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Recurrent Fevers for the Pediatric Immunologist: It’s Not All Immunodeficiency

  • Immune Deficiency and Dysregulation (DP Huston and C Kuo, Section Editors)
  • Published:
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Abstract

Autoinflammatory diseases are disorders of the innate immune system, characterized by systemic inflammation independent of infection and autoreactive antibodies or antigen-specific T cells. Similar to immunodeficiencies, these immune dysregulatory diseases have unique presentations, genetics, and available therapies. Given the presentation of fevers, rashes, and mucosal symptoms in many of the disorders, the allergist/immunologist is the appropriate medical home for these patients: to appropriately rule out immunodeficiencies, evaluate for allergic disease, and diagnose and treat recurrent fever disorders. However, many practicing physicians are unfamiliar with the clinical presentation, diagnosis, and treatment of autoinflammatory disorders. This review will focus on understanding the signs and symptoms of classic autoinflammatory disorders, introduce newly described monogenic and polygenic disorders, and address the approach to the patient with recurrent fevers to distinguish autoinflammation from immunodeficiency and autoimmunity.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Massin MM, Montesanti J, Gerard P, Lepage P. Spectrum and frequency of illness presenting to a pediatric emergency department. Acta Clin Belg. 2006;61(4):161–5.

    Article  CAS  PubMed  Google Scholar 

  2. CDC/NCHS NHAMCS. National Hospital Ambulatory Medical Care Survey: 2011 Emergency Department Summary Tables 2011 [cited 2015]. http://www.cdc.gov/nchs/data/ahcd/nhamcs_emergency/2011_ed_web_tables.pdf

  3. Wier LM, Yu H, Owens PL, Washington R. Overview of Children in the Emergency Department, 2010: Statistical Brief #157. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville (MD) 2006. http://www.ncbi.nlm.nih.gov/pubmed/?term=Wier%20LM,%20Yu%20H,%20Owens%20PL,%20Washington%20R

  4. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Holzinger D, Kessel C, Omenetti A, Gattorno M. From bench to bedside and back again: translational research in autoinflammation. Nat Rev Rheumatol. 2015;11(10):573–85. Up-to-date review on characterization of autoinflammatory diseases, with emphasis on the importance of ex vivo and in vitro studies in the development of novel therapeutics.

    Article  CAS  PubMed  Google Scholar 

  6. Consortium IF. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90(4):797–807.

    Article  Google Scholar 

  7. Cuisset L, Drenth JP, Berthelot JM, Meyrier A, Vaudour G, Watts RA, et al. Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44. Am J Hum Genet. 1999;65(4):1054–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22(2):178–81.

    Article  CAS  PubMed  Google Scholar 

  9. French FMFC. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25–31.

    Article  Google Scholar 

  10. Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66(5):1693–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22(2):175–7.

    Article  CAS  PubMed  Google Scholar 

  12. McDermott MF, Aganna E, Hitman GA, Ogunkolade BW, Booth DR, Hawkins PN. An autosomal dominant periodic fever associated with AA amyloidosis in a north Indian family maps to distal chromosome 1q. Arthritis Rheum. 2000;43(9):2034–40.

    Article  CAS  PubMed  Google Scholar 

  13. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–44.

    Article  CAS  PubMed  Google Scholar 

  14. McDermott MF, Ogunkolade BW, McDermott EM, Jones LC, Wan Y, Quane KA, et al. Linkage of familial Hibernian fever to chromosome 12p13. Am J Hum Genet. 1998;62(6):1446–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. 1998;351(9103):659–64.

    Article  CAS  PubMed  Google Scholar 

  16. Hull KM, Drewe E, Aksentijevich I, Singh HK, Wong K, McDermott EM, et al. The TNF receptor- associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore). 2002;81(5):349–68.

    Article  CAS  Google Scholar 

  17. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108(4):615–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, et al. Hearing loss in Muckle-Wells syndrome. Arthritis Rheum. 2013;65(3):824–31.

    Article  CAS  PubMed  Google Scholar 

  20. Hashkes PJ, Lovell DJ. Recognition of infantile-onset multisystem inflammatory disease as a unique entity. J Pediatr. 1997;130(4):513–5.

    CAS  PubMed  Google Scholar 

  21. Prieur AM, Griscelli C, Lampert F, Truckenbrodt H, Guggenheim MA, Lovell DJ, et al. A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol Suppl. 1987;66:57–68.

    Article  CAS  PubMed  Google Scholar 

  22. Hill SC, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R. Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol. 2007;37(2):145–52.

    Article  PubMed  Google Scholar 

  23. Obici L, Merlini G. Amyloidosis in autoinflammatory syndromes. Autoimmun Rev. 2012;12(1):14–7.

    Article  CAS  PubMed  Google Scholar 

  24. Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol. 2015;10:395–424. Review of autoinflammation at the molecular level.

    Article  CAS  PubMed  Google Scholar 

  25. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold- associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364(9447):1779–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, Wittkowski H, Bialkowski A, Tzaribachev N, et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum. 2011;63(3):840–9.

    Article  PubMed  Google Scholar 

  28. Hoffman HM. Therapy of autoinflammatory syndromes. J Allergy Clin Immunol. 2009;124(6):1129–38.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223–44. Overview of the critical role for IL-1 in autoinflammation.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6. First description of patients with mutations in NLRC4 (with Romberg et al.).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46(10):1135–9. First description of patients with mutations in NLRC4 (with Canna et al.).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K. An inherited mutation in NLRC4 causes autoinflammation in human and mice. J Exp Med. 2014;211(12):2385–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360(23):2438–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Brau-Javier CN, Gonzales-Chavez J, Toro JR. Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra. Arch Dermatol. 2012;148(3):301–4.

    Article  PubMed  Google Scholar 

  36. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365(7):620–8.

    Article  CAS  PubMed  Google Scholar 

  37. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011;89(3):432–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Rossi-Semerano L, Piram M, Chiaverini C, De Ricaud D, Smahi A, Kone-Paut I. First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra. Pediatrics. 2013;132(4):e1043–7.

    Article  PubMed  Google Scholar 

  39. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18. First description of SAVI syndrome.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendinez F, Hernandez A, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol. 2010;62(3):489–95.

    Article  PubMed  Google Scholar 

  41. Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64(3):895–907.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, et al. 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(17):7148–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. 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.

    Article  PubMed  Google Scholar 

  46. Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 2010;99(2):178–84.

    CAS  PubMed  Google Scholar 

  47. Lierl MB. Efficacy of montelukast for treatment of periodic fever with aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). J Allergy Clin Immunol. 2008;121(2 (Suppl 1)):S228.

    Article  Google Scholar 

  48. 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. 2014;9:CD008669. Cochrane review discussing role of tonsillectomy in PFAPA syndrome.

    PubMed  Google Scholar 

  49. Garavello W, Romagnoli M, Gaini RM. Effectiveness of adenotonsillectomy in PFAPA syndrome: a randomized study. J Pediatr. 2009;155(2):250–3.

    Article  PubMed  Google Scholar 

  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(11):1203–8.

    Article  PubMed  Google Scholar 

  51. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cgamma2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012;91(4):713–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med. 2012;366(4):330–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Aksentijevich I, D Putnam C, Remmers EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56(4):1273–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol. 2012;13(12):1178–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001;27(3):277–85.

    Article  CAS  PubMed  Google Scholar 

  57. Nilsson J, Schoser B, Laforet P, Kalev O, Lindberg C, Romero NB, et al. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann Neurol. 2013;74(6):914–9.

    Article  CAS  PubMed  Google Scholar 

  58. Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015;212(6):939–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–31. First description of patients with ADA2 deficiency (with Zhou et al.).

    Article  PubMed  Google Scholar 

  60. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911–20. First description of patients with ADA2 deficiency (with Navon et al.).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Chan B, Wara D, Bastian J, Hershfield MS, Bohnsack J, Azen CG, et al. Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Clin Immunol. 2005;117(2):133–43.

    Article  CAS  PubMed  Google Scholar 

  62. Alkhateeb A, Jarun Y, Tashtoush R. Polymorphisms in NLRP1 gene and susceptibility to autoimmune thyroid disease. Autoimmunity. 2013;46(3):215–21.

    Article  CAS  PubMed  Google Scholar 

  63. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356(12):1216–25.

    Article  CAS  PubMed  Google Scholar 

  64. Zurawek M, Fichna M, Januszkiewicz-Lewandowska D, Gryczynska M, Fichna P, Nowak J. A coding variant in NLRP1 is associated with autoimmune Addison’s disease. Hum Immunol. 2010;71(5):530–4.

    Article  CAS  PubMed  Google Scholar 

  65. Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, et al. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1beta processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A. 2013;110(8):2952–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Magitta NF, Boe Wolff AS, Johansson S, Skinningsrud B, Lie BA, Myhr KM, et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison’s disease and type 1 diabetes. Genes Immun. 2009;10(2):120–4.

    Article  CAS  PubMed  Google Scholar 

  67. Dieude P, Guedj M, Wipff J, Ruiz B, Riemekasten G, Airo P, et al. NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis. Ann Rheum Dis. 2011;70(4):668–74.

    Article  CAS  PubMed  Google Scholar 

  68. Pontillo A, Vendramin A, Catamo E, Fabris A, Crovella S. The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease. Am J Gastroenterol. 2011;106(3):539–44.

    Article  CAS  PubMed  Google Scholar 

  69. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Kopfnagel V, Wittmann M, Werfel T. Human keratinocytes express AIM2 and respond to dsDNA with IL-1beta secretion. Exp Dermatol. 2011;20(12):1027–9.

    Article  CAS  PubMed  Google Scholar 

  71. Zhang W, Cai Y, Xu W, Yin Z, Gao X, Xiong S. AIM2 facilitates the apoptotic DNA-induced systemic lupus erythematosus via arbitrating macrophage functional maturation. J Clin Immunol. 2013;33(5):925–37.

    Article  PubMed  Google Scholar 

  72. Dombrowski Y, Peric M, Koglin S, Kammerbauer C, Goss C, Anz D, et al. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci Transl Med. 2011;3(82):82ra38.

    Article  PubMed Central  PubMed  Google Scholar 

  73. Ciccia F, Accardo-Palumbo A, Alessandro R, Alessandri C, Priori R, Guggino G, et al. Interleukin-36alpha axis is modulated in patients with primary Sjogren’s syndrome. Clin Exp Immunol. 2015;181(2):230–8.

    Article  CAS  PubMed  Google Scholar 

  74. Baldini C, Rossi C, Ferro F, Santini E, Seccia V, Donati V, et al. The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjogren’s syndrome. J Intern Med. 2013;274(5):480–9.

    Article  CAS  PubMed  Google Scholar 

  75. Norheim KB, Harboe E, Goransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary Sjogren’s syndrome—a double blind, randomised clinical trial. PLoS One. 2012;7(1):e30123.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Kallinich T, Gattorno M, Grattan CE, de Koning HD, Traidl-Hoffmann C, Feist E, et al. Unexplained recurrent fever: when is autoinflammation the explanation? Allergy. 2013;68(3):285–96.

    Article  CAS  PubMed  Google Scholar 

  77. Long SS. Distinguishing among prolonged, recurrent, and periodic fever syndromes: approach of a pediatric infectious diseases subspecialist. Pediatr Clin N Am. 2005;52(3):811–35. vii.

    Article  Google Scholar 

  78. Gattorno M, Sormani MP, D’Osualdo A, Pelagatti MA, Caroli F, Federici S, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum. 2008;58(6):1823–32.

    Article  CAS  PubMed  Google Scholar 

  79. Nield LS, Fever, Kamat K. In: Kliegman RM, Stanton B, St. Geme J, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics 20th ed. Philadelphia: Elsevier; 2015. eBook.

  80. Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res. 2004;10(4):201–22.

    CAS  PubMed  Google Scholar 

  81. Padeh S, Livneh A, Pras E, Shinar Y, Lidar M, Feld O, et al. Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr. 2010;156(6):985–9.

    Article  PubMed  Google Scholar 

  82. Lankisch P, Schiffner J, Ghosh S, Babor F, Borkhardt A, Laws HJ. The Duesseldorf warning signs for primary immunodeficiency: is it time to change the rules? J Clin Immunol. 2015;35(3):273–9. Prospective study comparing three established sets of symptoms warning signs, to a newly proposed set, emphasizing need for improved, and earlier selection of patients needing specialty care.

    Article  CAS  PubMed  Google Scholar 

  83. Soylemezoglu O, Arga M, Fidan K, Gonen S, Emeksiz HC, Hasanoglu E, et al. Unresponsiveness to colchicine therapy in patients with familial Mediterranean fever homozygous for the M694V mutation. J Rheumatol. 2010;37(1):182–9.

    Article  CAS  PubMed  Google Scholar 

  84. Drewe E, Huggins ML, Morgan AG, Cassidy MJ, Powell RJ. Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford). 2004;43(11):1405–8.

    Article  CAS  Google Scholar 

  85. Drewe E, McDermott EM, Powell PT, Isaacs JD, Powell RJ. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology (Oxford). 2003;42(2):235–9.

    Article  CAS  Google Scholar 

  86. Hull KM, Aksentijevich I, Singh HK. Efficacy of etanercept for the treatment of patients with TNF receptor-associated periodic syndrome (TRAPS). Arthritis Rheum. 2002;46:S378(abst).

    Article  Google Scholar 

  87. Bodar EJ, Drenth JP, Simon A, van der Meer JW. A Dutch family with the hereditary periodic fever or tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Ned Tijdschr Geneeskd. 2007;151(14):836–7.

    CAS  PubMed  Google Scholar 

  88. Nedjai B, Hitman GA, Quillinan N, Coughlan RJ, Church L, McDermott MF, et al. Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2009;60(2):619–25.

    Article  CAS  PubMed  Google Scholar 

  89. Delevaux I, Andre M, Colombier M, Albuisson E, Meylheuc F, Begue RJ, et al. Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis. 2003;62(4):337–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Yazgan H, Keles E, Yazgan Z, Gebesce A, Demirdoven M. C-reactive protein and procalcitonin during febrile attacks in PFAPA syndrome. Int J Pediatr Otorhinolaryngol. 2012;76(8):1145–7.

    Article  PubMed  Google Scholar 

  91. Yoshihara T, Imamura T, Yokoi K, Shibata M, Kano G, Osone S, et al. Potential use of procalcitonin concentrations as a diagnostic marker of the PFAPA syndrome. Eur J Pediatr. 2007;166(6):621–2.

    Article  PubMed  Google Scholar 

  92. Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009;30(6):875–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Ben-Chetrit E. Familial Mediterranean fever (FMF) and renal AA amyloidosis—phenotype-genotype correlation, treatment and prognosis. J Nephrol. 2003;16(3):431–4.

    CAS  PubMed  Google Scholar 

  94. Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, et al. MEFV-Gene analysis in Armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet. 1999;65(1):88–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, et al. MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid. 1999;6(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  96. Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, Caorsi R, et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 2011;63(3):830–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63(11):3625–32. First description of somatic mosaicism in NOMID patients, underscoring ongoing issues in genetic testing of patients.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Rowczenio D, Omoyinmi E, Trojer H, Lane T, Brogan P, Hawkins P, et al. First case of somatic mosaicism in TRAPS caused by a novel 24 nucleotides deletion in the TNFRSF1A gene. Pediatr Rheumatol Online J. 2015;13 Suppl 1:O60.

    Article  PubMed Central  Google Scholar 

  99. Broderick L, Kastner DL, Hoffman HM. Recurrent Fever Syndromes. In: Ochs HD, Smith CIE, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 3rd ed. NewYork: Oxford University Press; 2013. p. 414–7.

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Acknowledgments

Dr. Broderick has received grant support from NIH NICHD 5K08HD075830 (current), Arthritis National Research Foundation (current), and previously from The Hartwell Foundation, Thrasher Research Fund, A.P. Giannini Foundation.

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  1. Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of California, San Diego, 9500 Gilman Dr. MC 0760, La Jolla, CA, 92093, USA

    Lori Broderick

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  1. Lori Broderick
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Correspondence to Lori Broderick.

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Conflicts of Interest

Dr. Broderick reports grants from NIH/NICHD, The Hartwell Foundation, Thrasher Research Fund, A.P. Giannini Foundation, Arthritis National Research Foundation, and personal fees from SOBI. She has participated in an advisory board for SOBI, Inc.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Immune Deficiency and Dysregulation

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Broderick, L. Recurrent Fevers for the Pediatric Immunologist: It’s Not All Immunodeficiency. Curr Allergy Asthma Rep 16, 2 (2016). https://doi.org/10.1007/s11882-015-0578-1

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