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

Ruud P H Raijmakers; Lise Lund Berven; Stephan P Keijmel; Chaturaka Rodrigo; Vegard B B Wyller; Ben Z Katz; Dedra Buchwald; Rachael A Evans; Patrick Gérardin; Hans Knoop; Maria Prins; Knut Stavem; Tonje Stiansen-Sonerud; Renee Taylor; Braulio Mark Valencia Arroyo; Knut-Arne Wensaas; Joel Pradeepkumar Selvakumar; Cees van den Wijngaard; Andrew R Lloyd; Carolina X Sandler

doi:10.1016/j.ebiom.2025.105970

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

EBioMedicine. 2025 Nov:121:105970. doi: 10.1016/j.ebiom.2025.105970. Epub 2025 Oct 27.

Authors

Ruud P H Raijmakers¹, Lise Lund Berven², Stephan P Keijmel³, Chaturaka Rodrigo⁴, Vegard B B Wyller⁵, Ben Z Katz⁶, Dedra Buchwald⁷, Rachael A Evans⁸, Patrick Gérardin⁹, Hans Knoop¹⁰, Maria Prins¹¹, Knut Stavem¹², Tonje Stiansen-Sonerud¹³, Renee Taylor¹⁴, Braulio Mark Valencia Arroyo¹⁵, Knut-Arne Wensaas¹⁶, Joel Pradeepkumar Selvakumar⁵, Cees van den Wijngaard¹⁷, Andrew R Lloyd¹⁸, Carolina X Sandler¹⁹

Affiliations

¹ Department of Experimental Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: ruud.raijmakers@radboudumc.nl.
² Microbiology and Infection Control, Akershus University Hospital, Nordbyhagen, Norway; Department of Paediatrics and Adolescent Medicine, Akershus University Hospital, Nordyhagen, Norway.
³ Clinical Diagnostics PAMM B.V, Veldhoven, the Netherlands; Bernhoven Hospital, Uden, the Netherlands.
⁴ School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
⁵ Department of Paediatrics and Adolescent Medicine, Akershus University Hospital, Nordyhagen, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶ Ann & Robert H Lurie Children's Hospital of Chicago, Division of Infectious Diseases, Chicago, Illinois, USA; Northwestern University Feinberg School of Medicine, Department of Pediatrics, Chicago, Illinois, USA.
⁷ Institute for Research and Education to Advance Community Health, Washington State University, Seattle, Washington, USA.
⁸ NIHR Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, United Kingdom.
⁹ Clinical Investigation Center INSERM CIC1410/Centre Hospitalier Universitaire, Saint-Pierre, Réunion, France.
¹⁰ Department of Medical Psychology, Amsterdam University Medical Center, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, University of Amsterdam, Amsterdam, the Netherlands; Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, the Netherlands; Department of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
¹² Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Pulmonary Department, Akershus University Hospital, Nordbyhagen, Norway; Health Services Research Unit, Akershus University Hospital, Nordbyhagen, Norway.
¹³ Department of Paediatrics and Adolescent Medicine, Akershus University Hospital, Nordyhagen, Norway.
¹⁴ College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁵ International Centre for Future Health Systems, UNSW, Sydney, NSW, Australia.
¹⁶ Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway.
¹⁷ National Institute for Public Health and Environment (RIVM), Center for Infectious Disease Control, Bilthoven, the Netherlands.
¹⁸ The Kirby Institute, UNSW Sydney, NSW, Australia.
¹⁹ School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, NSW, Australia.

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.

Publication types

Systematic Review
Meta-Analysis

MeSH terms

Biomarkers
COVID-19* / complications
COVID-19* / immunology
Fatigue* / etiology
Fatigue* / immunology
Humans
SARS-CoV-2

Substances

Biomarkers

Grants and funding

R01 AI105781/AI/NIAID NIH HHS/United States