Penicillium marneffei infection
Penicillium marneffei infection is very rare in the immunocompetent but one of the most common opportunistic infections in HIV-infected people in South-East 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.
Penicillium marneffei was first isolated from Chinese bamboo rats Rhizomys sinensis in Vietnam in 1956. The fungus is endemic in South-East Asia, north-east India, south China, Hong Kong, and Taiwan. Less than 40 cases of infection with P. marneffei were reported before the HIV epidemic. Since then, the incidence of disseminated P. marneffei infection has increased markedly. This increase is mainly due to infection in patients immunocompromised by HIV. Most patients have been reported from Thailand, Hong Kong, and Taiwan. Cases have also been reported in HIV-infected individuals from the United States of America, Europe, Japan, and Australia following visits to the endemic region. P. marneffei infections have also been reported in HIV-negative immunosuppressed patients, e.g. solid organ and bone marrow transplant recipients.
P. marneffei is the only dimorphic fungus of the genus 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 on to brain-heart-infusion agar and incubating at 37°C. Microscopic examination of the mycelial form shows typical structures of the genus Penicillium; examination of the yeast form reveals unicellular, pleomorphic, ellipsoidal-to-rectangular cells (c.2 μm × 6 μm in dimension) that divide by fission and not by budding.
Many features of the natural reservoir, mode of transmission, and natural history of P. marneffei infection remain unknown. The fungus was isolated from several species of bamboo rats in the endemic 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 P. marneffei from a common source, rather than patients’ being infected by rats. By analogy with other endemic systemic mycosis, such as histoplasmosis, it is likely that P. 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 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 P. marneffei infection. In other cases, the clinical manifestation of P. marneffei infection occurred within weeks of exposure to the fungus.
The majority of patients with P. marneffei infection have already been infected with HIV. 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 observed in up to two-thirds of the patients. As in other systemic mycoses such as histoplasmosis or paracoccidioidomycosis, skin lesions resemble molluscum contagiosum (Fig. 220.127.116.11). They may break down and bleed (Fig. 18.104.22.168) while some larger lesions become indurated and appear infarcted. Mucosal and palatal lesions are also seen (Fig. 22.214.171.124). Arthritis and osteomyelitis are not uncommon. Cases with mesenteric lymphangitis, colitis, genital or oropharyngeal ulcer, retropharyngeal abscess, or pericarditis have been reported.
In HIV-infected patients, P. marneffei infection occurs late in the course of the disease. The patient’s CD4+ cell count at presentation is typically 50 cells/μl or less. HIV-infected patients with P. marneffei infection have a more acute onset and higher fever. They are more likely to have fungaemia and their skin lesions are more numerous and tend to be papules with central necrotic umbilication. Non-HIV-infected patients are more likely to have one or several subcutaneous nodules, which may develop into abscesses and cause skin ulceration.
Biochemical and haematological laboratory findings are nonspecific and include elevation of liver enzymes, anaemia, and leukocytosis. 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 reported (Fig. 126.96.36.199).
Diagnosis depends on familiarity with the clinical syndrome and a high index of suspicion. Presumptive diagnosis can be 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 extracellular basophilic, spherical, oval, and elliptical yeast cells can be seen with this technique, some of which have clear central septation, a characteristic feature of P. marneffei (Fig. 188.8.131.52). 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 P. marneffei infection can clinically resemble tuberculosis, histoplasmosis, and cryptococcosis. Tests to detect the antibody or antigen of P. marneffei as well as tests based on the polymerase chain reaction (PCR) have been developed. Clinical trials are needed to show their usefulness in the diagnosis of active P. marneffei infection and in predicting relapses. They may also be used to identify HIV-infected individuals, who are infected with P. marneffei but are still asymptomatic. These individuals may then benefit from pre-emptive treatment with an antifungal agent.
P. marneffei infection is a potentially fatal disease. The mortality rate is high if the diagnosis has not been made promptly. The fungus is sensitive to ketoconazole, fluconazole, itraconazole, and amphotericin B. The recommended treatment is to give amphotericin B intravenously in the dose of 0.6 mg/kg per day for 2 weeks, followed by itraconazole 400 mg/day orally in two divided doses for the next 10 weeks. Patients with less severe symptoms may be treated with itraconazole in the same dosage for 12 weeks without the initial treatment with amphotericin B. The majority of patients respond well, with resolution of fever and other signs of infection within the first 2 weeks. After initial treatment, HIV-infected patients should be given 200 mg/day of itraconazole orally as secondary prophylaxis for life in countries where antiretroviral treatment is not available. In patients who are treated with highly active antiretroviral drugs, secondary prophylaxis with itraconazole can be stopped after their CD4+ cell counts reach 100 cells/μl and remain at or above that level for at least 6 months.
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