D24 Talaromyces marneffei
Talaromyces marneffei (T. marneffei, formerly Penicillium marneffei) is a thermally dimorphic fungus that grows as a mould at 25°C in living tissue and as a yeast at 37°C. Endemic in Southeast Asia, it is an important cause of systemic mycosis in the region since the beginning of the HIV/AIDS pandemic. Disseminated T. marneffei infection presents as an opportunistic infection in those who has impaired cell-mediated immunity. Once a common AIDS-defining illness (ADI), the incidence of systemic talaromycosis (penicilliosis) among person living with HIV/AIDS (PLWHA) has decreased, thanks to the effectiveness of highly active antiretroviral therapy (HAART).
In 1956, T. marneffei was first isolated from the hepatic lesions of a bamboo rat (Rhizomys sinensis). It was later discovered that bamboo rats (Rhizomys sp. and Cannomys sp.) and soil from their burrows act as enzootic and environmental reservoirs respectively. Soil exposure, especially during rainy season, appears to be a critical risk factor of T. marneffei infection. It is believed that T. marneffei infection starts in lungs after inhalation of infectious spores followed by dissemination via haematogenous and reticuloendothelial systems.
T. marneffei mainly affects patients with impaired cell-mediated immunity. The severity of clinical diseases depends on the degree of immunosuppression. In HIV-infected individuals, it usually occurs in patients at advanced immunodeficiency with CD4+ T lymphocyte count below 100 cells/μL. The initial symptoms and signs of disseminated T. marneffei infection can be non-specific, including fever, malaise, weight loss, anaemia, generalised lymphadenopathy and hepatosplenomegaly. Respiratory signs, skeletal involvement and skin lesions have also been described, with the latter classically manifesting as papules with central necrosis on the face and neck. Leukopaenia, anaemia, thrombocytopaenia or pancytopaenia are commonly seen in disseminated infection, as the bone marrow is a frequent site of T. marneffei involvement. Haemophagocytic syndrome has also been described. Radiological abnormalities can be quite variable; apart from localised infiltrates, reticulonodular and diffuse alveolar shadows, pleural effusions, and lung mass have also been reported. The possibility of concurrent pulmonary infections such as bacterial pneumonia, pulmonary tuberculosis or PCP should also be considered.
Diagnosis of talaromycosis
Clinical, microbiological and histological diagnoses
Mortality of disseminated talaromycosis is high, especially in patients with delayed diagnosis and treatment. High clinical suspicion and timely appropriate investigations enable clinicians to make an early diagnosis and achieve a better outcome with early antifungal therapy. Diagnosis is mainly made by demonstrating fungal presence in clinical specimens using microscopy and culture techniques. These specimens include blood, bone marrow aspirate, lymph node biopsies, skin scrapings or biopsies, sputum, bronchoalveolar lavage fluid, pleural fluid, cerebrospinal fluid, urine, stool samples, and tissue samples of the infected organs. Fungal elements could be directly observed in blood smears in cases of fulminant infection. T. marneffei is readily isolated in most standard media including automated blood culture systems and Sabouraud dextrose agar. It usually takes a few days to one week to yield positive culture. The presence of a diffusible red pigmentation in fungal culture, demonstration of thermal dimorphism, and typical microscopic features of the mould forms with brush-like phialide clusters are required for confirmation of the diagnosis.
Presumptive diagnosis can be readily made by the characteristic cytologic or histologic findings of the fungus in tissue samples. Haematoxylin and Eosin, Grocott’s methenamine silver, or Periodic acid-Schiff (PAS) stains are commonly used for diagnosis on histopathological sections. The organisms appear as small sausage-shaped cells with a transverse septum. The yeast-form cells of T. marneffei and Histoplasma capsulatum are histologically similar, both being intracellular and of similar size. However, a clear central septum in the yeast-form cells with no budding is characteristic of T. marneffei, whereas round yeasts with narrow-based budding is seen in H. capsulatum.
Bone marrow biopsy may give prompt diagnosis, especially in patients presenting with haematologic abnormalities. In a case series, 16 of 17 HIV-infected patients who had marrow aspiration and trephine biopsy at the time of culture-positive T. marneffei infection had bone marrow involvement. It was also reported that the cytologic and/or histologic diagnosis of marrow talaromycosis preceded the microbiologic culture confirmation. Marrow talaromycosis is sometimes characterised by a lack of histiocytic response or by a prominent histiocytic proliferation without granuloma formation. Therefore, marrow involvement by T. marneffei can be easily missed. Sensitivity of detection could be improved if silver methenamine staining is performed regardless of the initial bone marrow findings.
An indirect immunofluorescent antibody test for Mp1p, a purified recombinant antigenic cell wall mannoprotein of T. marneffei, has been developed. Serum galactomannan testing is used to aid the diagnosis of invasive aspergillosis. It has been demonstrated that at least one identical epitope is shared by T. marneffei and Aspergillus spp. and this explains cross-reactivity. Since invasive aspergillosis is infrequently seen in PLWHA in Hong Kong, a positive serum galactomannan could facilitate the diagnosis of T. marneffei infection for patients with compatible clinical presentations before the results of microbiologic culture are available. Molecular technique has an advantage of higher sensitivity in pathogen detection and hence an attractive alternative diagnostic tool. Various polymerase chain reaction (PCR) assays with different targets have been developed and showed promising results. Further evaluation is required before these new tools can be routinely used.
Clinical management [Algorithm 24]
Untreated disseminated T. marneffei infection is almost always fatal, whereas timely antifungal therapy can result in good clinical outcome. In general, induction of two weeks of intravenous amphotericin B (0.6 mg/kg/day) followed by 10 weeks of oral itraconazole 200 mg twice daily is recommended for patients with disseminated talaromycosis, giving a response rate of 97%. Initial oral itraconazole may be considered for patients with mild to moderately severe T. marneffei infection. In vitro studies showed that itraconazole, voriconazole and micafungin have good activity against T. marneffei whereas fluconazole is the least active and some strains of the fungus may even be resistant to it. Amphotericin B has intermediate antifungal activity against T. marneffei. Micafungin could enhance the antifungal activity of amphotericin B and itraconazole in vitro, and hence such combination antifungal therapy may have a role in the treatment of patients with severe disseminated T. marneffei infection.
It was reported that up to 57% of HIV-infected patients with initially successful treatment for T. marneffei infection had relapses within 6 months of discontinuing the antifungal therapy. However, such relapses can be prevented if maintenance therapy with itraconazole is given. It is recommended to give long term secondary prophylaxis with oral itraconazole 200 mg daily in HIV-infected patients with talaromycosis. Generally speaking, secondary antifungal prophylaxis can be discontinued in HIV-infected patients with penicilliosis who have responded favourably to HAART. A retrospective cohort study in Thailand showed that there was no relapse of T. marneffei after discontinuing itraconazole secondary prophylaxis in 33 HIV-infected patients who had responded to HAART with CD4 counts of 100/μL or higher for at least 6 months after a median follow-up of 18 months.
A note on using itraconazole
When giving itraconazole therapy, the patient’s medications should be thoroughly reviewed for potential drug interactions before start and end of therapy. Itraconazole is both a substrate and an inhibitor of the CYP450 enzymes. Co-administration with one of the numerous interacting drugs may either reduce the clearance of the co-administered drug or itraconazole or increase itraconazole metabolism. These potential interactions often require dose adjustment or occasionally avoidance of the drug.
Itraconazole is a weak base, virtually insoluble in water and is ionised only at a low pH. As a result, dissolution and absorption of itraconazole is mainly dependent on acid gastric conditions in the stomach. Drugs that increase gastric pH (e.g. H2 antagonists, proton pump inhibitors) slow the dissolution of the solid dosage forms and decrease the drug available for absorption in the intestinal lumen. Pharmacokinetic studies have demonstrated 30-60% reductions in serum itraconazole concentration in healthy persons who were administered itraconazole capsules with either famotidine or omeprazole. Absorption of the solution formulation of itraconazole, however, is not substantially reduced by drugs that increase gastric pH. The oral solution formulation of itraconazole is preferred to the capsule.
Algorithm 24. Diagnosis and management of Talaromyces marneffei in HIV infected patients
- Li PC, Tsui MC, Ma KF. Penicillium marneffei: indicator disease for AIDS in South East Asia. AIDS 1992;6(2):240-1. link
- Chan JFW, Lau SKP, Yuen K-Y, Woo PCY. Talaromyces (Penicillium) marneffei infection in non-HIV-infected patients. Emerg Microbes Infect 2016;5:e19. link
- Vanittanakom N, Cooper CR Jr, Fisher MC, Sirisanthana T. Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects. Clin Microbiol Rev 2006;19(1):95-110. link
- Wu TC, Chan JWM, Ng CK, Tsang DNC, Lee MP, Li PCK. Clinical presentations and outcomes of Penicillium marneffei infections: a series from 1994 to 2004. Hong Kong Med J 2008;14(2):103–9. link
- Supparatpinyo K, Khamwan C, Baosoung V, Nelson KE, Sirisanthana T. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994;344(8915):110-3. link
- Wang Y-F, Xu H-F, Han Z-G, Zeng L, Liang C-Y, Chen X-J, Cai JP, Hao W, Chan JF, Wang M, Fu N, Che XY. Serological surveillance for Penicillium marneffei infection in HIV-infected patients during 2004-2011 in Guangzhou, China. Clin Microbiol Infect 2015;21(5):484-9. link
- Cao L, Chen D-L, Lee C, Chan C-M, Chan K-M, Vanittanakom N, Tsang DN, Yuen KY. Detection of Specific Antibodies to an Antigenic Mannoprotein for Diagnosis of Penicillium marneffei. J Clin Microbiol 1998;36(10):3028-31. link
- Notermans S, Veeneman GH, van Zuylen CW, Hoogerhout P, van Boom JH. (1-5)-linked beta-D-galactofuranosides are immunodominant in extracellular polysaccharides of Penicillium and Aspergillus species. Mol Immunol 1988;25(10):975-9. link
- Prariyachatigul C, Chaiprasert A, Geenkajorn K, Kappe R, Chuchottaworn C, Termsetjaroen S, Srimuang S. Development and evaluation of a one-tube seminested PCR assay for the detection and identification of Penicillium marneffei. Mycoses 2003;46(11-12):447-54. link
- Hien HTA, Thanh TT, Thu NTM, Nguyen A, Thanh NT, Lan NPH, Simmons C, Shikuma C, Chau NVV, Thwaites G, Le T. Development and evaluation of a real-time polymerase chain reaction assay for the rapid detection of Talaromyces marneffei MP1 gene in human plasma. Mycoses 2016;59(12):773-80. link
- Sirisanthana T, Supparatpinyo K, Perriens J, Nelson KE. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis 1998;26(5):1107-10. link
- Cao C, Liu W, Li R, Wan Z, Qiao J. In vitro interactions of micafungin with amphotericin B, itraconazole or fluconazole against the pathogenic phase of Penicillium marneffei. J Antimicrob Chemother 2009;63(2):340-2. link
- Supparatpinyo K, Perriens J, Nelson KE, Sirisanthana T. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficiency virus. N Engl J Med 1998;339(24):1739-43. link
- Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007;21(3):365-7. link