Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1β positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.
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Fetal bovine serum
Glyceraldehyde 3-phosphate dehydrogenase
Inhibitor of kappa B kinase
Interleukin-1 receptor antagonist (protein)
Interleukin-1 receptor antagonist (gene)
Nuclear factor kappa-light-chain enhancer of activated B cells
Obstructive sleep apnea
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis
Reverse transcription quantitative polymerase chain reaction
Standard error of mean
Tumor necrosis factor
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The authors would like to acknowledge Dr. Hal M. Hoffman (University of California, San Diego) for helpful discussion, and the patients and families who participated.
This work was supported by National Institutes of Health 1K08HD075830-01A1 (L.B.), Thrasher Research Fund (L.B.), The Hartwell Foundation (L.B), and A.P. Giannini (L.B.).
Conflict of Interest
L.B. is a speaker for Novartis, Inc., and has an ongoing research collaboration with Regeneron, Inc. The other authors declare no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the UCSD Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Dr. Pransky is now affiliated with Pediatric Specialty Partners, La Jolla, CA
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Luu, I., Sharma, A., Guaderrama, M. et al. Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. J Clin Immunol 40, 179–190 (2020). https://doi.org/10.1007/s10875-019-00724-2