Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature

Abstract

Autoinflammatory disorders of the innate immune system present with recurrent episodes of inflammation often beginning in early childhood. While there are now more than 30 genetically-defined hereditary fever disorders, many patients lack a clear diagnosis. Many pediatric patients are often grouped with patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome despite failing to meet diagnostic criteria. Here, we categorize these patients as syndrome of undifferentiated recurrent fever (SURF), and identify the unique features which distinguish them from the PFAPA syndrome. SURF patients were more likely to report gastrointestinal symptoms of nausea, vomiting and abdominal pain, and experienced inconsistent responses to on-demand steroid therapy compared to PFAPA patients. For this previously undefined cohort, an optimal course of therapy remains uncertain, with medical and surgical therapies largely driven by parental preference. A subset of patients with SURF underwent tonsillectomy with complete resolution. Flow cytometric evaluation demonstrates leukocytic populations distinct from PFAPA patients, with reduced CD3+ T cell numbers. SURF patient tonsils were predominantly characterized by an IL-1 signature compared to PFAPA, even during the afebrile period. Peripheral blood signatures were similar between groups suggesting that PFAPA and SURF patient tonsils have localized, persistent inflammation, without clinical symptoms. These data suggest that SURF is a heterogenous syndrome on the autoinflammatory disease spectrum.

Keywords: Autoinflammation; Pediatrics; Periodic fever; Recurrent fever.

Figure 1.. Tonsillectomy leads to rapid resolution of febrile episodes in SURF patients.

Time to resolution of febrile symptoms post-tonsillectomy (n=15), compared to patients who did not undergo tonsillectomy (n=13).

Figure 2.. SURF tonsils have an inflammatory cell infiltrate distinct from PFAPA tonsils.

A-C, CD3+ T cells, and CD3+ CD4+ T cells from tonsils of patients with SURF are decreased, with similar percentages of CD8+ T cells, and subsequently a reduced CD4:CD8 ratio (D). E-F, Total CD19+ B cells are similar between groups, but CD19+CD20+CD27+CD38- memory B cells are reduced in SURF tonsils compared to PFAPA tonsils. G,H, CD56+ NK cells (G) and CD11c+CD14+ monocytes (H) are similar between the two groups. Data shown as mean ± SEM, with *, p<0.05, by Student’s t test.

Figure 3.. SURF and PFAPA patient tonsils have a localize inflammatory signature.

A, Gene expression analysis from whole tonsillar tissue from PFAPA (n=7) and SURF tonsils (n=6), demonstrates significant increases in IL1B and IL1RN gene expression in SURF tonsils compared to PFAPA tonsils from patients of similar age. Expression of IL1A, IFNB and TNF are similar between fever disorders. OSA, obstructive sleep apnea. B. Pro-inflammatory gene expression in peripheral blood mononuclear cells does not differ between SURF and PFAPA patients (n=5 per group). Each symbol represents a different patient, average of technical triplicates, shown as the mean ± SEM. *, p<0.05, **, p<0.01 by Student’s two-tailed t-test.