Emergomyces: The global rise of new dimorphic fungal pathogens
Authors:
Ilan S. Schwartz aff001; Nelesh P. Govender aff002; Lynne Sigler aff004; Yanping Jiang aff005; Tsidiso G. Maphanga aff002; Barbra Toplis aff008; Alfred Botha aff008; Karolina Dukik aff005; J. Claire Hoving aff009; Jose F. Muñoz aff010; Sybren de Hoog aff005; Christina A. Cuomo aff010; Robert Colebunders aff012; Chris Kenyon aff013
Authors place of work:
Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
aff001; National Institute for Communicable Diseases, a Division of the National Health Laboratory Service, Johannesburg, Gauteng, South Africa
aff002; Department of Clinical Microbiology and Infectious Diseases, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
aff003; Department of Biological Sciences, Faculty of Sciences, University of Alberta, Edmonton, Alberta, Canada
aff004; Westerdijk Fungal Biodiversity Institute, Utrecht, the Netherlands
aff005; Department of Dermatology, The Affiliated Hospital, Guizhou Medical University, Guiyang, China
aff006; University of the Free State, Bloemfontein, Free State, South Africa
aff007; Department of Microbiology, Stellenbosch University, Stellenbosch, Western Cape, South Africa
aff008; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, Western Cape, South Africa
aff009; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
aff010; Center of Expertise in Mycology of RadboudUMC/ Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
aff011; Global Health Institute, University of Antwerp, Antwerp, Belgium
aff012; Clinical Sciences Unit, Institute of Tropical Medicine, Antwerp, Belgium
aff013; Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa
aff014
Published in the journal:
Emergomyces: The global rise of new dimorphic fungal pathogens. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1007977
Category:
Pearls
doi:
https://doi.org/10.1371/journal.ppat.1007977
Unknown until recently, the genus Emergomyces is composed of dimorphic fungi with human pathogenic potential. Five described species have been implicated as causes of disease in immunocompromised persons on at least 4 continents. In some regions, such as southern Africa, this disease, emergomycosis, is now the most commonly diagnosed dimorphic fungal infection. Herein, we review the history of these fungi, clinical features and pathogenesis of disease, what is known of their biology, and future research directions.
Origin story and current status
In 1994, an Italian woman with advanced HIV disease and widespread cutaneous lesions was diagnosed with an atypical disseminated mycosis. A biopsy of skin tissue demonstrated small budding yeasts, resembling those of Histoplasma capsulatum, in addition to larger pleomorphic cells. Moreover, the fungus that grew in culture had a dissimilar microscopic appearance [1, 2]. The conidia were arranged in complex “florets” on slightly swollen stalks reminiscent of Emmonsia crescens or Ea. parva, fungi for which the thermodependent phase is characterized by swollen, thick-walled, nonreplicating cells called adiaspores, usually observed in the lungs of small terrestrial mammals in a disease called adiaspiromycosis [3]. Genetic analysis suggested the clinical isolate was related to Ea. crescens, and the fungus was therefore described in 1998 as Ea. pasteuriana [2].
In 2013, following the introduction of molecular identification procedures in some South African laboratories, a dimorphic fungus most closely related to Ea. pasteuriana was found to be the cause of a disseminated mycosis in patients with advanced HIV disease [4]. Since then, infection with this fungus has been established to comprise the most frequently diagnosed dimorphic mycosis in South Africa [5–7]. In light of these reports, global collections were re-examined for dimorphic Emmonsia-like fungi. Archived isolates were examined phenotypically and with genetic analyses based on ribosomal DNA sequences, ultimately leading to a taxonomic revision within the family Ajellomycetaceae [8, 9]. In brief, Ea. parva, the type species of Emmonsia, was transferred to the genus Blastomyces (as B. parvus), and the genus Emmonsia was more narrowly defined to include Ea. crescens and Ea. soli, the latter currently known only from soil [8, 9]. A new genus, Emergomyces, was created to accommodate Emmonsia-like systemic dimorphic pathogens related to Es. pasteurianus (formerly Ea. pasteuriana) and characterized in the thermodependent phase by small yeast cells with narrow-based buds [8, 9].
Five species are now described within Emergomyces [8, 9], and cases of disease have been reported globally (Fig 1). Es. pasteurianus, the type species, has been reported from Europe (including from Italy [1], Spain [10], France [ex-Georgia] [11], and the Netherlands [12]), Asia (China [13, 14] and India [ex-Nepal] [15]) and Africa (Uganda [ex-Rwanda] [16] and South Africa [9]). Es. africanus has been reported from South Africa and Lesotho [4, 9]. Es. canadensis has been reported from Canada (Saskatchewan) and the United States (Colorado and New Mexico) [17]. Es. orientalis has been reported from China [18], and Es. europaeus has been reported once from Germany [19].
Global geographic distribution of reported cases of emergomycosis [1, 4–7, 10–19, 28–30].
Each icon represents a single case except for Emergomyces africanus in South Africa, as indicated. Map created by Institute of Tropical Medicine, Antwerp.
The earliest known isolate among these Emergomyces species was from 1992 [17]. It remains unclear if these fungi have truly emerged or whether they are only now recognized because of an increase in the number of susceptible hosts, improved microbiology capacity, and/or the widespread adoption of molecular identification techniques in clinical and research laboratories.
Ecology
As with other systemic dimorphic fungi, infection is presumed to occur from inhalation of conidia, followed by a temperature-dependent transformation to a yeast-like phase that is capable of causing disease and of extrapulmonary dissemination (Fig 2).
Potential model for exposure and pathogenesis of Emergomyces.
1) Emergomyces species exist in soil in a mold phase, from where 2) conidia are released and aerosolized. 3) Upon inhalation by humans, the conidia undergo a temperature-dependent transformation in the lungs to yeast-like cells that replicate by budding and are capable of causing pulmonary disease in susceptible individuals. 4) Yeast-like cells disseminate hematogenously in macrophages throughout the body, causing extrapulmonary disease. 5) Cutaneous disease is most frequently reported, although virtually any body site can be affected.
Studies in search of an environmental reservoir for Emergomyces species have focused on Es. africanus in South Africa due to the large number of cases there [20–22]. Es. africanus DNA was detected in 30% of soil samples tested in the Western Cape Province, including from a wide range of soil habitats, such as soils associated with human activities like agriculture and horticulture and soils associated with plants endemic to the Cape Floral Kingdom. However, to date, the fungus has not been successfully isolated in culture from the environment, even with passage of soils through mice [20]. Es. africanus DNA was also detected in 10% of air samples collected in an urban location in the Cape Town metropole [21]. Naturally occurring infections of animals have not been demonstrated [22].
Emergomycosis
Disease caused by Emergomyces infection has been called emergomycosis (formerly disseminated emmonsiosis), and similarities have been noted among cases caused by different species. In general, patients with reported emergomycosis have been immunocompromised, including with HIV infection, solid organ transplantation, hematological malignancies, and immunosuppressant use [23]. Most patients with Es. africanus infection have had cutaneous lesions, which most commonly appear as papules, plaques, nodules, or ulcers, typically with widespread distributions [4, 6]. Pulmonary disease is also common: 86% of patients had abnormal chest X-rays in a series from South Africa [6]. Chest radiograph abnormalities have included diffuse reticulonodular disease, consolidation, effusions, and/or lymphadenopathy [6]. Other sites of disease that have been reported include the gastrointestinal tract, liver, lymph nodes, and bone marrow [6]. Limited pulmonary disease has rarely been described, observed in the sole reported case of disease caused by Es. europaeus [19]. For other species, all reported cases have involved disseminated disease. This may reflect a diagnostic bias in clinical practice due to late disease presentation and limited access to more invasive (e.g., bronchoscopic) pulmonary sampling in resource limited settings or reporting bias in the medical literature.
The diagnosis of emergomycosis can be made by biopsy of affected tissue for histopathology and fungal culture. Histopathology findings include small (2–5-μm) yeasts with narrow-based budding, best seen with fungal stains [4]. The findings are insufficiently distinct from H. capsulatum to allow definitive identification from histopathological appearance alone [5]. The diagnosis can be confirmed by culture of Emergomyces species from clinical samples. Where fungal cultures are negative (or omitted), PCR of fresh, affected tissue using amplification and sequencing of the internal transcribed spacer (ITS) can establish the correct diagnosis [6, 9].
Emergomyces species grow readily on standard fungal media (e.g., Sabouraud agar, malt extract agar, or potato dextrose agar), incubated at 24–30°C. Colonies are yellowish white to tan, initially glabrous, becoming powdery, slightly raised, and furrowed, and reach diameters of 2.5 to 3.5 cm in 3 weeks. Microscopically, Emergomyces spp. are characterized in the mold phase by slender conidiophores that arise from hyphae at right angles and form “florets” of short secondary conidiophores bearing single small subspherical conidia (see Fig 2, step 1 [inset]). Conversion from the mold to the yeast phase occurs readily when colonies are streaked onto potato dextrose agar or malt extract agar and incubated at 35°C [8, 9, 17].
Clinical microbiologists should be aware that Emergomyces species can cross react with a commercial DNA probe for B. dermatitidis [17]. There are neither sensitive nor specific serological tests nor biomarkers for the diagnosis of emergomycosis, though cross-reactivity can be observed with tests for related fungal infections [5, 6]. Emergomyces species may cross react with Histoplasma urinary antigen tests [5, 6], but a negative test cannot exclude the diagnosis: in a series of 10 patients with culture-proven emergomycosis, only 3 tested positive by Histoplasma urinary antigen test [5].
Current treatment recommendations for emergomycosis are based on observational studies and expert opinion and are the same as those for patients with histoplasmosis [6, 23]. Initially, immunocompromised patients with emergomycosis should be treated with amphotericin B for 10–14 days; where available, liposomal formulations are preferred over deoxycholate because of a more favorable toxicity profile. Thereafter, patients should be treated with itraconazole or another newer azole for 12 months pending immune reconstitution. Fluconazole should be avoided because high minimum inhibitory concentrations have been observed [7, 17, 24]. Among HIV-infected persons with emergomycosis who are antiretroviral therapy (ART)–naive (or on a failing ART regimen), the optimal timing of ART initiation (or modification) has not been established.
Pathogenesis
There remains much to learn about the virulence factors of these fungi and pathogenesis involved in infection. Known virulence factor genes of dimorphic fungi are conserved in Es. africanus and Es. pasteurianus [25]. The role of these in Emergomyces pathogenesis still needs to be evaluated. Strains of Es. africanus, Es. europaeus, and Es. pasteurianus (but not Es. canadensis or Es. orientalis) express urease [8, 26], a known virulence factor for some pathogenic fungi like Cryptococcus neoformans and C. gattii. Experimental infections have demonstrated susceptibility of golden hamsters and mice [20, 27]. Schwartz and colleagues found that intraperitoneal inoculations with Es. africanus were fatal to wild-type mice at doses of 106 conidia, whereas lower doses did not cause disease (although the organism could still be cultured from their livers and spleens with inoculae as low as 102 conidia) [20]. Moreover, C57BL/6 mice were more susceptible to disease than BALB/c mice [20]. Further work is underway to understand the pathogenesis of disease and the immunology of infection.
Future directions
There are many unresolved questions about Emergomyces. The true geographic range of Emergomyces species remains speculative, given the sporadic reports of disease from areas with limited mycological diagnostic capacity. For example, a case of emergomycosis caused by Es. pasteurianus in Uganda was diagnosed after a visiting doctor returned to Germany with a skin biopsy specimen that was collected from a Ugandan patient with a disseminated mycosis [16]. There, the diagnosis was made by nucleic acid amplification and sequencing, technology lacking in most African settings. It is presumed that this case and those diagnosed in South Africa represent the “ears of the hippo” on the African continent and that many other cases there and possibly on other continents go unrecognized. The development of an affordable, accessible, and feasible diagnostic test for emergomycosis should be prioritized to enable the diagnosis in places where the disease is widespread and to detect the presence of it elsewhere for epidemiological surveillance.
Zdroje
1. Gori S, Drouhet E, Gueho E, Huerre M, Lofaro A, Parenti M, et al. Cutaneous disseminated mycosis in a patient with AIDS due to a new dimorphic fungus. J Mycol Med. 1998;8(2):57–63.
2. Drouhet E, Gueho E, Gori S, Huerre M, Provost F, Borgers M, et al. Mycological, ultrastructural and experimental aspects of a new dimorphic fungus, Emmonsia pasteuriana sp. nov. isolated from a cutaneous disseminated mycosis in AIDS. J Mycol Med. 1998;8(2):64–77.
3. Sigler L. Adiaspiromycosis and other infections caused by Emmonsia species. In: Hay RJ, Merz WG, editors. Topley and Wilson's Microbiology and Microbial Infections. 10th ed. London, U.K.: Arnold Hodder; 2005. p. 809–24.
4. Kenyon C, Bonorchis K, Corcoran C, Meintjes G, Locketz M, Lehloenya R, et al. A dimorphic fungus causing disseminated infection in South Africa. N Engl J Med. 2013;369(15):1416–24. doi: 10.1056/NEJMoa1215460 24106934
5. Schwartz IS, Kenyon C, Lehloenya R, Claasens S, Spengane Z, Prozesky H, et al. 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. Open Forum Infect Dis. 2017;4(4):ofx186. doi: 10.1093/ofid/ofx186 29164168
6. Schwartz IS, Govender NP, Corcoran C, Dlamini S, Prozesky H, Burton R, et al. Clinical characteristics, diagnosis, management and outcomes of disseminated emmonsiosis: a retrospective case series. Clin Infect Dis. 2015;61(6):1004–12. doi: 10.1093/cid/civ439 26060283
7. Maphanga TG, Britz E, Zulu TG, Mpembe RS, Naicker SD, Schwartz IS, et al. 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. J Clin Microbiol. 2017;55(6). doi: 10.1128/JCM.02524-16 28356416
8. Jiang Y, Dukik K, Munoz J, Sigler L, Schwartz IS, Govender NP, et al. Phylogeny, ecology and taxonomy of systemic pathogens and their relatives in Ajellomycetaceae (Onygenales): Blastomyces, Emergomyces, Emmonsia, Emmonsiellopsis. Fungal Divers. 2018;90(1):245–91. https://doi.org/10.1007/s13225-018-0403-y.
9. Dukik K, Muñoz JF, Jiang Y, Feng P, Sigler L, Stielow JB, et al. Novel taxa of thermally dimorphic systemic pathogens in the Ajellomycetaceae (Onygenales). Mycoses. 2017;60(5):296–309. doi: 10.1111/myc.12601 28176377
10. Pelegrín I, Alastruey-Izquierdo A, Ayats J, Cuenca-Estrella M, Cabellos C. A second look at Emmonsia infection can make the difference. Transpl Infect Dis. 2014;16(3):519–20. doi: 10.1111/tid.12214 24796631
11. Lavergne R-A, Kandel-Aznar C, Khatchatourian L, Garcia-Hermoso D, Jeddi F, Boutoille D, et al. Emmonsia pasteuriana: une cause rare d'infection fongique chez l'immunodéprimé. J Mycol Med. 2017;27(3):e7–e8. doi: 10.1016/j.mycmed.2017.04.025
12. Gast KB, van der Hoeven A, de Boer MGJ, van Esser JWJ, Kuijper EJ, Verweij JJ, et al. Two cases of Emergomyces pasteurianus infection in immunocompromised patients in the Netherlands. Med Mycol Case Rep. 2019. doi: 10.1016/j.mmcr.2019.01.005 30733915
13. Feng P, Yin S, Zhu G, Li M, Wu B, Xie Y, et al. Disseminated infection caused by Emmonsia pasteuriana in a renal transplant recipient. J Dermatol. 2015;42(12):1179–82. doi: 10.1111/1346-8138.12975 26105618
14. Tang XH, Zhou H, Zhang XQ, Han JD, Gao Q. Cutaneous disseminated emmonsiosis due to Emmonsia pasteuriana in a patient with cytomegalovirus enteritis. JAMA Dermatol. 2015;151(11):1263–4. doi: 10.1001/jamadermatol.2015.1792 26200259
15. Malik R, Capoor MR, Vanidassane I, Gogna A, Singh A, Sen B, et al. Disseminated Emmonsia pasteuriana infection in India: a case report and a review. Mycoses. 2016;59(2):127–32. doi: 10.1111/myc.12437 26647904
16. Wilmes D, Rooms I, Heidemarie L, McCormick Smith I, Haase G, Rickerts V. Emergomycosis: Case report of a disseminated Emergomyces pasteurianus infection and review of an emerging fungal infection. 52nd Scientific Conference of the German speaking Mycological Society (DMykG) together with the Austrian Society for Medical Mycology (ÖGMM), 6 September– 8 September 2018; 6–8 September, 2018; Innsbruck, Austria: Mycoses; 2018.
17. Schwartz IS, Sanche S, Wiederhold NP, Patterson TF, Sigler L. Emergomyces canadensis, a dimorphic fungus causing fatal systemic human disease in North America. Emerg Infect Dis. 2018;24(4). doi: 10.3201/eid2404.171765 29553321
18. Wang P, Kenyon C, de Hoog S, Guo L, Fan H, Liu H, et al. A novel dimorphic pathogen, Emergomyces orientalis (Onygenales), agent of disseminated infection. Mycoses. 2017;60(5):310–9. doi: 10.1111/myc.12583 28240390
19. Wellinghausen N, Kern WV, Haase G, Rozdzinski E, Kern P, Marre R, et al. Chronic granulomatous lung infection caused by the dimorphic fungus Emmonsia sp. Int J Med Microbiol. 2003;293(6):441–5. doi: 10.1078/1438-4221-00281 14760976
20. Schwartz IS, Lerm B, Hoving JC, Kenyon C, Horsnell WG, Basson WJ, et al. Emergomyces africanus in soil, South Africa. Emerg Infect Dis. 2018;24(2). doi: 10.3201/eid2402.171351 29350144
21. Schwartz IS, McLoud JD, Berman D, Botha A, Lerm B, Colebunders R, et al. Molecular detection of airborne Emergomyces africanus, a thermally dimorphic fungal pathogen, in Cape Town, South Africa. PLoS Negl Trop Dis. 2018;12(1). doi: 10.1371/journal.pntd.0006174.
22. Cronjé N, Schwartz IS, Retief L, Bastos ADS, Matthee S, Preiser W, et al. Attempted molecular detection of the thermally dimorphic human fungal pathogen Emergomyces africanus in terrestrial small mammals in South Africa. Med Mycol. 2018;56(4):510–3. doi: 10.1093/mmy/myx065 28992307
23. Schwartz IS, Maphanga TG, Govender NP. Emergomyces: a new genus of dimorphic fungal pathogens causing disseminated disease among immunocompromised persons globally. Curr Fungal Infect Rep. 2018. doi: 10.1007/s12281-018-0308-y
24. Dukik K, Al-Hatmi AMS, Curfs-Breuker I, Faro D, De Hoog S, Meis JF. Antifungal susceptibility of emerging dimorphic pathogens in the family Ajellomycetaceae. Antimicrob Agents Chemother. 2018;62(1):e01886–17. doi: 10.1128/AAC.01886-17 29084748
25. Munoz JF, McEwen JG, Clay OK, Cuomo CA. Genome analysis reveals evolutionary mechanisms of adaptation in systemic dimorphic fungi. Sci Rep. 2018;8(1):4473. Epub 2018/03/16. doi: 10.1038/s41598-018-22816-6 29540755
26. Lerm B, Kenyon C, Schwartz IS, Kroukamp H, de Witt R, Govender NP, et al. First report of urease activity in the novel systemic fungal pathogen Emergomyces africanus: A comparison with the neurotrope Cryptococcus neoformans. FEMS Yeast Research. 2017;17(7). doi: 10.1093/femsyr/fox069 28934415
27. Drouhet E, Huerre M. Yeast tissue phase of Emmonsia pasteuriana inoculated in golden hamster by intratesticular way. Mycoses. 1999;42 Suppl 2:11–8. doi: 10.1111/j.1439-0507.1999.tb00006.x 29265616
28. Crombie K, Spengane Z, Locketz M, Dlamini S, Lehloenya R, Wasserman S, et al. Paradoxical worsening of Emergomyces africanus infection in an HIV-infected male on itraconazole and antiretroviral therapy. PLoS Negl Trop Dis. 2018;12(3):e0006173. doi: 10.1371/journal.pntd.0006173 29518092
29. Lochan H, Naicker P, Maphanga T, Ryan A, Pillay K, Govender NP, et al. A case of emmonsiosis in an HIV-infected child. South Afr J HIV Med 2015;16(1). doi: 10.4102/sajhivmed.v16i1.352 29568581
30. Bhagoobhai L, Seetharam S, Wadula J, editors. Dimorphic fungus (Emmonsia species) isolated from sterile sites between March 2014 to April 2015. 6th FIDSSA Congress 2015. Drakensberg, KwaZulu-Natal, South Africa: South Afr J of Infect Dis.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2019 Číslo 9
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Is reliance on an inaccurate genome sequence sabotaging your experiments?
- The molecular clock of Mycobacterium tuberculosis
- Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancester of CH235 lineage CD4bs broadly neutralizing antibodies
- HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11