[Genetic predisposition to mucocutaneous fungal infections]. / Prédisposition génétique aux infections fongiques cutanéomuqueuses.

Mucocutaneous fungal infections are common and usually occur in the presence of certain risk factors. However, these infections can occur in patients with no known risk factors. This indicates the presence of an underlying genetic susceptibility to fungi reflecting an innate or adaptive immune deficiency. In this review, we highlight genetic factors that predispose to mucocutaneous fungal infections specially candidiasis and dermatophytosis.

Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults.

Autosomal recessive CARD9 deficiency underlies life-threatening, invasive fungal infections in otherwise healthy individuals normally resistant to other infectious agents. In less than 10 years, 58 patients from 39 kindreds have been reported in 14 countries from four continents. The patients are homozygous (n = 49; 31 kindreds) or compound heterozygous (n = 9; 8 kindreds) for 22 different CARD9 mutations. Six mutations are recurrent, probably due to founder effects. Paradoxically, none of the mutant alleles has been experimentally demonstrated to be loss-of-function. CARD9 is expressed principally in myeloid cells, downstream from C-type lectin receptors that can recognize fungal components. Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo. The proportion of Th17 cells is low in most, but not all, patients tested. Up to 52 patients suffering from invasive fungal diseases (IFD) have been reported, with ages at onset of 3.5 to 52 years. Twenty of these patients also displayed superficial fungal infections. Six patients had only mucocutaneous candidiasis or superficial dermatophytosis at their last follow-up visit, at the age of 19 to 50 years. Remarkably, for 50 of the 52 patients with IFD, a single fungus was involved; only two patients had IFDs due to two different fungi. IFD recurred in 44 of 45 patients who responded to treatment, and a different fungal infection occurred in the remaining patient. Ten patients died from IFD, between the ages of 12 and 39 years, whereas another patient died at the age of 91 years, from an unrelated cause. At the most recent scheduled follow-up visit, 81% of the patients were still alive and aged from 6.5 to 75 years. Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora, Exophiala, Corynesprora, Aureobasidium, and Ochroconis. Human CARD9 is essential for protective systemic immunity to a subset of fungi from this phylum but seems to be otherwise redundant. Previously healthy patients with unexplained invasive fungal infection, at any age, should be tested for inherited CARD9 deficiency. KEY POINTS: • Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state. • CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands. • Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein). • The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity. • The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis. • The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned. • Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease. • All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed. • The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

Epidemiology, Clinical Characteristics, Sites of Infection and Treatment Outcomes of Mucocutaneous Candidiasis Caused by Non-Albicans Species of Candida at a Dermatologic Clinic.

BACKGROUND: Increasing numbers of mucocutaneous infection due to non-albicans species of Candida (N-CA) had been reported. Laboratory based studies showed multidrug resistance in N-CA population. OBJECTIVE: Demonstrate epidemiology, clinical characteristics, sites of infection, and treatment outcomes of mucocutaneous candidiasis caused by N-CA at a dermatologic clinic, including statistical evaluation data between N-CA and C. albicans infections. MATERIAL AND METHOD: This was a cross sectional study of outpatients with mucocutaneous infection due to Candida at Dermatologic clinic between January 2012 and June 2014. Vaginal candidiasis was excluded. Demographic, clinical, laboratory data, and treatment outcomes were collected. RESULTS: Among 760 patients presented with mucocutaneous candidiasis, 307 (40.4%) were infected with N-CA. The mean age (SD) of N-CA patients was 63.6 (10.4) years and 74.6% were female. The majority of N-CA cases were isolated from patients' nails (n = 293, 95.4%) while eight (2.6%) were detected from their skin, and six (2%)from oral mucosa. Comparison between N-CA and C. albicans, skin, and mucosa infection were significantly demonstrated in C. albicans groups (p < 0.001). Among nail infected patients, C. albicans infections had significant higher severity than the N-CA infection (p = 0.017). Median time to cure in N-CA population was 169 days, which had no significant difference from C. albicans groups (211 days, p = 0.499). CONCLUSION: Forty percent of mucocutaneous candidiasis was caused by N-CA. Nails were the most common sites of N-CA infections but N-CA was sometime found in skin and mucosa. Treatment outcomes of N-CA population were not significantly different from those of C. albicans groups.

Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications.

Much has been learnt about the mechanisms of thymic self-tolerance induction from work on both the rare autosomal recessive disease autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and the autoimmune regulator (AIRE) protein mutated in this disease. Normally, AIRE drives low-level expression of huge numbers of peripheral tissue-specific antigens (TSAgs) in medullary thymic epithelial cells (mTECs), leading to the deletion of TSAg-reactive thymocytes maturing nearby. The very recently discovered neutralizing autoantibodies (autoAbs) against Th17-related cells and cytokines in two autoimmunity-related syndromes associated with AIRE-mutant thymi or AIRE-deficient thymomas help to explain the chronic mucocutaneous candidiasis (CMC) seen in both syndromes. The surprising parallels between these syndromes also demand new hypotheses and research into the consequences of AIRE deficiency and the ensuing autoimmunizing pathways, and suggest more appropriate treatment regimens as discussed in this review.

Mucocutaneous manifestations in children with human immunodeficiency virus infection.

Skin is one of the most frequently involved organs in human immunodeficiency virus (HIV) infection, and mucocutaneous manifestations may be one of the earliest markers of AIDS. The prevalence of cutaneous abnormalities in HIV approaches nearly 90%. Mucocutaneous manifestations may also act as a prognostic marker of HIV infection. Children are increasingly being affected by HIV infection and it is important to realize the presence of the infection early in the disease process as their immune status is not mature enough to handle the stress of various infections. Skin manifestations can serve as early markers and prognostic indicators of HIV infection. This review highlights the epidemiology, transmission, pathogenesis, and the mucocutaneous manifestations of HIV infection in children.

Profile of opportunistic infections in HIV-infected patients at a tertiary care center in Lebanon.

OBJECTIVES: According to statistics published in December 2007 by the National AIDS Program, Lebanon is home to 1056 individuals infected with HIV. Little is known about the clinical profile of opportunistic infections (OIs) and AIDS defining illnesses (ADIs) and their relative contribution to the morbidity and mortality of HIV-infected patients in Lebanon. The aim of this study is to describe the spectrum of OIs and ADIs in HIV-infected patients diagnosed and/or treated at the American University of Beirut Medical Center (AUBMC) in Lebanon. METHODS: Data on various OIs and ADIs were collected from the medical records of patients with HIV infection who were diagnosed or received their medical care at AUBMC from 1984 to January 2008. RESULTS: Eighty-nine HIV-infected patients were included in the analysis. The incidence of ADIs was 72% (64/89). The most commonly diagnosed OIs were cerebral toxoplasmosis (21%), followed by fungal infections (17%). The majority of ADIs (75%) occurred when the CD4 count was below 200 cells/mm(3). CONCLUSION: Clinical guidelines for the prevention of OIs in HIV-infected individuals have been developed on the basis of natural history data collected in industrialized countries. Our results can be used to define local priorities for opportunistic infection prophylaxis.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is known as a rare hereditary disease with classic triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure, two of which, diagnostic dyad, are required for the diagnosis. Evidently many patients suffer unrecognized because the condition is more variable and complex. OBJECTIVE: The objective of the study was to describe the variability of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy for promoting recognition and adequate follow-up of patients. SETTING: The Finnish series of patients is the largest internationally. PATIENTS: The study population was all 91 known Finnish patients. RESULTS: Besides the classical triad, a dozen autoimmune endocrine and other components occurred variably, several of them dangerous. The initial manifestation appeared within the age range of 0.2-18 yr, mucocutaneous candidiasis being part of it in 60% of the patients, hypoparathyroidism in 32%, and adrenocortical failure in 5%. But 23% of the patients had one to six other components before the diagnostic dyad: hepatitis, keratoconjunctivitis, chronic diarrhea, periodic rash with fever. The dyad appeared 0.2-20 yr later. Prevalence of most components increased with age, diabetes mellitus, hypothyroidism, and testicular failure becoming common toward middle age. Tubulointerstitial nephritis occurred in 9% of the patients, apparent mineralocorticoid excess in 9%, asplenia in 19% of adults, and oral or esophageal squamous cell carcinoma in 10% of patients older than 25 yr. CONCLUSIONS: Any child or young adult with one of the many disease components should be examined for others and consideration of AIRE mutation assay.

[Statistical surveillance of mucocutaneous candidiasis in Showa University Fujigaoka Hospital in the past 5 years].

We investigated the epidemiology of 618 patients of mucocutaneous candidiasis who visited our outpatient clinic between 1993 and 1997. Compared with previous reports in Japan, the incidence of candida intertrigo increased and that of erythema mycoticum infantile decreased. The incidence of "others", such as nail candidiasis and candidiasis developed under plaster increased. We identified the species of Candida from patients in 496 recent cases, and these species were cultured successfully in 79.2%. As reported by previous authors, a majority or our results were Candida albicans serotype A. We also investigated the risk factors such as diseases or conditions which might be related to immunodeficiency (neoplasm, AIDS) and that might force a patient to restrict himself to bed for a long period (neurological disease). The former was found in 22.7%, and the latter in 23.3% of patients.

[Candida infections in premature infants weighing less than 1,500 g. Mucocutaneous colonization and incidence of systemic infections]. / Candidainfektionen bei Frühgeborenen < 1,500 g. Mukokutane Kolonisation und Inzidenz systemischer Infektionen.

BACKGROUND: An increasing incidence of systemic candidiasis has been reported in low birth weight infants requiring intensive care. We have retrospectively analyzed mucocutaneous Candida-colonization and infection rate in 422 preterm infants with a birthweight < 1,500 g. METHODS: All infants were treated at the NICU, University of Göttingen, from 1/1985-5/1991. 359 neonates (85%) were on mechanical ventilation, no prophylactic antimycotic regimen was applied. Mucocutaneous swabs and cultures from various anatomic sites were regularly obtained from all infants. RESULTS: 37/422 preterm infants (8.8%) had mucocutaneous colonization with candida, none of our patients developed systemic candidiasis. In 7 mechanically ventilated patients (1.9%) Candida albicans or Candida tropicalis was repeatedly detected in the bronchial secretions; 1 patient who had invasive Candida-pneumonia was effectively treated with 5-Fluocytosin and Fluconazol. 4/352 (1.1%) central silastic catheters were colonized with Candida albicans; none of these patients required specific treatment. CONCLUSION: The low rate of mucocutaneous Candida-colonization and invasive infection found in our patients may be explained--at least in part--by epidemiological and obstetrical factor as well as by the procedures of the neonatal management.

Epidemiological and clinical aspects of mycoses in patients with AIDS-related pathologies.

Mycological, cultural and/or serological studies were performed on 98 patients hospitalized in the Department of Infectious Diseases of the Catholic University in Rome with diagnoses of acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) diseases. The incidence of mycoses was evaluated by retrospectively analyzing the results of mycological examinations and comparing them with clinical manifestations. The presence of concomitant bacterial, viral and parasitic infections was also examined. For epidemiological purposes, the study was extended to include the biotyping of all yeasts isolated from patients hospitalized between September 1988 and February 1989 in the same Department. Antimycotic susceptibility was also determined for the first yeast isolate obtained from each of these patients. Oral candidiasis (50 cases) caused by Candida albicans was the most frequent mycosis, followed by esophageal candidiasis (13 cases) and cryptococcosis (6 cases). Four out of the 6 cryptococcosis patients had meningeal involvement. Systemic candidiasis (2 cases) and aspergillosis (1 case) were less common. Biotyping of yeasts isolated between September 1988 and February 1989 with the killer system revealed type 377 to be the most common among the C. albicans isolates. It represented 70% of all the yeasts isolated.

Treatment of chronic mucocutaneous candidiasis with 5-fluorocytosine.

A four-year-old girl with chronic mucocutaneous candidiasis (CMC) and an immunologic deficiency syndrome was studied in detail over a period of two years. Her lymphocytes neither produced migratory inhibitory factor nor responded consistently with an increased 3H-thymidine uptake when placed in tissue culture medium with candida antigen. The serum IgE was increased. No autoantibody was demonstrated in the patient's serum and she did not have nay kind of endocrine disorder. Eradication of the candida infection with 5-fluorocytosine, although resulting in marked clinical improvement, did not alter the immunologic abnormalities.

Primary immunodeficiency disorders in Sweden: cases among children, 1974-1979.

A nationwide survey of symptomatic primary immunodeficiency disorders in children in Sweden during the 6-year period 1974-1979 resulted in 201 reported cases. The reported data for 174 children were analyzed. Antibody deficiencies were the most frequent (45.0%), followed by phagocytic disorders (22.0%) and combined T- and B-cell disorders (20.8%). Thirty-two children (18.4%) died, with the highest mortality for combined T- and B-cell defects. The sex ratio for all disorders was 2:1 for boys:girls. Neutropenia was significantly more common in the northern part of Sweden.