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

Significance:

Long COVID, a chronic multisystemic health condition, impacts hundreds of millions around the world. Long COVID has brought light to other related post-acute infection syndromes (PAIS) that are triggered by a wide array of pathogens. This opinion article highlights historical accounts of PAIS through the centuries and emphasizes the need for integrated approaches to understanding and treating PAIS.

Highlights:

New or persistent symptoms following COVID-19, known as ‘long COVID’, occur in an estimated 4–20% of pediatric and 10–20% of adult patients after acute infection with SARS-CoV-2. Long COVID is associated with dysregulation of both innate and adaptive immunity.

While long COVID is a relatively new clinical entity, post-acute infection syndromes (PAIS) have been well documented for over a century.

A wide variety of pathogens are associated with PAIS, including divergent classes of viruses, bacteria, and parasites. While each PAIS has a unique trigger and pathology, similarities in symptom profiles and immunological findings suggest these conditions may share features or involve overlapping biological mechanisms.

Despite being well described in the literature, PAIS remain understudied relative to their high disease burden. Patients often face stigma and psychologization from medical professionals when disease biomarkers are not readily apparent, exemplified by the historic dismissal of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Abstract:

The SARS-CoV-2 pandemic has drawn global attention to post-acute infection syndromes (PAIS), with millions affected by post-acute sequelae of COVID-19 (PASC, or Long COVID). While Long COVID is newly defined, PAIS have been described for over a century following epidemic infections. Multiple pathogens – including influenza, Epstein-Barr virus, and Borrelia burgdorferi, among others – can precipitate persistent, poorly understood symptoms. Chronic illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have long been linked to infectious triggers. This recurring association highlights critical knowledge gaps and underscores the need for systematic investigation. Unlike prior pandemics, the current era offers advanced technologies and analytic tools to address these gaps. Defining the biology of Long COVID may yield broader insights into host–pathogen interactions and mechanisms of chronic illness.

Source: Miller CM, Moen JK, Iwasaki A. The lingering shadow of epidemics: post-acute sequelae across history. Trends Immunol. 2025 Dec 4:S1471-4906(25)00267-4. doi: 10.1016/j.it.2025.10.010. Epub ahead of print. PMID: 41350176. https://www.cell.com/trends/immunology/fulltext/S1471-4906(25)00267-4 (Full text)