# 8.7.6 Talaromyces (Penicillium) marneffei infectio

# 8.7.6 Talaromyces (Penicillium) marneffei infection 1375

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8.7.6  Talaromyces (Penicillium) marneffei infection
more commonly in individuals who have prior exposure. There is con-
flicting evidence as to whether DHPS mutations are associated with 
poor outcomes (failure to respond to co-​trimoxazole, or death) from 
PCP. Drug toxicity remains the biggest issue in the treatment of PCP, 
particularly with co-​trimoxazole therapy. Novel treatment regimens 
with reduced toxicity would be clinically useful. Caspofungin (and 
the other echinocandins) have been shown in animal models to be 
fungistatic. In a mouse model of PCP a combination of caspofungin 
together with low dose co-​trimoxazole (at a dose normally used for 
prophylaxis) was more effective than high-​dose co-​trimoxzole alone. 
Preliminary data in humans suggests a combination of caspofungin 
with low dose co-​trimoxazole is clinically effective and is associated 
with a low incidence of co-​trimoxazole-​associated adverse events. 
Rtt109 is a fungus-​specific histone acetyltransferase, recently charac-
terized in Pneumocystis jirovecii. This protein plays a significant role 
in the virulence of pathogenic fungi by reducing genomic instability; 
Rtt109-​knockout strains have significantly attenuated pathogenesis in 
animal models. This provides an attractive molecular target for future 
drug development.
FURTHER READING
Carmona EM, Limper AH (2011). Update on the diagnosis and 
treatment of Pneumocystis pneumonia. Ther Adv Respir Dis, 5, 
41–​59.
Miller RF, Huang L, Walzer PD (2013). Pneumocystis pneumonia as-
sociated with human immunodeficiency virus. Clin Chest Med, 34, 
229–​41.
Morris A, et al. (2004). Current epidemiology of Pneumocystis pneu-
monia. Emerg Infect Dis, 10, 1713–​20.
National Institutes of Health, AIDSinfo (2013). Guidelines for preven­
tion and treatment of opportunistic infections in HIV-​infected adults 
and adolescents, 2013. http://​www.aidsinfo.nih.gov
Redhead SA, et al. (2006). Pneumocystis and Trypanosoma cruzi: no-
menclature and typifications. J Eukaryot Microbiol, 53, 2–​11.
Thomas CF, Limper AH (2004). Pneumocystis pneumonia. N Engl J 
Med, 350, 2487–​98.
Walzer PD, Cushion MT (eds) (2004). Pneumocystis carinii pneu-
monia, 3rd edition. Marcel Dekker, New York, NY.
8.7.6  Talaromyces (Penicillium) 
marneffei infection
Romanee Chaiwarith, Khuanchai Supparatpinyo, 
and Thira Sirisanthana
ESSENTIALS
Talaromyces (formerly Penicillium) marneffei infection is very rare in 
the immunocompetent but one of the most common opportunistic 
infections in HIV-​infected people in Southeast Asia, north-​eastern 
India, southern China, Hong Kong, and Taiwan. Presentation is 
usually with fever, chills, lymphadenopathy, hepatomegaly, and 
splenomegaly, with skin lesions—​most commonly papules with 
central necrotic umbilication—​in two-​thirds of cases. Diagnosis is 
made by microscopy of bone marrow aspirate or biopsy specimens. 
Standard treatment, which is usually effective, is with amphotericin B 
followed by itraconazole.
Introduction
Talaromyces (formerly Penicillium) marneffei was first isolated 
from bamboo rats Rhizomys sinensis in Vietnam in 1956. The 
fungus is endemic in Southeast Asia, north-​east India, south 
China, Hong Kong, and Taiwan. Fewer than 40 cases of infec-
tion with T. marneffei were reported before the HIV epidemic. 
Since then, the incidence of disseminated T.  marneffei infec-
tion has increased markedly. This increase is mainly due to in-
fection in patients immunocompromised by HIV. Most patients 
have been reported from Thailand, Vietnam, Hong Kong, and 
Taiwan. Cases have also been reported in HIV-​infected indi-
viduals from the United States of America, Europe, Japan, and 
Australia following visits to the endemic region. T.  marneffei 
infection has also been reported in HIV-​negative immunocom-
promised patients (e.g. solid organ and bone marrow transplant 
recipients). Recently, the increased number of patients with 
adult-​onset immunodeficiency in Southeast Asia, especially in 
Thailand and Taiwan, means that these patients are at risk for 
T. marneffei infection.
Aetiology
T. marneffei is the only dimorphic fungus of the genus Talaromyces 
(formerly Penicillium). The fungus grows in a mycelial phase at 
25°C on Sabouraud dextrose agar. Mould-​to-​yeast conversion is 
achieved by subculturing the fungus onto brain-​heart-​infusion 
agar and incubating at 37°C. Microscopic examination of the 
mycelial form shows typical structures of the genus Talaromyces; 
examination of the yeast form reveals unicellular, pleomorphic, 
ellipsoidal-​to-​rectangular cells (2 μm × 6 μm in dimension) that 
divide by fission and not by budding.
Natural history
Many features of the natural reservoir, mode of transmission, and 
natural history of T.  marneffei infection remain unknown. The 
fungus was isolated from several species of bamboo rats in the en-
demic area. Since the bamboo rats usually live near the forest and 
have limited contact with people, it is believed that both humans 
and bamboo rats are infected with T. marneffei from a common 
source, rather than by direct exposure to bamboo rats. By analogy 
with other endemic systemic mycosis, such as histoplasmosis, it is 
likely that T. marneffei conidia are inhaled from a contaminated 
reservoir in the environment and subsequently disseminate from 
the lungs if and when the host becomes immunosuppressed. The 


section 8  Infectious diseases
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disease is significantly more likely to occur in the rainy season, 
suggesting that there may be an expansion of the environment 
reservoirs with favourable conditions for growth during these 
rainy months.
In endemic areas, it is likely that a certain proportion of the 
population is infected, but remains asymptomatic. Patients have 
been reported with long periods of asymptomatic infection before 
presentation with clinical T. marneffei infection. In other cases, the 
clinical manifestation of T.  marneffei infection occurred within 
weeks of exposure to the fungus. A study from Vietnam using a 
mathematical model estimated that the incubation period of this 
fungal infection was approximately 1 week.
Clinical features
Most patients with T. marneffei infection have already been in-
fected with HIV and usually present late in the course of the HIV 
disease. The patient’s CD4+ cell count at presentation is typically 
100 cells/​μl or less. Commonly, they present with symptoms and 
signs of infection of the reticuloendothelial system. These include 
fever, chills, lymphadenopathy, hepatomegaly, and splenomegaly. 
Cough, dyspnoea, and lung crepitations may be present. Other 
manifestations are secondary to dissemination of the fungus via 
the bloodstream. Cutaneous and subcutaneous lesions are ob-
served in up to 80% of the patients. As in other systemic mycoses, 
such as histoplasmosis or paracoccidioidomycosis, skin lesions 
resemble molluscum contagiosum. (Fig. 8.7.6.1). They may break 
down and bleed (Fig. 8.7.6.2) while some larger lesions become in-
durated and appear infarcted. Mucosal and palatal lesions are also 
seen (Fig. 8.7.6.3). Arthritis and osteomyelitis are not uncommon. 
Cases with mesenteric lymphangitis, colitis, genital or oropharyn-
geal ulcer, retropharyngeal abscess, brain abscess, or pericarditis 
have been reported.
HIV-​negative immunocompromised patients with T.  marneffei 
infection are less likely to have fever, splenomegaly, unbilicated skin 
lesions, and fungaemia, but more likely to have bone and joint infec-
tions, with a longer duration of illness before the diagnosis can be 
made. Subcutaneous nodules, with or without subsequent abscess 
formation, are more commonly seen.
Biochemical and haematological laboratory findings are non-​
specific and include elevation of liver enzymes, anaemia, and 
leucocytosis. The chest radiograph may show diffuse interstitial, 
localized alveolar, or diffuse alveolar infiltrates. Cases with chest 
radiographs showing cavitary lesions or lung masses have been re-
ported (Fig. 8.7.6.4).
Fig. 8.7.6.1  T. marneffei in an HIV-​infected Thai patient: typical 
molluscum-​like lesions.
Copyright G. Watt, Bangkok, Thailand.
Fig. 8.7.6.2  Bleeding into T. marneffei skin lesions.
Copyright D. Walsh.
Fig. 8.7.6.3  T. marneffei palatal lesions.
Copyright D. Walsh.


1377
Diagnosis
Diagnosis depends on familiarity with the clinical syndrome and a 
high index of suspicion. Presumptive diagnosis can be simply made 
by microscopic examination of Wright-​stained samples of bone 
marrow aspirate, touch smears of the skin biopsy specimen, and/​
or the lymph-​node biopsy specimen. Many intracellular and extra-
cellular basophilic, spherical, oval, and elliptical yeast cells can be 
seen with this technique, some of which have clear central septation, 
a characteristic feature of T. marneffei (Fig. 8.7.6.5). The diagnosis 
is confirmed by histopathological sections and/​or by culturing the 
fungus from the blood, skin biopsy specimens, bone marrow, or 
lymph nodes. Cases of T. marneffei infection can clinically resemble 
tuberculosis, histoplasmosis, and cryptococcosis. Tests to detect 
the antibody or antigen of T. marneffei as well as tests based on the 
polymerase chain reaction have been developed. Clinical trials are 
needed to show their usefulness in the diagnosis of active T. marnef­
fei infection and in predicting relapses. They might also be used to 
identify HIV-​infected individuals who are infected with T. marnef­
fei but are still asymptomatic. These individuals might then benefit 
from pre-​emptive treatment with an antifungal agent.
Treatment
T. marneffei infection is a potentially fatal disease. The mortality rate 
is high in patients with delayed diagnoses. The fungus is sensitive to 
azoles, flucytosine, and amphotericin B. Among azoles, the fungus 
is sensitive to ketoconazole, miconazole, and itraconazole, but less 
sensitive to fluconazole. In HIV-​infected patients, the recommended 
Fig. 8.7.6.4  Pulmonary lesion in an HIV-​infected patient from Hong Kong.
Copyright D. A. Warrell.
(a)
(b)
Fig. 8.7.6.5  Microscopic appearance of T. marneffei yeasts in (a) skin biopsy 
and (b) bone marrow aspirate, showing characteristic septation.
Copyright Thira Sirisanthana.
8.7.6  Talaromyces (Penicillium) marneffei infection