Inflammatory biomarkers in pediatric PFAPA syndrome: a systematic review

Vollständiger Abstract

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Background PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) is the most common periodic fever syndrome in childhood, yet remains a diagnosis of exclusion. No recent synthesis has quantitatively evaluated its circulating biomarkers. We aimed to assess the behavior of inflammatory biomarkers during febrile flares vs. asymptomatic intervals and evaluate their ability to distinguish PFAPA from acute infections and other auto inflammatory diseases. Methods Following PRISMA 2020, PubMed and Scopus were searched for English-language studies (1 January 2018–07 June 2026) including children (0–18 years) with confirmed PFAPA reporting at least one of eleven predefined biomarkers (WBC, neutrophils, lymphocytes, CRP, SAA, serum calprotectin, IL-6, IL-1β, IL-18, TNF-α, IFN- γ ). Results Seven studies (710 children; five countries; two prospective, five retrospective; 2019–2026) were included from 170 records. CRP and SAA increased markedly during flares and normalized between episodes, with SAA showing the greatest dynamic range. However, neither CRP, WBC, neutrophils, nor IL-6 reliably distinguished PFAPA flares from acute infections. IL-1β was consistently undetectable in serum despite the inflammasome-driven pathophysiology. IFN- γ emerged as the only consistently discriminating biomarker, elevated in PFAPA compared with infections across three independent cohorts. In one cohort, the IFN- γ /IL-6 ratio (AUC 0.79) and a composite model including IL-10 and platelet count (AUC 0.95) demonstrated promising diagnostic performance. Both cut-offs were derived and tested in the same at-risk-of-bias cohort without external validation and should be read as derivation-stage estimates. No biomarker differentiated PFAPA from other auto inflammatory diseases: the only direct comparison (with SURF) showed overlapping values without comprehensive statistical testing, and differentiation from familial Mediterranean fever relied on clinical criteria. For discrimination outcomes, GRADE certainty did not exceed low; CRP as an activity marker reached moderate-to-high certainty. Conclusions CRP and SAA are reliable markers of PFAPA activity but lack discriminating value vs. infection. IFN- γ , particularly in combination with IL-6, is the most promising candidate for differentiation, though current evidence is limited and may be biased. No circulating biomarker distinguishes PFAPA from other autoinflammatory diseases, representing a major unmet need. PFAPA, therefore, remains a clinical diagnosis requiring exclusion of monogenic syndromes.