Association of Bacillus Calmette-Guerin (BCG) vaccination with reduced risk of PFAPA: nationwide matched case-control study using electronic health records

Abstract Objectives Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common autoinflammatory disorder of childhood, characterized by recurrent febrile episodes driven by dysregulated innate immune activation. Although genetic susceptibility contributes to disease risk, environmental modifiers remain poorly defined. Vaccinations may induce long-lasting modulation of innate immune responses and influence PFAPA incidence. We aimed to assess whether childhood vaccinations, including Bacillus Calmette-Guerin (BCG), are associated with PFAPA risk in a large national cohort. Methods We conducted a matched case-control study using electronic health records from a national healthcare provider in Israel. Children diagnosed with PFAPA were matched to children without PFAPA by age, sex, socioeconomic status, ethnic sector, and enrolment year. Vaccination history was obtained from the electronic immunization registry. A systematic screen of associations was performed across all recorded childhood vaccines, followed by adjusted conditional logistic regression models. Prior laboratory test results were analysed to characterize the immune profile. Results The study included 1,641 PFAPA cases and 32,820 matched controls. Among all vaccines examined, prior Bacillus Calmette-Guerin (BCG) vaccination, received by 401 children (3 cases, 398 controls), showed the strongest association with reduced PFAPA risk (adjusted odds ratio 0.15, 95% confidence interval [CI] 0.05-0.46, p=0.001). Associations with other vaccines were heterogeneous and of smaller magnitude. PFAPA cases demonstrated a myeloid-skewed inflammatory profile prior to diagnosis, including elevated C-reactive protein, neutrophilia, increased neutrophil-to-lymphocyte ratio, and relative lymphopenia. Conclusions In this nationwide study, prior BCG vaccination emerged from a systematic screen as strongly associated with reduced PFAPA risk, supporting a role for immune programming in susceptibility to childhood autoinflammatory disease.