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Cytomegalovirus-associated hemophagocytic syndrome with clonal cytogenetic abnormalities in an elderly male
Leukemia Research 31 (2007) 117–120
Letters to the Editor
Cytomegalovirus-associated hemophagocytic syndrome with clonal cytogenetic abnormalities in an elderly male An 80-year old male with a history of benign brain tumor and tuberculosis was admitted to the National Medical Center Hospital Tokyo, Japan with persistent high fever, general fatigue and weight loss in June 2005. Physical examination showed hepatosplenomegaly, but no lymphadenopathy was observed. The patient’s laboratory findings showed mild pancytopenia and liver dysfunction with the following characteristics: leukocyte count, 2.4 × 109 /l, with normal leukocyte differential; hemoglobin, 11.6 g/dl; platelet count, 8.8 × 109 /l; aspartate aminotransferase (AST), 73 IU/l; alanine aminotransferase (ALT), 41 IU/l; lactate dehydrogenase (LDH), 788 IU/l; soluble interleukin two receptor (sIL-2R), 15905 U/ml; ferritin, 9500 ng/ml. Cytomegalovirus (CMV)positive leukocytes were detected. The patient tested negative for other virus titers including Epstein-Barr virus (EBV) and varicella-zoster virus (VZV), and no bacterial, tubercular, fungal or parasitic infections were detected. Bone marrow aspiration revealed hemophagocytosis of the erythrocytes, leukocytes and platelets by monocytes and macrophages (Fig. 1). Additionally, cytogenetic analysis showed (2/20) positivity for 49, XY, +5, add(6)(p23), +20, +21, and (12/20) positivity for 46, XY (Fig. 2), but no other reasons to suspect malignancy or collagen diseases were detected. Based on these findings, the patient was diagnosed with virusassociated hemophagocytic syndrome (VAHS). His elevated levels of LDH, ferritin and sIl2-R were normalized by steroid (Solucortef, 200 mg/day) and ganciclovir treatments, which also brought about a dramatic improvement in the patient’s general condition; the hemophagocytosis and cytogenetic abnormalities in the bone marrow disappeared completely. However, in August 2005, when the steroid treatment was tapered off, the patient experienced high fever again every day as well as the progression of his mild pancytopenia. CMVpositive leukocytes were again detected, and the patient’s bone marrow also revealed mild hemophagocytosis and the same cytogenetic abnormalities. Steroid treatment was reinitiated, and the patient’s general condition improved including the disappearance of the cytogenetic abnormalities in the 0145-2126/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
bone marrow. During the course of treatment, no neoplasms were detected. We found a parallel association between the disease activity of hemophagocytic syndrome (HPS) and cytogenetic abnormalities in the bone marrow. HPS is a clinical condition characterized by the activation of macrophages or histiocytes with prominent hemophagocytosis in the bone marrow and other reticuloendothelial systems. Macrophages are sometimes stimulated inappropriately via the dysregulation of host immunity and subsequently phagocytose self blood cells, resulting in HPS [1]. In 1939, Scott and Rob-Smith reported a neoplastic disorder showing hemophagocytosis by histiocytes [2]. Rappaport first reported the disease entity of malignant histiocytosis as HPS [3]. Furthermore, in 1979, Risdall et al. reported cases of active viral infections with prominent hemophagocytosis [4], suggesting that these conditions might be cases of VAHS, which is often the first report of reactive or secondary HPS [1]. HPS has been associated not only with viruses, but also with various types of disseminated infections such as bacterial, tubercular, fungal and parasitic infections [1]. In HPS, the immune system becomes overactive due to its
Fig. 1. The bone marrow aspirated smear showed a histiocyte with active hemophagocytosis.
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Letters to the Editor / Leukemia Research 31 (2007) 117–120
Fig. 2. Cytogenetic abnormalities showing 49, XY, +5, add(6) (p23), +20, +21. Arrows indicate rearranged chromosomes.
inability to respond to infections or shuts down in response to such infections. Uncontrolled T lymphocyte activation is responsible for increased secretion of Th1 cytokines secretion such as Interferon gamma, IL-12 and IL-18, which promotes macrophage activation [1,5,6]. Genetic defects in the secretory pathway of natural killer (NK) cells and cytotoxic T cells have been identified in patients with primary HPS, and are responsible for altered cell death and apotosis or target kill [1,5,6]. The present case is consistent with the diagnostic criteria of HPS. In general, the immune system decreases with advancing age. Our patient had a history of brain tumor and tuberculosis, and was therefore an immunocompromised host with underlying immunological derangement [7]. The clonal expansion of CMV-infected T or NK cells is associated with CMV infection. Moreover, in the present case, in addition to normal mitotic cells, cells with clonal cytogenetic abnormalities were observed. Ohshima et al. reported that chromosomal abnormalities in the lymph nodes of patients with chronic EBV infection [8]. In their study, 50% of the patients examined had chromosomal aberrations in their peripheral blood cells and 79% of patients showed monoclonality of EBV [8]. There were no specific patterns of genetic aberrations; the chromosomal abnormalities seen in patients with chronic active EBV infection might reflect only chromosomal fragility. Clonality of the CMV genome and chromosomal aberrations generally indicate clonal expansion of CMV-infected cells, so HPS might therefore be considered lymphoproliferative as well as infectious. During the present course of treatment, there was no reason to suspect malignancy, and our patient’s dramatic improvement by steroid and gancilovir treatment supports this. Never-
theless, HPS patients should be carefully observed for the possible development of neoplasms including leukemia and lymphoma.
Acknowledgement The authors would like to thank the doctors and nurses of the hematology wards of National Tokyo Medical Center Hospital for providing their excellent patient care.
References [1] Kumakura S. Hemophagocytic syndrome. Intern Med 2005;44(4): 278–80. [2] Scott RB, Smith R. Histiocytic medullary reticulosis. Lancet 1939;2:194–8. [3] Rappaport H. Tumors of the hematopoietic systems. Atlas Tumor Pathol 1966:49–63. [4] Risdall RJ, Mckenna RW, Nesbit ME. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. [5] Kimura H, Hoshino Y, kanegane H, Tsuge I, Okamura T, Kawa K, et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 2001;98(2):280–6. [6] Chen JS, Tzeng CC, Tsao CJ, Su WC, Chen TY, Jung YC, et al. Clonal Karyotype abnormalities in EBV-associated hemophagocytic syndrome. Hematologica 1997;82:572–6. [7] Danish EH, Dahms BB, Kumar ML. Cytomegalovirus-associated hemophagocytic syndrome. Pediatrics 1985;75(2):280–3. [8] Ohshima K, Suzumiya J, Ohga S, Ohgami A, Kikuchi M. Intergrated Epstein-Barr virus (EBV) and chromosomal abnormality in chronic active EBV infection. Int J Cancer 1997;71:943–7.
Letters to the Editor / Leukemia Research 31 (2007) 117–120
Hiroko Nishida a,b,∗ Yoji Ogura b Natsuko Yoshimizu b Hironori Ueno a,b Jae Wong Park b Takahiro Yano b Yasuo Ikeda a a Division of Hematology, Department of Internal Medicine, Keio University, School of Medicine, Tokyo, Japan b Division
of Hematology, Department of Internal Medicine, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan
119
∗ Corresponding
author at: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 3785; fax: +81 3 3353 3515/1211. E-mail address: [email protected] (H. Nishida) 24 February 2006 Available online 2 May 2006 doi: 10.1016/j.leukres.2006.02.030
Cryptococcus lung infection complicating fludarabine treatment in a chronic lymphocytic leukemia patient Keywords: Fludarabine; Cryptococcus; Antifungal prophylaxis
To the Editor, Chronic lymphocytic leukemia (CLL) is a monoclonal disease characterized by the progressive accumulation of peripheral CD5+ B cells in lymphoid tissues, bone marrow, and peripheral blood. During the last years the introduction of purine nucleoside analogues, and monoclonal antibodies has prolonged the progression-free interval [1]. A 70-year-old male patient was diagnosed with CLL, stage Rai I, in June 1994, and since then treated with clorambucil and prednisone, and rituximab, but no signs of complete or partial remission were evident after completing a total of eight cycles of the monoclonal antibody therapy, and so fludarabine was administered at a dosage of 40 mg/m2 , for five consecutive days every 28 days. Prophylaxis consisted in daily administration of valacyclovir, and cotrimoxazole thrice weekly and was interrupted 3 months after the last fludarabine cycle. Four months later and while not under therapy for CLL he presented with mild cough and fever up to 37.6 ◦ C. His hematocrit levels were 37.3%, hemoglobin levels 12.3 gr/dl, white blood cell count 2660 l−1 , neutrophil count 2050 l−1 , lymphocyte count 400 l−1 , and platelet count 80,000 l−1 . The chest radiograph revealed coin lesions in his right lung and so he underwent a high-resolution computerized tomography (HRCT) of the chest, which showed two infiltrates in the right lower lobe with radial projections, maximum 32 mm of diameter, in contact with the pleura, another lesion, 18 mm of diameter, and other smaller lesions always in the right lung (Fig. 1a,b). Our first thought was that these lesions could be neoplastic–metastatic lesions, as CLL patients are known to often present second malignancies. Next, a CT-
guided biopsy was performed, which demonstrated granulomatous inflammation with isolated Langhans cells and extended necrotic areas. Small numerous, round microorganisms compatible with Cryptococcus were observed, a finding confirmed by immunochemistry. The patient received fluconazole (600 mg/day) and at the time of writing he is free of signs and symptoms. Fludarabine is a purine nucleoside analogue active in both newly diagnosed and refractory CLL, used as a single agent or in various combinations [2]. The most common pathogens in CLL patients receiving fludarabine include Listeria monocytogenes, Candida, Aspergillus, Cryptococcus, VaricellaZoster Virus, Cytomegalovirus, Pneumocystis carinii, and Tubercolosis [3]. Cryptococcus neoformans infection is usually contracted through inhalation and symptoms are similar to bacterial pneumonia, which can progress to acute respiratory failure [4]. To the best of our knowledge, only three cases have been reported in English literature of Cryptococcus infection associated with the use of fludarabine, of which two cases of meningitis and one of disseminated infection [5–7], thus making our case the first documented of Cryptococcal pneumonia reported. As purine nucleoside analogues cause CD4 depletion and probably increase the risk of opportunistic infections, prophylactic use of cotrimoxazole is strongly recommended even after stopping fludarabine therapy, while use of antiviral and antifungal drugs remains at physicians’ discretion [2,3]. Perhaps it would be prudent that these immunosuppressed patients also receive antifungal prophylaxis in order to diminish the risk of fungal infections, which can be fatal, and whether prophylactic antifungals are effec-
Letters to the Editor
Cytomegalovirus-associated hemophagocytic syndrome with clonal cytogenetic abnormalities in an elderly male An 80-year old male with a history of benign brain tumor and tuberculosis was admitted to the National Medical Center Hospital Tokyo, Japan with persistent high fever, general fatigue and weight loss in June 2005. Physical examination showed hepatosplenomegaly, but no lymphadenopathy was observed. The patient’s laboratory findings showed mild pancytopenia and liver dysfunction with the following characteristics: leukocyte count, 2.4 × 109 /l, with normal leukocyte differential; hemoglobin, 11.6 g/dl; platelet count, 8.8 × 109 /l; aspartate aminotransferase (AST), 73 IU/l; alanine aminotransferase (ALT), 41 IU/l; lactate dehydrogenase (LDH), 788 IU/l; soluble interleukin two receptor (sIL-2R), 15905 U/ml; ferritin, 9500 ng/ml. Cytomegalovirus (CMV)positive leukocytes were detected. The patient tested negative for other virus titers including Epstein-Barr virus (EBV) and varicella-zoster virus (VZV), and no bacterial, tubercular, fungal or parasitic infections were detected. Bone marrow aspiration revealed hemophagocytosis of the erythrocytes, leukocytes and platelets by monocytes and macrophages (Fig. 1). Additionally, cytogenetic analysis showed (2/20) positivity for 49, XY, +5, add(6)(p23), +20, +21, and (12/20) positivity for 46, XY (Fig. 2), but no other reasons to suspect malignancy or collagen diseases were detected. Based on these findings, the patient was diagnosed with virusassociated hemophagocytic syndrome (VAHS). His elevated levels of LDH, ferritin and sIl2-R were normalized by steroid (Solucortef, 200 mg/day) and ganciclovir treatments, which also brought about a dramatic improvement in the patient’s general condition; the hemophagocytosis and cytogenetic abnormalities in the bone marrow disappeared completely. However, in August 2005, when the steroid treatment was tapered off, the patient experienced high fever again every day as well as the progression of his mild pancytopenia. CMVpositive leukocytes were again detected, and the patient’s bone marrow also revealed mild hemophagocytosis and the same cytogenetic abnormalities. Steroid treatment was reinitiated, and the patient’s general condition improved including the disappearance of the cytogenetic abnormalities in the 0145-2126/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
bone marrow. During the course of treatment, no neoplasms were detected. We found a parallel association between the disease activity of hemophagocytic syndrome (HPS) and cytogenetic abnormalities in the bone marrow. HPS is a clinical condition characterized by the activation of macrophages or histiocytes with prominent hemophagocytosis in the bone marrow and other reticuloendothelial systems. Macrophages are sometimes stimulated inappropriately via the dysregulation of host immunity and subsequently phagocytose self blood cells, resulting in HPS [1]. In 1939, Scott and Rob-Smith reported a neoplastic disorder showing hemophagocytosis by histiocytes [2]. Rappaport first reported the disease entity of malignant histiocytosis as HPS [3]. Furthermore, in 1979, Risdall et al. reported cases of active viral infections with prominent hemophagocytosis [4], suggesting that these conditions might be cases of VAHS, which is often the first report of reactive or secondary HPS [1]. HPS has been associated not only with viruses, but also with various types of disseminated infections such as bacterial, tubercular, fungal and parasitic infections [1]. In HPS, the immune system becomes overactive due to its
Fig. 1. The bone marrow aspirated smear showed a histiocyte with active hemophagocytosis.
118
Letters to the Editor / Leukemia Research 31 (2007) 117–120
Fig. 2. Cytogenetic abnormalities showing 49, XY, +5, add(6) (p23), +20, +21. Arrows indicate rearranged chromosomes.
inability to respond to infections or shuts down in response to such infections. Uncontrolled T lymphocyte activation is responsible for increased secretion of Th1 cytokines secretion such as Interferon gamma, IL-12 and IL-18, which promotes macrophage activation [1,5,6]. Genetic defects in the secretory pathway of natural killer (NK) cells and cytotoxic T cells have been identified in patients with primary HPS, and are responsible for altered cell death and apotosis or target kill [1,5,6]. The present case is consistent with the diagnostic criteria of HPS. In general, the immune system decreases with advancing age. Our patient had a history of brain tumor and tuberculosis, and was therefore an immunocompromised host with underlying immunological derangement [7]. The clonal expansion of CMV-infected T or NK cells is associated with CMV infection. Moreover, in the present case, in addition to normal mitotic cells, cells with clonal cytogenetic abnormalities were observed. Ohshima et al. reported that chromosomal abnormalities in the lymph nodes of patients with chronic EBV infection [8]. In their study, 50% of the patients examined had chromosomal aberrations in their peripheral blood cells and 79% of patients showed monoclonality of EBV [8]. There were no specific patterns of genetic aberrations; the chromosomal abnormalities seen in patients with chronic active EBV infection might reflect only chromosomal fragility. Clonality of the CMV genome and chromosomal aberrations generally indicate clonal expansion of CMV-infected cells, so HPS might therefore be considered lymphoproliferative as well as infectious. During the present course of treatment, there was no reason to suspect malignancy, and our patient’s dramatic improvement by steroid and gancilovir treatment supports this. Never-
theless, HPS patients should be carefully observed for the possible development of neoplasms including leukemia and lymphoma.
Acknowledgement The authors would like to thank the doctors and nurses of the hematology wards of National Tokyo Medical Center Hospital for providing their excellent patient care.
References [1] Kumakura S. Hemophagocytic syndrome. Intern Med 2005;44(4): 278–80. [2] Scott RB, Smith R. Histiocytic medullary reticulosis. Lancet 1939;2:194–8. [3] Rappaport H. Tumors of the hematopoietic systems. Atlas Tumor Pathol 1966:49–63. [4] Risdall RJ, Mckenna RW, Nesbit ME. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. [5] Kimura H, Hoshino Y, kanegane H, Tsuge I, Okamura T, Kawa K, et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 2001;98(2):280–6. [6] Chen JS, Tzeng CC, Tsao CJ, Su WC, Chen TY, Jung YC, et al. Clonal Karyotype abnormalities in EBV-associated hemophagocytic syndrome. Hematologica 1997;82:572–6. [7] Danish EH, Dahms BB, Kumar ML. Cytomegalovirus-associated hemophagocytic syndrome. Pediatrics 1985;75(2):280–3. [8] Ohshima K, Suzumiya J, Ohga S, Ohgami A, Kikuchi M. Intergrated Epstein-Barr virus (EBV) and chromosomal abnormality in chronic active EBV infection. Int J Cancer 1997;71:943–7.
Letters to the Editor / Leukemia Research 31 (2007) 117–120
Hiroko Nishida a,b,∗ Yoji Ogura b Natsuko Yoshimizu b Hironori Ueno a,b Jae Wong Park b Takahiro Yano b Yasuo Ikeda a a Division of Hematology, Department of Internal Medicine, Keio University, School of Medicine, Tokyo, Japan b Division
of Hematology, Department of Internal Medicine, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan
119
∗ Corresponding
author at: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 3785; fax: +81 3 3353 3515/1211. E-mail address: [email protected] (H. Nishida) 24 February 2006 Available online 2 May 2006 doi: 10.1016/j.leukres.2006.02.030
Cryptococcus lung infection complicating fludarabine treatment in a chronic lymphocytic leukemia patient Keywords: Fludarabine; Cryptococcus; Antifungal prophylaxis
To the Editor, Chronic lymphocytic leukemia (CLL) is a monoclonal disease characterized by the progressive accumulation of peripheral CD5+ B cells in lymphoid tissues, bone marrow, and peripheral blood. During the last years the introduction of purine nucleoside analogues, and monoclonal antibodies has prolonged the progression-free interval [1]. A 70-year-old male patient was diagnosed with CLL, stage Rai I, in June 1994, and since then treated with clorambucil and prednisone, and rituximab, but no signs of complete or partial remission were evident after completing a total of eight cycles of the monoclonal antibody therapy, and so fludarabine was administered at a dosage of 40 mg/m2 , for five consecutive days every 28 days. Prophylaxis consisted in daily administration of valacyclovir, and cotrimoxazole thrice weekly and was interrupted 3 months after the last fludarabine cycle. Four months later and while not under therapy for CLL he presented with mild cough and fever up to 37.6 ◦ C. His hematocrit levels were 37.3%, hemoglobin levels 12.3 gr/dl, white blood cell count 2660 l−1 , neutrophil count 2050 l−1 , lymphocyte count 400 l−1 , and platelet count 80,000 l−1 . The chest radiograph revealed coin lesions in his right lung and so he underwent a high-resolution computerized tomography (HRCT) of the chest, which showed two infiltrates in the right lower lobe with radial projections, maximum 32 mm of diameter, in contact with the pleura, another lesion, 18 mm of diameter, and other smaller lesions always in the right lung (Fig. 1a,b). Our first thought was that these lesions could be neoplastic–metastatic lesions, as CLL patients are known to often present second malignancies. Next, a CT-
guided biopsy was performed, which demonstrated granulomatous inflammation with isolated Langhans cells and extended necrotic areas. Small numerous, round microorganisms compatible with Cryptococcus were observed, a finding confirmed by immunochemistry. The patient received fluconazole (600 mg/day) and at the time of writing he is free of signs and symptoms. Fludarabine is a purine nucleoside analogue active in both newly diagnosed and refractory CLL, used as a single agent or in various combinations [2]. The most common pathogens in CLL patients receiving fludarabine include Listeria monocytogenes, Candida, Aspergillus, Cryptococcus, VaricellaZoster Virus, Cytomegalovirus, Pneumocystis carinii, and Tubercolosis [3]. Cryptococcus neoformans infection is usually contracted through inhalation and symptoms are similar to bacterial pneumonia, which can progress to acute respiratory failure [4]. To the best of our knowledge, only three cases have been reported in English literature of Cryptococcus infection associated with the use of fludarabine, of which two cases of meningitis and one of disseminated infection [5–7], thus making our case the first documented of Cryptococcal pneumonia reported. As purine nucleoside analogues cause CD4 depletion and probably increase the risk of opportunistic infections, prophylactic use of cotrimoxazole is strongly recommended even after stopping fludarabine therapy, while use of antiviral and antifungal drugs remains at physicians’ discretion [2,3]. Perhaps it would be prudent that these immunosuppressed patients also receive antifungal prophylaxis in order to diminish the risk of fungal infections, which can be fatal, and whether prophylactic antifungals are effec-