Clinical, immunological characterisation and treatment response of patients with syndrome of undifferentiated recurrent fever in Chinese children and adolescents: a single-centre cohort study.

Background: Syndrome of undifferentiated recurrent fevers (SURF) is a heterogeneous disorder characterised by recurrent fevers and autoinflammation in the absence of a confirmed molecular diagnosis of hereditary recurrent fever (HRF) and periodic fever, adenitis, pharyngitis, aphthous stomatitis (PFAPA) syndrome. The aim of this study is to characterise the clinical and immunological features of SURF patients and to analyse their cytokine signature and treatment patterns. Methods: Between 2022 and 2024, we enrolled 191 patients who presented to Bei Jing Children's Hospital, Department of Immunology, with the chief complaint of recurrent fever. Fifty-seven patients met the criteria for SURF, 70 met the criteria for PFAPA and 64 met the criteria for FMF. Baseline data and blood samples were collected from patients at enrolment or at routine clinical visits. Clinical and immunological characteristics and cytokine levels were analysed. Results: In SURF patients, gastrointestinal symptoms(abdominal pain and vomiting or diarrhoea) were more prominent than in PFAPA patients. However, the difference in gastrointestinal symptoms between SURF patients and FMF patients was not significant. Pharyngitis and cervical adenitis were both seen in SURF and PFAPA patients while the frequency was higher in PFAPA patients. Family history was significantly higher in FMF patients than in SURF patients. The family history was similar between SURF patients and PFAPA patients. Treatment patterns differ between SURF and PFAPA (or FMF) patients. On-demand steroids were more likely prescribed in PFAPA patients, while colchicine was more commonly prescribed in SURF patients. However, no statistically significant differences were found in the prescription of colchicine between SURF and FMF patients. FMF patients were more commonly prescribed on-demand steroids than SURF patients. But SURF patients were more likely prescribed NSAIDs than FMF patients. The B-cell populations and immunoglobulin (Ig) levels (IgG, IgA, IgM and IgE) were similar in both SURF and PFAPA patients (or FMF patients). The proportion of helper T cells (Th cells) (CD3+CD4+) was significantly lower in SURF patients compared to PFAPA patients. However, the proportion of natural killer cells (NK cells) (CD3-CD56+) was significantly higher in SURF patients compared to PFAPA patients. The proportion of cytotoxic T cells (CD3+CD8+) was significantly higher in FMF patients compared to SURF patients. But the proportion and absolute count of natural killer cells (NK cells) (CD3-CD56+) was significantly lower in FMF patients compared to SURF patients. Cytokine levels between SURF and PFAPA patients (or FMF patients) were similar. SURF patients tended to have higher levels of pro-inflammatory cytokines (including IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-α). Both SURF, PFAPA, and FMF patients showed favourable responses to colchicine treatment. Conclusion: This study describes the clinical and immunological characteristics of a large cohort of patients with SURF. This suggests us that SURF is a heterogenous disease. However, the clinical and immunological features and treatment options of SURF patients differ from PFAPA and FMF patients.