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Infection due to Penicillium marneffei
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Infection due to Penicillium marneffei Thira Sirisanthana, Khuanchai Supparatpinyo
INTRODUCTION Penicillium marneffei infection is one of the most common opportunistic infections in persons with advanced human immunodeficiency virus (HIV) infection in Southeast Asia, northeastern India, southern China, Hong Kong, and Taiwan. In northern Thailand. It is one of the four most common opportunistic infections, which include tuberculosis, cryptococcal infection, and Pneumocystis jiroveci pneumonia [1]. Cases have also been reported in HIV-infected patients from the USA, Europe, Japan, and Australia following visits to the endemic area [2]. Diagnosis depends on familiarity with the clinical syndrome and a high index of suspicion. This can be problematic when the patient presents for medical care outside the endemic area. As in other systemic fungal infections, confirmation of the diagnosis requires demonstration of the fungus in the infected organ and culturing the organism from clinical specimens. The response to antifungal treatment is good if the treatment is started early. After the initial treatment, the patients need prolonged suppressive therapy to prevent relapse at least until their immune system is sufficiently restored by antiretroviral therapy.
EPIDEMIOLOGY Penicillium marneffei was first isolated from a bamboo rat in Vietnam in 1956 [2]. It is the only known Penicillium species that exhibits temperature-dependent dimorphic growth. At temperatures below 37 C, the fungus grows as mycelia with the formation of septate hyphae, bearing conidiophores and conidia typical of the genus Penicillium.
At 37 C on artificial medium or in human tissue, the fungus grows in a yeast-like form with the formation of fission arthroconidium cells. The fission yeast cells represent the parasitic form of P. marneffei. This form is seen in the intracellular infection of the macrophages as well as extracellularly. The first naturally infected case was reported in 1973 in an American missionary with Hodgkin’s disease who had been living in Southeast Asia. Between 1973 and 1988 less than 40 cases of P. marneffei infection had been reported in the literature [3]. The rarity of P. marneffei infection changed when the global HIV/AIDS epidemic arrived in Southeast Asia. The first case of P. marneffei infection in an HIVinfected native of Southeast Asia was reported in 1989 from Bangkok. The number of cases has markedly increased since then. At one tertiary hospital in Chiang Mai, northern Thailand, a total of 1,592 patients with P. marneffei infection were seen between January 1991 and December 2000; almost all of these patients were also infected with HIV. Patients would typically be in the late stage of HIV disease with CD4 count <100 cells/mm3. Common manifestations were fever, anemia, weight loss, lymphadenopathy, hepatosplenomegaly, and skin lesions. Cases had been reported in 21 children with perinatally acquired HIV infection from the same hospital. The clinical manifestations in these children were similar to those in adults [4]. There is extensive seasonal variation in the incidence of P. marneffei infection, with increased number of cases in the rainy season [5]. Between 1991 and 2003, more than 6,000 cases of P. marneffei infection in HIV-infected patients were reported to the Thai Ministry of Public Health (MOPH). However, between 2006 and 2010, when the Thai MOPH free access to antiretroviral program was fully implemented, the average number of cases reported to the MOPH fell to 148 cases per year. As the HIV/AIDS epidemic spread in the region, the
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Diseases associated with HIV infection Figure 30.1 Geographic regions of Penicillium marneffei infection. The endemic area of P. marneffei infection includes Southeast Asia, northeastern India, the Guangxi and Guangdong provinces of China, Taiwan, and Hong Kong.
Guangdong Guangxi
Taiwan Manipur Myanmar Thailand
With kind permission from Springer Science þ Business Media. From Supparatpinyo K, Sirisanthana T. Penicillium marneffei infections. In: Kauffman CA, ed. Atlas of Fungal Infections, 2nd edn. Philadelphia; Springer, 2006:191–201.
Hong Kong Laos Vietnam
Cambodia
Malaysia
P. marneffei infection has also increased in other countries, including Vietnam [6], India [7, 8], China [9, 10], Hong Kong [11], and Taiwan [12]. Figure 30.1 shows the endemic area of this fungal pathogen.
NATURAL HISTORY AND PATHOGENESIS Many important features of the natural history and pathogenesis of P. marneffei infection remain unknown. Human and bamboo rats are the only known animal hosts. The fungus can infect four species of bamboo rats: namely, Rhyzomys sinensis, R. pruinosus, R. sumatraensis, and the reddish-brown subspecies of Cannomys badius [13]. These infected animals showed no signs of illness. The geographic ranges of these bamboo rats (Cannomys spp. and Rhizomys spp.) broadly follow the distribution of human cases of P. marneffei infection: namely, Southeast Asia, northeastern India, and southern China [14]. This suggests that bamboo rats may be an obligate stage in the life cycle of the fungus. However, an attempt to epidemiologically link bamboo rats and human infection was not successful. Chariyalertsak and colleagues compared 80 patients with AIDS who had P. marneffei infection with 160 AIDS patients who did not have P. marneffei infection, in a case–control study [15]. The main risk factor found was a recent history of occupational or other exposures to soil, especially during the rainy season. Both cases and controls were often
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familiar with and had seen bamboo rats; 31.3% of cases and 28.1% of controls had eaten bamboo rats but this difference was not statistically significant. Reported cases of P. marneffei in HIV-infected infants also suggest that human and bamboo rat infection are not connected [4]. Bamboo rats live in the wild and have limited or no contact with these infants. In another study from Chiang Mai, it was found that disseminated P. marneffei infections have been markedly seasonal, with a doubling of cases during the rainy season [5]. This suggested that there might be an expansion of the environmental reservoir with favorable conditions for growth during these rainy seasons and that both humans and bamboo rats are infected with P. marneffei from this common reservoir. A recent genotypic study of P. marneffei isolated from humans and bamboo rats in China also supports the existence of a common reservoir [16]. However, attempts in culturing the fungus from environmental sources, for example, soil samples, air samples (using high-volume air samplers), domestic animals, and vegetation including bamboo, have been unsuccessful [17, 18]. The mode of transmission of P. marneffei to humans is not known. Analogous to other endemic fungal pathogens, such as Coccidioides immitis and Histoplasma capsulatum, it is likely that P. marneffei conidia are inhaled from an environmental reservoir. Also by analogy to histoplasmosis, it is likely that subclinical infections with P. marneffei may occur commonly in persons living in endemic areas who are exposed to the fungus in nature. The existence of subclinical infection in humans is supported by a case report
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from Australia of an HIV-infected patient who had a latent period of more than a decade between exposure in an endemic area and the subsequent onset of clinical infection in Australia [19]. However, in many other instances, the clinical appearance of disseminated infection occurred within a few weeks of exposure to the organism. The seasonal variation of cases with disseminated P. marneffei infection, as well as cases of P. marneffei in HIV-infected infants reported from northern Thailand [4], also suggest that progress from infection to clinical dissemination is usually brisk. There is no evidence of person-to-person spread.
CLINICAL FEATURES Penicillium marneffei infection occurs late in the course of HIV infection. The Thai MOPH as well as the health authority of Hong Kong have included P. marneffei infection as one of the AIDS-defining illnesses in those countries [11, 20]. The CD4 count at the time of the diagnosis of P. marneffei infection is usually <100 cells/mm3. Cases were reported in which P. marneffei infection occurred with other late HIV-related infections, such as cryptococcal meningitis, Pneumocystic jiroveci pneumonia, cerebral toxoplasmosis, tuberculosis or Salmonella bacteremia. Table 30.1 shows the more common clinical presentations of HIV-infected patients with P. marneffei infection from case series from Thailand [20, 21], India [7], Hong Kong [11], and Vietnam [6]. Patients commonly present with symptoms and signs of
infection of the reticuloendothelial system. These include fever, generalized lymphadenopathy, hepatomegaly, and splenomegaly. Clinical manifestations associated with late HIV infection such as anorexia, asthenia, anemia, diarrhea, weight loss, and cachexia are also seen in the majority of the patients. Other presentations, such as skin lesions, mucosal lesions, and bone and joint infection [22], are secondary to dissemination of the fungus via the bloodstream. Skin lesions are seen in more than 70% of the patients in most case series and, when present, are the best clues to the diagnosis (see Fig. 30.2). They are usually found as papules on the face, chest, and extremities. The center of the papule subsequently becomes necrotic, giving the appearance of an umbilicated papule (also called papulonecrotic skin lesion or molluscum-contagiosum-like skin lesion). Biochemical and hematologic laboratory values are non-specific and may include elevation of liver enzymes and bilirubin, anemia, and leukocytosis or leukopenia. In patients with symptoms and signs of the respiratory system, the chest radiograph may show diffuse reticular infiltration, diffuse or localized alveolar infiltrates, or pleural effusion [23]. As the HIV epidemic spread and more patients were seen, other less common clinical presentations of P. marneffei infection in HIV-infected patients were encountered. Cases with chest radiographs showing lung mass or single or multiple cavitary lesions have been reported [24, 25]. Bone infections have been reported in the ribs, long bones, flat bone of the skull, mandible, lumbar vertebrae, scapula, and small bones of the fingers. Arthritis involving both large peripheral joints and small joints of the fingers has
Table 30.1 Clinical features of HIV-infected patients with Penicillium marneffei infection from 5 case series THAILAND [20] AUG 87–JUN 92 (n ¼ 80)
THAILAND [21] JUN 90–AUG 97 (n ¼ 74)
INDIA [7] APR 98–OCT 99 (n ¼ 36)
HONG KONG [11] JAN 94–FEB 04 (n ¼ 47)a
VIETNAM [6] JUL 05–JUN 08 (n ¼ 94)
Clinical features Fever
93%
96%
97%
96%
99%
Skin lesion
71%
85%
81%
28%
86%
Anemia
78%
76%
86%
79%
77%
Hepatomegaly
51%
65%
39%b
28%
69%c
Splenomegaly
16%
23%
—
15%
—
Lymphadenopathy
58%
84%
33%
62%
68%
CD4 count (cells/mm3)
NA
Mean: 63.8 SD: 47
NA
Median: 20 IQR: 8.0–43.5
Mean: 29 Range: 2-196
NA, not available; SD, standard deviation; IQR, interquartile range. a 44 of the 47 subjects are confirmed HIV-infected. b Hepatosplenomegaly. c Hepatomegaly and/or splenomegaly.
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Figure 30.2 Skin lesions of HIV-positive patient with P. marneffei infection. Some of the papules had central umbilication resembling lesions of molluscum contagiosum. Reprinted from the Lancet. From Supparatpinyo K, Khamwan C, Baosoung V, et al. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
been seen [22]. Ukarapol and colleagues reported three children who presented with fever, mesenteric lymphadenitis, and abdominal pain. Two of the patients had had unnecessary abdominal operations for the diagnosis of peritonitis and acute appendicitis, respectively. All three cases had positive blood and bone marrow cultures for P. marneffei [26]. Kantipong and colleagues reported six patients who presented with fever, hepatomegaly, and markedly elevated serum alkaline phosphatase levels. Penicillium marneffei was demonstrated in the liver and cultured from the blood [27]. Mucosal lesions in the oral cavity, oropharynx, hypopharynx, stomach, colon, and genitalia have been reported [20, 28–30]. Penicillium marneffei could be demonstrated in or cultured from these lesions. Twentyone patients from Vietnam whose cerebrospinal fluid (CSF) culture grew P. marneffei have been reported. They presented with fever and symptoms of altered mentation including confusion, agitation, or drowsiness. Symptoms of increased intracranial pressure and signs of meningeal inflammation were uncommon. CSF pleocytosis was seen in only one-third of the cases. A total of 71% of the cases had elevated CSF protein and 24% had a CSF glucose/serum glucose ratio <0.5. The disease course was rapidly progressive with a high mortality rate [31].
PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS [32] In evaluating an HIV-infected patient with the possible diagnosis of P. marneffei infection, it is important to keep in mind that the majority of the patients were first
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diagnosed to have HIV infection at the time of diagnosis of P. marneffei infection [11, 20]. Taking time to explain and answer the patient’s questions about HIV infection, the course of the disease, and what it means to them is important to ensure the patient’s trust and cooperation in the process of establishing the diagnosis and management. Also, because the disease is usually seen in the advanced stage of HIV infection, the majority may have other concurrent opportunistic infections such as cryptococcal meningitis, Pneumocystic jiroveci pneumonia, cerebral toxoplasmosis, tuberculosis, or Salmonella bacteremia. These should be watched out for. For physicians who are not in the endemic area, a high degree of suspicion and a careful travel history are essential. Antinori et al. have reviewed the literature and found reports of 36 HIV-infected patients whose diagnosis of P. marneffei infection were made in European countries, the USA, the UK, Japan, and Australia. Practically all patients had a clear history of exposure in the endemic area before their subsequent diagnosis [33]. The diagnosis of P. marneffei infection rests on the microscopic demonstration of the fungus in the tissues and/or isolation of the fungus from clinical specimens. Penicillium marneffei can be seen in histopathological sections stained with Grocott methenamine silver or periodic–acid Schiff. The organisms appear as unicellular round to oval cells that divide by cross-wall formation in macrophages or histiocytes. Extracellular elongated or sausage-shaped cells with one of two septa may also be seen. Neither the cell wall nor the cytoplasm of P. marneffei cells takes up the hematoxylin-eosin stain well (see Fig. 30.3). Penicillium marneffei can be readily cultured from various clinical specimens. Both automated blood culture system and blood culture medium for mycobacteria (for example, BD
Figure 30.3 Photomicrograph of a tissue section stained with Gomori methenamine silver, showing the black fungal elements in subcutaneous tissue underneath the skin lesion. Note the typical yeast-like organism with central septation. (1000) From Hay RJ. Fungal infections. Clin Dermatol 2006; 24:201–212. Copyright Elsevier 2006.
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Table 30.2 Sources of isolation in 80 HIV-infected patients with disseminated Penicillium marneffei infection in northern Thailand [20] SPECIMEN TYPE
NUMBER OF SPECIMENS Total
Positive (%)
Blood
78
59 (76)
Skin biopsy
52
47 (90)
Bone marrow
26
26 (100)
Sputum
41
14 (34)
Lymph node biopsy
9
9 (100)
BACTEC Myco/F Lytic Medium) support the growth of P. marneffei. Bone marrow culture is the most sensitive, followed by culture of a specimen obtained from skin biopsy, and blood culture (Table 30.2). At 25–30 C on Sabouraud dextrose agar, the colonies of P. marneffei are granular with shade of greenish-yellow color and a characteristic red diffusible pigment. The fungus grows as mycelia with the formation of septate hyphae, bearing conidiophores and conidia typical of the genus Penicillium. Mold-to-yeast conversion is achieved by subculturing the fungus on to brain–heart-infusion agar and incubating at 35–37 C. Demonstration of this conversion is required before concluding that the isolate is P. marneffei. Several methods of obtaining cytology specimens such as fine-needle aspiration of lymph nodes, bone-marrow aspiration, touch-smears of skin, or lymph-node biopsy specimens allow rapid presumptive diagnosis of P. marneffei infection. In one such method, a knick of the skin lesion is made with a surgical blade or the tip of a hypodermic needle, and a small amount of tissue is scraped from under the skin and smeared on a glass slide. The slide is stained with Wright’s stain. Examination under the microscope shows intracellular and extracellular basophilic, spherical, oval, and elliptical yeast cells. Some of these cells have clear central septation, which is a characteristic feature of P. marneffei (see Fig. 30.4) [20]. In addition, in patients with fulminant infection, P. marneffei can be seen in the peripheral blood smear [34]. Several tests that detect antigen or antibody specific to P. marneffei, as well as molecular tests such as PCR, have been described [2]. However, these tests are not widely used because commercial reagents are not available. Also, large clinical trials are needed to show the usefulness of these tests in the diagnosis of active P. marneffei infection or to predict relapses, as well as to identify individuals who are infected with P. marneffei but who are still asymptomatic. This latter group of individuals may then benefit from
Figure 30.4 Photomicrograph of Wright’s-stained touch smear of skin-biopsy specimen from patient infected with HIV and P. marneffei. Note spherical, oval, and elliptical yeast-like organisms with central septation in a macrophage. (1000) Reprinted from the Lancet. From Supparatpinyo K, Khamwan C, Baosoung V, et al. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
pre-emptive treatment with an antifungal agent similar to isoniazid treatment in asymptomatic persons with a positive tuberculin skin test. In the endemic area when a patient in late-stage HIV infection presents with fever, generalized lymphadenopathy, hepatosplenomegaly, and papular lesions of the skin, the differential diagnoses include P. marneffei infection, cryptococcosis, and histoplasmosis. If the patient does not have skin lesions, additional differential diagnoses should include tuberculosis, Salmonella bacteremia, and lymphoma. Evaluation should include blood culture, skin and/or lymph node biopsy for histopathology, fungal culture, and cytology.
TREATMENT The mortality rate of patients with disseminated P. marneffei infection has been high, mostly because of a lack of timely diagnosis [20]. The outcome has been much better in the hospital where physicians have been aware of the clinical features of the infection and the diagnosis has been made early. Although there is no standardized technique for susceptibility testing for dimorphic fungus, a study of 30 clinical isolates from northern Thailand revealed that all were susceptible to amphotericin B, itraconazole, ketoconazole, and miconazole [35]. Sirisanthana and colleagues conducted an open-label non-comparative study to evaluate the combination of 0.6 mg/kg/day of amphotericin B given intravenously for 2 weeks followed by 400 mg/day of itraconazole taken orally for 10 weeks [36]. Of the 74 patients treated, 72 (97.3%) responded. No serious adverse drug effects were observed. This regimen is recommended as the treatment of choice in HIV-infected patients with disseminated P. marneffei infection [37]. However, in
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a report of 46 patients from northeastern India treatment with oral itraconazole alone was effective in all but one patient [7]. Thus, oral treatment with 400 mg/day of itraconazole for 8 weeks is an alternative recommendation in patients with less severe disease [37]. A new antifungal drug, voriconazole, has been evaluated, but further study involving more patients is needed [38]. Relapses of P. marneffei infection are common. In one study, 12 out of 40 patients who responded to initial treatment relapsed within 6 months [35]. Secondary prophylaxis is required for as long as a significant immunocompromised status persists. Supparatpinyo and colleagues conducted a controlled trial of 71 patients in northern Thailand [39]. A total of 20 of the 35 patients (57%) assigned to the placebo group relapsed, whereas none of the 36 patients given itraconazole 200 mg orally once daily relapsed. The drug was well tolerated. With the increased access to combination antiretroviral treatment for patients in the endemic area, the immune restoration inflammatory syndrome (IRIS) has increasingly been reported in patients with P. marneffei infection [40]. It usually occurs within a few weeks or months after starting combination antiretroviral treatment. Antifungal therapy should be started or continued (if the patient is already taking it). Antiretroviral therapy should not be stopped. Shortcourse glucocorticosteroids may be given in patients with severely symptomatic IRIS [37]. No controlled study exists that demonstrates the safety of discontinuation of secondary prophylaxis for P. marneffei
infection. However, in an open-label historical-controlled study, no relapse of P. marneffei infection occurred after discontinuation of itraconazole in patients receiving combination antiretroviral treatment and a CD4 count >100/ mm3 [41]. Thus, discontinuation of secondary prophylaxis is recommended for patients who receive combination antiretroviral treatment and have a CD4 count >100/mm3 for 6 months [37]. Primary prophylaxis with an antifungal agent should be considered in areas where fungal infections are common AIDS-associated opportunistic infections. In northern Thailand, disseminated fungal infections due to P. marneffei, Cryptococcus neoformans, and Histoplasma capsulatum as well as other fungal infections, such as candidiasis, are common, accounting for over one-third of the reported AIDS-defining illnesses [1]. Chariyalertsak and colleagues evaluated the efficacy of primary prophylaxis with 200 mg/day of itraconazole given orally in a controlled study [42]. The trial was conducted in 129 HIVinfected patients who had CD4 counts <200/mm3 and had not experienced a systemic fungal infection. In the intention-to-treat analysis, disseminated P. marneffei infection developed in 1 of 63 patients (1.6%) assigned to receive itraconazole and a systemic fungal infection developed in 11 of 66 patients (16.7%) given placebo (7 patients had cryptococcal meningitis, and 4 patients had disseminated P. marneffei infection). However, there was no survival advantage of being on itraconazole when compared to placebo.
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[5] Chariyalertsak S, Sirisanthana T, Supparatpinyo K, et al. Seasonal variation of disseminated Penicillium marneffei infections in northern Thailand: a clue to the reservoir? J Infect Dis 1996;173:1490–3. [6] Vu Hai V, Ngo AT, Ngo VH, et al. Penicilliosis in Vietnam: a series of 94 patients. Rev Med Interne 2010;31:812–18. [7] Ranjana KH, Priyokumar K, Singh TJ, et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India. J Infect 2002;45:268–71. [8] Devi SB, Devi TS, Ningshen R, et al. Penicillium marneffei, an emerging AIDS-related pathogen—a RIMS study. J Indian Med Assoc 2009;107:208–10. [9] Liyan X, Changming L, Xianyi Z, et al. Fifteen cases of penicilliosis in
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[35] Supparatpinyo K, Nelson KE, Merz WG, et al. Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens. Antimicrob Agents Chemother 1993;37:2407–11. [36] Sirisanthana T, Supparatpinyo K, Perriens J, et al. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis 1998;26:1107–10. [37] Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Report 2009;58:RR.4. [38] Supparatpinyo K, Schlamm HT. Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. Am J Trop Med Hyg 2007;77:350–3. [39] Supparatpinyo K, Perriens J, Nelson KE, et al. 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;339:1739–43. [40] Gupta S, Mathur P, Maskey D, et al. Immune restoration syndrome with disseminated Penicillium marneffei and cytomegalovirus co-infections in an AIDS patient. AIDS Res Ther 2007;4:21. [41] Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007; 21:365–7. [42] Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis 2002;34:277–84.
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INTRODUCTION Penicillium marneffei infection is one of the most common opportunistic infections in persons with advanced human immunodeficiency virus (HIV) infection in Southeast Asia, northeastern India, southern China, Hong Kong, and Taiwan. In northern Thailand. It is one of the four most common opportunistic infections, which include tuberculosis, cryptococcal infection, and Pneumocystis jiroveci pneumonia [1]. Cases have also been reported in HIV-infected patients from the USA, Europe, Japan, and Australia following visits to the endemic area [2]. Diagnosis depends on familiarity with the clinical syndrome and a high index of suspicion. This can be problematic when the patient presents for medical care outside the endemic area. As in other systemic fungal infections, confirmation of the diagnosis requires demonstration of the fungus in the infected organ and culturing the organism from clinical specimens. The response to antifungal treatment is good if the treatment is started early. After the initial treatment, the patients need prolonged suppressive therapy to prevent relapse at least until their immune system is sufficiently restored by antiretroviral therapy.
EPIDEMIOLOGY Penicillium marneffei was first isolated from a bamboo rat in Vietnam in 1956 [2]. It is the only known Penicillium species that exhibits temperature-dependent dimorphic growth. At temperatures below 37 C, the fungus grows as mycelia with the formation of septate hyphae, bearing conidiophores and conidia typical of the genus Penicillium.
At 37 C on artificial medium or in human tissue, the fungus grows in a yeast-like form with the formation of fission arthroconidium cells. The fission yeast cells represent the parasitic form of P. marneffei. This form is seen in the intracellular infection of the macrophages as well as extracellularly. The first naturally infected case was reported in 1973 in an American missionary with Hodgkin’s disease who had been living in Southeast Asia. Between 1973 and 1988 less than 40 cases of P. marneffei infection had been reported in the literature [3]. The rarity of P. marneffei infection changed when the global HIV/AIDS epidemic arrived in Southeast Asia. The first case of P. marneffei infection in an HIVinfected native of Southeast Asia was reported in 1989 from Bangkok. The number of cases has markedly increased since then. At one tertiary hospital in Chiang Mai, northern Thailand, a total of 1,592 patients with P. marneffei infection were seen between January 1991 and December 2000; almost all of these patients were also infected with HIV. Patients would typically be in the late stage of HIV disease with CD4 count <100 cells/mm3. Common manifestations were fever, anemia, weight loss, lymphadenopathy, hepatosplenomegaly, and skin lesions. Cases had been reported in 21 children with perinatally acquired HIV infection from the same hospital. The clinical manifestations in these children were similar to those in adults [4]. There is extensive seasonal variation in the incidence of P. marneffei infection, with increased number of cases in the rainy season [5]. Between 1991 and 2003, more than 6,000 cases of P. marneffei infection in HIV-infected patients were reported to the Thai Ministry of Public Health (MOPH). However, between 2006 and 2010, when the Thai MOPH free access to antiretroviral program was fully implemented, the average number of cases reported to the MOPH fell to 148 cases per year. As the HIV/AIDS epidemic spread in the region, the
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Diseases associated with HIV infection Figure 30.1 Geographic regions of Penicillium marneffei infection. The endemic area of P. marneffei infection includes Southeast Asia, northeastern India, the Guangxi and Guangdong provinces of China, Taiwan, and Hong Kong.
Guangdong Guangxi
Taiwan Manipur Myanmar Thailand
With kind permission from Springer Science þ Business Media. From Supparatpinyo K, Sirisanthana T. Penicillium marneffei infections. In: Kauffman CA, ed. Atlas of Fungal Infections, 2nd edn. Philadelphia; Springer, 2006:191–201.
Hong Kong Laos Vietnam
Cambodia
Malaysia
P. marneffei infection has also increased in other countries, including Vietnam [6], India [7, 8], China [9, 10], Hong Kong [11], and Taiwan [12]. Figure 30.1 shows the endemic area of this fungal pathogen.
NATURAL HISTORY AND PATHOGENESIS Many important features of the natural history and pathogenesis of P. marneffei infection remain unknown. Human and bamboo rats are the only known animal hosts. The fungus can infect four species of bamboo rats: namely, Rhyzomys sinensis, R. pruinosus, R. sumatraensis, and the reddish-brown subspecies of Cannomys badius [13]. These infected animals showed no signs of illness. The geographic ranges of these bamboo rats (Cannomys spp. and Rhizomys spp.) broadly follow the distribution of human cases of P. marneffei infection: namely, Southeast Asia, northeastern India, and southern China [14]. This suggests that bamboo rats may be an obligate stage in the life cycle of the fungus. However, an attempt to epidemiologically link bamboo rats and human infection was not successful. Chariyalertsak and colleagues compared 80 patients with AIDS who had P. marneffei infection with 160 AIDS patients who did not have P. marneffei infection, in a case–control study [15]. The main risk factor found was a recent history of occupational or other exposures to soil, especially during the rainy season. Both cases and controls were often
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familiar with and had seen bamboo rats; 31.3% of cases and 28.1% of controls had eaten bamboo rats but this difference was not statistically significant. Reported cases of P. marneffei in HIV-infected infants also suggest that human and bamboo rat infection are not connected [4]. Bamboo rats live in the wild and have limited or no contact with these infants. In another study from Chiang Mai, it was found that disseminated P. marneffei infections have been markedly seasonal, with a doubling of cases during the rainy season [5]. This suggested that there might be an expansion of the environmental reservoir with favorable conditions for growth during these rainy seasons and that both humans and bamboo rats are infected with P. marneffei from this common reservoir. A recent genotypic study of P. marneffei isolated from humans and bamboo rats in China also supports the existence of a common reservoir [16]. However, attempts in culturing the fungus from environmental sources, for example, soil samples, air samples (using high-volume air samplers), domestic animals, and vegetation including bamboo, have been unsuccessful [17, 18]. The mode of transmission of P. marneffei to humans is not known. Analogous to other endemic fungal pathogens, such as Coccidioides immitis and Histoplasma capsulatum, it is likely that P. marneffei conidia are inhaled from an environmental reservoir. Also by analogy to histoplasmosis, it is likely that subclinical infections with P. marneffei may occur commonly in persons living in endemic areas who are exposed to the fungus in nature. The existence of subclinical infection in humans is supported by a case report
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from Australia of an HIV-infected patient who had a latent period of more than a decade between exposure in an endemic area and the subsequent onset of clinical infection in Australia [19]. However, in many other instances, the clinical appearance of disseminated infection occurred within a few weeks of exposure to the organism. The seasonal variation of cases with disseminated P. marneffei infection, as well as cases of P. marneffei in HIV-infected infants reported from northern Thailand [4], also suggest that progress from infection to clinical dissemination is usually brisk. There is no evidence of person-to-person spread.
CLINICAL FEATURES Penicillium marneffei infection occurs late in the course of HIV infection. The Thai MOPH as well as the health authority of Hong Kong have included P. marneffei infection as one of the AIDS-defining illnesses in those countries [11, 20]. The CD4 count at the time of the diagnosis of P. marneffei infection is usually <100 cells/mm3. Cases were reported in which P. marneffei infection occurred with other late HIV-related infections, such as cryptococcal meningitis, Pneumocystic jiroveci pneumonia, cerebral toxoplasmosis, tuberculosis or Salmonella bacteremia. Table 30.1 shows the more common clinical presentations of HIV-infected patients with P. marneffei infection from case series from Thailand [20, 21], India [7], Hong Kong [11], and Vietnam [6]. Patients commonly present with symptoms and signs of
infection of the reticuloendothelial system. These include fever, generalized lymphadenopathy, hepatomegaly, and splenomegaly. Clinical manifestations associated with late HIV infection such as anorexia, asthenia, anemia, diarrhea, weight loss, and cachexia are also seen in the majority of the patients. Other presentations, such as skin lesions, mucosal lesions, and bone and joint infection [22], are secondary to dissemination of the fungus via the bloodstream. Skin lesions are seen in more than 70% of the patients in most case series and, when present, are the best clues to the diagnosis (see Fig. 30.2). They are usually found as papules on the face, chest, and extremities. The center of the papule subsequently becomes necrotic, giving the appearance of an umbilicated papule (also called papulonecrotic skin lesion or molluscum-contagiosum-like skin lesion). Biochemical and hematologic laboratory values are non-specific and may include elevation of liver enzymes and bilirubin, anemia, and leukocytosis or leukopenia. In patients with symptoms and signs of the respiratory system, the chest radiograph may show diffuse reticular infiltration, diffuse or localized alveolar infiltrates, or pleural effusion [23]. As the HIV epidemic spread and more patients were seen, other less common clinical presentations of P. marneffei infection in HIV-infected patients were encountered. Cases with chest radiographs showing lung mass or single or multiple cavitary lesions have been reported [24, 25]. Bone infections have been reported in the ribs, long bones, flat bone of the skull, mandible, lumbar vertebrae, scapula, and small bones of the fingers. Arthritis involving both large peripheral joints and small joints of the fingers has
Table 30.1 Clinical features of HIV-infected patients with Penicillium marneffei infection from 5 case series THAILAND [20] AUG 87–JUN 92 (n ¼ 80)
THAILAND [21] JUN 90–AUG 97 (n ¼ 74)
INDIA [7] APR 98–OCT 99 (n ¼ 36)
HONG KONG [11] JAN 94–FEB 04 (n ¼ 47)a
VIETNAM [6] JUL 05–JUN 08 (n ¼ 94)
Clinical features Fever
93%
96%
97%
96%
99%
Skin lesion
71%
85%
81%
28%
86%
Anemia
78%
76%
86%
79%
77%
Hepatomegaly
51%
65%
39%b
28%
69%c
Splenomegaly
16%
23%
—
15%
—
Lymphadenopathy
58%
84%
33%
62%
68%
CD4 count (cells/mm3)
NA
Mean: 63.8 SD: 47
NA
Median: 20 IQR: 8.0–43.5
Mean: 29 Range: 2-196
NA, not available; SD, standard deviation; IQR, interquartile range. a 44 of the 47 subjects are confirmed HIV-infected. b Hepatosplenomegaly. c Hepatomegaly and/or splenomegaly.
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Figure 30.2 Skin lesions of HIV-positive patient with P. marneffei infection. Some of the papules had central umbilication resembling lesions of molluscum contagiosum. Reprinted from the Lancet. From Supparatpinyo K, Khamwan C, Baosoung V, et al. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
been seen [22]. Ukarapol and colleagues reported three children who presented with fever, mesenteric lymphadenitis, and abdominal pain. Two of the patients had had unnecessary abdominal operations for the diagnosis of peritonitis and acute appendicitis, respectively. All three cases had positive blood and bone marrow cultures for P. marneffei [26]. Kantipong and colleagues reported six patients who presented with fever, hepatomegaly, and markedly elevated serum alkaline phosphatase levels. Penicillium marneffei was demonstrated in the liver and cultured from the blood [27]. Mucosal lesions in the oral cavity, oropharynx, hypopharynx, stomach, colon, and genitalia have been reported [20, 28–30]. Penicillium marneffei could be demonstrated in or cultured from these lesions. Twentyone patients from Vietnam whose cerebrospinal fluid (CSF) culture grew P. marneffei have been reported. They presented with fever and symptoms of altered mentation including confusion, agitation, or drowsiness. Symptoms of increased intracranial pressure and signs of meningeal inflammation were uncommon. CSF pleocytosis was seen in only one-third of the cases. A total of 71% of the cases had elevated CSF protein and 24% had a CSF glucose/serum glucose ratio <0.5. The disease course was rapidly progressive with a high mortality rate [31].
PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS [32] In evaluating an HIV-infected patient with the possible diagnosis of P. marneffei infection, it is important to keep in mind that the majority of the patients were first
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diagnosed to have HIV infection at the time of diagnosis of P. marneffei infection [11, 20]. Taking time to explain and answer the patient’s questions about HIV infection, the course of the disease, and what it means to them is important to ensure the patient’s trust and cooperation in the process of establishing the diagnosis and management. Also, because the disease is usually seen in the advanced stage of HIV infection, the majority may have other concurrent opportunistic infections such as cryptococcal meningitis, Pneumocystic jiroveci pneumonia, cerebral toxoplasmosis, tuberculosis, or Salmonella bacteremia. These should be watched out for. For physicians who are not in the endemic area, a high degree of suspicion and a careful travel history are essential. Antinori et al. have reviewed the literature and found reports of 36 HIV-infected patients whose diagnosis of P. marneffei infection were made in European countries, the USA, the UK, Japan, and Australia. Practically all patients had a clear history of exposure in the endemic area before their subsequent diagnosis [33]. The diagnosis of P. marneffei infection rests on the microscopic demonstration of the fungus in the tissues and/or isolation of the fungus from clinical specimens. Penicillium marneffei can be seen in histopathological sections stained with Grocott methenamine silver or periodic–acid Schiff. The organisms appear as unicellular round to oval cells that divide by cross-wall formation in macrophages or histiocytes. Extracellular elongated or sausage-shaped cells with one of two septa may also be seen. Neither the cell wall nor the cytoplasm of P. marneffei cells takes up the hematoxylin-eosin stain well (see Fig. 30.3). Penicillium marneffei can be readily cultured from various clinical specimens. Both automated blood culture system and blood culture medium for mycobacteria (for example, BD
Figure 30.3 Photomicrograph of a tissue section stained with Gomori methenamine silver, showing the black fungal elements in subcutaneous tissue underneath the skin lesion. Note the typical yeast-like organism with central septation. (1000) From Hay RJ. Fungal infections. Clin Dermatol 2006; 24:201–212. Copyright Elsevier 2006.
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Table 30.2 Sources of isolation in 80 HIV-infected patients with disseminated Penicillium marneffei infection in northern Thailand [20] SPECIMEN TYPE
NUMBER OF SPECIMENS Total
Positive (%)
Blood
78
59 (76)
Skin biopsy
52
47 (90)
Bone marrow
26
26 (100)
Sputum
41
14 (34)
Lymph node biopsy
9
9 (100)
BACTEC Myco/F Lytic Medium) support the growth of P. marneffei. Bone marrow culture is the most sensitive, followed by culture of a specimen obtained from skin biopsy, and blood culture (Table 30.2). At 25–30 C on Sabouraud dextrose agar, the colonies of P. marneffei are granular with shade of greenish-yellow color and a characteristic red diffusible pigment. The fungus grows as mycelia with the formation of septate hyphae, bearing conidiophores and conidia typical of the genus Penicillium. Mold-to-yeast conversion is achieved by subculturing the fungus on to brain–heart-infusion agar and incubating at 35–37 C. Demonstration of this conversion is required before concluding that the isolate is P. marneffei. Several methods of obtaining cytology specimens such as fine-needle aspiration of lymph nodes, bone-marrow aspiration, touch-smears of skin, or lymph-node biopsy specimens allow rapid presumptive diagnosis of P. marneffei infection. In one such method, a knick of the skin lesion is made with a surgical blade or the tip of a hypodermic needle, and a small amount of tissue is scraped from under the skin and smeared on a glass slide. The slide is stained with Wright’s stain. Examination under the microscope shows intracellular and extracellular basophilic, spherical, oval, and elliptical yeast cells. Some of these cells have clear central septation, which is a characteristic feature of P. marneffei (see Fig. 30.4) [20]. In addition, in patients with fulminant infection, P. marneffei can be seen in the peripheral blood smear [34]. Several tests that detect antigen or antibody specific to P. marneffei, as well as molecular tests such as PCR, have been described [2]. However, these tests are not widely used because commercial reagents are not available. Also, large clinical trials are needed to show the usefulness of these tests in the diagnosis of active P. marneffei infection or to predict relapses, as well as to identify individuals who are infected with P. marneffei but who are still asymptomatic. This latter group of individuals may then benefit from
Figure 30.4 Photomicrograph of Wright’s-stained touch smear of skin-biopsy specimen from patient infected with HIV and P. marneffei. Note spherical, oval, and elliptical yeast-like organisms with central septation in a macrophage. (1000) Reprinted from the Lancet. From Supparatpinyo K, Khamwan C, Baosoung V, et al. Disseminated Penicillium marneffei infection in southeast Asia. Lancet 1994; 344:110–113. Copyright Elsevier 1994.
pre-emptive treatment with an antifungal agent similar to isoniazid treatment in asymptomatic persons with a positive tuberculin skin test. In the endemic area when a patient in late-stage HIV infection presents with fever, generalized lymphadenopathy, hepatosplenomegaly, and papular lesions of the skin, the differential diagnoses include P. marneffei infection, cryptococcosis, and histoplasmosis. If the patient does not have skin lesions, additional differential diagnoses should include tuberculosis, Salmonella bacteremia, and lymphoma. Evaluation should include blood culture, skin and/or lymph node biopsy for histopathology, fungal culture, and cytology.
TREATMENT The mortality rate of patients with disseminated P. marneffei infection has been high, mostly because of a lack of timely diagnosis [20]. The outcome has been much better in the hospital where physicians have been aware of the clinical features of the infection and the diagnosis has been made early. Although there is no standardized technique for susceptibility testing for dimorphic fungus, a study of 30 clinical isolates from northern Thailand revealed that all were susceptible to amphotericin B, itraconazole, ketoconazole, and miconazole [35]. Sirisanthana and colleagues conducted an open-label non-comparative study to evaluate the combination of 0.6 mg/kg/day of amphotericin B given intravenously for 2 weeks followed by 400 mg/day of itraconazole taken orally for 10 weeks [36]. Of the 74 patients treated, 72 (97.3%) responded. No serious adverse drug effects were observed. This regimen is recommended as the treatment of choice in HIV-infected patients with disseminated P. marneffei infection [37]. However, in
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a report of 46 patients from northeastern India treatment with oral itraconazole alone was effective in all but one patient [7]. Thus, oral treatment with 400 mg/day of itraconazole for 8 weeks is an alternative recommendation in patients with less severe disease [37]. A new antifungal drug, voriconazole, has been evaluated, but further study involving more patients is needed [38]. Relapses of P. marneffei infection are common. In one study, 12 out of 40 patients who responded to initial treatment relapsed within 6 months [35]. Secondary prophylaxis is required for as long as a significant immunocompromised status persists. Supparatpinyo and colleagues conducted a controlled trial of 71 patients in northern Thailand [39]. A total of 20 of the 35 patients (57%) assigned to the placebo group relapsed, whereas none of the 36 patients given itraconazole 200 mg orally once daily relapsed. The drug was well tolerated. With the increased access to combination antiretroviral treatment for patients in the endemic area, the immune restoration inflammatory syndrome (IRIS) has increasingly been reported in patients with P. marneffei infection [40]. It usually occurs within a few weeks or months after starting combination antiretroviral treatment. Antifungal therapy should be started or continued (if the patient is already taking it). Antiretroviral therapy should not be stopped. Shortcourse glucocorticosteroids may be given in patients with severely symptomatic IRIS [37]. No controlled study exists that demonstrates the safety of discontinuation of secondary prophylaxis for P. marneffei
infection. However, in an open-label historical-controlled study, no relapse of P. marneffei infection occurred after discontinuation of itraconazole in patients receiving combination antiretroviral treatment and a CD4 count >100/ mm3 [41]. Thus, discontinuation of secondary prophylaxis is recommended for patients who receive combination antiretroviral treatment and have a CD4 count >100/mm3 for 6 months [37]. Primary prophylaxis with an antifungal agent should be considered in areas where fungal infections are common AIDS-associated opportunistic infections. In northern Thailand, disseminated fungal infections due to P. marneffei, Cryptococcus neoformans, and Histoplasma capsulatum as well as other fungal infections, such as candidiasis, are common, accounting for over one-third of the reported AIDS-defining illnesses [1]. Chariyalertsak and colleagues evaluated the efficacy of primary prophylaxis with 200 mg/day of itraconazole given orally in a controlled study [42]. The trial was conducted in 129 HIVinfected patients who had CD4 counts <200/mm3 and had not experienced a systemic fungal infection. In the intention-to-treat analysis, disseminated P. marneffei infection developed in 1 of 63 patients (1.6%) assigned to receive itraconazole and a systemic fungal infection developed in 11 of 66 patients (16.7%) given placebo (7 patients had cryptococcal meningitis, and 4 patients had disseminated P. marneffei infection). However, there was no survival advantage of being on itraconazole when compared to placebo.
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