BRIEF OBSERVATIONS Reactive Hemophagocytic Syndrome Associated with Penicillium marneffei Infection C.S. Chim, MD, C.Y. Fong, MD, S.K. Ma, MD, S.S. Wong, MD, K.Y. Yuen, MD R eactive hemophagocytic syndrome (RHS) is char- acterized by the proliferation of benign but acti- vated histiocytes throughout the reticuloendothe- lial system, resulting in fever, cytopenia, abnormal liver function, and, often, hepatosplenomegaly and coagu- lopathy. It was first described by Risdall et al (1) in asso- ciation with viral infections. Since then many other types of infections, have been reported to be associated with RHS (2). Penicillium marneffei is a dimorphic fungus that is prevalent in Southeast Asia (3), especially in patients with AIDS (4). We report a case of opportunistic Penicil- lium infection complicated by RHS that responded readily to amphotericin B treatment. CASE REPORT The patient was a 45-year-old woman who was admitted because of a 1-week history of fever and abdominal pain. She had Sjogren’s syndrome diagnosed 9 years before. Four years before, she was found to have significant pro- teinuria; renal biopsy revealed acute on chronic tubular interstitial nephritis. She was started on prednisolone 40 mg/day and oral cyclophosphamide 75 mg/day. How- ever, her renal function continued to deteriorate and a repeat biopsy revealed superimposed diffuse mesangial proliferative glomerulonephritis. Cyclophosphamide was stopped and she was continued on prednisolone 15 mg/day. On admission, physical examination showed that she was ill, febrile (38°C), and pale. There was mild tenderness in the paraumbilical region, a palpable liver edge, and moderate ascites. Laboratory investigation re- vealed a hemoglobin of 12 g/dL, leukocyte count of 7.3  10 9 /L and a platelet count 73  10 9 /L. Prothrombin time, International Normalized Ratio (INR), and activated partial thromboplastin time were within normal limits. Renal function tests revealed elevated blood urea nitro- gen 39 mmol/L (normal 3.2 to 7.5) and creatinine 391 Umol/L (normal 82–126). Liver function tests revealed normal bilirubin level, elevated serum glutamic-oxalo- acetic transaminase (SGOT) 62 U/L (normal: 15 to 33 U/L), and serum gamma-glutamyl transpeptidase (GT) 283 U/L (normal: 8 to 37). HIV antibody test was nega- tive. Immunology investigation showed positive antinu- clear factor (ANF). With a 1/1080 titer and anti-La and anti Ro antibodies, while C3, C4, and immunoglobulin levels were normal. Paracentesis yielded yellow ascitic fluid in which the leukocyte count was 80  10 6 /L (72% lymphocytes, 28% neutrophils); bacterial culture was negative. She was started on broad-spectrum antibiotics. However, she developed a precipitous drop of peripheral blood counts in the second week on day 10 the Hb was 9.8 g/dL, the leukocyte count was 0.6  10 9 /L, and the plate- let count was 13  10 9 /L. Bone marrow aspirate revealed histiocytic hyperplasia (4% of all nucleated cells) with prominent hemophagocytosis (Figure). Despite broad- spectrum antibiotics, she developed increasing abdomi- nal tenderness. Emergency laparotomy was performed which revealed multiple nodules over the peritoneum and the surfaces of the liver and spleen. A wedge liver biopsy showed fungal hyphae consisting of slightly elon- gated yeast cells separated by a cross wall without con- striction at the partition, with necrotizing granulomatous inflammation. Blood culture and bone marrow aspirate for culture were both positive for P marneffei. The fungus was identified by the characteristics of: (1) existence as a mold form when cultured at room temperature, (2) growth in the yeast form when cultured at 37°C (thermal dimorphism), and (3) elaboration of a diffusible red pig- ment from colonies (5). Antibody titer against P marnef- fei by indirect immunofluorescence (6) was positive at 1/1280. Intravenous amphotericin B (1 mg/kg) was started promptly and the patient became afebrile after 4 days. Repeat blood culture for fungus was negative and immunofluorescent antibody titre against P marneffei dropped to 1/320 3 weeks after amphotericin therapy. However, she developed line-related sepsis in the inten- sive care unit with refractory septic shock and she even- tually died of staphylococcal septicemia. DISCUSSION P marneffei is a dimorphic fungus that infects both im- munocompromised and healthy hosts. In our patient, this was likely to be an opportunistic infection because she was received previous immunosuppressive therapy with cyclophosphamide and corticosteroids. The gold standard of diagnosis of penicilliosis is a positive culture from appropriate tissues, although blood cultures may be positive in HIV-positive patients (4). Serological diagno- sis was reported to be useful in early diagnosis of P marneffei (6) infection and the titer was very high (1/ 1280) in our patient. Response to amphotericin B treat- ment was marked by resolution of fever, recovery of blood counts, negative subsequent blood culture, and a rapid drop in the Penicillium antibody titer. 196 1998 by Excerpta Medica, Inc. 0002-9343/98/$19.00 All rights reserved. PII S0002-9343(97)00253-2