Development of an Animal Model of Onychomycosis in Guinea Pigs.

Onychomycosis is a common and intractable superficial mycosis that occurs worldwide. Treatment with both oral and topical drugs is recommended, but the objective evaluation procedure to determine the efficacy of and the appropriate delivery system for the drugs remains controversial. This may be attributed to the lack of a reliable animal model that not only mirrors the pathophysiology of human onychomycosis but is also feasible. Therefore, we attempted to establish an animal model of onychomycosis using immunosuppressed guinea pigs and elucidate the pathophysiology of human onychomycosis. In the present study, we applied Trichophyton mentagrophytes TIMM2789 to the hind limb nails of corticosteroid-treated guinea pigs. The nails were examined macroscopically and histopathologically at 0, 14, and 42 days after a 2-week exposure period to the fungus. A large portion of the experimentally infected nails showed discoloration, which is an important clinical sign, and most infections were confirmed histopathologically in the deep layer of the nail plate at all time points. The infection rates at 0, 14, and 42 days after exposure were 39%, 61%, and 78%, respectively. Thus, we established an animal model of onychomycosis with good reproducibility and that might be appropriate for extrapolation to the pathophysiology of the human disease.

A Stealthy Fungal Attack Requires an Equally Clandestine Approach to Onychomycosis Treatment.

Onychomycosis is a chronic fungal infection of the nail that is recalcitrant to treatment. It is unclear why normally effective antifungal therapy results in low cure rates. Evidence suggests that there may be a plethora of reasons that include the limited immune presence in the nail, reduced circulation, presence of commensal microbes, and fungal influence on immune signaling. Therefore, treatment should be designed to address these possibilities and work synergistically with both the innate and adaptive immune responses.

Factors associated with onychomycosis in nail psoriasis: a multicenter study in Pakistan.

BACKGROUND: Treatment of psoriatic nail disease is challenging, and dystrophic psoriatic nails can get secondarily infected with fungi. METHODS: This 2-year, matched case-control study was conducted at three tertiary care centers of Karachi, Pakistan. Data were collected from patients with nail psoriasis as cases with age- and gender-matched controls. A detailed questionnaire was filled for all study participants. Nail Psoriasis Severity Index (NAPSI) scoring tool was used to assess dystrophy. Fungal infection was inferred by nail clippings for fungal hyphae and culture. RESULTS: Among 477 participants, 159 cases and 318 controls completed the study. Their mean age was 44 years, and one-third were female. Fungal culture positivity was statistically significant in cases as compared to the control group (P < 0.001). The most frequent species identified was Candida parapsilosis in both cases and controls. Body mass index, NAPSI scoring, socioeconomic status, elevated diastolic blood pressure, smoking status psoriasis among first-degree relatives, and longstanding disease of more than 10 years were significant factors in univariable analysis. Multivariable logistic regression identified independent factors like low to middle socioeconomic status, history of psoriasis in first-degree relative, current smoker, and obesity. CONCLUSION: We found nearly one-third of the psoriatic patients with nail involvement having concomitant fungal infection. We emphasize that nail clipping for fungal smear and culture should be advised to those patients with coexisting factors found significant in our study results. This opinion can be incorporated in psoriasis management guidelines for improving treatment of psoriatic nails.

Proximal Subungual Onychomycosis in the Immunocompetent: A Case Report and Review of the Literature.

Proximal subungual onychomycosis (PSO), which predominantly involves the nail plate from the proximal nail fold, is the rarest form of onychomycosis. Classically associated with an immunocompromised state, PSO is an uncommon diagnosis in individuals without immunodeficiency. We present a case of a healthy 51-year-old man, who presented with a three-month history of white discoloration of multiple toenails. Physical examination revealed white, opaque patches on the proximal third nail plates of multiple toenails. The affected digits also demonstrated proximal onycholysis, subungual debris, and mild paronychia. Laboratory examinations, including routine serologic studies as well as human immunodeficiency virus and antinuclear antibodies, were within normal limits. Proximal nail fragments of the left hallux showed sections of dystrophic nail plate with mounds of parakeratosis, collections of neutrophils, and hyphae that highlighted with periodic acid-Schiff staining. The patient was diagnosed with PSO and tinea pedis bilaterally and treated with oral fluconazole with gradual improvement. This case of PSO highlights the potential for its rare occurrence in a healthy host. However, the clinical presentation of PSO should trigger an evaluation for possible immunodeficiency.

J Drugs Dermatol. 2018;17(4):475-478.

Invasive cutaneous infection due to Scopulariopsis brevicaulis unsuccessfully treated with high-dose micafungin in a neutropenic patient.

Scopulariopsis brevicaulis onychomycosis with local cutaneous invasion was diagnosed in an acute leukemia patient and unsuccessfully treated with high-dose micafungin, based on antifungal susceptibility testing. This case should alert clinicians to the possible severe evolution of onychomycosis in neutropenic patients and suggests that surgery should be preferred in such a situation.

Ungual hyalohyphomycosis caused by Fusarium proliferatum in an immunocompetent patient.

The patient was a 73-year-old healthy female farmer who had been treated with terbinafine for 25.5 months by a primary physician. She exhibited a discoloration and thickening of the right big toenail. She had no concomitant paronychia. Direct microscopy revealed chlamydoconidia and hyphae, and periodic acid-Schiff stained nail specimen showed septate hyphae. On the basis of these morphological features and gene analysis, the final diagnosis was ungual hyalohyphomycosis caused by Fusarium proliferatum. Topical application of 10% efinaconazole solution cured the disease in 10 months.

Sensitization and cross-reactions of dermatophyte and Candida albicans allergens in patients with chronic urticaria.

BACKGROUND: Chronic fungal infections are known to exacerbate allergic symptoms, including those of asthma and chronic urticaria (CU). We applied four prepared fungal antigens of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Candida albicans to examine sensitization to each in subjects with CU and onychomycosis and in healthy subjects, and to evaluate the etiologic role of dermatophytic infection in CU and observe any cross-reactions among these four antigens. METHODS: Participants were divided into four groups, including those with CU with onychomycosis (experiment group), those with onychomycosis without allergic diseases (control group 1), those with CU without fungal infections (control group 2), and a healthy group (control group 3). In all subjects, skin prick tests with the four fungal antigens were performed. Subjects in the experiment group and control group 1 were also submitted to mycologic investigations. RESULTS: The experiment group showed significantly higher rates of positivity than the three control groups to T. rubrum, E. floccosum, and T. mentagrophytes antigens. Control group 1 showed rates higher than those in control groups 2 and 3; no significant difference emerged between control groups 2 and 3. Positivity to the C. albicans antigen did not differ among the four groups. In control group 1, rates of positivity to the three dermatophytic antigens did not differ significantly but did for C. albicans. CONCLUSIONS: Fungal infection seems to be an important determinant of trichophyton hypersensitivity. Cross-reactions among T. mentagrophytes, T. rubrum, and E. floccosum antigens were obvious, but none emerged between the antigens of the three dermatophytes and that of C. albicans.

Nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent host.

Fusarium onychomycosis is not uncommon in tropical countries but is worth reporting. We report a case of nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent woman from Buldhana district of Maharashtra (India). Bilateral involvement of great toe nail, chronic duration and acquisition of infection due to peculiar practice of daily pasting floors with mud and dung, is interesting. The case was successfully treated with topical and oral terbinafine with a dose of 250 mg daily for 3 weeks.

Possible Role of Trichophytin Antigen in Inducing Impaired Immunological Clearance of Fungus in Onychomycosis.

The immunology of onychomycosis is poorly understood. Th1 and Th17 are the principal effector cells responsible for protective immunity against fungi, while it is assumed that Th2 responses are associated with deleterious effects. The study was conducted to appraise the role of interleukin-6 (IL-6), transforming growth factor ß (TGF-ß) and immunoglobulin E (IgE) in onychomycosis patients and to study skin reactivity to trichophytin antigen in them. Serum samples of 60 cases of chronic onychomycosis and 30 healthy controls were assayed for serum IgE, IL-6 and TGF-ß levels using specific immunoassay kits; 0.01 ml of trichophytin antigen, Candida antigen and phosphate-buffered saline using separate syringes were injected intradermal at three independent sites of the forearm in cases and controls. Serum IL-6 levels were significantly lower in cases as compared to controls, while serum TGF-ß levels in both cases and controls were comparable. Serum IgE levels in cases were significantly higher when compared with controls. Thirty-eight patients showed immediate hypersensitivity response to trichophytin antigen, while none showed delayed hypersensitivity reaction to trichophytin antigen. Constant fungal antigenic stimuli induce a state of anergy as indicated by low serum IL-6 levels and the absence of delayed hypersensitivity reaction to trichophytin antigen in cases, leading to chronicity of infection. High total IgE may indicate a high probability of prior fungal sensitization.

Evaluation of improvement of onychomycosis in HIV-infected patients after initiation of combined antiretroviral therapy without antifungal treatment.

Onychomycosis in HIV-infected patients has a prevalence of 20-44% and is more frequently seen with CD4(+) T cell counts ≤450 cel µl(-1). There are case reports of improvement in onychomycosis after initiation of combined antiretroviral therapy (cART), but there are no prospective studies that prove the existence and frequency of this phenomenon. The aim of this study was to evaluate if HIV-infected patients with onychomycosis who begin cART improve and/or cure without antifungal treatment. We included HIV-infected patients with onychomycosis who had not started cART and nor received antifungal therapy during 6 months prior to the study. We evaluated affected the nails with the Onychomycosis Severity Index (OSI); nail scrapings were collected and direct microscopy with potassium hydroxide (KOH) as well as mycological culture were performed. We repeated these procedures at 3 and 6 months to assess changes. CD4 T cell counts and HIV viral load were obtained. A total of 16 patients were included, with male gender predominance (68.7%); distal and lateral subungual onychomycosis (DLSO) was the most common form (31.3%). Trichophyton rubrum was the most frequently isolated microorganism. OSI decreased 21.5% at 3 months and 40% at 6 months after initiation of antiretrovirals (P = 0.05). We found a non-significant tendency towards improvement with higher CD4(+) T cell counts and with viral loads <100 000 copies ml(-1). This could be due to the increase in CD4(+) T cells, decreased percentage of Treg (CD4(+)CD25(+)) among CD4(+) Tcells and/or a decreased viral load; further studies are necessary to prove these hypothesis.

Do genetic mutations and genotypes contribute to onychomycosis?

BACKGROUND: The variability in susceptibility to onychomycosis for individuals exposed to the same environmental risk factors raises the possibility that there may be individuals with a genetic predisposition to dermatophyte infection. OBJECTIVE: To determine whether there are genetic mutations or genotypes which contribute to onychomycosis. METHODS: The PubMed database was searched for examples of immune deficiencies resulting in dermatophyte infections. RESULTS: There are mutations in the innate immune receptors Dectin-1 and its adaptor protein CARD9 which result in familial mucocutaneous infections. There are also specific human leukocyte antigen genotypes that are more common in individuals and families with a high prevalence of onychomycosis. In addition, some patients have been reported with insufficient levels of CD4+CD25+ regulatory T cells. These deficits impair a full innate and adaptive immune response and may result in chronic or recurrent infections. CONCLUSIONS: There are documented mutations and genotypes that contribute to familial and individual susceptibility to onychomycosis.

Onychomycosis in immunosuppressed children receiving chemotherapy.

Onychomycosis in children has a low incidence worldwide; certain conditions such as immunosuppression have been described as risk factors for it. We studied 72 children receiving chemotherapy for different neoplasms to determine the frequency of onychomycosis. Only one patient had white superficial onychomycosis from Trichophyton rubrum, a frequency of 1.3%, not different from that reported in healthy patients.

Improvement in onychomycosis after initiation of combined antiretroviral therapy.

BACKGROUND: Onychomycosis is frequent in patients with late and advanced HIV disease; immunocompromised patients may develop atypical clinical presentations that can be difficult to control. Current treatment for onychomycosis is based on the prolonged administration of antifungal therapies that may have significant interactions with combined antiretroviral therapy (cART). An improvement in certain HIV-associated opportunistic infections has been associated with initiation of cART. OBJECTIVES: The aim of this study was to analyze the influence of cART on the outcome of onychomycosis in HIV-infected patients. METHODS: HIV-infected patients with dermatologic lesions attending the National Institute of Respiratory Diseases were asked to undergo physical examination. Detailed clinical histories were recorded. Routine laboratory tests, CD4 T cell count, and HIV viral load were performed. Onychomycosis was diagnosed on the basis of clinical appearance. Nail scrapings were collected from toenails and fingernails. Specimens were analyzed using direct microscopy. Nail changes after cART initiation were assessed by clinical examination. RESULTS: Improvement in onychomycosis was observed in six patients with late and advanced HIV disease after initiation of cART. Complete resolution of onychomycosis was observed in one patient without the use of antifungal therapy; one patient required topical antifungal treatment, and two patients required systemic antifungal treatment to achieve complete resolution. CONCLUSIONS: Onychomycosis should be included in the group of pathologies that improve with cART-induced immune reconstitution. The pathogenesis of onychomycosis in HIV disease warrants investigation in the context of cell-mediated immunity restoration.

Análisis del polimorfismo genético de los loci HLA-B y HLA-DR en pacientes con onicomicosis dermatofítica y familiares en primer grado / Analysis of Genetic Polymorphism of the HLA-B and HLA-DR Loci in Patients with Dermatophytic Onychomycosis and in Their First-Degree Relatives

En la onicomicosis hay factores predisponentes conocidos y una alta prevalencia en familiares no explicada por transmisión intrafamiliar. Analizamos la frecuencia génica de alelos de los genes HLA-B y HLA-DR en 25 familias de pacientes mexicanos con onicomicosis para conocer el papel del complejo mayor de histocompatibilidad (MHC) clase II en la susceptibilidad genética a esta enfermedad. Se estudiaron 78 individuos, 47 de ellos con onicomicosis y 31 sanos. Se determinaron las frecuencias génicas de los alelos de los loci HLA-B y HLA-DR y se compararon con las presentes en familiares de primer grado sin onicomicosis y con un grupo de individuos sanos. Estas fueron semejantes a las de familiares sanos; sin embargo, al comparar pacientes con controles históricos se encontró un aumento de la frecuencia del alelo HLA-DR8 (p=0,03; OR=1,89; IC 95%: 0,98-36). Estos datos sugieren que dentro del MHC existen genes de susceptibilidad al desarrollo de onicomicosis; en particular con el alelo HLA-DR8 (AU)

Onychomycosis is known to have predisposing factors and a high prevalence within families that cannot be explained by within-family transmission. We determined the frequency of HLA-B and HLA-DR haplotypes in 25 families of Mexican patients with onychomycosis in order to define the role of the class II major histocompatibility complex (MHC) in genetic susceptibility to this infection. Seventy-eight subjects participated in the study, 47 with onychomycosis and 31 healthy individuals. The frequencies of the HLA-B and HLA-DR haplotypes were compared with those found in first-degree relatives without onychomycosis and in a historic control group of healthy individuals. The frequencies in the controls were similar to those of the healthy relatives of the patients. However, on comparison of the patients with historic controls, we detected a higher frequency of the HLA-DR8 haplotype (P=0.03; odds ratio, 1.89; 95% confidence interval, 0.98-36). These findings suggest that there are polymorphisms in genes of the MHC that increase susceptibility to onychomycosis, particularly haplotype HLA-DR8 (AU)

[Mucocutaneous candidiasis]. / Mukokutane Candida-Infektionen.

Infection with the yeast candida is a quite common disease. Its occurrence might be harmless, however, Candida infections often present with an underlying systemic disease. Thus, candidiasis in some cases can be considered as an indicator for e.g. diabetes mellitus or immune deficiency (i.e. HIV or leukaemia). Of note, we have to distinguish the colonisation and the infection with Candida because only the presence of the yeast together with clinical symptoms is an indication for treatment. The latter has to be adapted according to age, localisation and potentially underlying systemic disease. A special form of Candidiasis constitutes the chronic mucocutaneous candidiasis which can occur in line with hereditary immune deficiencies or also isolated. In the present review we discuss the current status of diagnostic and therapy of mucocutaneous candidiasis as well as the (patho-) immunologic background of yeast infections using the example of a special case of chronic mucocutaneous candidiasis.