In this part 1 of a 2-part continuing medical education series, the epidemiology, clinical features, and diagnostic methods for fungal skin neglected tropical diseases (NTDs), which include eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis, are reviewed. These infections, several of which are officially designated as NTDs by the World Health Organization (WHO), cause substantial morbidity and stigma worldwide and are receiving increased attention due to the potential for climate change-related geographic expansion. Domestic incidence may be increasing in the setting of global travel and immunosuppression. United States dermatologists may play a central role in early detection and initiation of appropriate treatment, leading to decreased morbidity and mortality.

In this part 2 of a 2-part continuing medical education series, the management, outcomes, and morbidities for fungal skin neglected tropical diseases (NTDs), including eumycetoma, chromoblastomycosis, paracoccidioidomycosis, sporotrichosis, emergomycosis, talaromycosis, and lobomycosis are reviewed. While fungal skin NTDs are associated with poverty in resource-limited settings, they are more often associated with immunosuppression and global migration in the United States. These infections have a high morbidity burden, including disfigurement, physical disability, coinfection, malignant transformation, mental health issues, and financial impact. For most fungal skin NTDs, management is difficult and associated with low cure rates. Dermatologists play a central role in initiating appropriate treatment early in disease course in order to improve patient outcomes.

Endemic systemic mycoses such as blastomycosis, coccidioidomycosis, histoplasmosis, talaromycosis, paracoccidioidomycosis are emerging as an important cause of morbidity and mortality worldwide. We conducted a systematic review on endemic systemic mycoses reported in Italy from 1914 to nowadays. We found out: 105 cases of histoplasmosis, 15 of paracoccidioidomycosis, 10 of coccidioidomycosis, 10 of blastomycosis and 3 of talaromycosis. Most cases have been reported in returning travelers and expatriates or immigrants. Thirtytwo patients did not have a story of traveling to an endemic area. Fortysix subjects had HIV/AIDS. Immunosuppression was the major risk factor for getting these infections and for severe outcomes. We provided an overview on microbiological characteristics and clinical management principles of systemic endemic mycoses with a focus on the cases reported in Italy.

Systemic mycoses have been viewed as neglected diseases and they are responsible for deaths and disabilities around the world. Rapid, low-cost, simple, highly-specific and sensitive diagnostic tests are critical components of patient care, disease control and active surveillance. However, the diagnosis of fungal infections represents a great challenge because of the decline in the expertise needed for identifying fungi, and a reduced number of instruments and assays specific to fungal identification. Unfortunately, time of diagnosis is one of the most important risk factors for mortality rates from many of the systemic mycoses. In addition, phenotypic and biochemical identification methods are often time-consuming, which has created an increasing demand for new methods of fungal identification. In this review, we discuss the current context of the diagnosis of the main systemic mycoses and propose alternative approaches for the identification of new targets for fungal pathogens, which can help in the development of new diagnostic tests.

Cryptococcosis is associated with high rates of morbidity and mortality, especially in AIDS patients. Its treatment is carried out by combining amphotericin B and azoles or flucytosine, which causes unavoidable toxicity issues in the host. Thus, the urgency in obtaining new antifungals drives the search for antimicrobial peptides (AMPs). This study aimed to extend the understanding of the mechanism of action of an AMP analog from wasp peptide toxins, MK58911-NH2, on Cryptococcus neoformans. We also evaluated if MK58911-NH2 can act on cryptococcal cells in macrophages, biofilms, and an immersion zebrafish model of infection. Finally, we investigated the structure-antifungal action and the toxicity relationship of MK58911-NH2 fragments and a derivative of this peptide (MH58911-NH2). The results demonstrated that MK58911-NH2 did not alter the fluorescence intensity of the cell wall-binding dye calcofluor white or the capsule-binding dye 18b7 antibody-fluorescein isothiocyanate (FITC) in C. neoformans but rather reduced the number and size of fungal cells. This activity reduced the fungal burden of C. neoformans in both macrophages and zebrafish embryos as well as within biofilms. Three fragments of the MK58911-NH2 peptide showed no activity against Cryptococcus and not toxicity in lung cells. The derivative peptide MH58911-NH2, in which the lysine residues of MK58911-NH2 were replaced by histidines, reduced the activity against extracellular and intracellular C. neoformans. On the other hand, it was active against biofilms and showed reduced toxicity. In summary, these results showed that peptide MK58911-NH2 could be a promising agent against cryptococcosis. This work also opens a perspective for the verification of the antifungal activity of other derivatives.

The physiopathologic characteristics of COVID-19 (high levels of inflammatory cytokines and T-cell reduction) promote fungal colonization and infection, which can go unnoticed because the symptoms in both diseases are very similar. The objective of this work was to study the current epidemiology of systemic mycosis in COVID-19 times. A literature search on the subject (January 2020-February 2021) was performed in PubMed, Embase, Cochrane Library, and LILACS without language restrictions. Demographic data, etiological agent, risk factors, diagnostic methods, antifungal treatment, and fatality rate were considered. Eighty nine publications were found on co-infection by COVID-19 and pneumocystosis, candidiasis, aspergillosis, mucormycosis, coccidioidomycosis, or histoplasmosis. In general, the co-infections occurred in males over the age of 40 with immunosuppression caused by various conditions. Several species were identified in candidiasis and aspergillosis co-infections. For diagnosis, diverse methods were used, from microbiological to molecular. Most patients received antifungals; however, the fatality rates were 11-100%. The latter may result because the clinical picture is usually attributed exclusively to SARS-CoV-2, preventing a clinical suspicion for mycosis. Diagnostic tests also have limitations beginning with sampling. Therefore, in the remainder of the pandemic, these diagnostic limitations must be overcome to achieve a better patient prognosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including >34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age >65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

Aim: Cryptococcosis causes significant morbidity and mortality worldwide, but pediatric data are limited. Methods: A retrospective literature review of Australian pediatric cryptococcosis and additional 10-year audit of cases from a large pediatric network. Results: 22 cases of cryptococcosis in children were identified via literature review: median age was 13.5 years (IQR 7.8-16 years), 18/22 (82%) had meningitis or central nervous system infection. Where outcome was reported, 11/18 (61%) died. Of six audit cases identified from 2008 to 2017, 5 (83%) had C. gattii disease and survived. One child with acute lymphoblastic leukemia and C. neoformans infection died. For survivors, persisting respiratory or neurological sequelae were reported in 4/6 cases (67%). Conclusion: Cryptococcosis is uncommon in Australian children, but is associated with substantial morbidity.

Blastomycosis is a systemic fungal infection that most commonly affects dogs and humans. The disease is thought to be endemic in southern regions of Michigan, USA, but epidemiologic investigations have not been reported in detail for this state. The primary aims of this study were to investigate the prevalence and distribution of canine blastomycosis cases in Michigan and to identify risk factors for infection. Over 200 primary care veterinary clinics throughout the state were surveyed regarding blastomycosis prevalence, and demographic information was obtained from medical records of affected dogs that were evaluated at these clinics. A retrospective case control study was conducted for an additional 49 dogs with blastomycosis that were evaluated at specialty referral centers located in the southern mid-Michigan region. Prevalence rates were calculated for each county, and cases were mapped using geocoding software. Univariable and multivariable analyses were used to identify risk factors for infection. Prevalence rates were ≥100 cases per 100,000 dogs in five counties. Most blastomycosis cases originated from the Upper Peninsula or from a high-density area in the northern Lower Peninsula. Multivariable regression analysis identified travel or residence north of the 45th parallel as a strong risk factor for infection (P < .001). Blastomycosis was uncommon in southern counties. These results refute previous speculations and should be of value to both human and animal health. Given that many heightened risk areas are popular tourist destinations, practitioners across the USA should be mindful of the spatial distribution of blastomycosis in Michigan.

The need for better antifungal therapy is commonly accepted in view of the high mortality rates associated with systemic infections, the low number of available antifungal classes, their associated toxicity and the increasing number of infections caused by strains with natural or acquired resistance. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets when compared to the conventional ones currently used. Although new potential targets are reported, translating the discoveries from bench to bedside is a long process and most of these drugs fail to reach the patients. In this review, we discuss the development of antifungal drugs focusing on the approach of drug repurposing and the search for novel drugs for classical targets, the most recently described gene targets for drug development, the possibilities of immunotherapy using antibodies, cytokines, therapeutic vaccines and antimicrobial peptides.