Ilan S. Schwartz

Novel taxa of thermally dimorphic systemic pathogens in the Ajellomycetaceae (Onygenales).

Recent discoveries of novel systemic fungal pathogens with thermally dimorphic yeast‐like phases have challenged the current taxonomy of the Ajellomycetaceae, a family currently comprising the genera Blastomyces, Emmonsia, Emmonsiellopsis, Helicocarpus, Histoplasma, Lacazia and Paracoccidioides. Our morphological, phylogenetic and phylogenomic analyses demonstrated species relationships and their specific phenotypes, clarified generic boundaries and provided the first annotated genome assemblies to support the description of two new species. A new genus, Emergomyces, accommodates Emmonsia pasteuriana as type species, and the new species Emergomyces africanus, the aetiological agent of case series of disseminated infections in South Africa. Both species produce small yeast cells that bud at a narrow base at 37°C and lack adiaspores, classically associated with the genus Emmonsia. Another novel dimorphic pathogen, producing broad‐based budding cells at 37°C and occurring outside North America, proved to belong to the genus Blastomyces, and is described as Blastomyces percursus.

Clinical Characteristics, Diagnosis, Management, and Outcomes of Disseminated Emmonsiosis: A Retrospective Case Series

BACKGROUND We describe the geographic distribution, clinical characteristics, and management of patients with disease caused by Emmonsia sp., a novel dimorphic fungal pathogen recently described in South Africa. METHODS We performed a multicenter, retrospective chart review of laboratory-confirmed cases of emmonsiosis diagnosed across South Africa from January 2008 through February 2015. RESULTS Fifty-four patients were diagnosed in 5/9 provinces. Fifty-one patients (94%) were human immunodeficiency virus coinfected (median CD4 count 16 cells/µL [interquartile range, 6-40]). In 12 (24%) of these, antiretroviral therapy had been initiated in the preceding 2 months. All patients had disseminated disease, most commonly involving skin (n = 50/52, 96%) and lung (n = 42/48, 88%). Yeasts were visualized on histopathologic examination of skin (n = 34/37), respiratory tissue (n = 2/4), brain (n = 1/1), liver (n = 1/2), and bone marrow (n = 1/15). Emmonsia sp. was cultured from skin biopsy (n = 20/28), mycobacterial/fungal and aerobic blood culture (n = 15/25 and n = 9/37, respectively), bone marrow (n = 12/14), lung (n = 1/1), lymph node (n = 1/1), and brain (n = 1/1). Twenty-four of 34 patients (71%) treated with amphotericin B deoxycholate, 4/12 (33%) treated with a triazole alone, and none of 8 (0%) who received no antifungals survived. Twenty-six patients (48%) died, half undiagnosed. CONCLUSIONS Disseminated emmonsiosis is more widespread in South Africa and carries a higher case fatality rate than previously appreciated. Cutaneous involvement is near universal, and skin biopsy can be used to diagnose the majority of patients.

50 Years of Emmonsia Disease in Humans: The Dramatic Emergence of a Cluster of Novel Fungal Pathogens

CITATION: Schwartz, I. S. et al. 2015. 50 years of Emmonsia disease in humans : the dramatic emergence of a cluster of novel fungal pathogens. PLoS Pathogens, 11(11): e1005198, doi:10.1371/journal.ppat.1005198.

In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients

ABSTRACT Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomycesafricanus, a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent.

AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults With Advanced HIV and Recent-Onset, Widespread Skin Lesions

Abstract Background Skin lesions are common in advanced HIV infection and are sometimes caused by serious diseases like systemic mycoses (SM). AIDS-related SM endemic to Western Cape, South Africa, include emergomycosis (formerly disseminated emmonsiosis), histoplasmosis, and sporotrichosis. We previously reported that 95% of patients with AIDS-related emergomycosis had skin lesions, although these were frequently overlooked or misdiagnosed clinically. Prospective studies are needed to characterize skin lesions of SM in South Africa and to help distinguish these from common HIV-related dermatoses. Methods We prospectively enrolled HIV-infected adult patients living in Western Cape, South Africa, with CD4 counts ≤100 cells/μL and widespread skin lesions present ≤6 months that were deemed clinically compatible with SM. We obtained skin biopsies for histopathology and fungal culture and collected epidemiological and clinical data. Results Of 34 patients enrolled and in whom a diagnosis could be made, 25 had proven SM: 14 had emergomycosis, and 3 each had histoplasmosis and sporotrichosis; for 5 additional patients, the fungal species could not be identified. Antiretroviral therapy (ART) had been initiated in the preceding 4 weeks for 11/25 (44%) patients with SM (vs no patients without SM). Plaques and scale crust occurred more frequently in patients with SM (96% vs 25%, P = .0002; and 67% vs 13%, P = .01, respectively). Conclusions Recent ART initiation and presence of plaques or scale crust should make clinicians consider SM in patients with advanced HIV infection in this geographic area. Clinical overlap between SM and other dermatoses makes early skin biopsy critical for timely diagnosis and treatment.

First report of urease activity in the novel systemic fungal pathogen Emergomyces africanus : a comparison with the neurotrope Cryptococcus neoformans

Abstract Cryptococcus neoformans is an opportunistic pathogen responsible for the AIDS‐defining illness, cryptococcal meningitis. During the disease process, entry of cryptococcal cells into the brain is facilitated by virulence factors that include urease enzyme activity. A novel species of an Emmonsia‐like fungus, recently named Emergomyces africanus, was identified as a cause of disseminated mycosis in HIV‐infected persons in South Africa. However, in contrast to C. neoformans, the enzymes produced by this fungus, some of which may be involved in pathogenesis, have not been described. Using a clinical isolate of C. neoformans as a reference, the study aim was to confirm, characterise and quantify urease activity in E. africanus clinical isolates. Urease activity was tested using Christensens urea agar, after which the presence of a urease gene in the genome of E. africanus was confirmed using gene sequence analysis. Subsequent evaluation of colorimetric enzyme assay data, using Michaelis‐Menten enzyme kinetics, revealed similarities between the substrate affinity of the urease enzyme produced by E. africanus (Km ca. 26.0 mM) and that of C. neoformans (Km ca. 20.6 mM). However, the addition of 2.5 g/l urea to the culture medium stimulated urease activity of E. africanus, whereas nutrient limitation notably increased cryptococcal urease activity.

HIV Prevalence Correlates with High-Risk Sexual Behavior in Ethiopia's Regions

Background HIV prevalence varies between 0.9 and 6.5% in Ethiopia’s eleven regions. Little has been published examining the reasons for this variation. Methods We evaluated the relationship between HIV prevalence by region and a range of risk factors in the 2005 and 2011 Ethiopian Demographic Health Surveys. Pearson’s correlation was used to assess the relationship between HIV prevalence and each variable. Results There was a strong association between HIV prevalence and three markers of sexual risk: mean lifetime number of partners (men: r = 0.87; P < 0.001; women: r = 0.60; P = 0.05); reporting sex with a non-married, non-cohabiting partner (men: r = 0.92; P < 0.001, women r = 0.93; P < 0.001); and premarital sex. Condom usage and HIV testing were positively associated with HIV prevalence, while the prevalence of circumcision, polygamy, age at sexual debut and male migration were not associated with HIV prevalence. Conclusion Variation in sexual behavior may contribute to the large variations in HIV prevalence by region in Ethiopia. Population-level interventions to reduce risky sexual behavior in high HIV incidence regions should be considered.

Attempted molecular detection of the thermally dimorphic human fungal pathogen Emergomyces africanus in terrestrial small mammals in South Africa

The ecological niche of Emergomyces africanus (formerly Emmonsia species), a dimorphic fungus that causes an AIDS-related mycosis in South Africa, is unknown. We hypothesized that natural infection with E. africanus occurs in wild small mammals. Using molecular detection with primers specific for E. africanus, we examined 1402 DNA samples from 26 species of mole-rats, rodents, and insectivores trapped in South Africa that included 1324 lung, 37 kidney, and 41 liver specimens. DNA of E. africanus was not detected in any animals. We conclude that natural infection of wild small mammals in South Africa with E. africanus has not been proven.

Partner concurrency and HIV infection risk in South Africa

BACKGROUND The relationship between concurrent sexual partnerships and HIV risk is not fully understood. Evidence on the relationship between partner concurrency (ones sexual partner has another partner) and individual HIV risk is limited. In this study, the relationship between reported sexual partner concurrency and the risk of HIV infection was explored among South Africans. METHODS Data from the third South African national HIV survey were used. In this survey, performed in 2008, questionnaires and HIV tests were administered to a nationally representative sample of 15031 persons. Bivariate analysis and multiple logistic regression were used to evaluate the relationship between partner concurrency and HIV serostatus. Spearmans correlation was used to test the association between the prevalence of HIV and partner concurrency by race in women. RESULTS The relationship between HIV prevalence and partner concurrency varied by race. At a cross-racial level there was a positive association between HIV prevalence and partner concurrency for women (rho=0.95, p=0.05). Among coloured, white, and Indian persons, HIV prevalence and partner concurrency rates were too low to allow further statistical testing. In the bivariate analysis, black African women who reported partner concurrency had a higher prevalence of HIV (36% (95% confidence interval (CI) 29.7-42.0) vs. 23% (95% CI 19.6-26.1), p<0.001). After controlling for demographic, social, biological, and behavioural variables, the association remained statistically significant (adjusted odds ratio (aOR) 1.4, p=0.04). The association was stronger among 15-29-year-old black African women (aOR 1.8, p=0.03) than among women aged 30 years and older (aOR 1.3, p=0.36). CONCLUSIONS These results suggest that partner concurrency may increase the HIV infection risk for black South African women, and in particular, for younger women.

Interferon-gamma release assays piloted as a latent tuberculous infection screening tool in Canadian federal inmates

BACKGROUND Interferon-gamma release assays (IGRAs) may be useful in diagnosing latent tuberculous infection (LTBI) in inmates; however, published experience in these settings is limited. OBJECTIVE To identify variables associated with IGRA positivity among Canadian federal inmates with positive tuberculin skin test (TST) results. DESIGN On intake, TST-positive (≥10 mm) inmates were offered an IGRA (QuantiFERON(®)-TB Gold), and demographic and historical data were collected. IGRA-positive and -negative inmates were compared using the χ(2) test and multivariable logistic regression; the final models goodness of fit was assessed using Hosmer-Lemeshow test and area under the receiver operating characteristic curve (AUC). RESULTS Of 96 TST-positive inmates, 31 (32.3%) were IGRA-positive. Variables associated with positive IGRA were age >45 years (11/20 vs. 20/75, P = 0.016) and previous LTBI treatment (9/20 vs. 13/55, P = 0.032) in univariate analysis, and being from a country with a moderate or high estimated tuberculosis (TB) incidence (OR 3.5, 95%CI 1.3-9.4, P = 0.013) and absence of bacille Calmette-Guérin (BCG) vaccination (OR 3.3, 95%CI 1.2-9.0, P = 0.017) in multivariable analysis. The data fit the model well, classifying the group better than chance alone (AUC 0.67, P = 0.007). CONCLUSION High discordance with TST, particularly among BCG-vaccinated inmates and those from low TB incidence countries, suggest that IGRA may be useful in Canadian federal penitentiary screening programmes.