Analogies or differences of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome in children and adults are barely known. The aim of our study was to compare the overall characteristics of a large cohort of patients, both children and adults, diagnosed with PFAPA syndrome.
In the last decade, we identified 120 children and 63 adults with periodically recurring fevers, who fulfilled the criteria for PFAPA diagnosis. The two subcohorts were analyzed according to demographic features, clinical manifestations, laboratory data, and responses to therapies.
The mean age of onset was 2.4 ± 1.5 and 19.7 ± 10.3 years, respectively, in children and adults, while attacks occurred every 3.8 ± 0.8 and every 4.3 ± 2.3 weeks, respectively, in children and adults. A higher prevalence of exudative pharyngitis was observed in children (58.8%), and the majority of children had only two cardinal signs during flares. In adults, there was a higher interpersonal variability of the intercritical periods. Inflammatory markers measured during non-febrile periods were normal in children but altered in the totality of adults during febrile periods. A strong efficacy of corticosteroids in controlling the pediatric syndrome was observed, but response rates to steroids were less brilliant in adults. Colchicine and interleukin-1 inhibitors were used in the management of the steroid-resistant adult syndrome. Conversely, tonsillectomy was performed in a very low number of children, but was effective in 60.7% of adults when treated after 16 years. The mean age of disappearance of PFAPA symptoms has been 6.4 ± 2.4 years in children, while only 27% of adults have shown a complete drug-free symptom regression.
A linear conformity of the PFAPA syndrome has been observed between pediatric and adult patients. PFAPA symptoms tended to disappear with no sequelae in 94.1% of children, while the disease was still active in almost 3/4 of adults at the time of our assessment.
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Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras M, Passwell JH. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999;135:98–101.
Esposito S, Bianchini S, Fattizzo M, Baggi E, Marchisio P, Rigante D. The enigma of periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Pediatr Infect Dis J. 2014;33:650–2.
Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110:43–6.
Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135:15–21.
Gentileschi S, Vitale A, Frediani B, Galeazzi M, Rigante D, Cantarini L. Challenges and new horizons in the periodic fever, aphthous stomatitis, pharingitis and adenitis (PFAPA) syndrome. Expert Opin Orphan Drugs. 2017;5:165–71.
Hofer M, Pillet P, Cochard MM, Berg S, Krol P, Koné-Paut I, Rigante D, Hentgen V, Anton J, Brik R, Neven B, Touitou I, Kaiser D, Duquesne A, Wouters C, Gattorno M. International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology. 2014;53:1125–9.
Cantarini L, Vitale A, Bartolomei B, Galeazzi M, Rigante D. Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers. Clin Exp Rheumatol. 2012;30:269–71.
Cantarini L, Vitale A, Sicignano LL, Emmi G, Verrecchia E, Patisso I, Cerrito L, Fabiani C, Cevenini G, Frediani B, Galeazzi M, Rigante D, Manna R. Diagnostic criteria for adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical Adenitis (PFAPA) syndrome. Front Immunol. 2017;8:1018.
Rigante D, Gentileschi S, Vitale A, Tarantino G, Cantarini L. Evolving frontiers in the treatment of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Isr Med Ass J. 2017;19:444–7.
Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 2010;99:178–84.
Cattalini M, Soliani M, Rigante D, Lopalco G, Iannone F, Galeazzi M, Cantarini L. Basic characteristics of adults with periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome in comparison with the typical pediatric expression of disease. Mediators Inflamm. 2015;2015:570418.
Wurster VM, Carlucci JG, Feder HM Jr, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159:958–64.
Gaggiano C, Rigante D, Sota J, Grosso S, Cantarini L. Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review. Clin Rheumatol. 2019;38:11–7.
Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2019;12:CD008669.
Rigante D, Vitale A, Natale MF, Lopalco G, Andreozzi L, Frediani B, D’Errico F, Iannone F, Cantarini L. A comprehensive comparison between pediatric and adult patients with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenopathy (PFAPA) syndrome. Clin Rheumatol. 2017;36:463–8.
Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med. 2007;65:318–24.
Ozen S. Familial Mediterranean fever: revisiting an ancient disease. Eur J Pediatr. 2003;162:449–54.
Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348–56.
Rigante D, Capoluongo E, Bertoni B, Ansuini V, Chiaretti A, Piastra M, Pulitanò S, Genovese O, Compagnone A, Stabile A. First report of macrophage activation syndrome in hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2007;56:658–61.
Rigante D. The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci. 2010;14:1–18.
Rigante D, Lopalco G, Vitale A, Lucherini OM, De Clemente C, Caso F, Emmi G, Costa L, Silvestri E, Andreozzi L, Iannone F, Galeazzi M, Cantarini L. Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. Clin Rheumatol. 2014;33:1197–207.
Cantarini L, Lucherini OM, Frediani B, Brizi MG, Bartolomei B, Cimaz R, Galeazzi M, Rigante D. Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. Int J Immunopathol Pharmacol. 2011;24:827–36.
Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Stabile A. Hydrocephalus in CINCA syndrome treated with anakinra. Childs Nerv Syst. 2006;22:334–7.
Rigante D. When, how, and why do fevers hold children hostage? J Evid Based Med. 2020a;13:85–8.
Rigante D, Corina L. Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome: a debate about diagnosis and treatment in children continues. Int J Pediatr Otorhinolaryngol. 2020;130:109830.
Rigante D, Frediani B, Galeazzi M, Cantarini L. From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int. 2013;2013:485103.
Rigante D. A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner. Expert Rev Clin Immunol. 2017;13:571–97.
Rigante D. A developing portrait of hereditary periodic fevers in childhood. Expert Opin Orphan Drugs. 2018a;6:47–55.
Rigante D. New mosaic tiles in childhood hereditary autoinflammatory disorders. Immunol Lett. 2018b;193:67–76.
Rigante D. The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children. Mediterr J Hematol Infect Dis. 2018c;10:e2018067.
Rigante D. Phenotype variability of autoinflammatory disorders in the pediatric patient: a pictorial overview. J Evid Based Med. 2020b;13:227–45.
Sangiorgi E, Azzarà A, Molinario C, Pietrobono R, Rigante D, Verrecchia E, Sicignano LL, Genuardi M, Gurrieri F, Manna R. Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Eur J Hum Genet. 2019;27:1361–8.
Lovšin E, Kovač J, Tesovnik T, Toplak N, Perko D, Rozmarič T, Debeljak M, Avčin T. PIK3AP1 and SPON2 genes are differentially methylated in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. Front Immunol. 2020;11:1322.
Manna R, Rigante D. Familial Mediterranean fever: assessing the overall clinical impact and formulating treatment plans. Mediterr J Hematol Infect Dis. 2019;11:e2019027.
Di Gioia SA, Bedoni N, von Scheven-Gête A, Vanoni F, Superti-Furga A, Hofer M, Rivolta C. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep. 2015;5:10200.
Gaggiano C, Rigante D, Vitale A, Lucherini OM, Fabbiani A, Capozio G, Marzo C, Gelardi V, Grosso S, Frediani B, Renieri A, Cantarini L. Hints for genetic and clinical differentiation of adult-onset monogenic autoinflammatory diseases. Mediators Inflamm. 2019;2019:3293145.
Cantarini L, Iacoponi F, Lucherini OM, Obici L, Brizi MG, Cimaz R, Rigante D, Benucci M, Sebastiani GD, Brucato A, Sabadini L, Simonini G, Giani T, Laghi Pasini F, Baldari CT, Bellisai F, Valentini G, Bombardieri S, Paolazzi G, Galeazzi M. Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults. Int J Immunopathol Pharmacol. 2011;24:695–702.
Ter Haar NM, Annink KV, Al-Mayouf SM, Amaryan G, Anton J, Barron KS, Benseler SM, Brogan PA, Cantarini L, Cattalini M, Cochino AV, De Benedetti F, Dedeoglu F, De Jesus AA, Della Casa Alberighi O, Demirkaya E, Dolezalova P, Durrant KL, Fabio G, Gallizzi R, Goldbach-Mansky R, Hachulla E, Hentgen V, Herlin T, Hofer M, Hoffman HM, Insalaco A, Jansson AF, Kallinich T, Koné-Paut I, Kozlova A, Kuemmerle-Deschner JB, Lachmann HJ, Laxer RM, Martini A, Nielsen S, Nikishina I, Ombrello AK, Ozen S, Papadopoulou-Alataki E, Quartier P, Rigante D, Russo R, Simon A, Trachana M, Uziel Y, Ravelli A, Gattorno M, Frenkel J. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis. 2017;76:821–30.
Ter Haar NM, van Delft ALJ, Annink KV, van Stel H, Al-Mayouf SM, Amaryan G, Anton J, Barron KS, Benseler S, Brogan PA, Cantarini L, Cattalini M, Cochino AV, de Benedetti F, Dedeoglu F, de Jesus AA, Demirkaya E, Dolezalova P, Durrant KL, Fabio G, Gallizzi R, Goldbach-Mansky R, Hachulla E, Hentgen V, Herlin T, Hofer M, Hoffman HM, Insalaco A, Jansson AF, Kallinich T, Kone-Paut I, Kozlova A, Kuemmerle-Deschner JB, Lachmann HJ, Laxer RM, Martini A, Nielsen S, Nikishina I, Ombrello AK, Özen S, Papadopoulou-Alataki E, Quartier P, Rigante D, Russo R, Simon A, Trachana M, Uziel Y, Ravelli A, Schulert G, Gattorno M, Frenkel J. In silico validation of the autoinflammatory disease damage index. Ann Rheum Dis. 2018;77:1599–605.
Amarilyo G, Rothman D, Manthiram K, Edwards KM, Li SC, Marshall GS, Yildirim-Toruner C, Haines K, Ferguson PJ, Lionetti G, Cherian J, Zhao Y, DeLaMora P, Syverson G, Nativ S, Twilt M, Michelow IC, Stepanovskiy Y, Thatayatikom A, Harel L, Akoghlanian S, Tucker L, Marques MC, Srinivasalu H, Propst EJ, Licameli GR, Dedeoglu F, Lapidus S, CARRA PFAPA Consensus Treatment Plan Workgroup. Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol Online J. 2020;18:31.
Hofer M. Why and how should we treat periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome? Paediatr Drugs. 2020;22:243–50.
Peridis S, Pilgrim G, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas K. PFAPA syndrome in children: a meta-analysis on surgical versus medical treatment. Int J Pediatr Otorhinolaryngol. 2010;74:1203–8.
Lantto U, Koivunen P, Tapiainen T, Renko M. Long-term outcome of classic and incomplete PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) syndrome after tonsillectomy. J Pediatr. 2016;179:172–7.
Rigante D, La Torraca I, Avallone L, Pugliese AL, Gaspari S, Stabile A. The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci. 2006;10:173–8.
Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Semin Arthritis Rheum. 2016;45:471–4.
Vitale A, Insalaco A, Sfriso P, Lopalco G, Emmi G, Cattalini M, Manna R, Cimaz R, Priori R, Talarico R, Gentileschi S, de Marchi G, Frassi M, Gallizzi R, Soriano A, Alessio M, Cammelli D, Maggio MC, Marcolongo R, La Torre F, Fabiani C, Colafrancesco S, Ricci F, Galozzi P, Viapiana O, Verrecchia E, Pardeo M, Cerrito L, Cavallaro E, Olivieri AN, Paolazzi G, Vitiello G, Maier A, Silvestri E, Stagnaro C, Valesini G, Mosca M, de Vita S, Tincani A, Lapadula G, Frediani B, De Benedetti F, Iannone F, Punzi L, Salvarani C, Galeazzi M, Rigante D, Cantarini L. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. 2016;7:380.
We thank the generous support by Novartis for paying the publication fee of this manuscript, all the PFAPA patients with their families met in the last decade, the Associazione Italiana Febbri Periodiche and the many colleagues with whom we have intensely collaborated in these years.
The Journal’s Rapid Service Fee was funded by Novartis.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.
Ludovico Luca Sicignano, Donato Rigante, Beatrice Moccaldi, Maria Grazia Massaro, Stefano Delli Noci, Isabella Patisso, Giovanna Capozio, Elena Verrecchia and Raffaele Manna have nothing to disclose.
Compliance With Ethics Guidelines
Anonymous retrospective data were collected during conventional clinical practices and analyzed according to the principles of the Helsinki Declaration, and accordingly no formal informed consent was required. All adult patients and pediatric patients' parents gave their assent to use anonymous data for this study; therefore, a direct involvement of the ethics committee was not required.
Specific material referred to this article can be available for those interested in evaluating raw data.
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Sicignano, L.L., Rigante, D., Moccaldi, B. et al. Children and Adults with PFAPA Syndrome: Similarities and Divergences in a Real-Life Clinical Setting. Adv Ther 38, 1078–1093 (2021). https://doi.org/10.1007/s12325-020-01576-8
- auto-inflammatory disorder
- Innovative biotechnologies
- Periodic fever
- Personalized medicine
- PFAPA syndrome
- Recurrent fever