Patients with Primary Immunodeficiencies: How Are They at Risk for Fungal Disease?

Purpose of Review

In this review, we focus on the inborn errors of immunity known to render the host susceptible to fungal infections, including candidias, aspergillosis, dermatophytosis, phaeohyphomycosis, pneumocystosis, fusariosis, cryptococcosis, and endemic mycoses.

Recent Findings

Classically, the burden of fungal disease in humans is believed to be carried by patients with a secondary immunodeficiency, either due to malignancy, to chemotherapy, to an immunocompromised state post hematopoietic stem cell transplantation, or to treatment with anti-cytokine therapies. However, in the last decade, the study of patients affected by fungal infections without any overt risk factors has led to the unraveling of several monogenic defects of human immunity to fungi. The study of these inborn errors of immunity has added vastly to our comprehension of antifungal immunity. For example, the role of IL-17 immunity in human defense against mucocutaneous candidiasis has been extensively characterized through the analysis of IL-17F, IL-17RA, IL-17Rc, ACT1, RORγT and, indirectly, CARD9 deficiency.

Summary

Many monogenic causes of susceptibility to superficial and/or invasive fungal infections have been recently unraveled. Most of these inborn errors of immunity associate with a specific type of fungal infection, and such a defect should always be suspected and sought in patients affected by fungal infection in the absence of predisposing factors.

     

<Emphasis Type="Italic">Microsporum praecox</Emphasis>: Molecular Identification of a New Case and Review of the Literature

We report a rare case of dermatophytosis due to Microsporum praecox in a 28-year-old female horse rider. The skin lesion was located on the right external malleolus. Microscopic examination of skin scrapings revealed a dermatophyte which was also isolated in culture. The identification of M. praecox was confirmed by molecular biology (sequence analysis of PCR products amplified from internal transcribed spacer regions with universal primers). Combined antifungal therapy with oral terbinafine and topical cyclopiroxolamide resulted in complete remission of the fungal lesion within 1 month. Since 1944, only 29 cases of human M. praecox infection have been reported in the literature. The clinical features and treatment of these cases are reviewed. The prevalence of M. praecox infection is probably underestimated, and systematic molecular identification could improve our understanding of the epidemiology of this fungal dermatosis.     

Dermatophyte–host relationship of a murine model of experimental invasive dermatophytosis

Recognizing the invasive potential of the dermatophytes and understanding the mechanisms involved in this process will help with disease diagnosis and with developing an appropriate treatment plan. In this report, we present the histopathological, microbiological and immunological features of a model of invasive dermatophytosis that is induced by subcutaneous infection of Trichophyton mentagrophytes in healthy adult Swiss mice. Using this model, we observed that the fungus rapidly spreads to the popliteal lymph nodes, spleen, liver and kidneys. Similar to the human disease, the lymph nodes were the most severely affected sites. The fungal infection evoked acute inflammation followed by a granulomatous reaction in the mice, which is similar to what is observed in patients. The mice were able to mount a Th1-polarized immune response and displayed IL-10-mediated immune regulation. We believe that the model described here will provide valuable information regarding the dermatophyte–host relationship and will yield new perspective for a better understanding of the immunological and pathological aspects of invasive dermatophytosis.     

Surveillance of Dermatophytosis in Northeast of Iran (Mashhad) and Review of Published Studies

Dermatophytoses are considered to be one of the major public health problems in the world and are among the most commonly diagnosed skin diseases in Iran. In spite of improved personal hygiene and living environment, dermatophytosis continues to spread and persist. To determine the prevalence of dermatophytosis and their etiologic agents in Mashhad (Iran), five hundred and sixty patients suspected to have fungal infection were studied. Subjects who participated in this study were 330 males and 230 females ranged in age from 4 months to 70 years with a mean age of about 25.5 years. Clinical materials including skin scraping, hair and scalp sample, nail clipping and subungual debris were collected. All of the specimens were assessed by direct examination and culture. Of 560 patients, 166 (29.6 %) had dermatophytosis. The types of tinea according to anatomical areas were as follows: tinea corporis (33.1 %), tinea capitis (32.5 %), tinea manuum (17.5 %), tinea cruris (10.2 %), tinea pedis (5.4 %), tinea unguium (0.6 %) and tinea barbae (0.6 %). Trichophyton verrucosum was the most prevalent species followed by Trichophyton violaceum and Trichophyton mentagrophytes. The prevalence of dermatophytosis in males was higher than in females. Based on a review of published studies from different parts of Iran, there are regional differences in the incidence of dermatophytosis. Epidermophyton floccosum has been the most prevalent species, and Microsporum canis has been isolated less than from the other countries.     

Burden of Chronic Dermatophytosis in a Tertiary Care Hospital: Interaction of Fungal Virulence and Host Immunity

Dermatophytosis is caused by keratinophilic dermatophytes and affects the superficial skin and its appendages. The nature of infection and response to treatment is influenced by host–pathogen factors like duration and severity of disease, prior drug history and type of causative organism. In our study, the burden of dermatophytosis affecting glabrous skin saw a rise in recalcitrant and reinfection cases with only 1.6% achieving complete cure. Chronicity of dermatophytic infection was reflected in the high serum IgE levels and immediate hypersensitivity reactions. Hence, it becomes pertinent for clinicians to identify the non-responders and modify therapy to achieve clinical cure with fungal clearance confirmed by mycological tools.     

Augmentation of innate host defenses against opportunistic fungal pathogens

Development of invasive fungal infection is the result of the complex interaction between fungal and host factors. The outcome of infection, once it has developed, depends upon appropriate use of antifungal therapy, surgical debridement as indicated, and improvement of host defenses. Thus, there have been major efforts for development of new strategies for immunomodulation and augmentation of host defenses in prevention and treatment of invasive mycoses. These modalities include granulocyte and granulocyte-macrophage colony-stimulating factors, interferon-γ, granulocyte transfusions, immunotherapy with infusion of dendritic cells and T cells, anti-heat shock protein 90 monoclonal antibodies, long pentraxin 3, mannose-binding lectin, and deferasirox. Although major strides in our understanding of augmentation of host response to invasive fungal infections are opening up novel avenues of therapy to harness patients’ innate immune systems against these frequently lethal pathogens, well-designed clinical trials are needed to demonstrate safety and efficacy of these new approaches.     

Human dermatophytosis caused by Trichophyton equinum

A case of dermatophytosis caused by Trichophyton equinum is reported. A 25-year-old man employed at a breeding center of a horse racing course was infected on the left arm in August, 1981. The lesion had a vesicle or a small pustule accompanied by severe itching. The fungal elements of the scale were identified by microscopic observation. Griseofulvin administration was found to be very effective for treating this infection. In a mycological examination, T. equinum was isolated mainly on cycloheximide-chloramphenicol Sabouraud's dextrose agar and chloramphenicol potato dextrose agar. Equine dermatophytosis was quite prevalent at this race course, so that this area as well as equipment used for the maintenance and care of the horse was very likely to be the source of the patient's infection.     

Invasive fungal infections in critically ill patients: different therapeutic options and a uniform strategy

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.     

Frequency and aetiology of dermatophytosis in children age 12 and under in the state of Amazonas,Brazil

BackgroundFew scientific studies have evaluated dermatophytosis among children in the state of Amazonas or in the greater northern region of Brazil.AimsThe aim of this study was to research the frequency and aetiology of dermatophytosis in children age 12 and under, who were seen between March 1996 and November 2005 at the Mycology Laboratory of the National Institute of Amazonian Research.MethodsFor mycological diagnoses, epidermal scales and/or hairs were used. A portion of this material was treated with potassium hydroxide for direct examination, and another portion was cultivated in Mycobiotic Agar for the isolation of dermatophytes.ResultsOf the 590 samples analysed, 210 showed positive diagnoses by direct examination and cultivation. Tinea capitis (153 cases) was the most frequent type of dermatophytosis, and Trichophyton tonsurans (121 cases) was the most frequently isolated fungal agent. Tinea corporis was observed in 48 cases where the most frequently isolated fungal agent was also T. tonsurans (17 cases), and the corporal regions most affected were the face, arms and trunk. The laboratory confirmed tinea pedis in 6 cases, and the principal fungal agents isolated were Trichophyton rubrum (3) and Trichophyton mentagrophytes (3). The presence of tinea cruris was confirmed in 3 cases, and T. rubrum, T. tonsurans and Epidermophyton floccosum were isolated from these cases.ConclusionsThe children examined were primarily affected by tinea capitis, and the main fungal agent for this dermatophytosis was T. tonsurans.     

An ancient haplotype containing antimicrobial peptide gene variants is associated with severe fungal skin disease in Persian cats

Dermatophytosis, also known as ringworm, is a contagious fungal skin disease affecting humans and animals worldwide. Persian cats exhibit severe forms of the disease more commonly than other breeds of cat, including other long-haired breeds. Certain types of severe dermatophytosis in humans are reportedly caused by monogenic inborn errors of immunity. The goal of this study was to identify genetic variants in Persian cats contributing to the phenotype of severe dermatophytosis. Whole-genome sequencing of case and control Persian cats followed by a genome-wide association study identified a highly divergent, disease-associated haplotype on chromosome F1 containing the S100 family of genes. S100 calcium binding protein A9 (S100A9), which encodes a subunit of the antimicrobial heterodimer known as calprotectin, contained 13 nonsynonymous variants between cases and controls. Evolutionary analysis of S100A9 haplotypes comparing cases, controls, and wild felids suggested the divergent disease-associated haplotype was likely introgressed into the domestic cat lineage and maintained via balancing selection. We demonstrated marked upregulation of calprotectin expression in the feline epidermis during dermatophytosis, suggesting involvement in disease pathogenesis. Given this divergent allele has been maintained in domestic cat and wildcat populations, this haplotype may have beneficial effects against other pathogens. The pathogen specificity of this altered protein should be investigated before attempting to reduce the allele frequency in the Persian cat breed. Further work is needed to clarify if severe Persian dermatophytosis is a monogenic disease or if hidden disease-susceptibility loci remain to be discovered. Consideration should be given to engineering antimicrobial peptides such as calprotectin for topical treatment of dermatophytosis in humans and animals.     

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

The secretome and chemistry of Metarhizium; a genus of entomopathogenic fungi

The major fungal phyla have independently and repeatedly evolved the ability to overcome the insect defense system, which is usually highly effective against fungal attack. During the genomic era of the last decade, extensive progress has been made in understanding the mechanisms of interactions between insects and their fungal pathogens, particularly Metarhizium spp., the focus of this article. New models of pathogenesis have been designed, new biological phenomena have been discovered, and a plethora of new molecules and functions have been determined that are crucial for successful establishment of fungal disease by permitting: attachment to the insect surface; germination and formation of infection structures; penetration of the host; colonization of host tissue; and sporulation on cadavers. Genomic technologies in particular are producing breakthroughs in some of the more intractable aspects of this field, e.g. evolution of host specificity.     

Identification and functional analysis of antifungal immune response genes in Drosophila

Essential aspects of the innate immune response to microbial infection appear to be conserved between insects and mammals. Although signaling pathways that activate NF-kappaB during innate immune responses to various microorganisms have been studied in detail, regulatory mechanisms that control other immune responses to fungal infection require further investigation. To identify new Drosophila genes involved in antifungal immune responses, we selected genes known to be differentially regulated in SL2 cells by microbial cell wall components and tested their roles in antifungal defense using mutant flies. From 130 mutant lines, sixteen mutants exhibited increased sensitivity to fungal infection. Examination of their effects on defense against various types of bacteria and fungi revealed nine genes that are involved specifically in defense against fungal infection. All of these mutants displayed defects in phagocytosis or activation of antimicrobial peptide genes following infection. In some mutants, these immune deficiencies were attributed to defects in hemocyte development and differentiation, while other mutants showed specific defects in immune signaling required for humoral or cellular immune responses. Our results identify a new class of genes involved in antifungal immune responses in Drosophila.     

Hypoxia and Fungal Pathogenesis: To Air or Not To Air?

Over the last 3 decades, the frequency of life-threatening human fungal infections has increased as advances in medical therapies, solid-organ and hematopoietic stem cell transplantations, an increasing geriatric population, and HIV infections have resulted in significant rises in susceptible patient populations. Although significant advances have been made in understanding how fungi cause disease, the dynamic microenvironments encountered by fungi during infection and the mechanisms by which they adapt to these microenvironments are not fully understood. As inhibiting and preventing in vivo fungal growth are main goals of antifungal therapies, understanding in vivo fungal metabolism in these host microenvironments is critical for the improvement of existing therapies or the design of new approaches. In this minireview, we focus on the emerging appreciation that pathogenic fungi like Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are exposed to oxygen-limited or hypoxic microenvironments during fungal pathogenesis. The implications of these in vivo hypoxic microenvironments for fungal metabolism and pathogenesis are discussed with an aim toward understanding the potential impact of hypoxia on invasive fungal infection outcomes.     

HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos

Cells of Candida albicans (C. albicans) can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape of the host immune responses. There is no doubt that the secretion of aspartyl-type proteases, designated as Saps, are one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal-host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of new anti-human immunodeficiency virus drugs of the aspartyl protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV-infected individuals might not solely have resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps. In this article, we review updates on the beneficial effects of HIV PIs against the human fungal pathogen C. albicans, focusing on the effects of these compounds on Sap activity, growth behavior, morphological architecture, cellular differentiation, fungal adhesion to animal cells and abiotic materials, modulation of virulence factors, experimental candidiasis infection, and their synergistic actions with classical antifungal agents.     

Bedside Diagnosis for Disseminated Deep Dermatophytosis: a Case Series Study

Mycopathologia - Deep cutaneous fungal infections including deep dermatophytosis are responsible for significant morbidity and mortality, especially in immunocompromised patients. Variable and...