Top

Current Allergy and Asthma Reports

Published in:

01-05-2017 | Pediatric Allergy and Immunology (W Dolen, Section Editor)

Chronic Candidiasis in Children

Authors: Laura Green, William K. Dolen

Published in: Current Allergy and Asthma Reports | Issue 5/2017

Abstract

Purpose of Review

Healthy children may develop candidal infections as the result of exposure to antibiotics or corticosteroids, but chronic candidiasis in children after the newborn period is unusual. Chronic mucocutaneous candidiasis (CMC) refers to a group of conditions characterized by recurrent or persistent infections with Candida species, particularly Candida albicans. CMC is a phenotype observed in a spectrum of immunologic disorders, some with endocrinologic and autoimmune features.

Recent Findings

CMC can arise secondary to inherited or acquired T cell deficiencies, but in children is largely due to inborn errors impairing the dectin pathway and IL-17 immunity. We review the current understanding of the pathogenesis of chronic mucocutaneous candidiasis and discuss the immunologic pathways by which the immune system handles Candida. We highlight the historical and recent knowledge of CMC in children, emphasizing recent insights into basic science aspects of the dectin pathway, IL-17 signaling, consequences of AIRE gene defects, and clinical aspects of inheritance, and features that distinguish the different syndromes.

Summary

The clinical phenotype of CMC has many underlying genetic causes. Genetic testing is required for definitive diagnosis.

Greenberg RG, Benjamin Jr DK. Neonatal candidiasis: diagnosis, prevention, and treatment. The Journal of Infection. 2014;69(Suppl 1):S19–22. doi:10.1016/j.jinf.2014.07.012.CrossRefPubMedPubMedCentral

Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361(18):1727–35. doi:10.1056/NEJMoa0810719.CrossRefPubMedPubMedCentral

Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J. 2001;20(2):197–206.CrossRefPubMed

Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science (New York, NY). 2011;332(6025):65–8. doi:10.1126/science.1200439.CrossRef

Online Mendelian Inheritance in Man, OMIM®. [database on the Internet]. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Available from: https://omim.org. Accessed: April 2017.

•• Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R, et al. The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-function mutations in STAT1. J Clin Immunol. 2016;36(1):73–84. doi:10.1007/s10875-015-0214-9. STAT1 gain of function mutations are the most common cause of inherited CMC. CrossRefPubMed

Hernandez-Santos N, Gaffen SL. Th17 cells in immunity to Candida albicans. Cell Host Microbe. 2012;11(5):425–35. doi:10.1016/j.chom.2012.04.008.CrossRefPubMedPubMedCentral

Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8(1):31–8. doi:10.1038/ni1408.CrossRefPubMed

Whibley N, Jaycox JR, Reid D, Garg AV, Taylor JA, Clancy CJ, et al. Delinking CARD9 and IL-17: CARD9 protects against Candida tropicalis infection through a TNF-alpha-dependent, IL-17-independent mechanism. Journal of Immunology (Baltimore, Md: 1950). 2015;195(8):3781–92. doi:10.4049/jimmunol.1500870.CrossRef

10.

• Lanternier F, Mahdaviani SA, Barbati E, Chaussade H, Koumar Y, Levy R, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol. 2015;135(6):1558–68 e2. doi:10.1016/j.jaci.2014.12.1930. Patients with invasive candidiasis may warrant CARD9 sequencing. CrossRefPubMedPubMedCentral

11.

Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013;369(18):1704–14. doi:10.1056/NEJMoa1208487.CrossRefPubMedPubMedCentral

12.

Wang X, Wang W, Lin Z, Wang X, Li T, Yu J, et al. CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies. J Allergy Clin Immunol. 2014;133(3):905–8 e3. doi:10.1016/j.jaci.2013.09.033.CrossRefPubMed

13.

• Alves de Medeiros AK, Lodewick E, Bogaert DJ, Haerynck F, Van Daele S, Lambrecht B, et al. Chronic and invasive fungal infections in a family with CARD9 deficiency. J Clin Immunol. 2016;36(3):204–9. doi:10.1007/s10875-016-0255-8. Patients with chronic or invasive candidiasis may warrant CARD9 sequencing. CrossRefPubMed

14.

Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol. 2012;12(6):616–22. doi:10.1097/ACI.0b013e328358cc0b.CrossRefPubMedPubMedCentral

15.

Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48. doi:10.1084/jem.20110958.CrossRefPubMedPubMedCentral

16.

•• Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64. doi:10.1182/blood-2015-11-679902. STAT1 gain of function mutations not only cause CMC, but also autoimmunity, carcinomas, and aneurysms. CrossRefPubMedPubMedCentral

17.

Dhalla F, Fox H, Davenport EE, Sadler R, Anzilotti C, van Schouwenburg PA, et al. Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility. Clin Exp Immunol. 2016;184(2):216–27. doi:10.1111/cei.12746.CrossRefPubMedPubMedCentral

18.

Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34. doi:10.1016/j.jaci.2013.01.052.CrossRefPubMedPubMedCentral

19.

Kumar N, Hanks ME, Chandrasekaran P, Davis BC, Hsu AP, Van Wagoner NJ, et al. Gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation-related primary immunodeficiency is associated with disseminated mucormycosis. J Allergy Clin Immunol. 2014;134(1):236–9. doi:10.1016/j.jaci.2014.02.037.CrossRefPubMedPubMedCentral

20.

Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science (New York, NY). 2015; 349(6248):606–613. doi:10.1126/science.aaa4282.

21.

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–89. doi:10.1146/annurev-immunol-030409-101212.CrossRefPubMedPubMedCentral

22.

•• Levy R, Okada S, Beziat V, Moriya K, Liu C, Chai LY, et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc Natl Acad Sci U S A. 2016;113(51):E8277–E85. doi:10.1073/pnas.1618300114. This is a report of 21 patients, providing extensive clinical and laboratory details. CrossRefPubMed

23.

Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med. 2015;212(5):619–31. doi:10.1084/jem.20141065.CrossRefPubMedPubMedCentral

24.

Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39(4):676–86. doi:10.1016/j.immuni.2013.09.002.CrossRefPubMed

25.

Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010;129(3):311–21. doi:10.1111/j.1365-2567.2009.03240.x.CrossRefPubMedPubMedCentral

26.

Davis SD, Schaller J, Wedgwood RJ. Job’s syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet (London, England). 1966;1(7445):1013–5.CrossRef

27.

Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972;49(1):59–70.PubMed

28.

Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin N Am. 2008;28(2):277–91, viii. doi:10.1016/j.iac.2008.01.005.CrossRef

29.

Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361(21):2046–55. doi:10.1056/NEJMoa0905506.CrossRefPubMedPubMedCentral

30.

Su HC. Dedicator of cytokinesis 8 (DOCK8) deficiency. Curr Opin Allergy Clin Immunol. 2010;10(6):515–20. doi:10.1097/ACI.0b013e32833fd718.CrossRefPubMedPubMedCentral

31.

Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC, Glocker C, et al. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015;136(2):402–12. doi:10.1016/j.jaci.2014.12.1945.CrossRefPubMedPubMedCentral

32.

Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17(4):393–8. doi:10.1038/ng1297-393.CrossRefPubMed

33.

Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322(26):1829–36. doi:10.1056/nejm199006283222601.CrossRefPubMed

34.

• Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35(5):463–78. doi:10.1007/s10875-015-0176-y. This recent review describes pathophysiology and clinical features of APECED/APS-1. CrossRefPubMed

35.

Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843–50. doi:10.1210/jc.2005-2611.CrossRefPubMed

36.

•• Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y, Kämer J, et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell. 2016;166:582–95. The autoantibody repertoire formed in APECED/APS1 patients can be beneficial in some patients. CrossRefPubMedPubMedCentral

37.

•• Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. Clinical & Translational Immunology. 2016;5(12):e114. doi:10.1038/cti.2016.71. This is a review of abnormalities in IL-17 signaling that cause CMC. CrossRef

38.

Good R. Agammaglobulinemia: a provocative experiment of nature. Bull University Minn Hosp Minn Med Fdn. 1954;26:1–19.

Title: Chronic Candidiasis in Children
Authors: Laura Green
William K. Dolen
Publication date: 01-05-2017
Publisher: Springer US
Published in: Current Allergy and Asthma Reports / Issue 5/2017
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI: https://doi.org/10.1007/s11882-017-0699-9

At a glance: The STEP trials

Springer Medicine

Chronic Candidiasis in Children

Abstract

Purpose of Review

Recent Findings

Summary

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 5/2017

Microbes and the Role of Antibiotic Treatment for Wheezy Lower Respiratory Tract Illnesses in Preschool Children

Mitochondrial Function in Allergic Disease

Natural Evolution of IgE Responses to Mite Allergens and Relationship to Progression of Allergic Disease: a Review

New Perspectives on the Diagnosis of Allergy to Anisakis spp.

Eosinophilic Otitis Media: the Aftermath of Eosinophil Extracellular Trap Cell Death

The Role of Macrolides in Chronic Rhinosinusitis (CRSsNP and CRSwNP)