Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches

Main Article Content

Natalia Egri
Ana Esteve-Solé
Àngela Deyà-Martínez
Iñaki Ortiz de Landazuri
Alexandru Vlagea
AP García
Celia Cardozo
Carolina Garcia-Vidal
Clara San Bartolomé
Marta Español-Rego
L Yiyi
Xavier Bosch-Amate
J Ferrando
Jordi Yagüe
Manel Juan
Laia Alsina


candidiasis, chronic mucocutaneous candidiasis, primary immunodeficiency, IL-17, STAT1 GOF


Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.

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1. Lilic D. Unravelling fungal immunity through primary immune deficiencies. Curr Opin Microbiol. 2012;15:420–426. 10.1016/j.mib.2012.06.003

2. Puel A, Picard C, Cypowyj S, Lilic D, Abel L, Casanova JL. Inborn errors of mucocutaneus immunity to Candida albicans in humans: a role for IL-17 cytokines. Curr Opin Immunol. 2010;22(4):467–474. 10.1016/j.coi.2010.06.009

3. 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. 2016;127(25):3154–3165. 10.1182/blood-2015-11-679902

4. Puel A, Cypowyj S, Bustamante J, Wright J F, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity*. Science 2011;332: 65–68. 10.1126/science.1200439

5. Bousfiha A, Jeddane L, Picard C, Al-herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):66–81. 10.1007/s10875-020-00758-x

6. Richardson JP, Moyes DL. Adaptive immune responses to Candida albicans infection. Virulence. 2015;6(4):327–337. 10.1080/21505594.2015.1004977

7. Mihai G. Netea, Neil A.R. Gow, Carol A. Munro, Steven Bates, Claire Collins, Gerben Ferwerda, et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. 2006;116(6):1642–1650. 10.1172/JCI27114

8. Ferwerda B, Ferwerda G, Platinga TS, Willment J A, van Spriel A B, Venselaar H, et al. UKPMC Funders Group author manuscript human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361(18):1760–1767. 10.1056/NEJMoa0901053

9. Mengesha B, Conti H. The role of IL-17 in protection against mucosal Candida infections. J Fungi. 2017;3(4):52. 10.3390/jof3040052

10. Li X, Bechara R, Zhao J, McGeachy MJ, Gaffen SL. IL-17 receptor-based signaling and implications for disease. Nat Immunol. 2019;20(12):1594–1602. 10.1038/s41590-019-0514-y

11. Hernández-Santos N, Gaffen SL. Th17 cells in immunity to Candida albicans. Cell Host Microbe. 2012;11(5):425–435. 10.1016/j.chom.2012.04.008

12. Green L, Dolen WK. Chronic candidiasis in children. Curr Allergy Asthma Rep. 2017;17(5):31. 10.1007/s11882-017-0699-9.

13. Al-Shaikhly T, Ochs HD. Hyper IgE syndromes: clinical and molecular characteristics. Immunol Cell Biol. 2019;97(4):368–379. 10.1111/imcb.12209

14. Schimke LF, Sawalle-Belohradsky J, Roesler J, Wollenberg A, Rack A, Borte M, et al. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol. 2010;126(3):611.e1–617.e1. 10.1016/j.jaci.2010.06.029

15. Davidson L, Netea MG, Kullberg BJ. Patient susceptibility to candidiasis–a potential for adjunctive immunotherapy. J Fungi. 2018;4(1):9. 10.3390/jof4010009

16. Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev. 2005;203:244–250. 10.1111/j.0105-2896.2005.00228.x

17. Bergerson JRE, Freeman AF. An update on syndromes with a Hyper-IgE phenotype. Immunol Allergy Clin N Am. 2019;39:49–61. 10.1016/j.iac.2018.08.007

18. Béziat V, Li J, Lin J X, Ma C, Li P, Bousfiha A, et al. A recessive form of Hyper IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci Immunol. 2018;3(24):eaat4956. 10.1126/sciimmunol.aat4956.

19. Frans G, Moens L, Schaballie H, Eyck L V, Borgers H, Wuyts M, et al. Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding. J Allergy Clin Immunol. 2014;134(5):1209–1213. 10.1016/j.jaci.2014.05.044

20. Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J Immunol. 2014;193(10):4880–4887. 10.4049/jimmunol.1401467

21. Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov D, et al. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2017;141(2):704.e5–717.e5. 10.26226/morressier.57bc1754d462b80290b4d4d7

22. Akarcan S, Severcan E, Karaca N, Isik E, Aksu G, Migaud M, et al. Gain-of-function mutations in STAT1: a recently defined cause for chronic mucocutaneous candidiasis disease mimicking combined immunodeficiencies. Case Reports Immunol. 2017;2017:1–6. 10.1155/2017/2846928 10.1155/2017/2676403

23. Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. A biallelic ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39(4):676–686. 10.1016/j.immuni.2013.09.002

24. Jhamnani RD, Rosenzweig SD. An update on gain-of-function mutations in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2017;17(6):391–397. 10.1097/ACI.0000000000000401

25. Tabellini G, Vairo D, Scomodon O, Tamassia N, Ferraro R S, Patrizi O, et al. Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. 2017;140(2):553.e4–564.e4. 10.1016/j.jaci.2016.10.051

26. Vargas-Hernández A, Mace EM, Zimmerman O, Zerbe C, Freeman A, Rosenzweing S, et al. Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2018;141(6):2142.e5–2155.e5. 10.1016/j.jaci.2017.08.040

27. Husebye ES, Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. N Engl J Med. 2018;378(2):1132–1141. 10.1056/NEJMra1713301

28. Nwosu I, Oladiran O, Ogbonna-Nwosu C, Anyata A. Autoimmune polyglandular syndrome type 1: a case report and brief review. J Community Hosp Intern Med Perspect. 2019;9(3):252–254. 10.1080/20009666.2019.1616523

29. Zirilli G, Santucci S, Cuzzupé C, Corica D, Pitrolo E, Salzano G. Peculiarities of autoimmune polyglandular syndromes in children and adolescents. Acta Biomed 2017;88(3):271–275. 10.23750/abm.v%vi%i.5898

30. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank M M, Hsu J, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2014;136(5):1186.e78–1205.e78. 10.1016/j.jaci.2015.04.049

31. 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):619–631. 10.1084/jem.20141065

32. Carey B, Lambourne J, Porter S, Hodgson T. Chronic mucocutaneous candidiasis due to gain-of-function mutation in STAT1. Oral Dis. 2019;25(3):684–692. 10.1111/odi.12881

33. García-García A, Gereda-Martínez D, Deyà-Martínez A, Alsina L. The new scenario of primary immunodeficiencies and the role of the clinical immunologist in the specialised clinic]. An Pediatr (Barc). 2020 Feb;92(2):117-118. doi: 10.1016/j.anpedi.2019.09.006. Epub 2019 Nov 7.

34. Garcia-Prat M, Alvarez-Sierra D, Aguiló-Cucurull A, Salgado-Perandrés S, Briongos-Sebastian S, Franco-Jarava C, et al. Extended immunophenotyping reference values in a healthy pediatric extended immunophenotyping reference values in a healthy pediatric population. Cytom Part B Clin Cytom. 2019;96B:223–233. 10.1002/cyto.b.21728

35. Gavino C, Cotter A, Lichtenstein D, Lejtenyi D, Fortin C, Legault C, et al. CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy. Clin Infect Dis. 2014;59(1):81–84. 10.1093/cid/ciu215

36. Rautemaa R, Richardson M, Pfaller MA, Perheentupa J, Saxén H. Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis. Diagn Microbiol Infect Dis. 2008;62(2):182–185. 10.1016/j.diagmicrobio.2008.05.007

37. van de Veerdonk FL, Netea MG. Treatment options for chronic mucocutaneous candidiasis. J Infect. 2016;72:S56–S60. 10.1016/j.jinf.2016.04.023

38. The European Medicines Agency – EMA. Jakavi: Ficha tecnica o resumen de las caracteristicas del producto 1. Agencia Eur Medicam. 2006.

39. Bloomfield M, Kanderová V, Paračková Z, Vrabcová P, Svaton M, Fronková E, et al. Utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation. J Clin Immunol. 2018:38(5);589–601. 10.1007/s10875-018-0519-6

40. Forbes LR, Vogel TP, Cooper MA, Castro-Wagner J, Shussler E, Weinacht K, et al. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. 2018;142(5):1665–1669. 10.1016/j.jaci.2018.07.020

41. Meesilpavikkai K, Dik WA, Schrijver B, Nagtzaam N, Posthumus-van Sluijs S, van Hagen M, et al. Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1). J Allergy Clin Immunol. 2018;142(1):328.e2–330.e2. 10.1016/j.jaci.2018.02.045

42. The European Medicines Agency – EMA. Olumiant: Ficha tecnica o resumen de las caracteristicas del producto 1. Agencia Eur Medicam. 2006

43. Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629.e2–1640.e2. 10.1016/j.jaci.2016.11.022

44. Aldave JC, Cachay E, Núñez L, Chunga A, Murillo S, Cypowyj S, et al. A 1-year-old girl with a gain-of-function STAT1 mutation treated with hematopoietic stem cell transplantation. J Clin Immunol. 2013;33(8):1273–1275. 10.1007/s10875-013-9947-5