Genetic Susceptibility to Fungal Infection in Children

Abstract

Purpose of review:

Fungal infections have steadily increased in incidence, emerging as a significant cause of morbidity and mortality in patients with iatrogenic immunosuppression. Simultaneously, we have witnessed a growing population of newly described inherited immune disorders that have enhanced our understanding of the human immune response against fungi. In this review we provide an overview and diagnostic roadmap to inherited disorders which confer susceptibility to superficial and invasive fungal infections.

Recent Findings:

Inborn errors of fungal immunity encompass a heterogeneous group of disorders some of which confer fungal infection-specific susceptibility while others also feature more broad infection vulnerability and/or non-infection manifestations. Infections by Candida, Aspergillus, endemic dimorphic fungi, Pneumocystis, and dermatophytes along with their organ-specific presentations provide clinicians with important clues in the assessment of patients with suspected immune defects.

Summary:

The absence of iatrogenic risk factors should raise suspicion for inborn errors of immunity in children and young adults with recurrent or severe fungal diseases. Expeditious diagnosis and prompt initiation of antifungal therapy and management of complications are paramount to achieve remission of fungal disease in the setting of primary immunodeficiency disorders.

Introduction:

Pathogenic fungi cause a wide variety of infections in children, ranging from superficial infections caused by dermatophytes and Candida to invasive infections in immune-compromised individuals. Refractory mucosal or invasive fungal infections most commonly occur in the setting of HIV/AIDS, hematologic malignancies, hematopoietic stem cell transplantation (HSCT), or immunosuppressive therapies for autoimmune conditions. Less often, children may present with severe fungal infection without identifiable risk factors. In such cases, clinicians should suspect a primary immunodeficiency disease (PID), caused by defects in genes involved in fungal immune surveillance. The spectrum of fungal infections differs depending on which specific pathways or limbs of the immune system are defective. For example, chronic mucocutaneous candidiasis (CMC) is associated with defects in IL-17 receptor-related signaling. Invasive infections by intramacrophagic endemic dimorphic fungi (i.e., Coccidioides, Histoplasma, Blastomyces, Paracoccidioides), Pneumocystis jirovecii, and Cryptococcus are associated with impaired type-1 immune responses reflective of defective CD4 T-cell and/or macrophage function. In contrast, invasive infections by Aspergillus and other environmental molds are associated with granulocyte defects. Here, we provide a practical diagnostic approach for the child with severe fungal infection in the absence of an identifiable secondary cause. The management of specific fungal infections is beyond the scope of this mini-review and is discussed elsewhere.

CMC

Despite colonization with Candida in the skin, gastrointestinal tract and female genital tract of the majority of healthy individuals, severe Candida infections are uncommon in the absence of perturbations in host immune responses or microbiota [1]. Mild superficial infections such as oral thrush and diaper dermatitis in young infants, nonrecurrent localized skin infections (e.g., athlete’s foot), Candida vulvovaginitis (especially in women receiving antibiotics), and oral thrush in patients receiving inhaled corticosteroids are common in healthy individuals, usually respond to topical antifungal treatment, and do not necessarily portend an underlying immune deficiency. More severe, diffuse or recurrent Candida infections of mucosal surfaces are most commonly seen in association with HIV/AIDS, diabetes mellitus, and mucositis related to cytotoxic chemotherapy for hematologic malignancy or HSCT. In contrast, invasive deep-seated Candida infection (such as hepatosplenic candidiasis) is typically seen in the setting of prolonged neutropenia or iatrogenic immunosuppression (e.g., corticosteroids) but not in HIV/AIDS. In patients with recurrent superficial Candida infection in the absence of a secondary cause, termed CMC, an evaluation for an underlying PID is warranted.

While many PIDs with severely impaired T-cell function such as severe combined immunodeficiency (SCID) [2*] can present with CMC and a wide variety of other infections, only a discrete number of PIDs display selective susceptibility to Candida or a narrow spectrum of infection that includes CMC (Table 1). Severe oropharyngeal, diffuse mucocutaneous, or esophageal candidiasis that is refractory to topical treatment or recurs rapidly after completion of antifungals or a family history of CMC or PID should alert clinicians of a possible underlying genetic cause. Establishing a genetic diagnosis may trigger evaluation for other associated clinical features, confers important prognostic information, and in some cases allows for early identification of patients who would benefit from HSCT before additional severe infectious complications occur.

Table 1.

Genetic and clinical characteristics of primary immunodeficiencies that manifest with fungal infection susceptibility

Primary Immunodeficiency	Associated Gene (mode of inheritance)	Clinical Presentation of Fungal Infection	Other PID associated manifestations	Unique Features	Diagnostic Testing
Inherited disorders underlying mucocutaneous fungal infections
Dectin-1 deficiency	CLEC7A (AR)	• Vulvovaginal candidiasis, onychomycosis	None		Genetic sequencing
DOCK8 deficiency(AR-HIES)	DOCK8 (AR)	• CMC	Recurrent sinopulmonary and skin/soft tissue bacterial infections, atopic dermatitis, elevated IgE, eosinophilia, severe food and environmental allergies, asthma, malignancy	Cutaneous viral (molluscum, HSV) infections	Genetic sequencing
ZNF341 deficiency	ZNF341 (AR)	• CMC	Bacterial infections, eczema, elevated IgE	Intellectual disability	Genetic sequencing
APECED	AIRE (AR or AD)	• CMC	Multiorgan autoimmunity, classically AI, HP but also a spectrum of nonendocrine manifestations (pneumonitis, hepatitis, gastritis, other)	Ectodermal dystrophy (enamel hypoplasia, nail dystrophy), anti-cytokine antibodies	IFN-α and IFN-ω autoantibodies, genetic sequencing
IRF8 deficiency	IRF8 (AR)	• CMC	Disseminated BCG infection	Monocytopenia	Genetic sequencing
JNK1 haploinsufficiency	MAPK8 (AR)	• CMC	Recurrent bacterial skin infections	Connective tissue disorder	Genetic sequencing
RORγt deficiency	RORC (AR)	• CMC	Disseminated BCG infection		Genetic sequencing
IL-12 p40 deficiency	IL12B (AR)	• CMC	Intracellular bacteria and NTM infections		Genetic sequencing
IL-17RA deficiency	IL17RA (AR)	• CMC	Superficial staphylococcal skin infections, bacterial pneumonias	Atopic dermatitis	Genetic sequencing
IL-17RC deficiency	IL17RC (AR)	• CMC			Genetic sequencing
IL-17F deficiency	IL17F (AD)	• CMC		Asthma	Genetic sequencing
ACT1 deficiency	TRAF3IP2 (AR)	• CMC	Superficial staphylococcal skin infections, bacterial pneumonias	Atopic dermatitis	Genetic sequencing
Inherited disorders underlying both mucocutaneous and invasive fungal infections
STAT3 LOF (AD-HIES)	STAT3 (AD)	• CMC, onychomycosis • Pulmonary aspergillosis, Aspergilloma involving pneumatoceles • Disseminated cryptococcosis, histoplasmosis, coccidioidomycosis	Recurrent sinopulmonary and skin/soft tissue bacterial infections, eczematous rash with onset in infancy, elevated IgE, eosinophilia	Pneumatocele formation, retained primary teeth, cranio-skeletal abnormalities, characteristic facies following pubertal period	Genetic sequencing
STAT1 GOF	STAT1 (AD)	• CMC • Disseminated histoplasmosis and coccidioidomycosis • Cutaneous fusariosis • Mucormycosis, fusariosis	Recurrent bacterial and viral infections, autoimmunity (diabetes, hypothyroidism)	Lymphopenia, recurrent oral ulcers	Genetic sequencing
IL12Rβ1 deficiency	IL12RB1 (AR or AD)	• CMC • Disseminated coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, cryptococcosis	Intracellular bacteria and NTM infections		Cell surface expression of IL12Rβ1 by FACS, genetic sequencing
CARD9 deficiency	CARD9 (AR)	• CMC • Candida meningitis • Extrapulmonary aspergillosis (e.g., brain abscess, intraabdominal) • Deep phaeohyphomycosis • Deep dermatophytosis	None	Absence of neutrophils in the CNS despite fungal-infected CNS	Genetic sequencing
SCID	IL2RG (XL) ADA (AR) IL7RA (AR) RAG1 (AR) RAG2 (AR) JAK3 (AR) ARTEMIS (AR)*	• CMC • PCP	Bacterial and viral infections Severe lymphopenia		NBS, Lymphocyte enumeration, serum ADA levels, genetic sequencing
CD40L deficiency (HIGM)	CD40L (XL)	• PCP • Cryptococcosis	Recurrent sinopulmonary infections, C. parvum infection.	Lack of germinal centers in peripheral lymphoid tissues	Impaired expression of CD40L on T cells, genetic sequencing
EDA-ID	IKBKG (XL) IKBA (AR)	• CMC • PCP	Recurrent sinopulmonary and NTM infections	Anhidrosis, conical teeth, sparse hair may be present in some patients
Inherited disorders underlying invasive fungal infections
CGD	CYBB (XL) CYBA (AR) NFC1 (AR) NCF2 (AR) NCF4 (AR)	• Aspergillosis: pneumonia with local or metastatic spread, lung nodules, osteomyelitis, cerebral abscesses • Candida meningitis and lymphadenitis	Infections with Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia species Inflammatory bowel disease	Infection with A. nidulans or Phellinus spp.	DHR testing, genetic sequencing
MPO deficiency	MPO (AR)	• Invasive candidiasis	None		Genetic sequencing
LAD1	ITGB2 (AR)	• Aspergillosis: Localized or disseminated infection • Invasive candidiasis	Skin/soft-tissue infections with Staphylococcus and gram-negative bacteria, periodontitis	Impaired pus formation, peripheral neutrophilia	Expression of CD18 on PMNs, genetic sequencing
SCN	ELANE (AD) HAX1 (AR)	• Aspergillosis: Pneumonia, skin/soft-tissue infections, disseminated disease	ANC <200/microL, often with monocytosis. No syndromic features.	None	Bone marrow examination, genetic sequencing
GATA2 Haploinsufficiency	GATA2 (AD)	• Aspergillosis • Disseminated blastomycosis, histoplasmosis, cryptococcosis	Heterogenous presentation which includes lymphedema, HPV-related warts, NTM infections, development of MDS/AML	Monocytopenia	Bone marrow examination, genetic sequencing
IFNGR1	IFNGR1 (AD)	• Disseminated histoplasmosis, coccidioidomycosis	Intracellular bacterial and NTM infections		Cell surface expression of IFNGR1 by FACS, genetic sequencing

Abbreviations: PID, primary immunodeficiency; AR, autosomal recessive; AD, autosomal dominant; CMC, chronic mucocutaneous candidiasis; HIES, hyper IgE syndrome; HSV, herpes simplex virus; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AI, adrenal insufficiency; HP, hypoparathyroidism; BCG, Bacillus Calmette-Guérin; NTM, nontuberculous mycobacteria; LOF, loss-of-function; GOF, gain-of-function; SCID, severe combined immunodeficiency disorder; HIGM, hyper IgM; EDA-ID, anhidrotic ectodermal dysplasia with immunodeficiency CGD, chronic granulomatous disease; DHR, dihydrorhodamine 123; MPO, myeloperoxidase; PMN, Polymorphonuclear leukocytes; LAD1, leukocyte adhesion deficiency type 1; SCN, severe congenital neutropenia; HPV, human papilloma virus; ANC, absolute neutrophil count; PCP, Pneumocystis pneumonia

The epithelial immune response to Candida largely overlaps with that of Staphylococcus aureus and dermatophytes, and requires recognition of pathogen-associated molecular patterns (PAMPs) by innate immune cells, production of cytokines that induce Th17 differentiation, and the action of cytokines IL-17A, IL-17F and IL-22 derived from a variety of type-17 lymphocytes (i.e., Th17 cells, Tc17 cells, γδ T cells and innate lymphoid cells) on epithelial cells, which promote neutrophil recruitment and epithelial barrier defense and integrity [3] (Figure 1). Deficiencies in STAT3, ZNF341, IRF8, MAPK8, NEMO/IKBKG, IKBA, RORγt, IL-12p40, IL12Rβ1, IL-17F, IL-17RA, IL-17RC, and ACT1 (TRAF3IP2) predispose to CMC, while CARD9 deficiency is the only known PID that predisposes to both CMC and invasive candidiasis [4–12**,13*] (Table 1). A common loss-of-function allele in CLEC7A (Y238Y) encoding the C-type lectin (CLR) receptor Dectin-1 has been associated with recurrent vulvovaginal candidiasis and onychomycosis. DOCK8 coordinates the actin cytoskeleton in response to multiple cytokine and chemokine signals and regulates STAT3-dependent Th17 differentiation [14]. Gain-of-function (GOF) mutations in STAT1 impair Th17 differentiation and predispose to CMC, representing the most common form of inherited CMC [15–17]. CMC is also seen in patients with autoantibodies against Th17 cell-derived autoantibodies such as those with thymoma or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) caused by AIRE mutations [18–20].

Figure 1. Immune pathways associated with chronic mucocutaneous candidiasis.

Fungal polysaccharides such as β-glucans and α-mannans from Candida are recognized by epithelial and innate immune cells via C-type lectin receptors (CLRs) such as Dectin-1 and Dectin-2, which signal through CARD9 to stimulate cytokine production. The Candida peptide toxin candidalysin also engages epithelial cells via a yet-unknown receptor. IL-6 and IL-23 bind to their receptors IL-6R and IL-23R (which signal through STAT3) to induce Th17 differentiation, a process that requires RORyt. Th17 cells in turn secrete IL-17A and IL-17F that act directly on epithelial cells through the IL-17 receptor complex (comprised of IL17RA and IL17RC subunits), activate downstream adaptor ACT1 (TRAF3IP2), and together with IL-22 lead to epithelial regeneration, production of antimicrobial peptides (e.g., β-defensins, S100A8/S100A9), and secretion of chemokines (e.g., CXCL1, CXCL5) that mediate neutrophil recruitment. Created with BioRender.com.

The clinical spectrum of infection and associated non-infectious clinical features can be a clue to the underlying specific genetic defect featuring CMC. A narrow spectrum of clinical manifestations with predominant CMC presentation is observed in autosomal-recessive (AR) IL17RA, IL17RC and ACT1 deficiencies and autosomal-dominant (AD) IL17F deficiency which can present with CMC as early as 6 months of age and some may develop atopic manifestations early in life. IL-17RA and ACT1, but not IL-17RC or IL17F deficiencies, may also develop staphylococcal skin infections and bacterial pneumonias [10,21] (Table 1). CMC with autoimmune endocrinopathies or enteropathy is suggestive of STAT1 GOF or APECED [16,22]. Patients with AD STAT1 GOF present with a highly variable clinical phenotype that includes recurrent infections by viruses (VZV and HSV), endemic fungi and mycobacteria, autoimmune endocrinopathy (hypothyroidism, type 1 diabetes), autoimmune cytopenias, systemic lupus erythematosus, enteropathy, cerebral aneurysms, and squamous cell carcinoma [17,18]. In contrast, APECED is predominantly of AR inheritance, causes predisposition to only one infection (CMC), and has a more uniform clinical presentation than STAT1 GOF. Clinical features of APECED during the first year of life include ectodermal dystrophy (enamel hypoplasia, nail dystrophy), intestinal malabsorption and a neutrophilic rash resembling urticaria [20]. The classic triad of CMC, hypoparathyroidism and adrenal insufficiency may take several years to manifest, which can lead to a delayed diagnosis [23]; a high index of suspicion for APECED is therefore warranted in children who develop CMC with any other classic triad manifestations or the adjunct triad of intestinal malabsorption, enamel hypoplasia and urticarial eruption. AR IL12p40 or IL12RB1 deficiency present predominantly with childhood onset disseminated infections by Salmonella and atypical mycobacteria, with only a minority of patients developing CMC [7,8]. Similarly, patients with AR RORyt deficiency have susceptibility to both CMC and atypical mycobacterial infection but not Salmonella infections [5], whereas patients with AR TYK2 deficiency manifest mycobacterial and viral infection susceptibility with a minority developing CMC or Salmonella infection [24,25]. Patients with AD STAT3 deficiency (Job’s syndrome) present with recurrent Staphylococcus aureus skin infections, distinctive facial features (i.e., broad nasal bridge, frontal bossing), skeletal abnormalities (i.e., hyperextensible joints, scoliosis, osteoporosis), aneurysm formation, pneumatoceles, eczema, elevated IgE and eosinophilia [26]. Although patients with DOCK8 deficiency can similarly present with recurrent staphylococcal skin infections, recurrent sinopulmonary infections, eczema, eosinophilia and elevated IgE, unlike Job’s syndrome the mode of inheritance is AR and patients present with recurrent severe cutaneous viral infections (molluscum, VZV, HSV, HPV), more severe atopy (i.e., eczema, food allergy, and eosinophilic esophagitis), and a greater predisposition to cancer [27]. Patients with heterozygous mutations in MAPK8 encoding JNK1 manifest with CMC and an Ehlers-Danlos syndrome-like connective tissue disorder [28**]. As mentioned above patients with AR CARD9 deficiency are at risk for both CMC and invasive candidiasis and will be discussed further in a later section of this review.

The diagnostic workup for CMC begins with a thorough clinical and laboratory evaluation for secondary causes, including CBC, hemoglobin A1c and HIV testing. Once secondary causes are excluded, workup should be guided by the clinical phenotype. CBC may demonstrate eosinophilia in STAT3 and DOCK8 deficiencies, while autoimmune cytopenias may be seen in STAT1 GOF. Evaluation for autoimmune endocrinopathy (i.e., TSH, HbA1c, calcium level, serum cortisol and ACTH stimulation test) can be useful in patients with suspected STAT1 GOF or APECED. Thyroid or adrenal autoantibodies can precede the onset of hormone deficiency [22**]. Autoantibodies to IFN-α and IFN-ω are typically positive in APECED children and are useful for early diagnosis [29]. Patients with APECED also carry autoantibodies targeting IL-17F, IL-22 and less often IL-17A cytokines [18,19]. Evaluation of immune function should include IgG, IgA, IgM and IgE levels and flow cytometric analysis of T, B and NK cells (TBNK). Hypogammaglobulinemia can be seen in some patients with DOCK8 deficiency [30]. Elevated IgE is suggestive of STAT3, ZNF341, or DOCK8 deficiency, but can be also seen with concomitant atopic disease in other PIDs, or without atopy in CARD9 deficiency [31]. TBNK may demonstrate low CD4 and CD8 cells in DOCK8 and RORyt deficiencies [5,27]. In contrast, total T cell, B cell and immunoglobulin levels are usually normal in APECED, and in IL12p40, IL12Rβ1, STAT3, IL17RA, IL17RC, IL17F and ACT1 deficiencies. Lymphocyte counts and immunoglobulin levels are variable in STAT1 GOF [17]. Imaging studies can show pneumatoceles and scoliosis in Job’s syndrome [26]. Diffuse lymphadenopathy and bone lytic lesions may underlie disseminated mycobacterial disease in IL12p40, IL12Rβ1, RORyt deficiencies or STAT1 GOF. While the aforementioned tests could suggest a specific disorder, the ultimate diagnosis requires demonstration of a pathogenic variant via genetic sequencing for individual genes when suspicion for a specific defect is high, or more commonly for select panels of genes associated with CMC, or by whole exome sequencing.

Invasive fungal infections

Disorders of Phagocyte Number and Function

The activation and recruitment of neutrophils and monocytes/macrophages to fungal-infected tissues are central to the recognition, uptake and elimination of ubiquitous inhaled molds (e.g., Aspergillus, Mucorales, Scedosporium) and the commensal yeast Candida [32–34]. Indeed, defects involving the subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase cause chronic granulomatous disease (CGD) (Table 1), resulting in impaired generation of superoxide and defective anti-microbial killing of both fungi and bacteria (Figure 2). The only exception is CGD caused by p40phox deficiency which manifests with inflammatory complications but no pronounced fungal susceptibility [35**]. Aspergillus infections are a leading cause of mortality in CGD patients [36,37]; most commonly, fungal pneumonia is caused by Aspergillus fumigatus following spore inhalation, while A. nidulans, a species nearly pathognomonic for CGD, is responsible for higher rates of osteomyelitis and infections that invade across contiguous tissue planes [38–40]. Emerging infections with other cryptic Aspergillus species [38] and other non-pathogenic fungi including Phellinus spp. [41] and Penicillium piceum [42] have also been reported. Although the oxidative burst protects against both molds and yeast, invasive candidiasis affects a minority of CGD patients [37]. During the respiratory burst myeloperoxidase (MPO) converts hydrogen peroxide to hypochlorous acid playing a critical role in killing pathogens such as Candida [43]. In contrast to CGD, the majority of patients with MPO deficiency remain asymptomatic, with <5% of such individuals suffering from invasive candidiasis, often in the setting of diabetes or other comorbidities [44–46] (Table 1). Together, these conditions underscore the role of oxidative cytotoxic mechanisms but also indicate the relevance of non-oxidative pathways in the protection against fungal pathogens. Indeed, in leukocyte adhesion deficiency type 1 (LAD1) neutrophils fail to migrate to infected tissues due to defective integrin beta-2 (CD18) (Figure 2) resulting in the retention of neutrophils in the periphery and resultant neutrophilia. Besides neutrophil trafficking, CD18 may also participate in fungal recognition and NADPH oxidase activation [47]. Patients with LAD1 classically present in infancy with delayed umbilical cord separation and omphalitis. Children who survive infancy suffer from periodontitis [48] and recurrent bacterial skin and soft-tissue infections while a minority of patients may develop invasive Candida, Aspergillus and Fusarium infections [49–51] (Table 1). Converse to the neutrophilia observed in LAD1, severe congenital neutropenia (SCN) syndromes also portend susceptibility to fungal infections. Presenting in infancy, SCN syndromes comprise a group of heterogeneous disorders caused by mutations in >20 genes [52] with deleterious variants involving ELANE, HAX1 being the most common [53] (Table 1). The duration and severity of neutropenia is directly correlated with the risk of infection, typically with Streptococci or Staphylococci, however invasive infections with Candida and Aspergillus have been reported [53]. Similarly, children and young adults with GATA2 haploinsufficiency may present with neutropenia, often associated with monocytopenia, prior to the development of myelodysplastic syndrome or acute myeloid leukemia [54] and may present with invasive aspergillosis and other fungal infections which will be discussed in further detail below.

Figure 2. Immune pathways involved with invasive fungal infection control.

Neutrophils traffic to fungus-infected tissues sites and undergo diapedesis via integrin β2. Yeast cells of Candida and conidia of inhaled molds (e.g., Aspergillus) are engulfed by phagocytes where they are exposed to ROS generated by the NADPH oxidase complex. Conidia of inhaled molds are recognized by Dectin-1 and other C-type lectin receptors, which activates Syk and PKC-δ resulting in activation of the CBM signaling complex leading to NF-kB activation and transcription of pro-inflammatory genes. Endemic dimorphic fungi phagocytosed by macrophages leading to secretion of IL-12, which binds to its receptor on T-lymphocytes results in IFN-γ production via JAK2/STAT4-dependent signaling. GATA2 regulates phagocytosis and effector functions of macrophages via yet-unclear mechanisms. IL-2 activates T-cells via autocrine and paracrine signaling. IL-23 binds to the IL-23 receptor, leading to STAT3 dimerization and nuclear translocation resulting in transcription of IL-17-, IL-21-, and IL-22-related genes. Created with BioRender.com.

ROS, reactive oxygen species; CBM; CARD9-BCL10-MALT1; JAK, janus kinase; NF-κB, nuclear factor-κB; NADPH, nicotinamide adenine dinucleotide phosphate; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2; GATA2, GATA binding factor 2; IFNG, interferon gamma; IFNGR, interferon gamma receptor; IL, interleukin; IL-12R, IL-12 receptor; IL2, TNFA, tumor necrosis factor alpha.

Disorders of Immune Recognition of Fungi

CARD9 is a signal adaptor protein downstream of CLRs such as Dectin-1 (Figure 2), which are important in fungal sensing and activation of the innate and adaptive immune response to fungi [55]. Deficiency in CARD9 results in specific fungal susceptibility involving both mucocutaneous and deep-seated tissues with a particular predilection for the central nervous system (CNS) caused by defective neutrophil recruitment to the fungus-infected CNS [56**,57] and impaired fungal killing [58]. In addition to CMC and candidal meningitis, children and young adults with CARD9 deficiency may also develop invasive aspergillosis including exclusively extrapulmonary disease [59], invasive phaeohyphomycosis (Figure 3) [60] and/or deep-seated dermatophytosis [61,62*] (Table 1).

Figure 3. Invasive phaeohyphomycosis in a child with CARD9 deficiency.

Radiographic images featuring a disfiguring subcutaneous infection caused by the dematiaceous fungus Corynespora cassiicola in the face of a child with CARD9 deficiency with contiguous infection spread into the frontal lobes of the brain bilaterally. The left panel shows a 3D-reconstructed image of a head and neck CT scan showing extensive infection of the face with destruction of the skull bilaterally caused by contiguous spread of the fungal process into the frontal lobes of the brain. The right panel shows an image from a PET-CT scan which shows large areas of soft-tissue defects caused by the locally invasive fungal infection and two PET-avid fungal abscesses within the left infratemporal fossa and the right parotid gland. PET, positron emission tomography; CT, computed tomography.

Disorders of Cytokine Signaling and Signal Transduction

Macrophages containing engulfed fungi secrete IL-12 that acts on T-lymphocytes resulting in IFN-γ production which upon binding on its receptor on macrophages enhances macrophage STAT1 activation and promotes killing of intramacrophagic pathogens [63] (Figure 2). As such, inborn errors of immunity involving the IL-12/IFN-γ axis classically cause mendelian susceptibility to mycobacterial disease (MSMD). In addition, patients with defects in IL12Rβ1, IFNγR1 or STAT4 demonstrate susceptibility to histoplasmosis [64], paracoccidioidomycosis [8,65], and coccidioidomycosis [66,67], highlighting the importance of IL-12/IFN-γ signaling in the control of endemic dimorphic fungi. Furthermore, IL12Rβ1 deficiency was associated with disseminated cryptococcosis in a 3 year-old child [68]. Similarly, STAT1 GOF mutations demonstrate aberrant IFN-γ regulation leading to infections with coccidioidomycosis and histoplasmosis [69] and mucormycosis [70].

Invasive pulmonary aspergillosis is a common complication of STAT3 deficiency, affecting over 20% of patients. Unlike CGD, Aspergillus (and Scedosporium) occurs later in life and preferentially involves areas of existing structural lung disease (i.e., bronchiectasis and pneumatoceles) implicating defective STAT3-dependent epithelial integrity in the pathogenesis [71]. In addition to Aspergillus, Job’s patients may also develop disseminated Cryptococcus, Histoplasma, and Coccidioides infections, often involving the CNS or gastrointestinal tract [72].

Introduced earlier, GATA2-haploinsufficiency is a protean disorder with a complex phenotype including monocytopenia, lymphopenia, and NK cell dysfunction, lending to a broad-spectrum infection susceptibility including histoplasmosis, cryptococcosis [73,74] and blastomycosis [74]. Patients may also suffer from disseminated mycobacterial and viral infections [75].

Combined Immunodeficiency Disorders

Significant impairment in T cell function underpins the vulnerability to Pneumocystis pneumonia (PCP) and therefore a variety of genetic disorders are implicated in PCP susceptibility. SCID is the most common syndrome predisposing to PCP, however other combined immunodeficiencies including CD40L deficiency (X-linked hyper-IgM syndrome) [76], and anhidrotic ectodermal dysplasias with immune deficiency caused by NEMO or IKBA mutations are at-risk [43].

Conclusion

The expansion in the characterization of PIDs continues at brisk pace [77*], yet several clinical, including fungal infection, phenotypes of affected patients remain without a molecular basis or mechanistic explanation. In addition, the ideal therapeutic approach for some PID-affected individuals remains unclear. Combining clinical phenotyping and scientific investigation will continue to provide important insights into understanding immunology and improving diagnostic approaches and therapies. The future discovery of novel inborn errors of immunity will further advance our understanding of the mechanisms of human antifungal host defense and help improve patient outcomes.

Key points:

• Recurrent and/or recalcitrant mucocutaneous candidiasis should prompt providers to consider the diagnosis of disorders resulting in impaired IL-17 immunity.

• Invasive aspergillosis and other mold disease in the absence of iatrogenic immunosuppression should prompt evaluation for underlying quantitative or qualitative disorders of myeloid phagocytes.

• Candida meningitis, invasive dermatophytosis or phaeohyphomycosis should raise suspicion for CARD9 deficiency.

• Invasive infections by intramacrophagic endemic dimorphic fungi in the absence of immunosuppression or HIV/AIDS are suggestive of defects involving IL-12/IFN-γ signaling.