The lingering shadow of epidemics: post-acute sequelae across history.

3 min read

Miller et al. (2025)
  • Authors: Christine M. Miller, Janna K. Moen, Akiko Iwasaki.
  • Institutes: Department of Pediatrics, Division of Infectious Diseases and Global Health, Yale University School of Medicine; Department of Immunobiology, Yale University School of Medicine; Center for Infection and Immunity, Yale University School of Medicine; Howard Hughes Medical Institute.
  • Publisher: Trends in Immunology
  • Link: DOI

Summary

This research serves as a high-level validation of the biological reality of ME/CFS by placing it within a century-long history of post-infectious syndromes. It suggests that the massive global effort currently directed at Long COVID is finally generating the data and scientific tools—such as advanced immune profiling—needed to understand why some people do not recover after an illness. For patients currently living with ME/CFS, this paper indicates a shift in the scientific community toward viewing these conditions as systemic biological disorders rather than psychological ones, potentially accelerating the path toward objective diagnostics and targeted therapies.

What was researched?

This paper examined the history and biological patterns of Post-Acute Infection Syndromes (PAIS), which are chronic illnesses that develop following an acute infection. The researchers focused on connecting well-known conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID to a broader historical context of similar syndromes triggered by various pathogens over the last century.

Why was it researched?

While Long COVID has recently brought global attention to post-infectious illness, ME/CFS and other related conditions have existed for decades with limited recognition and research funding. The authors aimed to demonstrate that these syndromes are a recurring consequence of epidemics and that the current “Long COVID era” provides a unique, high-tech opportunity to solve the biological mysteries that have historically left ME/CFS patients without clear answers.

How was it researched?

The authors conducted a comprehensive review of historical medical literature and contemporary scientific data regarding post-acute sequelae. They synthesized evidence from multiple infectious triggers—including influenza, Epstein-Barr virus (EBV), and Borrelia burgdorferi (Lyme disease)—and compared their clinical presentations and immunological profiles to Long COVID. The analysis specifically focused on common themes such as immune dysregulation, autoimmunity, and the historical dismissal of these patients by the medical establishment.

What has been found?

The review finds that PAIS are not new or unique to COVID-19; rather, they have been documented for over 100 years following various viral, bacterial, and parasitic outbreaks. Despite different initial triggers, these conditions often share a “common core” of symptoms, including profound fatigue and cognitive impairment, and exhibit overlapping biological signatures like persistent inflammation and altered immune cell behavior. The authors also highlight how the lack of visible biomarkers has historically led to the “psychologization” of these illnesses, particularly in the case of ME/CFS.

Discussion

The authors discuss the significant knowledge gaps that persist due to a historical lack of systematic investigation into post-infectious chronic illness. They emphasize that while the scale of the SARS-CoV-2 pandemic is unprecedented, the biological pathways involved likely represent a general host response to infection that can go awry. A major limitation noted is the difficulty in diagnosing these conditions in the past due to a reliance on static measurements rather than advanced, dynamic immunological profiling.

Conclusion & Future Work

The authors conclude that defining the specific biology of Long COVID will likely provide a breakthrough “blueprint” for understanding ME/CFS and other post-acute infection syndromes. They call for an integrated research approach that uses modern “omics” technologies to identify diagnostic biomarkers and therapeutic targets. Future research must focus on how different pathogens can trigger similar chronic immune dysfunctions to finally develop effective treatments for all PAIS.