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Penicilliosis marneffei, an opportunistic infectious disease caused the dimorphic fungus Penicillium marneffei that grows as a mold at 25°C and as a yeast at 37°C. It is encountered in human immunodeficiency virus (HIV)–infected patients in southeast Asia,1 and is an emerging infectious disease among immunocompromised patients in Taiwan.2,3 The mortality rate in patients with acute disseminated penicilliosis marneffei is high if the infection is not diagnosed early enough and a timely and effective anti-fungal therapy is not used.1,4 We report a case of acute disseminated penicilliosis marneffei that manifested as hemophagocytic syndrome (HPS) in a patient with acquired immunodeficiency syndrome (AIDS). Numerous circulating nucleated erythrocytes were also found in the peripheral blood of this patient. The implications of this case are discussed.
A 34-year-old homosexual man visited our emergency service with the chief complaint of a two-week fever with respiratory distress and a weight loss of approximately 15 pounds in the previous two months. Physical examinations showed oral thrush, hepatosplenomegaly, and diffuse cutaneous erythematous papular lesions with or without central umbilication over his face and body (Figure 1
). A chest radiograph showed consolidation in the lower lobe of his right lung. His hemogram values at admission were a leukocyte count =8.25 x 103 cells/µL (normal range = 4–11 x 103 cells/µL) comprising 85% neutrophils, 5% bands, 4% myelocytes, 3% lymphocytes, and 3% monocytes; hemoglobin level = 7.8 g/dL (normal range = 13.5–17.5 g/dL); mean corpuscular volume = 70.8 fL (normal range = 80–100 fL); erythrocyte distribution width = 17.4% (normal range = 11.0–14.0%); reticulocytes =1.96%; platelet count =64 x 103 cells/µL (normal range = 150–400 x 103 cells/µL); and peripheral nucleated erythrocytes = 3/100 leukocytes. Blood chemistry data showed an aspartate aminotransferase level of 128 U/L (normal range = 0–37 U/L), an alanine aminotransferase level of 26 U/L (normal range = 0–40 U/L), and a creatinine level of 2.6 mg/dL (normal range = 0.4–1.4 mg/dL). The patient was serologically positive for HIV and his CD4 T lymphocyte count was 119 cells/µL. Because of oral candidiasis and systemic fungal infection was suspected, parenteral fluconazole (600 mg/day) was empirically prescribed. Three days later, his circulating peripheral nucleated erythrocytes increased to 202/100 leukocytes; his hemoglobin level decreased to 7.1 g/dL; his platelet count decreased to 10 x 103 cells/µL; and his leukocyte count decreased to 2.3 x 103 cells/µL, with 1% metamyelocytes, 2% bands, 76% segments, 8% lymphocytes, and 13% monocytes.
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). Periodic acid-Schiff staining of bone marrow aspirate showed a prominent central septum in some of the non-budding yeasts (Figure 2B). Therefore, the prescribed fluconazole was switched to amphotericin B. Subsequently, cultures of peripheral blood, skin biopsy specimens, bone marrow, and sputum all showed P. marneffei.
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Hemophagocytic syndrome is characterized by fever, cytopenia, splenomegaly, abnormal liver function, and the pathologic finding of hemophagocytosis (phagocytosis of erythrocytes, leukocytes, platelets, and their precursors by macrophages) in bone marrow.5 This uncommon clinicopathologic entity is associated with lymphoma (T cell lymphoma in particular), autoimmune diseases, and an array of infections.5 As for infections, etiologies known to be inducers of HPS include a variety of viruses, bacteria, rickettsiae, fungi, and parasites.5 An HIV-negative woman with Sjögren’s syndrome treated with prednisolone and cyclophospamide was reported to have penicilliosis-mediated HPS in which P. marneffei was absent from bone marrow.6 The bone marrow of our patient showed hemophagocytosis and P. marneffei (Figure 2
). These findings suggested the high burden of P. marneffei and the severely immunocompromised status of the host, and this observation is consistent with a report that among patients suffering with penicilliosis, higher P. marneffei antigen titers and lower P. marneffei antibody titers were found in HIV-infected patients than in non–HIV-infected patients.7
The presence of circulating peripheral nucleated erythrocytes usually indicates bone marrow infiltration if severe hemolysis, bleeding, or sepsis is absent.8 The common causes of extensive marrow infiltration include leukemia, lymphoma, fibroblasts, metastatic neoplasms, and infections (e.g., military tuberculosis and disseminated fungal infection).8 The high ratio of peripheral nucleated erythrocytes to leukocytes (202/100) detected in our patient is a valuable clue for potential bone marrow infiltration. This finding warrants further research for confirming and identifying its cause once bone marrow infiltration is confirmed.
The incidence of penicilliosis marneffei has increased over the past few years.9 Skin lesions are of particular importance for rapid diagnosis of disseminated penicilliosis because they draw the clinician’s attention and provide an easily accessibly biopsy specmen.10 Penicillium marneffei in biopsy specimens should be differentiated from other possible pathogens that include Histoplasma capsulatum, Blastomyces dermatidis, Candida glabrata, Cryptococcus neoformans, Leishmania spp., Pneumocystis jirovecii, and Toxoplasma gondii.10–12 The yeast form of P. marneffei proliferates by fission, and the yeast form of H. capsulatum proliferates by budding.10–12
Special stains such as periodic acid-Schiff or Gomorimethamin silver may be helpful in highlighting the central transverse septum of P. marneffei.13 Unfortunately, papules with or without central necrotic umbilication, maculopapular rash, or folliculitis were nonspecific for penicilliosis marneffei,14 and were found in only approximately 50% of affected patients outside disease-endemic regions15 and in approximately 70% of affected patients in Thailand.16 Because of the extreme importance of timely effective therapy for which an early diagnosis is prerequisite in lowering the mortality rate in patients with acute disseminated penicilliosis marneffei,10 and because of the suboptimal incidence and nonspecificity of skin lesions in the affected patients when it comes to diagnosis, HPS may play a complementary role in alerting clinicians to the potential of acute disseminated P. marneffei infection, and a workup for confirmation may be conducted. In the AIDS era, any clue that suggests a possible opportunistic infection and the underlying HIV infection should be highly valued.
Received September 10, 2007. Accepted for publication October 9, 2007.
* Address correspondence to Chen-Hsiang Lee, Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, 123, Ta Pei Road, Niao Sung Hsiang 833, Kaohsiung Hsien, Taiwan, Republic of China. E-mail: lee900{at}adm.cgmh.org.tw 
Authors’ addresses: Sung-Nan Pei, Division of Hematology/ Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan 833, Republic of China. Chen-Hsiang Lee and Jien-Wei Liu, Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan 833, Republic of China.
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