Immunological associations in post-infective fatigue syndromes including Long COVID-a systematic review and meta-analysis
Raijmakers, Ruud PH Lund Berven, Lise Keijmel, Stephan P Rodrigo, Chaturaka Wyller, Vegard BB Katz, Ben Z Buchwald, Dedra Evans, Rachael A Gérardin, Patrick Knoop, Hans
Raijmakers, Ruud PH
Lund Berven, Lise
Keijmel, Stephan P
Rodrigo, Chaturaka
Wyller, Vegard BB
Katz, Ben Z
Buchwald, Dedra
Evans, Rachael A
Gérardin, Patrick
Knoop, Hans
Series / Report no.
Open Access
Type
Journal Article
Article
Article
Language
en
Date of publication
2025-10-27
Year of publication
Research Projects
Organizational Units
Journal Issue
Title
Immunological associations in post-infective fatigue syndromes including Long COVID-a systematic review and meta-analysis
Translated Title
Published in
EBioMedicine 2025; 121:105970
Abstract
BACKGROUND: The pathophysiology of post-infective fatigue syndromes (PIFS), including Long COVID, is unknown. This systematic review and meta-analysis aimed to investigate if PIFS is associated with persistent immune activation.
METHODS: PubMed, EMBASE, and Web of Science were searched for terms related to infection, fatigue, persistent symptoms, and immunological markers.
POPULATION: adults and adolescents; Exposure: documented acute infection; Comparator: those who developed PIFS vs. recovered controls from the same exposure; and Outcomes: immunological biomarkers. Studies which documented acute infection, applied diagnostic criteria for PIFS, and assayed circulating immunologic markers were eligible.
FINDINGS: From 14,985 studies screened, 30 articles were included (n = 5102 participants; 833 PIFS/PIFS-like cases, n = 4269 recovered control participants) with many studies excluded by inadequate quality in eligibility criteria. The meta-analysis (11 studies; n = 413 PIFS cases, analysed with random-effects models) showed PIFS cases had increased: white cell counts at 3-6 months (Cohen's d: 0.41, 95% CI 0.09-0.74); and circulating levels of RANTES and TNFα at 6-12 months (Cohen's d: 0.45 [95% CI 0.16-0.73] and 0.30 [95% CI 0.04-0.57], respectively) compared to controls recovered from the same exposure.
INTERPRETATION: These findings provide cautious support for persistent immune activation in PIFS, but warrant further replication. Future studies should include better documentation of acute infection and PIFS case characterisation.
FUNDING: ARL is supported by a National Health and Medical Research Council Practitioner Fellowship (Grant 1041897). CXS is supported by a Cancer Institute New South Wales Early Career Fellowship (2021/ECF1310). BZK is supported by the National Institute of Allergy and Infectious Diseases (AI 105781). RE is supported by the National Institute for Health and Care.