Sallansonnet E, Gualtieri R, Margot H, Mejbri M, Posfay-Barbe K , et al.
Pediatric rheumatology online journal •
PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) is the most common periodic fever condition in children. Vaccination in this population can be challenging due to concerns about immune hyperreactivity, the potential to trigger febrile episodes, and uncertainty regarding vaccine efficacy. Data on immunization coverage and vaccine response in PFAPA remain limited. This study aimed to describe the clinical characteristics of children with PFAPA, with a particular focus on vaccination coverage and serological responses. We conducted a prospective study of children with PFAPA followed at Geneva University Hospitals between February 2022 and April 2025. Clinical, laboratory, and genetic data were collected, along with vaccination status according to the Swiss national immunization schedule and serological results for major vaccine antigens. Forty-one patients were included. All exhibited elevated inflammatory markers during febrile episodes, and none had a monogenic cause identified. Vaccination coverage was high, with 90–95% of patients receiving the primary DTaP-IPV-Hib-HBV series on time. Minor delays were observed for the third pneumococcal and second MMR doses. Meningococcal (MenC/MenACWY) vaccination was administered on time in 58% of patients. Serological testing confirmed protective antibody levels for most antigens, including diphtheria, tetanus, and measles, but only 40% achieved protective pneumococcal titers. Only 65% showed varicella immunity because of past infection, as none had received the vaccine, which was only introduced in Switzerland in 2023. Children with PFAPA demonstrate high adherence to vaccination schedules and adequate immune responses, supporting the safety and effectiveness of routine immunization in this group. The reduced pneumococcal seroprotection suggests that monitoring antibody levels and considering booster doses may be warranted. Larger controlled studies are needed to assess vaccine immunogenicity and reactogenicity, particularly for highly reactogenic vaccines such as meningococcal B.
Theodoropoulou K, Wittkowski H, Busso N, Von Scheven-Gête A, Moix I , et al.
Frontiers in immunology •
The inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of , that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. We aimed to investigate the potential genetic impact of the variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. We report 42 patients with the Q703K genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The production of IL-1β was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. The evidence we report in our study shows an increased prevalence of Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F , et al.
Annals of the rheumatic diseases •
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
PFAPA syndrome represents the most common cause of recurrent fever in children in European populations, and it is characterized by recurrent episodes of high fever, pharyngitis, cervical adenitis, and aphthous stomatitis. Many possible causative factors have been explored so far, including infectious agents, immunologic mechanisms and genetic predisposition, but the exact etiology remains unclear. Recent findings demonstrate a dysregulation of different components of innate immunity during PFAPA flares, such as monocytes, neutrophils, complement, and pro-inflammatory cytokines, especially IL-1β, suggesting an inflammasome-mediated innate immune system activation and supporting the hypothesis of an autoinflammatory disease. Moreover, in contrast with previous considerations, the strong familial clustering suggests a potential genetic origin rather than a sporadic disease. In addition, the presence of variants in inflammasome-related genes, mostly in NLRP3 and MEFV, suggests a possible role of inflammasome-composing genes in PFAPA pathogenesis. However, none of these variants seem to be relevant, alone, to its etiology, indicating a high genetic heterogeneity as well as an oligogenic or polygenic genetic background.
Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I , et al.
The Journal of allergy and clinical immunology •
The exact pathogenesis of the pediatric disorder periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome is unknown. We hypothesized that PFAPA might be due to dysregulated monocyte IL-1β production linked to genetic variants in proinflammatory genes. Fifteen patients with PFAPA syndrome were studied during and outside a febrile episode. Hematologic profile, inflammatory markers, and cytokine levels were measured in the blood. The capacity of LPS-stimulated PBMCs and monocytes to secrete IL-1β was assessed by using ELISA, and active IL-1β secretion was visualized by means of Western blotting. Real-time quantitative PCR was performed to assess cytokine gene expression. DNA was screened for variants of the MEFV, TNFRSF1A, MVK, and NLRP3 genes in a total of 57 patients with PFAPA syndrome. During a febrile attack, patients with PFAPA syndrome revealed significantly increased neutrophil counts, erythrocyte sedimentation rates, and C-reactive protein, serum amyloid A, myeloid-related protein 8/14, and S100A12 levels compared with those seen outside attacks. Stimulated PBMCs secreted significantly more IL-1β during an attack (during a febrile episode, 575 ± 88 pg/mL; outside a febrile episode, 235 ± 56 pg/mL; P < .001), and this was in the mature active p17 form. IL-1β secretion was inhibited by ZYVAD, a caspase inhibitor. Similar results were found for stimulated monocytes (during a febrile episode, 743 ± 183 pg/mL; outside a febrile episode, 227 ± 92 pg/mL; P < .05). Genotyping identified variants in 15 of 57 patients, with 12 NLRP3 variants, 1 TNFRSF1A variant, 4 MEFV variants, and 1 MVK variant. Our data strongly suggest that IL-1β monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants, suggesting that inflammasome-related genes might be involved in this autoinflammatory syndrome.