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Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10 -9 ). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4 , IL10 , and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis., Competing Interests: Competing interest statement: F.D. is a consultant to Novartis and receives royalties from UpToDate. K.M.E. is on the Data Safety and Monitoring Board for Seqirus, Pfizer, Sanofi, Moderna, and X4 Pharma, and serves as an advisor to Bio-Net and Merck. P.F.W. is on the scientific advisory boards for GlaxoSmithKline, Sanofi-Pasteur, and Meissa Vaccines., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: To assess the long-term outcomes of patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome., Study Design: Patients enrolled in a PFAPA registry were contacted and surveyed., Results: Patients in the registry (n = 59) were surveyed with a follow-up time ranging from 12 to 21 years. Fifty patients had complete symptom resolution, with mean symptom duration of 6.3 years (95% CI, 5.4-7.3), and no sequelae developed. Nine patients continued to have persistent symptoms for a mean duration of 18.1 years (95% CI, 17.4-18.8). There were no differences in initial presentation between subjects with resolved PFAPA and subjects with persistent PFAPA. In subjects with persistent PFAPA, the mean duration of fever >38.3°C decreased from 3.6 days at onset to 1.8 days at follow-up (P = .01), and the mean symptom-free interval between episodes increased from 29 to 159 days (P < .005). Thirty-seven of 44 patients treated with corticosteroids reported prompt symptom resolution. Twelve patients underwent tonsillectomy or adenotonsillectomy; 9 of these patients experienced markedly reduced symptoms, and 6 patients had resolution of symptoms. Two subjects received other diagnoses., Conclusions: In long-term follow-up, most patients with PFAPA experienced spontaneous symptom resolution without sequelae. Patients with persistent symptoms had episodes of shorter duration and reduced frequency., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Periodic fevers (fevers that occur predictably at fixed intervals) are unusual in infants and children. The classic periodic fever syndrome is cyclic neutropenia (neutropenia followed by infections and fever that recur every 21 days). A new periodic fever syndrome PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) has been characterized over the past decade. PFAPA is defined clinically, because specific laboratory abnormalities have not been found. The clinical characteristic of PFAPA is high fevers (usually 40.0 degrees C to 40.6 degrees C) recurring at fixed intervals every 2 to 8 weeks. The fevers last for about 4 days, then resolve spontaneously. Associated with the fevers are aphthous stomatitis in 70% of patients, pharyngitis in 72% of patients, and cervical adenitis in 88% of patients. PFAPA is not familial and begins before the age of 5 years. An episode of PFAPA can be aborted with one or two small doses of prednisone. The episodes of PFAPA may last for years and the patient is well between episodes. The cause of PFAPA is unknown and there are no reported sequelae.

Objectives: To describe the presentation, clinical course, therapeutic response, and long-term follow-up of patients with a syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA)., Study Design: Patients with PFAPA (n = 94) referred over a 10-year period completed a registry form and provided medical records. Follow-up telephone calls were made in late 1997 to determine the persistence of episodes and sequelae., Results: PFAPA episodes lasted 4.8 days (95% confidence interval 4.5 to 5.1) and recurred every 28 days (confidence interval 26 to 30), with a maximal temperature of 40.5 degrees C (confidence interval 40. 4 degrees to 40.6 degrees ). Of the 83 children available for follow-up, 34 no longer had episodes. In the remainder the episodes did not differ in character but recurred less frequently over time. The affected children had no long-term sequelae. Glucocorticoids were highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients., Conclusions: PFAPA is a not uncommon cause of periodic fever in children. In some children the syndrome resolves, whereas symptoms in others persist. Long-term sequelae do not develop. The syndrome is easily diagnosed when regularly recurring episodes of fever are associated with aphthous stomatitis, pharyngitis, or cervical adenitis.

Objective: An orally administered antimicrobial regimen for the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis given once rather than multiple times each day would be more convenient and might result in improved patient compliance. The purpose of this study was to evaluate the effectiveness of once-daily amoxicillin in the treatment of GABHS pharyngitis., Patients: Children presenting to a private pediatric office with GABHS pharyngitis., Design: Patients were randomly assigned to receive orally either amoxicillin (750 mg once daily) or penicillin V (250 mg three times a day) for 10 days. Compliance was monitored by urine antimicrobial activity., Outcomes: Outcomes were measured by impact on the clinical course, eradication of GABHS within 18 to 24 hours, and bacteriologic treatment failure rate as determined by follow-up throat cultures 4 to 6 and 14 to 21 days after completing therapy. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (same serotype as initial throat culture) from new acquisitions (different serotypes)., Results: During the 16 months of this study, 152 children between 4 and 18 years of age (mean, 9.9 years) were enrolled; 79 children were randomly assigned to receive once-daily amoxicillin and 73 were assigned to receive penicillin V three times a day. The children in the two treatment groups were comparable with respect to age, duration of illness before initiation of therapy, compliance, and signs and symptoms at presentation. There was no significant difference in the clinical or bacteriologic responses of the patients in the two treatment groups at the 18- to 24-hour follow-up visit. Bacteriologic treatment failures occurred in 4 (5%) of the 79 patients in the amoxicillin group and in 8 (11%) of the 73 patients in the penicillin V group., Conclusions: These data demonstrate that once-daily amoxicillin therapy is as effective as penicillin V therapy given three times a day for the treatment of GABHS pharyngitis, and if confirmed by additional investigations, once-daily amoxicillin therapy could become an alternative regimen for the treatment of this disease.

To determine if a single daily dose of penicillin V would be effective in the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis, 154 patients with GABHS pharyngitis were randomly assigned to receive 750 mg of penicillin V once daily for ten days or 250 mg of penicillin V three times daily for ten days. The two regimens were comparable in their ability to eradicate GABHS from the upper respiratory tract in 18 to 24 hours and in their impact on the clinical course of the disease. However, a bacteriologic treatment failure occurred in six (8%) of the 76 patients in the three-times-daily group and in 16 (22%) of the 74 patients in the once-daily group. These findings support the current recommendation that penicillin V be given in two or more divided doses for a full ten days for the treatment of GABHS pharyngitis.