Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2025 Nov:121:105970.
doi: 10.1016/j.ebiom.2025.105970. Epub 2025 Oct 27.

Immunological associations in post-infective fatigue syndromes including Long COVID-a systematic review and meta-analysis

Ruud P H Raijmakers  1 , Lise Lund Berven  2 , Stephan P Keijmel  3 , Chaturaka Rodrigo  4 , Vegard B B Wyller  5 , Ben Z Katz  6 , Dedra Buchwald  7 , Rachael A Evans  8 , Patrick Gérardin  9 , Hans Knoop  10 , Maria Prins  11 , Knut Stavem  12 , Tonje Stiansen-Sonerud  13 , Renee Taylor  14 , Braulio Mark Valencia Arroyo  15 , Knut-Arne Wensaas  16 , Joel Pradeepkumar Selvakumar  5 , Cees van den Wijngaard  17 , Andrew R Lloyd  18 , Carolina X Sandler  19
Affiliations
Meta-Analysis

Immunological associations in post-infective fatigue syndromes including Long COVID-a systematic review and meta-analysis

Ruud P H Raijmakers et al. EBioMedicine. 2025 Nov.

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). RAE is supported by the National Institute for Health and Care.

Keywords: COVID-19; Cohort; Immunological; Long COVID; Post-viral.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests RAE was provided a speaker fee for a lecture on Long COVID by Boeringher June 2021 and Moderna April 2023). PG has provided expert testimony for Takeda and Vanelva.

Figures

Fig. 1
Fig. 1
PRISMA flow-chart.
Fig. 2
Fig. 2
Meta-analyses of RANTES (A) and TNFα (B) within cytokines and chemokines, and WBC within clinical inflammatory markers (C). Analyses were made for each biomarker per timepoint window (e.g. 0–1 month, 3–6 months, 6–12 months). Effects size (Cohen's d) on X-axis. Bio, biomarker; CI, Confidence interval; Inf, Acute infection; RANTES, Regulated on activation normal T-cell expressed and secreted; SD, Standard deviation; Size, PIFS sample size; TNF, Tumour necrosis factor; WBC, White blood cells. Results are statistically significant when P ≤ 0.05.
See this image and copyright information in PMC

References

    1. Choutka J., Jansari V., Hornig M., Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. 2022;28(5):911–923. - PubMed
    1. Katz B.Z., Collin S.M., Murphy G., et al. The international collaborative on fatigue following infection (COFFI) Fatigue. 2018;6(2):106–121. - PMC - PubMed
    1. Wessely S., Chalder T., Hirsch S., Pawlikowska T., Wallace P., Wright D.J. Postinfectious fatigue: prospective cohort study in primary care. Lancet. 1995;345(8961):1333–1338. - PubMed
    1. Kedor C., Freitag H., Meyer-Arndt L., et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13(1):5104. - PMC - PubMed
    1. Sandler C.X., Wyller V.B.B., Moss-Morris R., et al. Long COVID and post-infective fatigue syndrome: a review. Open Forum Infect Dis. 2021;8(10) - PMC - PubMed