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. — CFSMEATLAS
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.
Jones, Ansley E, Khan, Zain, McGroder, Claire F et al. · Critical care explorations · 2026 · DOI
Quick Summary
This study followed people who were hospitalized with severe COVID-19 for 3 years after they left the hospital. About one-quarter of them continued to experience long COVID symptoms like fatigue, brain fog, and difficulty with physical activity. Surprisingly, when researchers measured inflammation and blood vessel markers in their blood, these markers were not elevated and did not explain why some people had ongoing symptoms.
Why It Matters
This study is relevant to ME/CFS because it demonstrates that post-viral long-term illness can persist for years without detectable persistent inflammation or endothelial dysfunction, suggesting similar mechanisms may underlie ME/CFS and PASC. The finding that standard inflammatory biomarkers do not explain long COVID symptoms highlights the need for novel approaches to understand post-viral disease mechanisms, which may apply to ME/CFS research and treatment development.
Observed Findings
PASC was present in 26% of survivors at both 15 months and 3 years post-hospitalization.
PASC and symptom phenotypes (post-exertional malaise, fatigue, brain fog) were consistently associated with higher frailty scores, worse short physical performance battery results, and reduced 6-minute walk distance.
Inflammatory biomarkers (IL-6, sTNFR-1), endothelial markers (angiopoietin), and complement markers (C2, C4b, C5) showed no significant association with PASC or symptom phenotypes in cross-sectional or longitudinal analyses.
The cohort was 67% Hispanic and 25% Black, with mean age 56 years.
Inferred Conclusions
PASC persists long-term (3 years) in a subset of severe COVID-19 survivors and is associated with physical frailty and deconditioning rather than persistent systemic biomarker abnormalities.
The mechanisms driving PASC differ from the acute-phase inflammatory and complement-driven pathology of severe COVID-19 ALI/ARDS.
Standard biomarkers of inflammation, endothelial dysfunction, and complement activation are insufficient to explain post-acute sequelae, suggesting multiomics approaches are needed to identify novel pathogenic mechanisms.
Remaining Questions
What are the underlying mechanisms of PASC if not persistent inflammation or endothelial dysfunction—could mitochondrial dysfunction, autonomic dysregulation, or other processes be responsible?
What This Study Does Not Prove
This study does not prove that inflammation plays no role in PASC or ME/CFS—it only shows that the specific inflammatory and endothelial markers measured were not elevated at the timepoints tested. The absence of detectable biomarker abnormalities does not exclude occult inflammation, mitochondrial dysfunction, autonomic dysfunction, or other mechanisms. Cross-sectional associations between frailty and PASC cannot establish causality or identify which symptoms drive physical decline.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
Does the frailty and physical deconditioning observed in PASC drive the persistent symptoms, or do symptoms drive loss of physical function?
How do the pathophysiological mechanisms of PASC relate to those of ME/CFS, and are there shared pathways that could be targeted therapeutically?
Could intracellular or tissue-level inflammation, microclot formation, or viral persistence explain symptoms when systemic serum biomarkers are not elevated?