Gharra A, Amarilyo G, Harel L, Levinsky Y, Tal R , et al.
Orphanet journal of rare diseases •
To characterize the clinical presentation of PFAPA and the response to treatment in an ethnic subgroup- Druze and analyze the differences compared to other ethnic groups. Retrospective data were collected from medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel between March 2014-December 2022. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, multiethnic and Druze. Of 386 patients with PFAPA, 52 (13.5%) were with a corresponding FMF diagnosis (PFAPA/FMF) information was lacking regarding FMF status in 9 (2.3%) patients and 8 (2.1%) patients were excluded because of poor follow-up. The study included 317 PFAPA patients, 178 (56.2%) of which were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 87 (27.4%) were multiethnic, 19 (6%) were of non-Mediterranean descent (all Ashkenazi Jews), and 33 (10.4%) were of Druze ethnicity. No noteworthy differences in age of onset or age of diagnosis were found among ethnic groups. Clinical presentation analysis revealed statistical significance ( = 0.025) of the prevalence of abdominal pain across ethnic groups. No significance association was found regarding other symptoms including pharyngitis, adenitis, aphthous, myalgia, arthralgia, rash, and headache. Additionally, no significant association was observed between the response to treatment and ethnic group. Genetic testing was performed in 127 (40%) patients, no significant association was shown between number of mutations and ethnic origin. The clinical presentation of PFAPA in patients of Druze ethnicity is not significantly different from other ethnic groups in Israel. This finding fails to support the hypothesis that PFAPA is on the Behҫet spectrum. The online version contains supplementary material available at 10.1186/s13023-026-04278-6.
Broide M, Levinsky Y, Tal R, Harel L, Shoham S , et al.
Pediatric rheumatology online journal •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA). The medical records of 365 patients with PFAPA who attended Schneider Children's Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson's chi-squared, and Fisher's exact tests. Forty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7-2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment. About half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.
Levinsky Y, Butbul Aviel Y, Ahmad SA, Broide M, Gendler Y , et al.
Pediatric rheumatology online journal •
It is common knowledge among clinicians who treat PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) patients that emotional stress can trigger PFAPA attacks similarly to other autoinflammatory diseases. However, it has never been proved scientifically. Our aim was to examine whether emotional stress serves as a trigger for PFAPA attacks. Patients aged 3-12 years, with active PFAPA, from two Israeli medical centers were enrolled to this study. Patient's parents were reached via phone calls in two occasions: a stressful period related to the COVID-19 pandemic restrictions and a less stressful period. In both times they were asked to report occurrence of PFAPA attacks in the preceding 2 weeks. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. The significance level was set at 0.05. Mean age was 7.28 ± 2.7 for the 99 paediatric patients enrolled in the study. Scores for the mean emotional distress questionnaire were statistically significant higher in the stressful period compared to the less stressful period (35.6 ± 8.1 vs. 32.1 ±7.7, respectively, P = 0.047). In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the less stressful period (p = 0.017). PFAPA flares during COVID-19 outbreak are described. This study is the first to suggest that emotional stress is associated with PFAPA attacks.
Veres T, Amarilyo G, Abu Ahmad S, Abu Rumi M, Brik R , et al.
Frontiers in pediatrics •
Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) is the most common periodic fever syndrome in the pediatric population, yet its pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed. To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) as compared to those with no family history (FH-). In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) had FH+. Data from patients with FH+ were compared to data from those with FH-. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demographic and clinical details. The FH+ group as compared to the FH- group had more myalgia (56 vs. 19%, respectively, = 0.001), headaches (32 vs. 2%, respectively, = 0.016), and a higher carrier frequency of M694V mutation (54% vs. 25%, respectively, = 0.05). Colchicine was seen to be a more beneficial treatment for the FH+ group as compared to the FH- group; however, with no statistical significance ( = 0.096). FMs displayed almost identical characteristics to patients in the FH+ group except for greater arthralgia during flares (64 vs. 23%, respectively, = 0.008), and compared to the FH- group they had more oral aphthae (68 vs. 43%, respectively, = 0.002), myalgia/arthralgia (64 vs. 19%/16%, respectively, < 0.0001), and higher rates of FH of Familial Mediterranean fever (FMF) (45 vs.15%, respectively, = 0.003). Our findings suggest that patients with a FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia, and might have a better response to colchicine compared to FH-. Colchicine prophylaxis for PFAPA should be considered in FH+.
Amarilyo G, Harel L, Abu Ahmad S, Abu Rumi M, Brik R , et al.
The Journal of pediatrics •
To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period. The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P < .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P < .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P < .04). PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.
Amarilyo G, Rothman D, Manthiram K, Edwards KM, Li SC , et al.
Pediatric rheumatology online journal •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.
Butbul Aviel Y, Harel L, Abu Rumi M, Brik R, Hezkelo N , et al.
The Journal of pediatrics •
To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA). Clinical, laboratory, and genetic data of all pediatric patients diagnosed with sPFAPA or PFAPA/FMF were retrospectively collected from 2 primary Israeli medical referral centers and compared. Of 270 patients with PFAPA, more than one-half were of Mediterranean ancestry. Among patients with PFAPA, 51 (18.9%) also were diagnosed with FMF (PFAPA/FMF). Genetic data on the 9 most common MEFV variants were available for 45 children (88%) in the PFAPA/FMF group. Two variants were found in 15 children (33.3 %), 1 variant was found 27 patients (60%), and 3 patients (6.6%) had no variants. Abdominal pain, myalgia, and arthralgia each were more commonly reported in the PFAPA/FMF group compared with the sPFAPA group (90% vs 49% [P < .0001]; 46% vs 23% [P = .02]; and 30% vs 17% [P = .049], respectively). Colchicine was more commonly prescribed for the PFAPA/FMF group compared with the sPFAPA group (82% vs 29%; P < .0001), but alleviation of PFAPA symptoms with colchicine was similar between groups (75% vs 63%; P = .23). We show a strong association between 2 common autoinflammatory syndromes, PFAPA and FMF, in patients from Mediterranean ancestry. Clinicians should be aware that presentation of 1 disease may clinically evolve into another. The association between PFAPA and FMF poses the question similar pathogenesis and genetic influence of the MEFV gene on PFAPA.
Manthiram K, Li SC, Hausmann JS, Amarilyo G, Barron K , et al.
Rheumatology international •
To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset <5 years, 33% did not require regular intervals between episodes, and 79% did not require the concomitant signs of aphthous stomatitis, adenitis, or pharyngitis during episodes as long as episodes were regular. Over half (58%) considered episode resolution with steroids to be diagnostic of PFAPA. Corticosteroids, antipyretics, tonsillectomy, and cimetidine were the most commonly prescribed treatments, while steroids and tonsillectomy were most effective. Subspecialists in pediatric rheumatology and infectious diseases showed limited adherence to the complete published criteria for diagnosing PFAPA suggesting heterogeneity in the characteristics of patients diagnosed with the disorder. These findings emphasize the need to develop consensus diagnostic and treatment guidelines in well-characterized patient populations.
Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature. 23 children with PFAPA (age 6.07 ± 2.94 years, range 5-9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1-17 years) participated in the study. Peripheral blood concentrations of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology. PFAPA febrile episodes were characterized by detection of GM-CSF - 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1β was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects. PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.