Skip to main content

Advertisement

SpringerLink
Log in

Risk factors for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a case-control study

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

The etiology and pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome are unclear. We performed a case-control study to evaluate potential environmental or lifestyle factors associated with PFAPA morbidity. We enrolled 119 patients with PFAPA syndrome who had undergone tonsillectomy in Oulu University Hospital between 1987 and 2007. We recruited 230 controls, matched for sex, birth date, and place from the database of the Population Register Center of Finland. All the patients and controls completed a questionnaire regarding exposure to environmental triggers during early childhood. Maternal smoking was more common among PFAPA syndrome patients than controls (23 vs. 14%; P = 0.005). PFAPA patients had lower breastfeeding rates than controls (94 vs. 99%; P = 0.006). No other environmental factors were associated with PFAPA syndrome, except having an aquarium at home (P = 0.007). The patient group also used natural or herbal medicines more often than the controls (P = 0.01).

Conclusion: Maternal smoking and lack of breastfeeding, known risk factors for common childhood infections, were more common in patients with PFAPA syndrome than in matched controls. Environmental factors may be important in the pathogenesis of PFAPA syndrome and should be evaluated in future studies.

What is Known:

• The pathogenesis and genetics of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome remain unsolved.

• PFAPA syndrome has been shown to cluster in families.

What is New:

• Maternal smoking and lack of breastfeeding are more common in patients with PFAPA syndrome than in the controls.

• Environmental risk factors may be important in the pathogenesis of the syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

A:

Adenoidectomy

aOR:

Adjusted odds ratio

CI:

Confidence interval

IL:

Interleukin

NA:

Not applicable

OR:

Odds ratio

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome

TE:

Tonsillectomy

TEA:

Adenotonsillectomy

References

  1. Marshall GS, Edwards KM, Butler J, Lawton AR (1987) Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110(1):43–46

    Article  PubMed  CAS  Google Scholar 

  2. Forsvoll J, Kristoffersen EK, Oymar K (2013) Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome: a population-based study. Acta Paediatr 102(2):187–192

    Article  PubMed  Google Scholar 

  3. Thomas KT, Feder HM, Jr LAR, Edwards KM (1999) Periodic fever syndrome in children. J Pediatr 135(1):15–21

    Article  PubMed  CAS  Google Scholar 

  4. 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 (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1beta production. J Allergy Clin Immunol 131(6):1635–1643

    Article  PubMed  CAS  Google Scholar 

  5. Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P et al (2006) Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur Cytokine Netw 17(2):90–97

    PubMed  CAS  Google Scholar 

  6. Lantto U, Koivunen P, Tapiainen T, Glumoff V, Hirvikoski P, Uhari M, Renko M (2015) Microbes of the tonsils in PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis) syndrome—a possible trigger of febrile episodes. APMIS 123(6):523–529

    Article  PubMed  Google Scholar 

  7. Tejesvi MV, Uhari M, Tapiainen T, Pirttila AM, Suokas M, Lantto U et al (2016) Tonsillar microbiota in children with PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome. Eur J Clin Microbiol Infect Dis 35(6):963–970

    Article  PubMed  CAS  Google Scholar 

  8. Adachi M, Watanabe A, Nishiyama A, Oyazato Y, Kamioka I, Murase M, Ishida A, Sakai H, Nishikomori R, Heike T (2011) Familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 158(1):155–159

    Article  PubMed  Google Scholar 

  9. Hofer M, Pillet P, Cochard MM, 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 (2014) International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients. Rheumatology (Oxford) 53(6):1125–1129

    Article  Google Scholar 

  10. Wurster VM, Carlucci JG, Feder HM, Edwards KM Jr (2011) Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 159(6):958–964

    Article  PubMed  Google Scholar 

  11. Manthiram K, Nesbitt E, Morgan T, Edwards KM (2016) Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics 138(3):e20154572. https://doi.org/10.1542/peds.2015-4572

    Article  PubMed  PubMed Central  Google Scholar 

  12. Di Gioia SA, Bedoni N, von Scheven-Gete A, Vanoni F, Superti-Furga A, Hofer M et al (2015) Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep 5:10200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lantto U, Koivunen P, Tapiainen T, Renko M (2016) Long-term outcome of classic and incomplete PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome after tonsillectomy. J Pediatr 179:172,177.e1

    Article  Google Scholar 

  14. Korppi M, Korhonen J, Lindstrom K, Mononen T (2003) Genetic fever—Internet consultation, mutation in the envelope. Duodecim 119(16):1567–1571

    PubMed  Google Scholar 

  15. Amatngalim GD, Broekman W, Daniel NM, van der Vlugt LE, van Schadewijk A, Taube C et al (2016) Cigarette smoke modulates repair and innate immunity following injury to airway epithelial cells. PLoS One 11(11):e0166255

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Iyengar SR, Walker WA (2012) Immune factors in breast milk and the development of atopic disease. J Pediatr Gastroenterol Nutr 55(6):641–647

    Article  PubMed  CAS  Google Scholar 

  17. Hosea Blewett HJ, Cicalo MC, Holland CD, Field CJ (2008) The immunological components of human milk. Adv Food Nutr Res 54:45–80

    Article  PubMed  CAS  Google Scholar 

  18. Duijts L, Ramadhani MK, Moll HA (2009) Breastfeeding protects against infectious diseases during infancy in industrialized countries. A systematic review. Matern Child Nutr 5(3):199–210

    Article  PubMed  Google Scholar 

  19. Reitan T, Callinan S (2017) Changes in smoking rates among pregnant women and the general female population in Australia, Finland, Norway, and Sweden. Nicotine Tob Res 19(3):282–289

    PubMed  Google Scholar 

  20. Manthiram K, Lapidus S, Edwards K (2017) Unraveling the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis through genetic, immunologic, and microbiologic discoveries: an update. Curr Opin Rheumatol 29(5):493–499

    Article  PubMed  Google Scholar 

  21. Cheung MS, Theodoropoulou K, Lugrin J, Martinon F, Busso N, Hofer M (2017) Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome is associated with a CARD8 variant unable to bind the NLRP3 inflammasome. J Immunol 198(5):2063–2069

    Article  PubMed  CAS  Google Scholar 

  22. Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, Ruuskanen O, Uhari M (2007) A randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr 151(3):289–292

    Article  PubMed  CAS  Google Scholar 

  23. Joly S, Ma N, Sadler JJ, Soll DR, Cassel SL, Sutterwala FS (2009) Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J Immunol 183(6):3578–3581

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C et al (2011) The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol 187(1):434–440

    Article  PubMed  CAS  Google Scholar 

  25. Jurelevicius D, Alvarez VM, Marques JM, de Sousa Lima LR, Dias Fde A, Seldin L (2013) Bacterial community response to petroleum hydrocarbon amendments in freshwater, marine, and hypersaline water-containing microcosms. Appl Environ Microbiol 79(19):5927–5935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Revetta RP, Gomez-Alvarez V, Gerke TL, Curioso C, Santo Domingo JW, Ashbolt NJ (2013) Establishment and early succession of bacterial communities in monochloramine-treated drinking water biofilms. FEMS Microbiol Ecol 86(3):404–414

    Article  PubMed  CAS  Google Scholar 

  27. Manthiram K, Li SC, Hausmann JS, Amarilyo G, Barron K, Kim H et al (2017) Physicians’ perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Rheumatol Int 37(6):883–889

    Article  PubMed  Google Scholar 

Download references

Funding

The present work was supported by Foundation for Pediatric Research and The Finnish Medical Foundation.

Author information

Authors and Affiliations

  1. PEDEGO Research Unit, Medical Research Centre, University of Oulu, BOX 5000, FI-90014, Oulu, Finland

    Sallamaaria Kettunen, Ulla Lantto, Terhi Tapiainen, Matti Uhari & Marjo Renko

  2. Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland

    Sallamaaria Kettunen, Terhi Tapiainen & Matti Uhari

  3. Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland

    Ulla Lantto & Petri Koivunen

  4. Tampere Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland

    Marjo Renko

Authors
  1. Sallamaaria Kettunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulla Lantto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Petri Koivunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terhi Tapiainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matti Uhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marjo Renko
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KS collected the data on the controls, participated in the analyses of the data, and wrote the first draft of the manuscript. UL collected the data on the cases and revised the manuscript. PK participated in the study design and revised the manuscript. TT participated in the analyses of the data and revised the manuscript. MU participated in the study design and revised the manuscript. MR participated in the study design, performed data analyses, and supervised drafting and revising the manuscript. All authors interpreted the data, contributed to the intellectual content, reviewed the manuscript, and approved the final version of the manuscript as submitted.

Corresponding author

Correspondence to Marjo Renko.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent and ethical approval

This study was approved by the ethical committee of Northern Osthrobothnia Hospital District. Informed consent was obtained from the subjects, guardians, or both, depending on the age of the subjects.

Additional information

Communicated by Nicole Ritz

Revisions received: 3 May 2018 / 4 May 2018

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kettunen, S., Lantto, U., Koivunen, P. et al. Risk factors for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a case-control study. Eur J Pediatr 177, 1201–1206 (2018). https://doi.org/10.1007/s00431-018-3175-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-018-3175-1

Keywords

Search

Navigation