Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood-transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1-mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

This case report describes a man in his 40s who presented with a 5-month history of recurrent pruritic papular erythema with mild scaling on the face, left forearm, and groin.

BACKGROUND: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity.
METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation.
RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment.
CONCLUSIONS: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) is an important and underestimated fungal infection.
OBJECTIVE: We aimed to determine the fungicidal and proliferative capacities of neutrophils and peripheral blood mononuclear cells (PBMCs), respectively and the clinical and microbiological characteristics of a cohort of Colombian patients diagnosed with RVVC.
METHODS: A cross-sectional study was conducted. A total of 66 women were included (40 diagnosed with RVVC and 26 healthy women [HW]). Demographic and clinical data were recorded. Vaginal fluid samples were obtained for isolation, identification and antifungal susceptibility testing of Candida species using selective culture media and the Vitek 2.0® system. Blood samples were also obtained to evaluate cell subpopulations; furthermore, neutrophils and PBMCs were isolated to determine their fungicidal and proliferative capacities, respectively.
RESULTS: The median age was 29 (IQR: 34-23) for RVVC and 24 (IQR: 30-23) for HW. Only two species of the genus Candida were identified: Candida albicans (92.5%) and Candida lusitaniae (7.5%). Resistance to fluconazole, voriconazole, flucytosine and amphotericin B was observed on six C. albicans isolates and one C. lusitaniae isolate. Only the family history of vulvovaginal candidiasis was associated with RVVC occurrence. The RVVC group exhibited a significantly higher number of neutrophils but with lower fungicidal activity in comparison to HW; likewise, PBMCs from RVVC patients presented a lower proliferation index when stimulated with C. albicans.
CONCLUSIONS: Contrary to what has been reported worldwide, in Colombian patients with RVVC, C. albicans was the main isolated species without increased antifungal resistance. The diminished fungicidal and proliferative capacities of neutrophils and PBMCs, respectively, could suggest a possible alteration in the innate and adaptive immune responses.

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.

BACKGROUND: Autosomal recessive deficiency in the caspase recruitment domain-containing protein 9 (CARD9) is a congenital immunological condition that leads to susceptibility to mucocutaneous and invasive fungal infections. There is growing incidence of fungal infections in patients with CARD9 deficiency, a phenomenon that is increasingly recognised.
OBJECTIVE: This study aimed to assess the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency, based on published papers in the literature until March 2023.
METHODS: We swiftly conducted a study to pinpoint every documented instance of fungal infections arising from CARD9 deficiency. We selected case reports from the databases of PubMed, Embase, Scopus and Google Scholar spanning the period from October 2009 to March 2023.
RESULTS: We analysed 90 cases of fungal infections and identified 32 mutations in the CARD9 gene. Notably, the homozygous (HMZ) p.Q295X (c.883C > T) mutation was associated with an increased risk of candidiasis. In contrast, the HMZ p.Q289X (c.865C > T) mutation is linked to a higher risk of dermatophytosis. We observed differences in the geographical distribution of these mutations. The primary mutations found in African patients differ from those in Asian patients. Specifically, Asian patients exhibit a broader spectrum of CARD9 mutations than African patients.
CONCLUSIONS: The diversity of mutations observed in the 90 cases revealed 32 distinct variations, emphasising the unique genetic alterations in the CARD9 gene associated with specific geographical areas and the corresponding prevalence of fungal infections.

Candidal granuloma is an uncommon type of deep chronic cutaneous candidiasis. Candida albican is the most common causative pathogen for candidal granuloma. We report herein the original case of a 69-year-old Chinese woman presented with a 3-year of painful cutaneous lesion on the back of left hand. Physical examination revealed a 4 × 5 cm large infiltrative reddish plaque with unclear boundaries. The yellow-white crusts were observed on the uneven surface of plaque. Histopathological examination of biopsy tissue revealed that yeast cells and the horizontal section of hyphae in the dermis by hematoxylin eosin staining and periodic acid-Schiff staining. Finally, the pathogen was identified as Candida parapsilosis by mycological examination and molecular identification. The patient was treated with itraconazole oral 200 mg twice daily combined with topical terbinafine hydrochloride cream for 2 months. The lesions were fully resolved and no recurrence was observed. Since the cutaneous infection caused by C. parasilosis were rarely reported, we also reviewed all 11 cases of cutaneous infection caused by C. parapsilosis in the PubMed. Our study highlighted that chronic unilateral infiltrated plaques or ulcers should be aware of the occurrence of fungal granuloma including candidal granuloma especially in immunocompromised patients.

BACKGROUND: Inborn errors of immunity offer important insights into mucosal immunity. In autoimmune polyendocrine syndrome type-1 (APS-1), chronic mucocutaneous candidiasis has been ascribed to neutralizing IL-17 autoantibodies. Recent evidence implicates excessive T-cell IFN-γ secretion and ensuing epithelial barrier disruption in predisposition to candidiasis, but these results remain to be replicated. Whether IL-17 paucity, increased type I inflammation, or their combination underlies susceptibility to chronic mucocutaneus candidiasis in APS-1 is debated.
OBJECTIVE: Our aim was to characterize the immunologic features in the cervicovaginal mucosa of females with APS-1.
METHODS: Vaginal fluid was collected with a flocked swab from 17 females with APS-1 and 18 controls, and cytokine composition was analyzed using Luminex (Luminex Corporation, Austin, Tex). Cervical cell samples were obtained with a cervix brush from 6 patients and 6 healthy controls and subjected to transcriptome analysis.
RESULTS: The vaginal fluid samples from patients with APS-1 had IFN-γ concentrations comparable to those of the controls (2.6 vs 2.4 pg/mL) but high concentrations of the TH1 chemokines CXCL9 and CXCL10 (1094 vs 110 pg/mL [P < .001] and 4033 vs 273 pg/mL [P = .001], respectively), whereas the IL-17 levels in the samples from the 2 groups were comparable (28 vs 8.8 pg/mL). RNA sequencing of the cervical cells revealed upregulation of pathways related to mucosal inflammation and cell death in the patients with APS-1.
CONCLUSIONS: Excessive TH1 cell response appears to underlie disruption of the mucosal immune responses in the genital tract of patients with APS-1 and may contribute to susceptibility to candidiasis in the genital tract as well.