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Concept: Histoplasmosis

28

We report the detection of high-titre anti-Histoplasma capsulatum IgM in the serum of three young adult males occupationally exposed to bat guano. Multidrug treatment with trimethoprim- sulfamethoxazole was started, followed by ciprofloxacin, clarithromycin, metamizole sodium, rifampicin/isoniazid/pyrazinamide, moxifloxacin and lastly amphotericin B and ceftriaxone. Despite treatment the condition of one patient deteriorated, and he died 23 days after exposure. The other two patients recovered after receiving similar therapy with the addition of voriconazole. They are currently being treated with itraconazole for a 1-year period.

Concepts: Patient, Amphotericin B, Bat, Antifungals, Ergosterol, Histoplasmosis, Guano, World Health Organization essential medicines

27

Histoplasmosis is a fungal infection that, although not endemic in Japan, has seen a rise in the number of Japanese cases since the mid-1980s. Diagnosis of the disease is not straightforward, and the main method of detection, fungal culture (which has biosafety-related issues), is of low sensitivity in general. Alternative methods that depend on antibody or antigen detection have had limited use. We have developed a histoplasmosis detection method based on PCR amplification of the Histoplasma capsulatum M antigen gene. We compared this method with fungal culture and serological diagnostic techniques. Among five cases that were finally diagnosed as histoplasmosis, the fungal culture method was only successful in identifying one such case. Although the presence of anti-H. capsulatum antibodies was confirmed in three cases, our PCR method identified four of five cases of histoplasmosis. The performance of our PCR method could not be compared with the antigen detection method, which is used in the United States but is not routinely used in Japan. However, the PCR method was shown to have high sensitivity and specificity for H. capsulatum. Although the number of histoplasmosis cases examined in this study was small, our data suggest that the molecular diagnosis technique has potential for increasing the reliability of histoplasmosis diagnosis when used in combination with established methods.

Concepts: Antibody, Infectious disease, Sensitivity and specificity, Histoplasmosis

27

We present a case of progressive disseminated histoplasmosis in an immunocompetent traveler. Histoplasmosis was acquired in South America; its manifestations included prolonged fever, splinter hemorrhages, erythema multiforme, arthritis, and mediastinal lymphadenopathy. To the best of our knowledge no splinter hemorrhages had previously been reported in a patient with histoplasmosis.

Concepts: Symptoms, Lymphadenopathy, Greatest hits albums, South America, Greatest hits, Histoplasmosis, Progressive disseminated histoplasmosis

25

To report on a case of Histoplasma capsulatum endogenous endophthalmitis in an immunocompetent patient.

Concepts: Histoplasmosis

9

Histoplasmosis in Africa has markedly increased since the advent of the HIV/AIDS epidemic but is under-recognised. Pulmonary histoplasmosis may be misdiagnosed as tuberculosis (TB). In the last six decades (1952-2017), 470 cases of histoplasmosis have been reported. HIV-infected patients accounted for 38% (178) of the cases. West Africa had the highest number of recorded cases with 179; the majority (162 cases) were caused by Histoplasma capsulatum var. dubuosii (Hcd). From the Southern African region, 150 cases have been reported, and the majority (119) were caused by H. capsulatum var. capsulatum (Hcc). There have been 12 histoplasmin skin test surveys with rates of 0% to 35% positivity. Most cases of Hcd presented as localised lesions in immunocompetent persons; however, it was disseminated in AIDS patients. Rapid diagnosis of histoplasmosis in Africa is only currently possible using microscopy; antigen testing and PCR are not available in most of Africa. Treatment requires amphotericin B and itraconazole, both of which are not licensed or available in several parts of Africa.

Concepts: HIV, AIDS, HIV/AIDS, Africa, Sub-Saharan Africa, Tuberculosis, Histoplasmosis, Botswana

5

Histoplasma capsulatum comprises a worldwide complex of saprobiotic fungi mainly found in nitrogen/phosphate (often bird guano) enriched soils. The microconidia of Histoplasma species may be inhaled by mammalian hosts, and is followed by a rapid conversion to yeast that can persist in host tissues causing histoplasmosis, a deep pulmonary/systemic mycosis. Histoplasma capsulatum sensu lato is a complex of at least eight clades geographically distributed as follows: Australia, Netherlands, Eurasia, North American classes 1 and 2 (NAm 1 and NAm 2), Latin American groups A and B (LAm A and LAm B) and Africa. With the exception of the Eurasian cluster, those clades are considered phylogenetic species.

Concepts: Evolution, Biology, Species, Fungus, United States, Phylogenetics, North America, Histoplasmosis

1

As eukaryotes, fungi posses few drug targets unique from mammalian cells. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g., Histoplasma) are of particular concern as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoring Histoplasma growth and employed it in a phenotypic screen of 3600 commercially available compounds. Seven hit compounds were identified that inhibited Histoplasma yeast growth. The compound 41F5 has fungistatic activity against Histoplasma yeast at micromolar concentrations, with an IC50 of 0.87 micromolar, and has the greatest selectivity for yeast (> 62) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5-position. 41F5 inhibits Histoplasma growth in liquid culture and similarly inhibits yeasts within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells from Histoplasma-induced macrophage death making this aminothiazole hit compound an excellent candidate for development as an antifungal for Histoplasma infections.

Concepts: Immune system, Bacteria, Eukaryote, Cell biology, Fungus, Yeast, Histoplasmosis, Host

0

We report a case of a Puerto Rican male with advanced AIDS who presented with multiple falls and pancytopenia. Magnetic resonance imaging (MRI) of the brain, as initial workup, revealed 2 ring-enhancing brain lesions. Initial cerebrospinal fluid analysis revealed minimal cells, mildly elevated protein, and no organism seen on gram stain. Due to prohibitive thrombocytopenia, brain biopsy was deferred. He had neither clinical nor radiographic improvement despite empiric therapy for both toxoplasmosis and bacterial abscesses. Indicated by pancytopenia, bone marrow (BM) aspiration was performed. Culture of BM aspirate grewHistoplasma capsulatum. Urine histoplasma antigen was markedly elevated. He was treated with liposomal amphotericin B (LamB) for progressive disseminated histoplasmosis with probable central nervous system involvement. Cerebrospinal fluid histoplasma antigen obtained after 2 months of LamB was detected. After prolonged course of LamB, he took itraconazole. Brain MRI at 7-month follow-up revealed significant improvement from baseline study.

Concepts: Central nervous system, Nervous system, Brain, Magnetic resonance imaging, Cerebrospinal fluid, Amphotericin B, Meninges, Histoplasmosis

0

Epidemiological cutoff values (ECV) have been used as a tool to detect the acquisition of resistance mechanisms to antifungal drugs. In this context, the objective of this study was to determine the epidemiological cutoff values for classic antifungals against Histoplasma capsulatum var. capsulatum isolates from HIV-infected patients with the diagnosis of disseminated histoplasmosis. Initially, the minimum inhibitory concentrations (MIC) for amphotericin B, itraconazole, fluconazole, voriconazole and caspofungin against 138 isolates of H. capsulatum in the filamentous form were determined by the broth microdilution method, then, the antifungal ECVs were calculated. MIC ranges were 0.0078-1 μg/mL for amphotericin B; 0.0005-0.0625 μg/mL for itraconazole; 2-≥256 μg/mL for fluconazole; 0.0078-1 μg/mL for voriconazole and 0.0156- ≥32 μg/mL for caspofungin. The obtained ECVs were 0.5; 0.0313; 128; 0.5 and 16 μg/mL for amphotericin B, itraconazole, fluconazole, voriconazole and caspofungin, respectively. The percentage of wild-type isolates was 96.38% for amphotericin B, 98.55% for itraconazole and 99.28% for fluconazole, voriconazole and caspofungin. Although these results do not cover all phylogenetic species of H. capsulatum, they bring important information on strains from Brazil. In addition, the assessed isolates were from HIV-positive patients, which may not reflect the antifungal ECVs against isolates from immunocompetent individuals and other sources. Finally, this study pioneers the initiative of establishing epidemiological cutoff values for five antifungal agents against H. capsulatum var. capsulatum, providing a criterion for the interpretation of susceptibility results; as well as a monitoring strategy for the emergence of antifungal resistance.

Concepts: Antifungals, Flucytosine, Candidiasis, Ergosterol, Antifungal drug, Fluconazole, Histoplasmosis, Echinocandin

0

Histoplasmosis is an important cause of mortality in patients with AIDS, especially in countries with limited access to antiretroviral therapies and diagnostic tests. However, many disseminated infections in Latin America go undiagnosed. A simple, rapid method to detectHistoplasma capsulatuminfection in endemic regions would dramatically decrease time to diagnosis and treatment, reducing morbidity and mortality. The aim of this study was to validate a commercial monoclonalHistoplasmagalactomannan (HGM) ELISA (Immuno-Mycologics [IMMY], Norman, Oklahoma, USA) in two cohorts of people living with HIV/AIDS (PLHIV). We analyzed urine samples from 589 people (466 from Guatemala and 123 from Colombia), including 546 from PLHIV and 43 from non-PLHIV controls. Sixty-three of these people (35 from Guatemala and 28 from Colombia) had confirmed histoplasmosis by isolation ofH. capsulatumUsing the standard curve provided by the quantitative commercial test, sensitivity was 98% (95% CI, 95-100) and specificity was 97% (95% CI, 96-99) (cutoff=0.5 ng/mL). Semi-quantitative results, using a calibrator of 12.5 ng/mL ofHistoplasmagalactomannan to calculate an EIA Index Value (EIV) of the samples, showed a sensitivity of 95% (95% CI, 89-100%) and specificity of 98% (95% CI, 96-99%) (cutoff ≥2.6 EIV). This relatively simple-to-perform commercial antigenuria test showed a high performance, with reproducible results in both countries, suggesting that it can used to detect progressive disseminated histoplasmosis in PLHIV in a wide range of clinical laboratories in countries where histoplasmosis is endemic.

Concepts: Antiretroviral drug, AIDS, Scientific method, United States, Spanish language, Brazil, Americas, Histoplasmosis