Distinct Fever Resolution Trajectories and Phenotypic Clustering in PFAPA and SURF: A Survival and Dimensional Analysis

Objectives Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is the most common pediatric autoinflammatory syndrome. However, many patients present with similar but non-classic features, now increasingly categorized under the umbrella of syndrome of undifferentiated recurrent fever (SURF). While both groups experience recurrent fever episodes, their long-term outcomes and treatment responses remain poorly defined. Main objective was to compare fever resolution between PFAPA and SURF using survival analysis, and to identify phenotypic clusters through principal component analysis. Methods The primary outcome was time to fever resolution, defined as at least 12 months follow-up period after the most recent clinic visit with reported absence of the recurrent fevers and assessed using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Principal Component Analysis (PCA) was applied to explore phenotypic clustering based on symptom patterns. Results In this retrospective cohort study, 235 pediatric patients followed at the Autoinflammatory Clinic of The Hospital for Sick Children from 2016 to 2024 were classified as PFAPA (n = 155) or SURF (n = 80) based on validated Eurofever/PRINTO classification criteria for PFAPA and proposed empirical indications for SURF. The median time to fever resolution was significantly longer in the SURF group compared to PFAPA (2,068 vs 1,738 days; log-rank p = 0.037). In a semiparametric Cox regression model, SURF diagnosis was independently associated with a lower likelihood of resolution over time (Hazard Ratio [HR] = 0.683; 95% CI 0.476–0.980; p = 0.038). Inclusion of tonsillectomy status in a multivariable model did not significantly alter the outcome (HR for tonsillectomy = 1.046; p = 0.803). PCA revealed 3 major clusters: a classic PFAPA phenotype (tonsillopharyngitis, cervical adenitis), a GI-dominant cluster (abdominal pain, nausea, diarrhea), and an intermediate group (with mix of the symptoms in lower frequency). The GI cluster was predominantly composed of patients with SURF and correlated with longer disease persistence. Conclusion Children with SURF exhibit significantly delayed fever resolution compared to those with PFAPA. PCA-derived clusters support the presence of a gastrointestinal-dominant phenotype within the SURF spectrum, suggesting that these syndromes may exist along a clinical continuum. These findings have implications for prognosis and management, highlighting the need for phenotype-driven approaches in pediatric autoinflammatory conditions.