Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment

Abstract

Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.

Candida species are the most common causative pathogen of fungal infections that can range from superficial (mucosal and cutaneous) and isolated disease to systemic involvement.¹

Among them, Candida albicans is mainly responsible for chronic mucocutaneous candidiasis (CMC), a disease characterized by recurrent or persistent infections of nails, skin, mouth, and genital organs.²

Candida infections are very common in adults and children and can appear in different settings, such as transient alterations of the normal flora or immune dysregulation in healthy individuals,³ in very or extremely low birth weight preterm babies⁴ or in case of diabetes.⁵

Primary [inborn errors of immunity(IEI)] or secondary (HIV or lymphoproliferative diseases) impairment of the immune system should be suspected in case of invasive or chronic Candida infections.⁶

Recent advances in genetics through an enhancement of next-generation sequencing techniques led to the discovery of new genes and improved the knowledge of the mechanisms involved in human host defense against fungi.⁷

Immune responses against Candida consist of both innate and adaptive immunity.⁸ Defects along these pathways can cause immune system diseases presenting with CMC (CANDF 1–9) as the only or the main clinical manifestation. However, CMC can be part of a broader spectrum of infectious manifestations and noninfectious comorbidities, as in the case of complex diseases such as Hyper-IgE syndromes (HIES) and the autoimmune polyendocrinopathy type 1/autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APS-1/APECED).⁹ These diseases are caused by a prevalent impairment of Th17 lymphocytes and can be classified into defects in Candida recognition, alterations in Interleukin (IL)-17 production or IL-17-mediated signaling pathway, and defects in Th17 cell development or function.

Other defects of the adaptive immune response, including severe combined immunodeficiencies (SCIDs), isolated CD4+ lymphopenia and DiGeorge syndrome (DGS), may present with mucocutaneous and invasive Candida infections, among other infectious manifestations they are predisposed to. Such susceptibility is caused by the lack of T lymphocytes, especially Th17.^10–12

Alterations in the number and function of neutrophils, as in the case of isolated neutropenia and chronic granulomatous disease (CGD) can present with local and systemic candida infections, because of a reduced or absent clearance in Candida infections.¹³

This review describes the most common IEI presenting with CMC by analyzing the pathogenetic mechanism predisposing to the development of Candida for each genetic disease, the main laboratory alterations and diagnostic strategies, and the novel treatment approaches to candida infections.

DEFECTS IN CANDIDA RECOGNITION

The innate response involves the recognition of pathogen-associated molecular patterns (PAMPs) by recognition receptors (PRRs) expressed on various cells of the innate immune system, inducing, in response to the binding of Candida albicans, the production of pro- and anti-inflammatory cytokines. Such PRRs include toll-like receptors (TLRs) 1-4, as well as other receptors, such as the macrophage-inducible Ca2+-dependent lectin receptor (mincle) and dectins 1-3. Specifically, TLRs 2 and 4 and dectin-2 recognize the outer portion of the C. albicans cell wall, while dectin-1, expressed on phagocytes, and mincle recognize β-glucans in the inner portion of the cell wall.¹⁴

Signals resulting from the binding of these receptors lead to downstream activation of nuclear factor-kB (NF-kB) through the adaptor protein MyD88 and activation of the caspase recruitment domain-containing protein 9 (CARD9)/B-cell leukemia-lymphoma 10 (BCL10)/mucosal-associated lymphoid tissue 1 (MALT1) complex.¹⁵ The downstream effect of NF-kB activation in phagocytes is the production of proinflammatory cytokines, including IL-1β, IL-6 and IL-23.¹⁶ For each disease, gene defect, type of inheritance, clinical manifestations and associated laboratory alterations are reported in Table 1.

TABLE 1.

Characteristics of the Main Diseases Predisposing CMC

Type of Defect	Disease	Mutated Gene/Inheritance	Laboratory Alterations	Clinical Manifestations
Defects in Candida recognition	CANDF4 (dectin-1 deficiency)	CLEC7A/AR	Functional defects in the cytokine production (including IL-17) after Candida or β-glucan stimulus	Recurrent vulvo-vaginal candidiasis and onychomycosis. Dectin-1 deficiency however did not impair Candida phagocytosis and killing, for the existence of alternative receptors for phagocytosis of yeasts.19 Moreover, defects in the Dectin pathway are not associated with endocrinopathy or other complications.
	CANDF2	CARD9/AR	High eosinophil and IgE levels; possible low Igs, memory B cells, percentage elevation of central memory (CM) CD8+ cells and decreased CD8+ TEMRA and altered T-cell to Candida17,18	Patients are prone to develop both mucocutaneous and invasive fungal diseases, in particular, CNS (ie, meningoencephalitis),20–22 bones, gut and lymph nodes.23,24 In addition, these patients may develop deep dermatophytosis with alteration initially of the nails and epidermis and subsequent invasion of the dermis up to organ dissemination.25 Spontaneous candidiasis of the CNS should pose suspicion of CARD9 deficiency. Besides Candida infections, invasive extrapulmonary aspergillosis has been described too, but no bacterial and viral or noninfective complications were reported.26
	CANDF1 and CANDF 3	Unknown/AD (https://www.omim.org/entry/114580).	None	Early onset with nail candidiasis, associated with a quantitative deficiency of intracellular adhesion molecule 1 (ICAM-1). Possible associated thyroid disease in CANDF1.
Defects in the production or signaling pathway of IL-17	CANDF9	IL17RC/AR	None	Isolated CMC28
	CANDF6	IL-17F/AD	None	Isolated CMC27
	CANDF527 (Immunodeficiency 51)	IL-17RA/AR	In some cases of CANDF5, impaired antibody response	CMC in the first 6 months of life, affecting the skin (intertrigo), the scalp, mucosal sites (oral thrush, anogenital candidiasis), or nails and later staphylococcal skin infections (mainly dermatitis and blepharitis). Some have recurrent respiratory tract infections.29 Only 1 family was described as having in 1 case hyperthyroidism and another asthma.30
	CANDF8 (ACT1 deficiency)	TRAF3IP2/AR	None	Several cases with early onset CMC. Different kinds of eczema, recurrent, S. aureus blepharitis, aphtous stomatitis, recurrent wheezing, recurrent pneumonia and bronchiectasis, recurrent parotitis and marked reactions to insect bites were described in the patients reported.31–35
Defects in the development and function of Th17	CANDF7	STAT1 GOF/AD	Possible lymphopenia, with reduced levels of CD4+ and memory B cells, low Th17 levels, impaired B, T and NK cell function, increase in STAT1 phosphorylation36–38	CMC, invasive candidiasis, histoplasmosis and coccidiomycosis or disseminated mucormycosis, dermatophytosis of the head, skin and nails caused by Trichophyton or Microsporon sp, recurrent bacterial respiratory tract infections, recurrent viral infections by herpes simplex virus, varicella zoster, coxsackie virus, cytomegalovirus and Epstein-Barr virus, autoimmunity, malignancy, aneurisms.55–61
	APS-1/APECED	AIRE/AR and AD	Different types of autoantibodies, anticytokine IL-17 autoantibodies39,40	Classic triad of CMC, hypoparathyroidism, and adrenal insufficiency (Addison’s disease). CMC (onset in most cases, usually with nails and oral cavity), autoimmune endocrinopathy in almost all patients (hypoparathyroidism and adrenal insufficiency, gonadal failure, chronic hepatitis, pernicious anemia, thyroiditis, type I diabetes, and pituitary dysfunction), ectodermal alterations. Bacterial and viral infections mainly of the upper and lower respiratory tract.62–66
	STAT3 deficiency (AD-HIES)	STAT3 LOF/AD	High eosinophil and IgE levels (typically >2000 IU/ml); low or absent Th17, possible reduced levels of memory B and T cells and impairment of their function.41–48 In most patients, plasma cell and serum immunoglobulin levels are in the normal range.47,48	Recurrent bacterial and fungal infections (mainly of the skin and lungs), dysmorphisms, retention of deciduous teeth, musculoskeletal and connective tissue abnormalities, including the development of aneurysms.
	DOCK8 deficiency (AR-HIES)	DOCK8/AR	High eosinophil and IgE levels; possible lymphopenia and impairment of the T and B-cell number and function, possible declining IgM levels49–51	Typical clinical HIES characteristics such as eczema and a failure to clear infections, mainly respiratory and cutaneous. Unlike patients with AD-HIES, there is increased susceptibility to viral infections (ie, herpes simplex, varicella zoster, human papilloma and molluscum contagiosum),49,51 connective tissue and skeletal disorders are not found in these cases, but an immune dysregulation phenotype is present, consisting of severe allergic disorders, such as asthma and food allergies, and the development of malignancy in young age.50
		ZNF341 LOF	Impaired production of Th17 cells52	Clinically similar to HIES with STAT3 LOF but with stronger inflammatory responses and milder nonimmunological manifestations.52
		TYK2 LOF	Impaired production of Th17 cells52	Increased risk of viral, fungal (including C. albicans) and mycobacterial infections.67
		Phosphoglucomutase 3 (PGM3) deficiency	Leukopenia, low CD8+ T cells and CD27+ memory B cells, high IgE, IgG, and IgA.53 Normal numbers of Th17 cells.	Severe atopy, recurrent infections, autoimmunity, vasculitis, renal failure, lymphoma, motor and neurocognitive impairment.53
		CARD11 LOF	Absent treg cells, and reduced memory B cells, pan-hypogammaglobulinemia, impaired T-cell proliferation and antibody response. Normal numbers of Th17 cells.54	Combined immunodeficiency associated with severe viral and fungal infections, severe atopy and immune dysregulation.54
	RORC deficiency	RORC/AR	T cell lymphopenia; impaired production of IL-17, IL-17F, IL-22 and IFNγ	Early onset CMC with different levels of severity, thymic and lymph node hypoplasia, and mycobacteriosis.
Miscellanea (Combined immunodeficiencies; numeric and functional alterations of the neutrophils)	CGD	CYBB (gp91phox) or NCF1 (p47phox) LAD-1		Fungal infections, mostly with invasive aspergillosis and in some cases also candidiasis, fungal and bacterial abscesses, of different organs, autoimmunity, and inflammatory disease.
	Leukocyte adhesion deficiencies (LADs)			Usually present in early childhood with delayed cord drop and omphalitis, later they may develop severe and recurrent bacterial skin and soft tissue infections and periodontitis, while a minority of patients develop invasive Candida and Aspergillus infections.68,69
	Severe congenital neutropenia syndromes (SCN)	ELANE and HAX1		The duration and severity of neutropenia are directly related to the risk of infection, typically by Streptococci or Staphylococci, but invasive Candida and Aspergillus infections have also been reported.70–72
	CID, SCID and idiopathic CD4+ lymphopenia,	Different genes		Different degree of bacterial and viral infections, some patients have been reported to develop CMC in childhood and invasive candidiasis. Possible autoimmunity and malignancy.73

ACT indicates activator; AD, autosomal dominant; AIRE, autoimmune regulator; APS-1/APECED, autoimmune polyendocrinopathy type 1/autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy AR, autosomal recessive; CANDF, familiar candidiasis; CGD, chronic granulomatous disease; CID, combined immune deficiency; CMC, chronic mucocutaneous candidiasis; CNS, central nervous system; DGS, DiGeorge syndrome; GOF, gain-of-function; IL, interleukin; LOF, loss-of-function; LAD-1, adhesion leukocyte deficiency type 1; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; Th, T helper; TRAF, tumor necrosis factor receptor-associated factor.

Dectin-1 Deficiency (CANDF4)

Homozygous mutations in the CLEC7A (dectin-1) gene cause a reduction in the expression of the dectin-1 receptor, whose role is to link to the β-glucan of the fungal cell wall.^16,19

CARD9 Deficiency (CANDF2)

CARD9 is a molecule whose role is particularly important in the signaling of dectin-1 and 2.⁷⁴

Autosomal recessive mutations in CARD9 lead to final defects in cytokine production, important for the differentiation of Th17¹⁵ and for the recruitment of neutrophils in the infection site, impairing their intracellular killing ability.^74,75 Biallelic loss-of-function (LOF) mutations in the CARD11/BCL10/MALT1 (CBM) complex, that affect CARD9 function have been recently reported as responsible for a particular form of combined immunodeficiency also presenting with CMC.^76,77

CANDF1 and 3

CANDF1 and CANDF3 are a type of familial chronic mucocutaneous candidiasis, whose genes are not still identified but whose pedigree analysis suggests autosomal dominant inheritance.⁷⁸

DEFECTS IN THE PRODUCTION OR SIGNALING PATHWAY OF IL-17

The adaptive immune system also plays a significant role in the antifungal response.⁷⁹ The proinflammatory cytokines produced after NF-kB activation bind to naïve CD4+ T cells via the Janus kinase family receptors and activate signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), leading to retinoic acid receptor-related orphan receptor (RORgT)-mediated transcription of genes coding for additional cytokines such as IL-17A, IL-17F and IL-21 by lymphocytes. These cytokines allow the differentiation of naïve CD4+ T cells into T helper (Th) 17 cells, which in turn produce IL-17 and IL-22, essential in defense against fungal pathogens.⁷³

Th17 cells are characterized by the production of IL-17A and F, whose signal, via the IL-17RA/RC heterodimer, stimulates the downstream formation of activator (ACT) 1-tumor necrosis factor receptor-associated factor 6, which leads to NF-kB activation and downstream gene expression, thereby promoting mucocutaneous antifungal immunity.⁸⁰

Autosomal recessive mutations in the genes encoding for IL-17RA (CANDF5), ACT1 (CANDF8) and IL-17RC (CANDF9) and autosomal dominant mutations in the genes for IL-17F (CANDF6) are rare and cause Th17 dysfunction.

CMC is observed in all these defects (Table 1); however, subjects with IL-17RA and ACT1 mutations also have a predisposition to staphylococcal infections, such as dermatitis and blepharitis.⁸¹

DEFECTS IN THE DEVELOPMENT OR FUNCTION OF TH17

Some monogenic disorders that alter Th17 development and function lead to the development of fungal infections, including CMC, as well as a spectrum of infectious and noninfectious symptoms involving various organs. The most common disorders are the gain-of-function (GOF) mutation of STAT1, APS-1/APECED syndrome and Hyper IgE syndromes (Table 1).

STAT-1 GOF Disease (CANDF7)

This disease also referred to as CANDF7, was first identified in 2011 as an autosomal dominant cause of CMC.⁸² Indeed, upon interferon (IFN) stimulation, STAT1 translocates into the nucleus and induces transcription of genes, such as RORgT, that play an important role in defense against pathogens, including fungi, as it is essential for the lymphoid organogenesis and thymopoiesis. GOF mutations cause hyperphosphorylation of STAT1 and accumulation of the phosphorylated protein in the nucleus, increasing the response to IFNs and IL-27, which inhibit Th17 development; at the same time, these cytokines alter the function of IL-6 and IL-21, thereby decreasing STAT3-mediated differentiation of naïve T cells into Th17.⁸³

APS-1/APECED

APS-1 syndrome, also called APECED, is a rare condition caused by biallelic LOF mutations in the autoimmune regulator (AIRE) gene, of which more than 100 are known, but autosomal dominant forms have also been described.⁸⁴ The AIRE gene encodes a transcription factor that plays an essential role in maintaining central and peripheral tolerance through the regulation of the expression of tissue-specific genes needed for the negative selection of autoreactive T cells. Indeed, AIRE is expressed in the epithelial cells of the thymic medullary, it is involved in the presentation of tissue-restricted antigens during T-cell development in the thymus and induces regulatory T cell (Treg) production.⁸⁵ However, AIRE is also expressed in peripheral lymphoid organs and tissues, such as stromal cells in the spleen and lymph nodes.⁸⁶

Mutations in AIRE allow the survival of autoreactive T cells and the loss of tolerance to self, causing the production of autoantibodies against several tissue-specific autoantigens, leading to the development of the typical clinical manifestations of the disease. In particular, the production of autoantibodies against cytokines, including IFN alpha, IL-17A and IL-22, in patients with APS-1 may be responsible for the development of mucocutaneous candidiasis.⁸⁵

The Hyper IgE Syndromes

HIES are IEI characterized by elevated serum IgE levels, eczema, recurrent bacterial and fungal infections, mainly involving the skin and respiratory tract, and reduced or absent Th17 levels leading to increased susceptibility to Candida infections.

Autosomal dominant hyper IgE syndrome (AD-HIES), also called Job’s syndrome, is caused by LOF mutations in the STAT3 gene, which encodes for a transcription factor of the dectin pathway, mediating the downstream signaling of many cytokines such as IL-6, IL-10, IL-17, IL-21, IL-22, IL-23 and IL-27 involved in Th17 differentiation and processes of inflammation, growth, and cell proliferation.^87,88 The wide expression of STAT3 in hematopoietic and nonhematopoietic cells explains its multiple biological activities not only on different cell types, including T and B lymphocytes, macrophages, neutrophils and dendritic cells, but also on the mechanisms of angiogenesis, wound repair, and programmed cell death.^89,90

The resulting deficiency of these cytokines leads to reduced induction of RORgT, which in turn causes decreased differentiation of Th17 cells, a hallmark of AD-HIES. Because the IL-17A signaling pathway is crucial in the chemotaxis and proliferation of neutrophils and epithelial antimicrobial peptides, the reduction in IL-17A production therefore also contributes to the development of recurrent staphylococcal infections in these patients.^91,92 In addition to infections, AD-HIES patients have distinctive nonimmunologic features such as dysmorphic facies, retention of deciduous teeth, possible development of aneurysms and musculoskeletal and connective tissue changes.⁹³

Autosomal recessive HIES is caused by mutations in the DOCK8, ZNF341 and TYK2 genes.⁷

DOCK8 is a member of the DOCK180-related atypical guanine nucleotide exchange factor family expressed mainly by monocytes, B lymphocytes and T lymphocytes. It has regulatory functions in cell migration, morphology, adhesion and phagocytosis, and acts in particular in cytoskeleton formation and actin reorganization.⁹⁴ Having this gene regulatory functions in the activation of STAT3, AR mutation of DOCK8 results in abnormal Th17 differentiation and function,⁹⁵ responsible for the development of CMC, which is observed in about half of patients.⁹⁶

This disease is considered a combined immunodeficiency, as it affects the function of T, B and NK cells.⁹⁴ Moreover, this defect leads to impaired T cell receptor signaling, a skewing response toward Th2, and impaired STAT5 phosphorylation with altered Treg function.⁵⁰

Other rarer forms of HIES are also reported in Table 1.

RORC Deficiency

RORC deficiency causes altered production of IL-17A, IL-17F and IL-22, which is responsible for the development of CMC, while the cellular T defect in these patients results in altered production of IFN γ, predisposing to the development of mycobacteria.^97,98

DISORDERS OF PHAGOCYTE NUMBERS AND FUNCTION AND OTHER IEIs-PREDISPOSING CMC

The activation and recruitment of neutrophils and monocytes/macrophages is fundamental to eliminating invading microorganisms, including fungi, through a mechanism of phagocytosis that activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, leading to the production of superoxide radicals and hydrogen peroxide as well as activation of cathepsin G, elastase, and myeloperoxidase and neutrophil extracellular trap (NET) formation.⁹⁶ CGD is the most known condition among these groups.^99–101 Leukocyte adhesion deficiencies occur due to defects in glycoproteins such as integrins and selectins involved in leukocyte trafficking, neutrophil phagocytosis, reactive oxygen species production and T-cell activation leading to the persistence of neutrophils in the periphery and subsequent neutrophilia.^102,103 Severe congenital neutropenia syndromes also result in increased susceptibility to fungal infections.^70–72

These diseases highlight the importance of sufficient numbers of phagocytic cells and the ability of granulocytes to reach the site of infection in preventing invasive candidiasis.

DIAGNOSTIC APPROACH TO CMC

CMC needs to be suspected in patients with chronic (more than 6 months) or recurrent candida infections of the nails, skin and mucosae as the main or exclusive clinical manifestation. However, a fungal culture of the site of infection must be always performed to show the positivity to candida.

Secondary causes must be excluded, such as prolonged use of antibiotics, systemic steroids (>10 mg/die or less with immunosuppressors or comorbidity), other kinds of immunosuppressors, and comorbidities such as diabetes and HIV infection. Other infectious or noninfectious complications must be considered in the clinical spectrum of these patients, which may lead to a specific genetic cause of CMC.¹⁰⁴

Having received a clinical and microbiological diagnosis of CMC, in the suspected case of IEI, immunological and genetic investigations are required to identify the underlying deficit (Fig. 1).

FIGURE 1.

Immunological and genetic investigations to identify the underlying deficit of CMC.

First, an evaluation of the white blood cells should be performed, whose levels of neutrophils, lymphocytes and eosinophils point to a specific form of primary immunodeficiency. For example, lymphopenia could be a sign of combined forms of B- and T-cell defects, while low neutrophil levels could raise suspicion of congenital neutropenia. High levels of eosinophils may be observed in the HIES forms.¹⁰⁵ Next, level I and II immunologic studies can be performed, which traditionally include¹⁰⁵:

1. total serum dosage of immunoglobulins (IgA, IgM, IgG and IgE);

2. evaluation of lymphocyte subsets (T, B, NK);

3. B immunophenotyping; and

4. T immunophenotyping, including Th1, Th2 and Th17.

Further functional studies on T and B cells are useful, such as the T cell proliferation test against mitogens and antigens, including Candida, and the evaluation of the antibody production against vaccinal antigens, specifically in patients with associated bacterial infections such as HIES and STAT1 GOF. The analysis of the levels and function of the Th17 cells by flow cytometry is a valid diagnostic tool to identify some causes of CMC, such as STAT3, DOCK8, CARD9 and STAT1 GOF. In addition, in patients with reduced Th17 levels, altered lymphocyte proliferation in vitro and cytokine secretion could be observed in response to a stimulus with Candida.¹⁰⁶ However, patients with mutations of CARD9 generally do not present other defects of the humoral or cellular immunity, as with STAT3 LOF, DOCK8 and STAT1 GOF. Th17 levels are, instead, normal in the case of IL17RA/RC, IL17F and ACT1 mutation. The dosage of IL-17A, IL-17F and IL-22 serum levels associated with the presence of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies and also against IFN can be useful in the diagnosis of APECED.¹⁰⁶

Functional tests, such as a phosphorylation assay of STAT1, can help in early diagnosing the GOF mutation of STAT1 while awaiting the result of the genetic investigation or may be useful in evaluating the functional impact of a STAT1 mutation already identified.³⁸

In any case, genetic tests remain the gold standard in the diagnosis of diseases associated with CMC, specifically by the Sanger single gene study, the employment of gene panels or sequencing the entire exome. Genetic investigation must not be delayed, particularly in the neonatal period, in patients with possible suggestive symptoms, and especially in the case of neonates and prematurity, when flow cytometry studies and functionality tests are difficult to interpret.¹⁰⁷ Indeed, a newborn with a Candida infection, if hospitalized in intensive care, often presents serious clinical conditions and is treated with antibiotic and systemic glucocorticoid therapy; hence, it is quite possible to observe anomalies of immunological tests as a consequence of these clinical circumstances.^4,107 If early screening is altered or even equivocal and there is substantial clinical evidence of an IEI (severe infection, numerous infections caused by unusual organisms or prolonged therapy), a genetic test is required. Screening with T-cell receptor excision circles (TRECs) dosage is of great value in this population because combined immune deficiency/SCID should be suspected first among IEIs with fungal infection in the neonatal/preterm period.¹⁰⁸

THERAPEUTIC STRATEGIES

Treatment of patients with CMC is based on preventing and curing acute infections (Table 2). In some IEIs, further treatments can be employed with a variable clinical efficacy (Table 3).

TABLE 2.

Antifungal Therapeutic Strategies for CMC

Antifungal Treatment and Prophylaxis	Indications
First line Azoles109–111: Fluconazole Itraconazole Posaconazole Voriconazole	-Restrict the azole use to not more than 3 episodes per year to reduce the risk of resistance112 -Perform cultures and sensitivity tests113 -Monitor the liver enzymes -Avoid prolonged use of voriconazole for the risk of skin, neurological, cardiac and dental complications113 -Following a full course of treatment of a new infection, to continue prophylaxis consisting of 1 week of a polyene antifungal every 3 weeks112
Second line Amphotericin B Echinocandin Rezafungin	-In CMC-azole-resistant patients114,115 -Rezafungin only in subjects older than 18 years of age116
Specific candida localizations Fingernail candidiasis Angular cheilitis Vaginal candidiasis	-Systemic treatment usually for 6 weeks112 -Natamycin, amorolfine hydrochloride cream, or chlorhexidine gel several times a day, continuing for 4–5 days after the corners of the mouth have healed112 -A short course of vaginal fluconazole112
Other uses Oral hygiene with both toothpaste and chlorhexidine solution Bathing with chlorhexidine impregnated washcloths or soap	-At bedtime or twice a day as prophylaxis112 -Daily to prevent hospital-acquired infections117

CMC indicates chronic mucocutaneous candidiasis.

TABLE 3.

Adjunctive Nonantimicrobial Therapeutic Strategies for CMC

Other Therapeutic Options	Main Disease	Rational	Limitations or Cautions
G-CSF and GM-CSF	CARD9 deficiency and neurologic involvement 118–120	These factors are secreted with other cytokines following the binding of IL-17A and IL-17F to their receptors, leading to the recruitment and activation of granulocytes and then providing protection against diverse infectious agents, including fungi121,122	Studies on their efficacy are discordant.123,124
Histone deacetylase inhibitors, such as specific HDACi class I entinostat and RGFP966125	STAT1 GOF	The inhibition of HDAC can acetylate STAT1 and activate STAT3, promoting thereby a Th17 response because it is capable of contrasting its phosphorylation, nuclear translocation and the expression of target gene,126 determining also an increase in the production of IL-22 in response to Candida.	Can modulate production of innate cytokines, leading to a possible risk of secondary infections127
JAK 1/2 inhibitors128,129 Ruxolitinib Baricitinib (orally available)	STAT1 GOF	Ruxolitinib reduces hyperphosphorylation of STAT1, promoting the Th17 differentiation and the maturation and function of NK cells, leading to an improvement of CMC and immune dysregulation130–137 Baricitinib hampers IFN-induced JAK-STAT1 signaling. It reduces STAT1 hyperphosphorylation and improves the capacity of PBMCs to produce IL-17A, IL-17F and IL-22, cytokines crucial for antifungal immune responses138–140	Duration of treatment undefined.
HSCT	CARD9 deficiency, STAT1 GOF DOCK8 deficiency STAT3 LOF	A complete clinical resolution of fungal infections in specific patients with CARD9 has been observed, despite the need for a second transplant in one of these18 HSCT is indicated also in patients with STAT1 GOF mutations with a severe infectious and noninfectious clinical phenotype, resistant to the above-stated treatments.141 Analysis revealed that the enhanced STAT1 phosphorylation can significantly decrease down to normal control levels following transplantation142 When studied, HSCT resolved almost all the clinical and laboratory manifestations, reconstituting the normal function of the immune system, with a survival rate of more than 80% in patients receiving HSCT after a median follow-up of 2 years143 HSCT seems to effectively cure the immunological aspects of the disease, such as recurrent skin infections and abscesses, and stabilize severe lung involvement.144	The lack of data on the expression and role of CARD9 in not hematopoietic–derived cells poses doubt on it145 High rate of HSCT failure in STAT1 GOF.142,146,147 It is suggested this effect could be related to increased levels of IFN-γ, which have been implicated in directly inhibiting hematopoietic stem cell function and also inducing Fas expression and increased apoptosis147 To be clarified which patients should receive it and the timing
Emapalumab (monoclonal antibody directed against IFNγ)	STAT1 GOF	Successfully used in a 6-year-old female with CMC, systemic necrotizing fungemia that caused vocal cord destruction, Mycobacterium abscessus infection, and failure to thrive, affected by a STAT1 GOF mutation (c.629G>A [p.Arg210Lys]) who received an unmodified HSCT from her haploidentical mother.148	A trial is ongoing to study the effect of emapalumab on inflammation before HSCT and aid in the engraftment process in people with a primary immune regulatory disorder and/or an autoinflammatory condition (NCT05787574)

CMC indicates chronic mucocutaneous candidiasis; G-CSF and GM-CSF, Granulocyte and Granulocyte-Macrophage Colony-Stimulating Factor; GOF, gain-of-function; HDAC, histone deacetylase; HSCT, Hematopoietic stem cell transplant; JAK, Janus Kinase; LOF, loss-of-function; STAT, signal transducer and activator of transcription.

CONCLUSIONS

Recent advances in the genetic diagnosis of these diseases have certainly contributed to a better understanding of the pathogenesis of CMC. At the same time, further knowledge of the immune response mechanisms against Candida infections has made it possible to improve the diagnostic approach and develop target therapies to better manage these patients. However, there is a need to expand the research in this area, especially on specific therapies already in use and in development. Moreover, a multidisciplinary approach involving different specialistic figures such as immunologists, infectious disease specialists and endocrinologists is fundamental to understanding the complexity of this field, leading to the correct diagnosis and choosing the optimal therapeutic regimen, targeting the treatment for each specific patient.