Clinical, Immunologic, and Genetic Characteristics in Patients With Syndrome of Undifferentiated Recurrent Fevers

Abstract

Objective: Syndrome of undifferentiated recurrent fevers (SURF) is characterized by recurrent fevers and autoinflammation without a confirmed molecular diagnosis of a hereditary recurrent fever syndrome, and not fulfilling criteria for periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome (PFAPA). The goal of this study was to characterize clinical features of patients with SURF compared to patients with PFAPA and to analyze their cytokine signature, genetic variations, and responses to treatment.

Methods: We enrolled 46 patients observed at Cincinnati Children's Hospital Medical Center. Baseline data and inflammatory cytokines were collected at enrollment, and their clinical course was followed. Cytokine analysis was performed using a cytokine multiplex assay. Many patients had specific or whole exome genetic testing.

Results: The prevalence of rash and arthralgias were higher in patients with SURF compared to patients with PFAPA. Pharyngitis and adenopathy were less frequent. A subset of patients with SURF clustered together with elevated proinflammatory cytokines and more frequently required biologic therapy. Focused analysis of whole exome sequencing data revealed that variants of unknown clinical significance (VUCS) were frequently identified in genes implicated in B cell development, immunodeficiencies, and inflammatory bowel disease risk. Treatments for patients with SURF commonly included on-demand steroids, colchicine, and anti-interleukin-1 therapy.

Conclusion: Our findings suggest SURF is a heterogeneous group but has distinct clinical and immunologic features from disorders such as PFAPA. Patients have frequent VUCS, which may have relevance to disease pathogenesis. A subset of patients showed more inflammation and an increased need for biologic therapy. Further research is necessary to define whether there exist distinct SURF endotypes and to better predict treatment outcomes.

Figure 1.

Proportion table of symptoms present during fever episodes in patients with SURF and patients with PFAPA. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. PFAPA, periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome; SURF, syndrome of undifferentiated recurrent fevers.

Figure 2.

Estimation plots of peripheral cytokines in patients with SURF and patients with PFAPA, showing a subgroup of patients with SURF who had much higher levels compared to patients with PFAPA. In each panel, the left side shows data, and the right side shows effect size and its confidence interval. n = 35 for SURF and n = 11 for PFAPA. IFNγ, interferon-γ; IL-6, interleukin-6; MIP-1β, macrophage inflammatory protein 1β; PFAPA, periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome; SURF, syndrome of undifferentiated recurrent fevers; TNFα, tumor necrosis factor α.

Figure 3.

Hierarchical clustering of peripheral cytokines for patients with SURF and patients with PFAPA. Red box represents cluster of patients with elevated levels of IL-12p70, interferon-γ, and IL-23, in addition to lower levels of MIP-1β. Clustering performed using Morpheus. GM-CSF, granulocyte–macrophage colony-stimulating factor; IL-1β, interleukin-1β; ITAC, interferon-inducible T cell alpha chemoattractant; MIP-1β, macrophage inflammatory protein 1β; PFAPA, periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome; SURF, syndrome of undifferentiated recurrent fevers; TNFα, tumor necrosis factor α.