Cluster Analysis in the Differential Diagnosis of PFAPA Syndrome

The differential diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) syndrome from recurrent upper respiratory tract infections (URTIs) and familial Mediterranean fever (FMF) presents significant clinical challenges due to shared symptomatic presentations. This study aimed to identify diagnostic variables that differentiate PFAPA from URTI and FMF by assessing similarities among cases based on demographic, clinical, and laboratory findings and subsequently forming homogeneous and heterogeneous groups. We included patients diagnosed with PFAPA syndrome, URTI, and acute FMF admitted to the hospital for fever attacks. Demographic data, clinical manifestations, and laboratory results were collected from medical records. Cluster analysis was applied to identify similarities and differences among patients based on these variables. A total of 566 patients (234 with PFAPA, 224 with FMF, 108 with URTI) were analyzed. Cluster analysis, based on demographic, medical history, and clinical/laboratory data, identified 3 distinct clusters: Cluster 1 (n = 231) consisted mostly of URTI patients, Cluster 2 (n = 233) of PFAPA patients, and Cluster 3 (n = 112) of FMF patients, with a similarity level of 0.357. Significant variables distinguishing PFAPA from both FMF and URTI (P < .05) included recurrent fevers before the age of 5 years, the presence of aphthous stomatitis, cervical lymphadenitis, and pharyngitis, an asymptomatic course between fever attacks, metallic taste during attacks, and elevated C-reactive protein and serum amyloid A levels during attacks. This study provides a comprehensive evaluation of PFAPA, using clinical and laboratory characteristics, and complements existing diagnostic criteria for distinguishing PFAPA from conditions commonly confused with it, such as URTI and FMF. The identified differences across demographic, clinical, and laboratory domains provide a strong basis for improving standardized, accurate diagnostic approaches for these disorders.