Talaromyces Marneffei Fungemia After Travel to China in a Canadian Patient with AIDS

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Talaromyces marneffei fungemia after travel to China in a Canadian patient with AIDS

Mara Waters MD, Alina Beliavsky MD, Kevin Gough MD MEd n Cite as: CMAJ 2020 January 27;192:E92-5. doi: 10.1503/cmaj.191136

62-year-old man was admitted to the general medicine service with a 2-month history of odynophagia, fevers, KEY POINTS rigors, a 22-kg unintentional weight loss and watery • Talaromyces marneffei should be considered in diarrhea.A He had moved to Canada 25 years earlier from Guang- immunocompromised people with a travel history to endemic zhou, China (Guangdong Province) and had last visited China areas including southeast Asia, northern India and southern China. 1 year before presentation. • Characteristic presentation features may include several The patient had been diagnosed with HIV infection 20 years weeks of fevers, weight loss and skin lesions (papules, ulcers earlier. One year before presentation, his CD4 count and viral load or abscesses). were 24 cells/μL and 144 copies/mL, respectively. He had been • Diagnosis is made by fungal culture and confirmed through treated for Pneumocystis jirovecii pneumonia on 2 occasions, 12 molecular techniques such as the polymerase chain reaction and 20 years previously. He intermittently complied with his anti- assay; however, diagnosis may be delayed if laboratories are not equipped with these techniques or samples need to be sent retroviral therapy (emtricitabine, tenofovir, darunavir, ritonavir to reference laboratories. and raltegravir) and his opportunistic infection prophylaxis • Treatment of T. marneffei fungemia is with liposomal (azithromycin for Mycobacterium avium complex prophylaxis, and amphotericin B induction for 2 weeks, followed by oral trimethoprim–sulfamethoxazole for P. jirovecii pneumonia and itraconazole therapy for 10 weeks. toxoplasmosis prophylaxis). Other medical comorbidities • Primary prophylaxis with oral itraconazole therapy should be included hepatitis B coinfection and chronic obstructive pulmon considered for patients with HIV infection and CD4 counts less ary disease. than 100 cells/μL who reside in or travel to endemic areas. On initial examination, the patient appeared thin and cachec- tic. Examination of the heart and lungs was within normal limits. There was no hepatosplenomegaly or palpable lymphadeno surface antigen, e antigen and core antibody. Biopsy of a skin pathy. The oropharynx was clear. Skin examination showed red lesion showed nonspecific interface dermatitis, with no fungal papular lesions scattered on the patient’s face and back. He had elements seen on periodic acid–Schiff staining; fungal cultures of daily fever (temperature > 38°C) for the first week of his hospital the skin lesion were not performed. Gastroscopy showed mild stay, with a maximum temperature of 38.4°C. At presentation, his gastritis, and Helicobacter pylori was identified on histopatho absolute CD4 count was 0 cells/μL, and his viral load was logical examination. Computed tomography of the thorax, 3243 copies/mL. He had severe neutropenia (nadir 0.2 × 109/L) abdomen, pelvis and head showed retroperitoneal and mesen- and thrombocytopenia (nadir 32 × 109/L). His liver enzyme levels teric lymphadenopathy, with no findings suggestive of meta- were mildly elevated (aspartate aminotransferase 88 U/L, alanine static fungal disease. Ultrasonography of the abdomen showed aminotransferase 39 U/L and alkaline phosphatase 128 IU/L). His mild hepatic steatosis; the gallbladder was normal. renal function and electrolytes were within normal limits. The infectious diseases service was consulted, and treatment On hospital day 5, a filamentous fungus was isolated in of the T. marneffei fungemia was initiated with liposomal ampho- 3 peripheral blood culture bottles after 5 days of incubation in an tericin B, 4 mg/kg daily for a 2-week induction period, followed automatic incubator. Subsequent speciation identified Talaro- by treatment-dose itraconazole, 200 mg administered orally myces marneffei (Figure 1). Stool examination for ova and para- twice daily for 10 weeks. The patient’s fevers, odynophagia and sites identified Clonorchis sinensis eggs. Stool culture was nega- diarrheal symptoms resolved over 2 weeks. The C. sinensis para- tive for Campylobacter, Escherichia coli 0157, Salmonella, Yersinia sitemia was treated with praziquantel, 25 mg/kg 3 times daily for and Shigella. Multiple sputum samples were negative for acid- 2 days. Helicobacter pylori treatment was advised, but the fast bacilli. Serologic testing gave negative results for hepatitis C patient declined. His antiretroviral regimen was changed to antibody and Strongyloides stercoralis IgG antibody by enzyme- emtricitabine, tenofovir, abacavir and dolutegravir to reduce linked immunosorbent assay, and positive results for hepatitis B drug interactions with his antifungal regimen.

E93 4 7 Treatment for Treatment for In our patient, 9 8 organ involvement with or organ involvement with or Because the other symptoms are non- 2 2,6 The skin lesions are present in 70% of cases The skin lesions are present in 70% of cases 2,6 ISSUE 4 ISSUE | However, there is little evidence of direct rat-to- there is little evidence However, Our patient’s illness likely represented reactivation Our patient’s illness 4 5 In a retrospective cohort study of patients with HIV/ with patients of study cohort retrospective a In on culture is the gold standard method of of T. marneffei on culture is the gold standard method 2,6 Common laboratory findings in disseminated T. marneffei Common laboratory findings in disseminated The bamboo rat is the only known nonhuman host of of host nonhuman only known is the rat The bamboo for T. marneffei is 1–3 weeksThe incubation period in patients both culture and the polymerase chain reaction assay were performed and yielded concordant positive results. T. marneffei. addition, latent T. marneffei infection can with acute disease. In immunocompro- in time any at reactivation disease with occur, mised hosts. human transmission. Although the mode of transmission of of the mode of transmission Although human transmission. T. marneffei environmental, likely is exposure unknown, remains environments such conidia from of T. marneffei with inhalation rat feces may be present. where bamboo as soil or plants moderate and severe disease (multi without respiratory failure or shock) without central nervous system involvement includes induction with liposomal amphotericin B, 3–5 mg/kg daily for 2 weeks, followed by itraconazole, 400 mg/d given orally for 10 weeks; in the setting of HIV infection, maintenance therapy with itraconazole, 200 mg/d administered orally, should be given for secondary prophylaxis until the CD4 AIDS in southern China, mortality was significantly greater in significantly greater in AIDS in southern China, mortality was patients with T. marneffei than in those without, with an in- hospital mortality rate of 17.5% and 7.6%, respectively. hospital mortality rate of 17.5% and 7.6%, Diagnosis Growing showing mould diagnosis, followed by confirmation that involves to yeast (Figure 1) conversion, at 25°C and 37°C respectively. as the polymerase More recently, molecular techniques such chain reaction assay and enzyme-linked immunosorbent assay, which often must be performed at a reference laboratory, have been used in an effort to expedite the diagnosis. Treatment Recommended treatment for severe disease with central nervous system involvement includes liposomal amphotericin B, 5 mg/kg for 4–6 weeks, followed by itraconazole, 400 mg/d given orally for 10 weeks, then secondary prophylaxis. infection Disseminated Talaromyces marneffei disseminated T. marneffei infection may Clinical features of loss, hepatomegaly, include fever, lymphadenopathy, weight abnormalities, splenomegaly, respiratory and gastrointestinal and skin lesions. and are classically described as necrotic papules, although they and are classically described as necrotic may vary in appearance. specific, the skin lesions may play an important role in prompt- in role important an play may lesions skin the specific, pretest probability ing consideration of this diagnosis, increasing of T. marneffeiand making the diagnosis through isolation on biopsy. of latent disease in the context of a low CD4 count. He may have context of a low CD4 count. He may have of latent disease in the during his time of residence in Guangzhou acquired the infection trips, most recently 1 yearor during one of his return before presentation at our institution. infection include elevated liver enzyme levels, anemia and levels, anemia and infection include elevated liver enzyme thrombocytopenia. VOLUME 192 VOLUME |

2 - L. The L. The /L, neu- 9 3 L and viral load L and viral load JANUARY 27, 2020 JANUARY | CMAJ disease is dysfunctional cell- is dysfunctional T. marneffei disease /L, CD4 count of 7 cells/μ 9 is a dimorphic fungus endemic to south to endemic fungus dimorphic a is identified on a potassium hydroxide Talaromyces marneffei identified on a potassium hydroxide The patient was seen by the hematology service, who recom- The patient was seen by the hematology of 451 copies/mL. mended granulocyte colony-stimulating factor for 5 daysmended granulocyte colony-stimulating for his have been related to neutropenia. His thrombocytopenia may purpura, the HIV-associated idiopathic thrombocytopenia trimethoprim–sulfamethoxazole or the T. marneffei infection. At 4 months count of 232 × 10 follow-up, he had a platelet trophil level of 0.5 × 10

Discussion marneffei Talaromyces Figure 1: arthroconidia and hyphae Yeast specimen. culture blood a from smear were seen under light microscopy at 37°C. The main risk factor for risk The main incidence has been increasing among patients with immunodeficiency disorders involving the interleukin-12/interferon-γ signal- ling pathway and among those receiving immunosuppressive T-cell–depleting agents (such as tacrolimus) or monoclonal anti- bodies (such as rituximab). These patients have higher mortality rates, potentially owing to lack of clinical suspicion. mediated immunity, commonly secondary to HIV infection, espe- cially in people with a CD4 count less than 100 cells/μ east Asia, northern India and southern China (Figure 2). The overt disease incidence increased substantially with the rise of HIV effective since incidence in decline a with 1980s, in the infection antiretroviral therapy became widely instituted in the region. PRACTICE of talaromycosis inpatientswithoutHIVinfection whohave people maywarrantprimaryprophylaxis (Box1).Despitetherisk E94 insoutheastAsia. T. marneffei cells/ 100 indicated forpatientswithHIVinfection andCD4countslessthan Primary prophylaxiswithitraconazole, 200mg/dgivenorally,is Primary prophylaxis μ count isgreaterthan100 cells/ tional FungalInfection(LIFE). Figure 2: Map showing regions endemic for zant ofpotentialdruginteractions. cytochrome P4503A4inhibitor;thus,prescribersmustbecogni - followedbysecondaryprophylaxis.Itraconazoleisa for 8 weeks, involvement alone) may betreatedwithitraconazole, 400 mg/d μ L who reside in or travel to areas endemic for 10 OtherinfectionsinHIV-infected L. 10 Milddisease(cutaneous Talaromyces marneffei (orange shading). Adapted from reference 1 with permission from Leading - Interna CMAJ | JANUARY 27, 2020 | VOLUME 192 mary preventioninthesepatients. medications, therearenocurrentguidelinesrecommendingpri - immunodeficiency disordersorwhotakeimmunosuppressive manifestations and sequelaeofthediseasecanbe severe. timely mannerisimportantsince effectivetreatmentisavailableand growing international travel. Establishing acorrect diagnosis ina populations, theincreasinguseof immunosuppressivetherapiesand inimmunocompromisedhostsgiven ourdiversepatient T. marneffei This case highlights the importance of increasing awareness of parts ofsoutheastAsia;however,itisuncommoninNorthAmerica. Our patient’spresentationwouldbeconsideredfairlycommon in Conclusion | ISSUE 4 11

PRACTICE

. 4 - E95 21- 12: Talaromyces Talaromyces 2018; et al. 10 , IDCases J (first line) (first Recommended prophylaxis prophylaxis Recommended Trimethroprim– 1 tablet sulfamethoxazole, daily orally double strength 1200 mg orally Azithromycin, weekly once Itraconazole, 200 mg/d orally Itraconazole, Itraconazole, 200 mg/dorally Itraconazole, Trimethroprim– 1 tablet sulfamethoxazole, daily orally single strength Fluconazole, 400 mg/d orally Fluconazole, Isoniazid, 300 mg/d orally, + mg/dIsoniazid, 300 orally, 25–50 mg/d orally pyridoxine, LLompart-Zeno , M Sierra-Hoffman MT, ISSUE 4 ISSUE Regions | http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf French Guiana, some other Guiana, some other French of South America regions Lawrence St. Mississippi, Ohio, Caribbean, valleys; River southern Mexico of Central Some regions Asia Africa, America, tion of the Infectious Diseases Society of America. Rockville (MD): AIDSinfo. Rockville (MD): AIDSinfo. tion of the Infectious Diseases Society of America. Available: (accessed 2019 Aug. 27). Castro-Lainez marneffei infection in a non-HIV non-endemic population. All regions All regions Northern Thailand, Vietnam, Northern Thailand, Vietnam, southern China • • • All regions Southern California, Arizona; Arizona; Southern California, New Nevada, southern Utah, Texas western Mexico; All regions tory for their contributions to the microbiologic testing in this case. Correspondence to: Mara Waters, [email protected] Competing interests: None declared. This article has been peer reviewed. The authors have obtained patient consent. Affiliations: Department of Medicine (Waters) and Division of Infec- tious Diseases (Beliavsky, Gough), Department of Medicine, Univer- Michael’sSt. Diseases (Gough), Infectious of Toronto; Division sity of Hospital, Toronto, Ont. Contributors: Mara Waters and Alina Beliavsky drafted the manuscript. All of the authors revised the manuscript critically for important intellectual content, approved the final version to be published and agreed to be accountable for all aspects of the work. Acknowledgements: The authors thank Dr. Manal Tadros, Dr. Larissa Matukas, Dr. Ramzi Fattouh, the St. Michael’s Microbiology labora Ontario Health Public the and Kus Julianne Dr. Laboratory, 11. VOLUME 192 VOLUME |

Lancet Infect Dis Indication e0195569. Case–control study of JANUARY 27, 2020 JANUARY | Opportunistic invasive Opportunistic invasive 13: . C et al. 2018; K, Residence in or travel to to in or travel Residence area hyperendemic (exploring High-risk activity exposure occupational caves, in droppings) or bat bird to endemic areas CMAJ Toxoplasma of IgG Toxoplasma result Positive testing gondii serologic Not receiving fully suppressive fully suppressive receiving Not active after therapy antiretroviral avium complex Mycobacterium ruled out Residence in or travel to endemic to in or travel Residence area • • All patients with CD4 count with CD4 count All patients μL < 200 cells/ New positive result of IgM or IgG of IgM New result positive testing serologic spp. Coccidiodes annually if residence (monitored in endemic area) Positive tuberculin skin test or skin test tuberculin Positive assay result γ release interferon- of active without evidence for treatment or previous disease tuberculosis or latent active 36. Clinical characteristics and outcome of 19: PLoS One et al. Franco-Paredes 2017; < 50 Supparatpinyo Effects of Talaromyces marneffei infection on < 100 < 100 < 200 < 250 ≤ 150 HF, Fungal infections in HIV/AIDS. Talaromyces (Penicillium) marneffei infection in AF, μL cells/ T, All counts CD4 count, CD4 count, et al. et al. et al. Accuracy of rapid diagnosis of Talaromyces marneffei: S, T, KY, Wertheim Le et al. 24. : , A, LH, 9 Sirisanthana W Huang Yuen Curr Infect Dis Rep S, S, Central nervous system infection with other endemic mycoses: Henao-Martínez SK, 2012; Wei , Adenis J Nguyen CA. DB, , Lau Meng M AH, Lai , J, JF, C infection. Cheshire (UK): Leading Fungal infections. Talaromyces marneffei infection. Cheshire (UK): Leading International Fungal Infection (LIFE). Available: www.life-worldwide.org/ 2019 Nov. 21). fungal-diseases/talaromyces-marneffei-infection (accessed Limper 2017;17:e334-43. Chan infection in human immunodeficiency risk factors for Penicillium marneffei infection in human immunodeficiency virus-infected patients in northern Thailand. Clin Infect Dis 1997;24:1080-6. Chastain mycoses in AIDS: cryptococcosis, histoplasmosis, coccidiodomycosis, and mycoses in AIDS: cryptococcosis, histoplasmosis, coccidiodomycosis, and talaromycosis. Larsson mortality of HIV/AIDS patients in southern China: a retrospective cohort study. Clin Microbiol Infect 2019;25:233-41. Ning rare manifestation of blastomycosis, paracoccidiodomycosis, talaromycosis and sporotrichosis. J Fungi (Basel) 2019;5:64. and Adolescents with HIV. Guide- Panel on Opportunistic Infections in Adults lines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Associa- non-HIV-infected patients. Emerg Microbes Infect 2016;5:e19. Chariyalertsak Kauffman Jiang Penicillium marneffei infection among HIV-infected patients in northern Vietnam. AIDS Res Ther a systematic review and meta-analysis.

. . . Mycobacterium avium Mycobacterium complex Toxoplasmosis Talaromycosis Histoplasmosis Pneumocystis jirovecii pneumonia Box 1: Primary prophylaxis of opportunistic infections with antimicrobial therapy in patients with HIV infection in patients therapy with antimicrobial infections opportunistic of 1: Primary prophylaxis Box Opportunistic infection Tuberculosis (treatment (treatment Tuberculosis tuberculosis of latent infection) Coccidiodomycosis 5 2. 1. 3. 4. 9. 7. 8 6

References

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