more severe COVID-19 ALI/ARDS are associated with post-acute sequelae of COVID-19 (PASC) phenotypes in the 3 years after hospitalization.

Design, setting, and participants: A single-center prospective cohort of 150 adult survivors of severe and critical COVID-19 from the first wave of the pandemic with sampling weighted to include 50% survivors of mechanical ventilation.

Main outcomes and measures: Eleven serum biomarkers at hospital discharge, 4 months, 15 months, and 3 years, and symptoms and physical function at 15 months and 3 years. PASC presence was defined using the 12 symptoms and scoring from the Researching COVID to Enhance Recovery (RECOVER) definition. We tested associations of biomarkers with PASC and symptom phenotypes of post-exertional malaise, fatigue, and brain fog while adjusting for age, sex, body mass index, comorbidities, and days since COVID-19 diagnosis.

Results: The mean (sd) age of the cohort was 56 years (13); 67% were Hispanic and 25% were Black. PASC was present in 26% of participants at both 15 months and 3 years. PASC and symptom phenotypes at 15 months and 3 years were consistently associated with higher frailty phenotype category, worse short physical performance battery scores, and shorter 6-minute walk distance. Biomarkers of inflammation, including interleukin-6 and soluble tumor necrosis factor receptor-1, endothelial function, including angiopoietin, and complement, including C2, C4b, and C5, were not associated with PASC or symptom phenotypes in cross-sectional or longitudinal analyses.

Conclusions and relevance: PASC persists for 3 years after acute COVID-19 ALI/ARDS, is associated with frailty, but not associated with persistently higher levels of inflammatory, endothelial, and complement biomarkers implicated in worse short-term outcomes in acute COVID-19, non-COVID-19 ARDS, and sepsis. Future studies should employ multiomics to elucidate potential mechanisms of PASC.