The lingering shadow of epidemics: post-acute sequelae across history.
Miller, Christine M, Moen, Janna K, Iwasaki, Akiko · Trends in immunology · 2026 · DOI
Quick Summary
This review examines how infections throughout history have sometimes led to lasting illnesses similar to Long COVID, including conditions like ME/CFS. The authors show that post-infection syndromes have occurred for over 100 years after various infections (flu, EBV, Lyme disease, and others), suggesting this is not a new phenomenon. They argue that modern tools and technology now give us a better opportunity to understand why some infections trigger these chronic conditions.
Why It Matters
This study validates that ME/CFS and similar post-infection conditions have a documented history predating COVID-19, which may strengthen advocacy for research funding and clinical recognition. By connecting Long COVID to the longer history of ME/CFS and other PAIS, the research emphasizes that understanding Long COVID mechanisms could unlock insights into ME/CFS biology. The framing of these conditions as recurring public health patterns (not novel anomalies) may encourage systematic investigation across disciplines.
Observed Findings
Post-acute infection syndromes have been documented for over 100 years following diverse pathogens including influenza, Epstein-Barr virus, and Borrelia burgdorferi
ME/CFS has long been epidemiologically and clinically linked to infectious triggers
Long COVID (PASC) affects millions globally and shares clinical features with historically described PAIS
Modern immunological and molecular technologies are now available to investigate these syndromes in ways not previously possible
Significant gaps remain in understanding the host-pathogen interaction mechanisms underlying persistent post-infection symptoms
Inferred Conclusions
Post-acute infection syndromes represent a recurring pattern across history and pathogens, suggesting a fundamental biological mechanism yet to be elucidated
Investigating Long COVID biology using contemporary tools may provide broader insights applicable to ME/CFS and other PAIS
Systematic, interdisciplinary research is urgently needed to close decades-old knowledge gaps in post-infection chronic illness
The current pandemic provides a unique opportunity to study PAIS mechanisms with advanced technologies before evidence collection windows close
Remaining Questions
What This Study Does Not Prove
This evidence map does not prove that all cases of ME/CFS are directly caused by infection, nor does it establish specific biological mechanisms linking pathogens to chronic illness. It describes historical associations but cannot determine causation or identify which infected individuals will develop PAIS. The review also does not provide new experimental data or molecular evidence distinguishing post-viral sequelae from other etiologies.
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 →