Volume 26 Number 9| September 2020| Dermatology Online Journal || Case Report 26(9):5

Talaromycosis clinically and histopathologically mimicking histoplasmosis in an immunocompromised patient

Sandra Widaty1 MD PhD, Irene Dorthy Santoso2 MD, Ricky Ricky3 MD, Evy Yunihastuti3 MD PhD, Rahadi Rihatmadja1 MD, Retno Wahyuningsih4 MD PhD Affiliations: 1Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia, 2Department of Dermatology and Venereology, Faculty of Medicine Universitas Tarumanegara, Jakarta, Indonesia, 3Department of Internal Medicine, Faculty of Medicine Universitas Indonesia, Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia, 4Department of Parasitology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia Corresponding Author: Sandra Widaty, Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia, 71 Diponegoro Street, Jakarta Pusat, DKI Jakarta, Indonesia, 10430, Tel: 62- 87878707048, Email: [email protected]

endemic in South and Southeast Asia and mostly Abstract affects immunocompromised hosts, including Talaromycosis is caused by the dimorphic fungus people with human immunodeficiency virus (HIV). Talaromyces marneffei (formerly Penicillium HIV-positive individuals with CD4 cell count <100/μL marneffei) endemic in South and Southeast Asia. Its have a higher risk of this opportunistic infection [1,2]. clinical similarity with other dimorphic fungal The clinical presentations are nonspecific and may infections (sometimes) make the diagnosis mimic other dimorphic fungal infections such as challenging. We report an immunocompromised patient with talaromycosis mimicking histoplamosis. histoplasmosis, making its diagnosis challenging. A 26-year-old HIV-positive man had suffered from Histoplasmosis is caused by Histoplasma capsulatum rashes over the face, trunk, and extremities for three and is an important opportunistic infection among months. His physical examination showed centrally HIV individuals in endemic areas. Both infections are necrotic, ulcerated papules and nodules. A biopsied serious opportunistic infections and have similar papule revealed granulomas containing numerous clinical presentations and laboratory findings. Skin oval, yeast-like cells, some displaying central lesions are more common in talaromycosis but are septation. Saboraud agar culture grew mold with not pathognomonic for either infection [3]. diffuse red pigment consistent with T. marneffei. Careful histopathological examination and microbiological culture are important for the accurate diagnosis of fungal infections. Case Synopsis A 26-year-old HIV-positive man, without history of antiretroviral treatment came to the dermatology- Keywords: talaromycosis, histoplasmosis, venereology outpatient clinic with multiple, small, immunocompromised, human immunodeficiency virus, crusted bumps and patches over the face, trunk, and diagnosis, Talaromyces marneffei, Penicillium marneffei extremities of three-months’ duration. The papules and nodules were asymptomatic and appeared first on the chest and neck before spreading to all body Introduction surfaces except the palms and soles in one week. Talaromycosis (formerly penicilliosis) is a systemic Some papules and nodules enlarged, broke down, mycosis caused by Talaromyces marneffei (formerly and secreted pus. The patient also experienced fever, Penicillium marneffei), a thermally dimorphic weight loss, mouth sores, night sweats, dry cough, pathogenic fungus. Talaromyces marneffei is and loss of appetite. He looked severely weak and

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Sabouraud agar grew into a mold with diffused red pigment within 7 days, consistent with a T. marneffei colony. Fungal culture and microscopic examination are shown in Figure 3. The patient was treated with oral itraconazole 200mg twice daily for four weeks.

A

Figure 1. Papules with central-necrotic ulceration on the back. malnourished. Aside from rhonchi from the upper part of the chest, there were no significant other physical findings. The cutaneous lesions included papules with centrally-necrotic ulceration, nodules, and hypopigmented and erythematous patches (Figure 1). The patient was sent for biopsy with provisional diagnoses of histoplasmosis and cryptococcosis. Specimens were taken for histopathologic examination, and microbial and fungal cultures . A sample from an umbilicated papule showed granulomas containing numerous oval, yeast-like cells, in the absence of gelatinous capsules, suggesting histoplasmosis (Figure 2A). However, once stained with Grocott-Gomori methenamine B silver (GMS), it revealed numerous intra and extracellular, round-to-oval, thin-walled yeast-like Figure 2. A) Hematoxylin and eosin staining B) Grocott-Gomori methenamine silver (GMS) revealed numerous intra and organisms, some of which had central septation extracellular, round to oval, thin-walled yeast-like organisms. instead of budding, which is more consistent with Central septation was more easily demonstrated with GMS talaromycosis (Figure 2B). Fungal culture at 25°C on staining.

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A B

Figure 3. A) Fungal culture on Sabouraud agar grew into a white mold with diffused red pigment. B) Microscopic examination showed filamentous hyphae with conidiophores and conidia.

The cutaneous eruption resolved completely. these include erosions or ulcers covered with slough Medication was continued for 12 months. that can extend into the oropharynx [12]. Oral manifestations of histoplasmosis occur less

frequently in HIV-positive patients [8]. Umbilicated Case Discussion crusted papules are more common in talaromycosis Talaromycosis is caused by the dimorphic fungus T. whereas erythematous plaques are more common in marneffei (formerly P. marneffei), which is endemic in histoplasmosis [3]. Cohen et al. reported that the South and Southeast Asia [1,4]. In this region, most commonly observed lesions of disseminated talaromycosis is considered to be an Acquired histoplasmosis in HIV-infected patients were Immunodeficiency Syndrome (AIDS)-defining illness, papules, nodules, macules and patches, and ulcers, which usually occurs with CD4 cells <100/μL [1]. both oral and skin. More than half the patients exhibited more than one morphology and Talaromycosis is also reported in HIV-negative involvement was usually located on the face, arms, patients with different clinical presentations than in trunk, and legs [13]. Nevertheless, skin lesions are not HIV-positive ones [1,5,6]. specific and not pathognomonic in either disease Constitutional symptoms are common such as fever, [3,9]. The different clinical features of histoplasmosis anemia, weight loss, malaise, respiratory and talaromycosis are shown in Table 1. involvement, and skin manifestations [7]. However, On histopathological examination, the these are not specific and can be found in other characteristics of T. marneffei are sausage-shaped dimorphic fungal infections such as histoplasmosis yeast with a central clear septum similar to cells caused by H. capsulatum. Mucocutaneous lesions are which undergo binary fission [3]. Meanwhile, present in nearly 20% of HIV-infected patients with Histoplasma characteristics are oval or round disseminated histoplasmosis [8]. In countries where budding yeasts intracellularly and extracellularly. two pathogens have been reported in However, since both fungi are organized in clusters immunocompromised patients such as Indonesia, and overcrowded in tissues along with phagocytic differentiating both pathogens is challenging [6,9- cells, it is hard to distinguish these forms based on 11]. Oral manifestations can occur in talaromycosis; histopathological examination alone [3]. It seems

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Table 1. Comparation of the features of HIV-associated talaromycosis and histoplasmosis [14-18]. Feature Talaromycosis Histoplasmosis Central necrotic papules, umbilicated Papules, nodules, macules, patches, oral papules. and skin ulcers. Lesion morphology Other morphology such as papules, Less frequent: pustules, fistulae, folliculitis, pustules, nodules, subcutaneous herpes-like. abcesses, cysts or ulcers can also occur. Focal necrosis surrounded by distended Intracellular and/or extracellular oval H&E staining histiocytes containing proliferating fungi structures Grocott-Gomori methenamine silver Sausage-shaped yeasts with a central Intracellular and/or extracellular budding (GMS) or periodic-acid Schiff (PAS) clear septum, resembling cells yeast staining undergoing binary fission At 25-30oC: yellow-green colonies with sulcate folds and diffuse red pigment in Fungal culture appearance the media White to light tan colony At 32-37oC: tan colonies without red pigment Mycelial form: hyphae with tuberculated Mycelial form: filamentous hyphae with macroconidia and smooth-walled Microscopic examination conidiophores and conidia spherical, pyriciform or cigar shaped Yeast form: sausage-shaped cells microconidia. Yeast form: ovoid thick-walled cells Liposomal amphotericin B 3-5mg/kg body Liposomal amphotericin B (3.0mg/kg weight or deoxycholate amphotericin B daily) for 1–2 weeks, followed by oral 0.7mg/kg body weight/day, IV for 2 weeks Treatment itraconazole (200mg 3-times daily for 3 followed by oral itraconazole, 200mg days and then 200mg twice daily for a every 12 hours for a subsequent duration total of at least 12 months) of 10 weeks that GMS staining visualizes the septae better than infections in AIDS patients and needs aggressive the routine hemotoxylin and eosin staining [19]. treatment. Source contact avoidance to prevent Other staining that can also be used to identify the reinfection is suggested [18,21]. intracytoplasmic fungal structure is periodic acid- Schiff. This staining should be used on all mucocutaneous biopsies whenever disseminated Conclusion histoplasmosis is being considered [20]. In this This report highlights the importance of report, microbiological culture was essential to confirm the diagnosis of talaromycosis and to microbiological culture together with histological exclude the possibility of histoplasmosis. T. marneffei special staining as diagnostic tools in colonies are colored red whereas the H. capsulatum immunocompromised patients. In this case, colonies are white [3,9]. Differentiating these two microbiological culture proved to be essential to diseases is important for the management and confirm the diagnosis of talaromycosis and to prognosis. Penicillium spp organisms are normal flora exclude the possibility of histoplasmosis. and easily found in environment. Therefore, prolonged medication is needed to avoid relapse. Histoplasma is a true pathogenic fungus causing Potential conflicts of interest high mortality and distinctive disseminated The authors declare no conflicts of interests.

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References 1. Kawila R, Chaiwarith R, Supparatpinyo K. Clinical and laboratory 12. Samaranayake L. Penicillium species—the good and the ugly. characteristics of penicilliosis marneffei among patients with and Comment in Oral Dis. 1999;5:269. [PMID: 10561712]. without HIV infection in Northern Thailand: A retrospective study. 13. Cohen PR, Bank DE, Silvers DN, Grosmann ME. Cutaneous lesions BMC Infect Dis. 2013;13:464. [PMID: 24094273]. of disseminated histoplasmosis in human immunodeficiency 2. Chen J, Zhang R, Shen Y, et al. Clinical characteristics and virus-infected patients. J Am Acad Dermatol. 1990;23:422-8. [PMID: prognosis of penicilliosis among human immunodeficiency 2212140]. virus–infected patients in Eastern China. Am J Trop Med Hyg. 14. Guimaraes AJ, Nosanchuk JD, Zancope-Oliveira R. Diagnosis of 2017;96:1350-4. [PMID: 28719279]. histoplasmosis. Braz J Microbiol. 2006;37:1-13. [PMID: 20445761]. 3. Mootsikapun P, Srikulbutr S. Histoplasmosis and penicilliosis: 15. Cao C, Xi L, Chaturvedi V. Talaromycosis (penicilliosis) due to Comparison of clinical features, laboratory findings and outcome. Talaromyces (penicillium) marneffei: Insights into the clinical IJID. 2006;10:66-71. [PMID: 16242368]. trends of a major fungal disease 60 years after the discovery of the 4. Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal pathogen. Mycopathologia. 2019;184:709-20. [PMID: 31811603]. tropical diseases. J Am Acad Dermatol. 2005;53:931-51. [PMID: 16. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice 16310053]. guidelines for the management of patients with histoplasmosis: 5. Liu G-n, Huang J-s, Zhong X-n, et al. Penicillium marneffei 2007 update by the Infectious Diseases Society of America. CID. infection within an osteolytic lesion in an HIV-negative patient. Int 2007;45:807-25. [PMID: 17806045]. J Infect Dis. 2014;23:1-3. [PMID: 24657269]. 17. US Department of Health and Human Services. Talaromycosis 6. Liyan X, Changming L, Xianyi Z, Luxia W, Suisheng X. Fifteen cases (formerly penicilliosis). Guidelines for the prevention and of penicilliosis in Guangdong, China. Mycopathologia. treatment of opportunistic infections in adults and adolescents 2004;158:151-5. [PMID: 15518342]. with HIV.. 2019. https://aidsinfo.nih.gov/guidelines/html/4/adult- 7. Wong SYN, Wong KF. Penicillium marneffei Infection in AIDS. and-adolescent-opportunistic-infection/349/talaromycosis-- Patholog Res Int. 2011;2011:763293. [PMID: 21331327]. penicilliosis-. Accessed on May 18, 2020. 8. Cohen PR. Oral histoplasmosis in HIV-infected patients. Oral Surg 18. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Oral Med Oral Pathol. 1994;78:277-8. [PMID: 7970584]. Clin Microbiol Rev. 2010;20:115-32. [PMID: 17223625]. 9. Chang P, Rodas C. Skin lesions in histoplasmosis. Clin Dermatol. 19. Guamer J, Brandt ME. Histopathologic diagnosis of fungal 2012;30:592-8. [PMID: 23068146]. infections in the 21st century. Clin Microbiol Rev. 2011;24: 247–80. 10. Dwiyana RF, Rowawi R, Lestari M, et al. Skin disorders in HIV- [PMID: 21482725]. infected patients from West Java. Acta medica Indonesiana. 20. Cohen PR, Grossman ME, Silvers DN. Disseminated histoplasmosis 2009;41 Suppl 1:18-22. [PMID: 19920293]. and human immunodeficiency virus infection. Int J Dermatol. 11. Karo FA, Kembaren T, Saragih R, et al. Cutaneous penicilliosis due 1991;30:614-22. [PMID: 1938071]. to penicillium marneffei infection in human immunodeficiency 21. Cano MV, Hajjeh RA. The epidemiology of histoplasmosis: A virus infected patients. IOP Conf Ser Earth Environ Sci. review. Semin Respir Infect. 2001;16:109-18. [PMID: 11521243]. 2018;125:012060. [PMID: 28719279].

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