Penicilliosis accounted for 11% of all HIV-related admissions at NHTD in Hanoi during 2007 and 2008 which is higher than the 4.4% reported from the major referral hospital for infectious diseases in Ho Chi Minh City, southern Vietnam [4
]. However as NHTD is a specialized tertiary hospital, and most (82%) of the cases were referred, and because other epidemiological data were lacking, it cannot be concluded that there is a difference in disease prevalence between northern and southern Vietnam. The clinical features of disseminated penicillosis are consistent with other studies including profound immunosuppression (median CD4+ T-cell count: 24 cells/μl) and high rate of co-infections with other opportunistic pathogens [2
]. One third of the patients were already on ART for in average 10
days, this indicates that many patients had an ongoing P. marneffei
infection that was not revealed before initiation of ART, but was probably unmasked by immune reconstitution inflammatory syndrome (IRIS) after initiation of ART, this has earlier been reported in a few case studies [8
In our study the presence of dyspnea, ascites, and high LDH levels on admission independently predicted hospital mortality. Of the six patients that had dyspnea and died no one had tuberculosis or Pneumocystis jiroveci diagnosis,
however two had septicemia. This may indicate that pulmonary involvement (i.e. P. marneffei
pneumonia) drives disease severity or that the disease severity result in pulmonary lesions. This is consistent with a prior study showing that high respiratory rates and dyspnea among penicilliosis patients predicted poor hospital outcome [4
]. Of the 11 patients with dyspnea 5 also had lung lesions, of these one was diagnosed with Pneumocystis jiroveci
and non with tuberculosis. Lung involvement of P. marneffei
has been shown in Taiwan where it was found to be the most common cause of cavities in the lungs of immunosuppressed HIV infected patients [10
]. The majority of patients with dyspnea did not have lung lesions, hence the dyspnea might be due to the severe condition with multi-organ involvement and acute respiratory distress syndrome (ARDS). It should be noted that there could be some under diagnosis of tuberculosis due to the poor sensitivity for sputum microcopy and culture in immunosuppressed individuals as well as for Pneumocystis jiroveci as microscopy of sputum, obtained by nebulizer or bronchoscopy, is not routinely performed.
Typical skin lesions were present in 80% of patients in this study. The pathogenesis and prognosis of skin involvement is poorly understood. Although a previous study showed that presence of typical skin lesions facilitates early initiation of empirical antifungal treatment and results in better outcome [4
], it is unclear whether skin involvement itself is a prognostic marker. In the absence of skin lesions, the differential diagnoses for an AIDS-associated febrile illness with reticuloendothelial system involvement are broad and include: Mycobacterium tuberculosisMycobacterium Avium
Complex, histoplasmosis and cryptococcosis among others [11
]. This poses a major challenge in diagnosis and treatment, especially in areas with poor access to blood culture and other diagnostic laboratory. Penicilliosis should be considered in all severely immunosuppressed HIV patients with one or more of the common presentations, skin lesions, lymphadenopathy, hepatomegaly, splenomegaly, ascites, jaundice and dyspnoea, who have been in P. marneffei
endemic areas, and empirical antifungal treatment in very ill patients may be indicated.
In this study 22% of the patients had a concurrent OI; of whom half had tuberculosis. Hence, multiple OIs, particularly pulmonary tuberculosis, need to be considered. Tuberculosis and penicilliosis co-infection poses a major therapeutic dilemma in resource-poor settings as rifampicin is a potent P450 inducer and markedly reduces itraconazole concentrations [12
] Amphotericin B is recommended for patients with concurrent tuberculosis treatment. An alternative tuberculosis drug rifabutin is not available in most penicilliosis endemic areas.
The WHO recommended treatment for severe penicilliosis, amphotericin B, was only given to 20.5% of patients. The majority (77.2%) was treated with either itraconazole or ketoconazole. Although itraconazole is a recommended alternative treatment for mild to moderate disease or when amphotericin B is unavailable [13
], in Vietnam both mild and severe cases are commonly treated with oral itraconazole because amphotericin B is often not available or is too expensive. In our study there was no significant difference between itraconazole and amphotericin B in treatment outcome. So far no randomized, prospective treatment trials have been conducted to compare the efficacy of different antifungal treatment regimens for penicilliosis.
Compared to northern Thailand and southern Vietnam where cases peak in the rainy season [4
], seasonality was not observed in our cohort. It should be noted that our small sample size and short time frame does not enable any conclusive results about seasonality. However, the cool and dry season in northern Vietnam is often damp with high humidity which might have an impact on the reservoirs of P. marneffei.
This study shows that penicilliosis in northern Vietnam presents with similar clinical characteristics as in other endemic areas, and that dyspnea is an important predictor of mortality. It is common practice to treat patients with oral itraconazole rather than amphotericin B, and no significant difference in treatment outcome was observed. It would be of clinical value to compare the efficacy of oral itraconazole and amphotericin B in a clinical trial to develop evidenced based guidelines.