TY - JOUR
T1 - Immunological associations in post-infective fatigue syndromes including Long COVID—a systematic review and meta-analysis
AU - Raijmakers, Ruud P.H.
AU - Lund Berven, Lise
AU - Keijmel, Stephan P.
AU - Rodrigo, Chaturaka
AU - Wyller, Vegard B.B.
AU - Katz, Ben Z.
AU - Buchwald, Dedra
AU - Evans, Rachael A.
AU - Gérardin, Patrick
AU - Knoop, Hans
AU - Prins, Maria
AU - Stavem, Knut
AU - Stiansen-Sonerud, Tonje
AU - Taylor, Renee
AU - Valencia Arroyo, Braulio Mark
AU - Wensaas, Knut Arne
AU - Selvakumar, Joel Pradeepkumar
AU - van den Wijngaard, Cees
AU - Lloyd, Andrew R.
AU - Sandler, Carolina X.
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2025/11
Y1 - 2025/11
N2 - 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.
AB - 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.
KW - Cohort
KW - COVID-19
KW - Immunological
KW - Long COVID
KW - Post-viral
UR - http://www.scopus.com/inward/record.url?scp=105019956173&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2025.105970
DO - 10.1016/j.ebiom.2025.105970
M3 - Article
AN - SCOPUS:105019956173
SN - 2352-3964
VL - 121
JO - EBioMedicine
JF - EBioMedicine
M1 - 105970
ER -
