Dermatology Online Journal

Penicillium marneffei infection in an African man
Felix Boon-Bin Yap MD MRCP, Suganthi Thevarajah MBBS MMed, Asmah Johar MD MMed
Dermatology Online Journal 16 (7): 2

Department of Dermatology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia. woodzlamp@yahoo.com

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Abstract

Penicilliosis is a systemic fungal infection caused by Penicillium marneffei. The infection is most commonly seen in Southeast Asia, Southern China, Hong Kong, and Taiwan. It is rarely seen among individuals of African descent. Here, we report a case of penicilliosis in an African man from Namibia who was studying in Malaysia. He presented with multiple umbilicated papules associated with cough, fever, loss of appetite, and weight. He also had urethral discharge and admitted to unprotected sexual intercourse with multiple partners. Histopathological examination of a skin papule showed the presence of multiple 2 to 4 µm intracellular yeast cells. Culture of the papule revealed Penicillium marneffei. The serology for human immunodeficiency virus (HIV) was positive. This case illustrates the need to recognize penicilliosis in any individuals staying or travelling to Southeast Asia and the need to look for underlying HIV infection in adults with umbilicated papules.

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Introduction

Penicilliosis is a systemic fungal infection caused by a dimorphic fungus, Penicillium marneffei. The infection is endemic in Southeast Asia, Southern China, Taiwan, Hong Kong and northeastern India [1-6]. This fungus was first isolated in 1956 in bamboo rats at the Pasteur Institute of Indochina, Vietnam [7]. The first human infection was reported in a laboratory technician working with the fungus [8]. The first naturally occurring human case was reported in 1973 in an American minister with Hodgkin lymphoma living in Southeast Asia [9]. The infection emerged as an important fungal pathogen in endemic countries since the onset of the human immunodeficiency virus-acquired immune deficiency syndrome (HIV-AIDS) epidemic in the mid-1980s [3, 5, 6, 10, 11, 12, 13]. To date, a great majority of the reported cases are seen in immunocompromised patients with HIV-AIDS. Imported cases of penicilliosis have been detected among HIV infected patients in Australia, Japan, United States, and countries in Europe (e.g., United Kingdom, Belgium, France, Germany, Sweden, and Holland) [14-22]. New cases have also been increasingly reported in non-endemic areas among the locals, who had never travelled to endemic countries [23, 24]. The infection is rarely reported in Africans [25].

Here, we report a patient with Penicillium marneffei infection, which we believe is the second reported case of penicilliosis in an individual from Africa.

Case report

A 23-year-old African college student from Namibia who was studying in Kuala Lumpur, Malaysia, presented to the Department of Dermatology, Hospital Kuala Lumpur, with a 2-month history of multiple papules on the face and upper part of his body. He also complained of dysuria and purulent urethral discharge for a month. There was a history of weight loss, loss of appetite, chronic cough, and low-grade fever for the last 3 months.

He admitted to having multiple unprotected sexual encounters with many women in Namibia and Malaysia. However, he denied having sex with men and did not use injectable drugs. He does not smoke but consumed alcohol moderately.

Figure 1	Figure 2
Figure 1. Multiple umbilicated papules on the face Figure 2. Multiple umbilicated papules on the chest, upper abdomen, and proximal upper limbs

Figure 3
Figure 3. Multiple umbilicated papules on the back

Examination revealed an anxious man with multiple umbilicated papules on the face, neck, chest, back, and proximal upper limbs (Figures 1 through 3). He also had spontaneous purulent urethral discharge and oral candidiasis. There was no lymph node enlargement. Cardiovascular, respiratory, neurological, and abdominal examinations were unremarkable.

A provisional diagnosis of deep fungal infection and urethritis with underlying human immunodeficiency virus (HIV) infection was made.

The blood profile showed that he was anemic (hemoglobin of 9.2 g/dL). The erythrocyte sedimentation rate was 30 mm in the first hour. The total white cell count, platelet count, fasting blood lipids, fasting blood sugar, liver function tests, and renal profile were normal. The rapid bedside test, a touch smear using Giemsa stain, was performed on the umbilicated papule on the face and it revealed yeast cells. The urethral smear showed the presence of abundant leukocytes but the Gram stain for intracellular diplococcic was negative. Culture for Neisseria gonorrhoeae and serology for Chlamydia trachomatis were also negative. The chest radiograph was clear without evidence suggestive of tuberculosis. Three consecutive early morning sputum collections for acid fast bacilli were also negative.

Figure 4	Figure 5
Figure 4. Presence of intracellular fungal cells within the histiocytes surrounded by macrophages, lymphocytes, and neutrophils in the dermis (H&E, x20) Figure 5. Higher power showing the presence of 2 to 4 µm intracellular fission arthroconidia within the histiocytes (H&E, x40)

The human immunodeficiency virus (HIV) serology came back as positive a week later. A 6 mm punch biopsy of the papule demonstrated the presence of ill defined granulomas filled with foamy macrophages in the upper and mid dermis with the presence of multiple yeast cells within the histiocytes (Figures 4 and 5). Culture of the papule revealed Penicillium marneffei.

Thus, a final diagnosis was penicilliosis and nonspecific urethritis secondary to human immunodeficiency virus (HIV) infection. He was immediately started on oral itraconazole 400 mg twice daily, oral doxycycline 100 mg twice daily, and nystatin oral suspension 500,000 units 4 times daily. He was also referred to the Infectious Disease department for continuation of care, further investigations such as CD4 count and viral load, and commencement of highly active antiretroviral therapy (HAART). However, he returned to his home country of Namibia for treatment before the initiation of HAART and planned treatment with intravenous amphotericin B.

Discussion

Penicillium marneffei is a dimorphic fungus that can exist in both yeast and mold forms. The phase transition between these two forms is temperature driven. It shows a unicellular yeast growth at the body temperature of 37°C and a multicellular hyphal growth at the room temperature of 25°C. The yeast form is essential for virulence. Many studies have been done to determine the genes needed for this transition; blockade of this transition will allow the virus to stay in the nonvirulent hyphal form. However, the genes are yet to be elucidated although various protein products needed for the morphogenesis are being described [26]. Recently, it has been found that the regulatory factor X (RfX) protein might be important for the phase transition [27]. There is also evidence that this morphogenesis has another pathway independent of temperature regulation, modulated by p21-activated kinases encoded by the pakB gene in vivo [28]. An improved Agrobacterium-mediated transformation system was recently developed to aid the functional genetic analysis to determine the genetic element needed for the phase transition [29].

The natural reservoir and mode of transmission of this fungus remain elusive [2]. In a case control study in Thailand, it was noted that exposure to soil, especially during the rainy season, was the single most important risk factor for acquisition of disease. However, exposure to and consumption of bamboo rats was not identified as a risk factor [30]. Moreover, gene analyses also provided evidence that this fungus is a soil organism [31]. It is theorized that the conidia in the environment is inhaled into the lungs causing pulmonary infection that later disseminates to the skin and other internal organs [1, 2].

The interaction of the fungus and the host immune response is complicated and not fully understood [1]. T-helper cells and macrophages are important in the host defense against the fungus. It was found that nude and T-cell deficient mice succumbed to Penicillium marneffei infection, whereas healthy mice cleared the infection in 2 to 3 weeks [1]. In humans, individuals with deficient T-helper cells, namely patients with HIV-AIDS, are prone to the infection. Most of these patients have a CD4 count less than 100 and have yet to be treated with highly active antiretroviral therapy (HAART). In endemic countries, Penicillium marneffei infection is regarded as an indicator disease of AIDS [1, 32]. Penicilliosis has also been reported as a manifestation of immune reconstitution inflammatory syndrome (IRIS) after initiation of HAART [33]. Besides infecting patients with HIV-AIDS, Penicillium marneffei infection can also occur in the setting of non-HIV immunosuppression, e.g., in patients with renal transplant and leprosy [6, 34, 35]. The infection can also occur in previously healthy individuals [36]. A recent study found that patients with apparently normal immunocompetence might have acquired immunodeficiency caused by autoantibody against interferon gamma predisposing them to disseminated penicilliosis [37]. In this study, it was noted that antibody against interferon gamma was seen in 80 percent of patients with serological evidence of penicilliosis. In a review of 47 patients with penicilliosis in Hong Kong, Wu et al. found that 94 percent of their patients were HIV positive, 4 percent were renal transplant recipients, and 2 percent had low T-cell counts caused by Hepatitis B [6].

In a review of 74 HIV infected patients with disseminated penicilliosis in Thailand, Sirisanthana et al. reported that 96 percent of patients presented with both fever and weight loss, 85 percent with skin lesions, 84 percent with generalized lymphadenopathy, 65 percent with hepatomegaly, 31 percent with cough, 23 percent with splenomegaly, and 15 percent with diarrhea [38]. Similarly, in Manipur, India, among the 36 HIV infected patients with penicilliosis, 100 percent presented with weight loss, 97 percent with fever, 86 percent with weakness, 86 percent with anemia, 81 percent with skin lesions, 39 percent with hepatosplenomegaly, 33 percent with generalized lymphadenopathy, and 22 percent with diarrhea [3]. This pattern was again replicated in the RIMS study in northeastern India [4]. However, in Hong Kong, although fever and malaise were seen in more than 90 percent of their 47 patients with Penicillium marneffei infection, only 28 percent presented with skin lesions [6]. The authors postulated that the low frequency of skin lesions might be attributable to poor documentation in this retrospective study. Nevertheless, skin lesions are the crucial link to the diagnosis of this deep fungal infection.

The majority of the skin lesions in patients with penicilliosis are papules with central necrotic umbilication [38]. These lesions are not unlike lesions of molluscum contagiosum and the differential diagnoses must include other deep fungal infections (e.g., cryptococcosis and histoplasmosis). Papules and maculopapules are also not uncommonly seen [1]. Atypical manifestations include ulcerated papulonodules and verrucous lesions [12]. The verrucous lesions can be confused with lupus vulgaris, lupus erythematosus, verruca vulgaris, and verrucous carcinoma [39]. Skin lesions are most commonly seen on the face and neck region [1]. Other affected sites include, in decreasing order, upper limbs, trunk, lower limbs, and oral mucosa [38].

Although these clinical features are mostly similar between patients with and without HIV, Zhang et al. found many differences in clinical characteristics of disseminated penicilliosis marneffei between these 2 groups of patients in China [40]. They noted that patients without HIV have longer disease duration, higher misdiagnosis rate, more underlying diseases, and a higher rate of generalized lympadenopathy, body aches, and chest pain. Those without HIV tended to have intermittent fever compared to high persistent fever in patients with HIV. HIV infected patients usually present with molluscum like skin lesions whereas those without HIV mostly present with subcutaneous nodules and abscesses.

A rapid bedside presumptive diagnosis can be made by finding intracellular and extracellular yeasts on a microscopic examination of Wright stained touch smears of the skin lesions [1, 2]. This technique can also be used for lymph node biopsy specimens and bone marrow aspirates [1]. Cytological study of the sputum, lung biopsy imprint smear, lung aspirates, and cervical lymph node aspirates can also allow rapid diagnosis [41]. Skin biopsy specimen stained with hematoxylin-eosin, Grocott methenamine silver, or periodic acid Schiff show the presence of 2 to 4 µm intracellular and extracellular fission arthroconidia or unicellular round oval cells. This fungus divides by cross wall division formation in the histiocytes, allowing differentiation from another intracellular fungus, Histoplasma capsulatum [1]. However, the gold standard investigation is mycological culture. The culture can be done from the blood, lymph node, sputum, skin, kidney, pericardium, stomach, liver or intestine, pleural fluid, cerebrospinal fluid, urine, and stool. Bone marrow, skin, and blood culture give the highest sensitivity of 100 percent, 90 percent and 76 percent respectively [42]. Penicillium marneffei can also be identified serologically via detection of specific antibodies in the blood and molecular techniques via PCR studies and loop mediated isothermal amplification (LAMP) in paraffin embedded specimens and the serum [1, 43, 44, 45]. However, serological and molecular diagnoses are very expensive and the reliability of these tests remains unproven in a clinical setting.

The treatment consists of administration of systemic antifungal agents. In a review of 86 patients with underlying HIV in Thailand from 1990 to 1992, it was noted that Penicillium marneffei was highly susceptible to 5-fluorocytosine, miconazole, ketoconazole, and itraconazole, moderately susceptible to amphotericin B and had low susceptibility to fluconazole in vitro [46]. In Cambodia between 2002 and 2004, Sar et al. found that the virulent yeast form is more susceptible than the mycelial form to amphotericin B and ketoconazole, whereas the mycelial and yeast forms displayed similar susceptibilities to flucytosine and itraconazole in vitro [47]. The typical treatment regime consists of 2 weeks of 0.6 mg/kg/day intravenous amphotericin B followed by 8 weeks of oral itraconazole 400 mg daily to achieve clinical cure [6, 48]. In Manipur, India, oral itraconazole 400 mg daily is administered for 3 to 4 weeks until clinical and microbiological cure when skin of bone marrow smears become negative [3]. A newer antifungal agent, voriconazole also proved to be an effective alternative. Patients were treated with loading doses for 1-4 days and then continued at 200 mg BID for up to 12 weeks [49]. The underlying immunosuppression should be addressed, especially the initiation of highly active antiretroviral therapy (HAART) for those with HIV-AIDS.

The relapse rate of penicilliosis after successful treatment was reported to be between 4 percent and 50 percent [6, 48, 50]. Sapparatpinyo et al. evaluated use of secondary prophylaxis with oral itraconazole 200 mg daily to prevent the high relapse rate in Thailand [48]. In this study, none of the 36 HIV infected patients treated with itraconazole had a relapse within one year compared to 20 of the 35 (57%) patients given placebo (P<0.001). It was recommended that patients be put on life-long itraconazole to prevent relapse [6, 48]. However, another study found that discontinuation of itraconazole as secondary prophylaxis once the CD4 count was 100 cells/ µL or higher was not associated with relapse [51]. In this retrospective study, none of the 33 HIV infected patients relapsed after a median follow-up of 18 months. A study in Taiwan also found that only 1 of 18 HIV infected patients on HAART relapsed after discontinuation of itraconazole prophylaxis once they achieved a median CD4 count of 95 cells/ µL [52]. The median follow up in this study was 35.3 months. Thus, it is recommended that HIV infected patients with clinical and microbiological cure be continued on itraconazole prophylaxis until the CD4 count reaches 100 cells/ µL. This secondary prophylaxis can be discontinued once the CD4 count is 100 cells/ µL or higher. However, there is no study on itraconazole prophylaxis among immunocompetent patients and those with immunosuppression other than HIV because they constituted the minority of patients with penicilliosis.

The prognosis appears promising with early accurate diagnosis and prompt treatment. In the series from Hong Kong, the mortality rate was 11.4 percent whereas in Manipur, the rate was only 2.7 percent [3, 6]. Thus it is of utmost importance for the attending physician to make the diagnosis early and initiate treatment promptly to prevent the high mortality associated with this infection.

This case was presented because penicilliosis is rarely seen among Africans and it highlights the importance of suspecting Penicillium marneffei infection in patients with HIV infection travelling and staying in the endemic Southeast Asian region. We also like to stress that finding umbilicated papules in an adult warrants a thorough search for deep fungal infection and underlying immunosuppression, especially HIV infection. Prompt diagnosis and early treatment will allow for better survival.

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