Long-term comorbidity associated with childhood periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a case–control study

The aim of this study was to evaluate the long-term morbidity of patients with PFAPA compared with controls selected from the general population. We identified 244 patients treated for PFAPA at Tampere, Oulu, and Kuopio University hospitals between 2008 and 2018. In May 2023, and January 2024, these patients were invited to complete a detailed questionnaire regarding their past and current health and lifestyle. A total of 2433 controls, matched for age, sex, and birthplace, were randomly selected from the Population Register Center of Finland and completed the same survey. We compared the occurrence of acute and chronic illnesses and childhood environmental exposures between PFAPA patients and controls 5-16 years after the initial PFAPA diagnosis. Responses were obtained from 98 PFAPA patients (40.1%) and 490 controls (20.1%). Atopy was the only chronic condition significantly more common among PFAPA patients than controls (14.3% vs 7.9%; OR 2.0, 95% CI 1.0-3.9). PFAPA patients more frequently reported recurrent otitis media (36.2% vs 20.9%; OR 2.3, 95% CI 1.4-3.8), tympanostomy (24.5% vs 15%; OR 1.9, 95% CI 1.1-3.2), bronchitis (4.2% vs 1.2%; OR 4.0, 95% CI 1.1-14.9) and hospitalization due to infections (30.2% vs 17.9%; OR 1.9, 95% CI 1.2-3.2). Fungal infections were also more common among PFAPA patients (8.5% vs 3.7%; OR 2.4, 95% CI 1.0-5.9). No differences were found in other chronic conditions or environmental exposures. CONCLUSION: Children with PFAPA did not exhibit greater long-term morbidity than controls, except for a higher prevalence of atopy. Respiratory infections, recurrent otitis media, and fungal infections were more frequent among cases than controls. These findings may reflect greater healthcare use rather than true susceptibility to infections. Environmental risk factors were similar between the groups. WHAT IS KNOWN: • Current evidence does not suggest an association between PFAPA and other chronic conditions. • Prior evidence on infection susceptibility in PFAPA has been inconsistent. WHAT IS NEW: • Children with a history of PFAPA show no increased long-term morbidity except for atopy. • PFAPA patients have more childhood AOM, bronchitis, and fungal infections than controls from the general population. Increased rates of diagnosed infections and hospitalizations in PFAPA patients may be influenced by healthcare‑seeking behavior and diagnostic practices, rather than reflecting true infection susceptibility.