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Published in: Pediatric Rheumatology 1/2016

Open Access 01-12-2016 | Review

PFAPA syndrome: a review on treatment and outcome

Authors: Federica Vanoni, Katerina Theodoropoulou, Michaël Hofer

Published in: Pediatric Rheumatology | Issue 1/2016

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Abstract

The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA syndrome) is the most common cause of periodic fever in childhood. The current pharmacological treatment includes corticosteroids, which usually are efficacious in the management of fever episodes, colchicine, for the prophylaxis of febrile episodes, and other medication for which efficacy has not been proven so far. Tonsillectomy is an option for selected patients. Usually PFAPA syndrome resolves during adolescence, but there is increasing evidence that this condition may persist into adulthood.
Literature
1.
go back to reference Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–6.PubMedCrossRef Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–6.PubMedCrossRef
2.
go back to reference Thomas KT, Feder Jr HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135(1):15–21.PubMedCrossRef Thomas KT, Feder Jr HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135(1):15–21.PubMedCrossRef
3.
go back to reference Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P, Huss K, Fraunberger P, Malley JD, Zellerer S, Albert MH, Belohradsky BH. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur Cytokine Netw. 2006;17(2):90–7.PubMed Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P, Huss K, Fraunberger P, Malley JD, Zellerer S, Albert MH, Belohradsky BH. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur Cytokine Netw. 2006;17(2):90–7.PubMed
4.
go back to reference Long S. “Syndrome of Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenitis (PFAPA) what it isn’t. What is it? J Pediatr. 1999;135(1):1–5.PubMedCrossRef Long S. “Syndrome of Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenitis (PFAPA) what it isn’t. What is it? J Pediatr. 1999;135(1):1–5.PubMedCrossRef
5.
go back to reference Stojanov S, Lapidusa S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun H-W, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A. 2011;108:7146–53.CrossRef Stojanov S, Lapidusa S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun H-W, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A. 2011;108:7146–53.CrossRef
6.
go back to reference Cochard M, Clet J, Le L, Pillet P, Onrubia X, Guéron T, Faouzi M, Hofer M. PFAPA syndrome is not a sporadic disease. Rheumatology (Oxford). 2010;49(10):1984–7.CrossRef Cochard M, Clet J, Le L, Pillet P, Onrubia X, Guéron T, Faouzi M, Hofer M. PFAPA syndrome is not a sporadic disease. Rheumatology (Oxford). 2010;49(10):1984–7.CrossRef
7.
go back to reference Perko D, Debeljak M, Toplak N, Avčin T. Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. Mediators Inflamm. 2015;2015:293417.PubMedPubMedCentralCrossRef Perko D, Debeljak M, Toplak N, Avčin T. Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. Mediators Inflamm. 2015;2015:293417.PubMedPubMedCentralCrossRef
8.
go back to reference Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int. 2010;30(5):633–6.PubMedCrossRef Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int. 2010;30(5):633–6.PubMedCrossRef
9.
go back to reference Kolly L, Busso N, Von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol. 2013;131(6):1635–43.PubMedCrossRef Kolly L, Busso N, Von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol. 2013;131(6):1635–43.PubMedCrossRef
10.
go back to reference Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, Cortis E, Calcagno G, Tommasini A, Consolini R, Simonini G, Pelagatti MA, Baldi M, Ceccherini I, Plebani A, Frenkel J, Sormani MP, Martini A. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009;124(4):e721–8.PubMedCrossRef Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, Cortis E, Calcagno G, Tommasini A, Consolini R, Simonini G, Pelagatti MA, Baldi M, Ceccherini I, Plebani A, Frenkel J, Sormani MP, Martini A. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009;124(4):e721–8.PubMedCrossRef
11.
go back to reference Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous stomatitis phayngitis and cervical adenitis syndrome (PFAPA syndrome) in adults. Isr Med Assoc J. 2008;10:358–60.PubMed Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous stomatitis phayngitis and cervical adenitis syndrome (PFAPA syndrome) in adults. Isr Med Assoc J. 2008;10:358–60.PubMed
12.
go back to reference Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 2010;99(2):178–84.PubMed Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 2010;99(2):178–84.PubMed
13.
go back to reference ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, Kone-Paut I, Cantarini L, Insalaco a, Neven B, Hofer M, Rigante D, Al-Mayouf S, Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S, Kuemmerle-Deschner J, Obici L, Iagaru N, Simon a, Nielsen S, Martini a, Ruperto N, Gattorno M, Frenkel J. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.PubMedCrossRef ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, Kone-Paut I, Cantarini L, Insalaco a, Neven B, Hofer M, Rigante D, Al-Mayouf S, Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S, Kuemmerle-Deschner J, Obici L, Iagaru N, Simon a, Nielsen S, Martini a, Ruperto N, Gattorno M, Frenkel J. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.PubMedCrossRef
14.
go back to reference Vigo G, Zulian F. Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). Autoimmun Rev. 2012;12(1):52–5.PubMedCrossRef Vigo G, Zulian F. Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). Autoimmun Rev. 2012;12(1):52–5.PubMedCrossRef
15.
go back to reference 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(11):1203–8.PubMedCrossRef 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(11):1203–8.PubMedCrossRef
16.
go back to reference Hofer M, Pillet P, Cochard M-M, Berg S, Krol P, Kone-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 (Oxford). 2014;53(6):1125–9.CrossRef Hofer M, Pillet P, Cochard M-M, Berg S, Krol P, Kone-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 (Oxford). 2014;53(6):1125–9.CrossRef
17.
go back to reference Wurster VM, Carlucci JG, Feder HM, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159(6):958–64.PubMedCrossRef Wurster VM, Carlucci JG, Feder HM, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159(6):958–64.PubMedCrossRef
19.
go back to reference Yazgan H, Gultekin E, Yazicilar O, Sagun OF, Uzun L. Comparison of conventional and low dose steroid in the treatment of PFAPA syndrome: preliminary study. Int J Pediatr Otorhinolaryngol. 2012;76(11):1588–90.PubMedCrossRef Yazgan H, Gultekin E, Yazicilar O, Sagun OF, Uzun L. Comparison of conventional and low dose steroid in the treatment of PFAPA syndrome: preliminary study. Int J Pediatr Otorhinolaryngol. 2012;76(11):1588–90.PubMedCrossRef
20.
go back to reference Licameli G, Jeffrey J, Luz J, Jones D, Kenna M. Effect of adenotonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2008;134(2):136–40.PubMedCrossRef Licameli G, Jeffrey J, Luz J, Jones D, Kenna M. Effect of adenotonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2008;134(2):136–40.PubMedCrossRef
21.
go back to reference Forsvoll J, Kristoffersen EK, Oymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr. 2013;102(2):187–92.PubMedCrossRef Forsvoll J, Kristoffersen EK, Oymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr. 2013;102(2):187–92.PubMedCrossRef
22.
go back to reference Leung YY, Yao Hui LL, Kraus VB. Colchicine-Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45(3):341–50.PubMedCrossRef Leung YY, Yao Hui LL, Kraus VB. Colchicine-Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45(3):341–50.PubMedCrossRef
23.
go back to reference Aviel YB, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Syndrome. Semin Arthritis Rheum. 2016;45:471–4.CrossRef Aviel YB, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Syndrome. Semin Arthritis Rheum. 2016;45:471–4.CrossRef
24.
go back to reference 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(1):98–101.PubMedCrossRef 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(1):98–101.PubMedCrossRef
25.
go back to reference Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr. 2008;97:1090–2.PubMedCrossRef Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr. 2008;97:1090–2.PubMedCrossRef
26.
go back to reference Dusser P, Hengten V, Neven B, Koné-Paut I. “Is colchicine an effective treatment in Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical adenitis (PFAPA) syndrome?” Joint Bone Spine. 2016; 83(4):406-11. Dusser P, Hengten V, Neven B, Koné-Paut I. “Is colchicine an effective treatment in Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical adenitis (PFAPA) syndrome?” Joint Bone Spine. 2016; 83(4):406-11.
27.
go back to reference Feder HM. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr Infect Dis. 1992;11(4):318–21.CrossRef Feder HM. Cimetidine treatment for periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr Infect Dis. 1992;11(4):318–21.CrossRef
28.
go back to reference Frediana B, Cantarini L, Vitale A, Galeazzi M. A case of resistant adult-onset Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical adenitis (PFAPA) syndrome responsive to anakinra”. Clin Exp Rheumatol. 2012;30(4):593. Frediana B, Cantarini L, Vitale A, Galeazzi M. A case of resistant adult-onset Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical adenitis (PFAPA) syndrome responsive to anakinra”. Clin Exp Rheumatol. 2012;30(4):593.
29.
go back to reference Mangin M, Sinha R, Fincher K. “Inflammation and vitamin D: the infection connection” Inflamm Res. 2014; col 63, no 10, pp 803–819. Mangin M, Sinha R, Fincher K. “Inflammation and vitamin D: the infection connection” Inflamm Res. 2014; col 63, no 10, pp 803–819.
30.
go back to reference Mahamid M, Agbaria K, Mahamid A, Nseir W. Vitamin D linked to PFAPA syndrome. Int J Pediatr Otorhinolaryngol. 2013;77:362–4.PubMedCrossRef Mahamid M, Agbaria K, Mahamid A, Nseir W. Vitamin D linked to PFAPA syndrome. Int J Pediatr Otorhinolaryngol. 2013;77:362–4.PubMedCrossRef
31.
go back to reference Stagi S, Bertini F, Rigante D, Falcini F. Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Int J Pediatr Otorhinolaryngol. 2014;78(6):964–8.PubMedCrossRef Stagi S, Bertini F, Rigante D, Falcini F. Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Int J Pediatr Otorhinolaryngol. 2014;78(6):964–8.PubMedCrossRef
32.
go back to reference Abramson JS TJ, Givner LB. Possible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis. Pediatr Infect Dis. 1989;8(2):119–20. Abramson JS TJ, Givner LB. Possible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis. Pediatr Infect Dis. 1989;8(2):119–20.
33.
go back to reference Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, Ruuskanen O, Uhari M. A Randomized, Controlled Trial of Tonsillectomy in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome. J Pediatr. 2007;151(3):289–92.PubMedCrossRef Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, Ruuskanen O, Uhari M. A Randomized, Controlled Trial of Tonsillectomy in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome. J Pediatr. 2007;151(3):289–92.PubMedCrossRef
34.
go back to reference Garavello W, Romagnoli M, Gaini RM. Effectiveness of adenotonsillectomy in PFAPA syndrome: a randomized study. J Pediatr. 2009;155(2):250–3.PubMedCrossRef Garavello W, Romagnoli M, Gaini RM. Effectiveness of adenotonsillectomy in PFAPA syndrome: a randomized study. J Pediatr. 2009;155(2):250–3.PubMedCrossRef
35.
go back to reference Licameli G, Lawton M, Kenna M, Dedeoglu F. Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2012;138(10):902–6.PubMedCrossRef Licameli G, Lawton M, Kenna M, Dedeoglu F. Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2012;138(10):902–6.PubMedCrossRef
36.
go back to reference Burton MJ, Pollard AJ, Ramsden JD, Chong LYe, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2014;9:CD008669.PubMed Burton MJ, Pollard AJ, Ramsden JD, Chong LYe, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2014;9:CD008669.PubMed
37.
go back to reference Berkun Y, Levy R, Hurwitz A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467–72.PubMedCrossRef Berkun Y, Levy R, Hurwitz A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467–72.PubMedCrossRef
38.
go back to reference 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(2):269–71.PubMed 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(2):269–71.PubMed
39.
go back to reference 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;2015:1–11.CrossRef 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;2015:1–11.CrossRef
40.
go back to reference Colotto M, Maranghi M, Durante C, Rossetti M, Renzi A, Anatra MG. PFAPA syndrome in a young adult with a history of tonsillectomy. Intern Med. 2011;50(3):223–5.PubMedCrossRef Colotto M, Maranghi M, Durante C, Rossetti M, Renzi A, Anatra MG. PFAPA syndrome in a young adult with a history of tonsillectomy. Intern Med. 2011;50(3):223–5.PubMedCrossRef
Metadata
Title
PFAPA syndrome: a review on treatment and outcome
Authors
Federica Vanoni
Katerina Theodoropoulou
Michaël Hofer
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Pediatric Rheumatology / Issue 1/2016
Electronic ISSN: 1546-0096
DOI
https://doi.org/10.1186/s12969-016-0101-9

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