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Hemophagocytosis in a Patient With Chronic Lymphocytic Leukemia and Histoplasmosis
Hemophagocytosis in CLL and Histoplasmosis
Mayo Clin Proc, March 2002, Vol 77
287
Case Report
Hemophagocytosis in a Patient With Chronic Lymphocytic Leukemia and Histoplasmosis RAVI D. RAO, MD; WILLIAM G. MORICE, MD, PHD; AND ROBERT L. PHYLIKY, MD We present a case of hemophagocytosis in the setting of a disseminated Histoplasma infection in a patient with B-cell chronic lymphocytic leukemia (CLL). A 68-year-old man with CLL presented with progressive pancytopenia and fevers after therapy with cyclophosphamide and fludarabine phosphate. Extensive evaluation for a source of infection revealed a pulmonary nodule. A biopsy specimen taken from the nodule showed granulomas containing Histoplasma organisms. A bone marrow biopsy specimen demonstrated disseminated histoplasmosis and intense hemophagocytosis. Antifungal therapy with amphotericin B was initiated, and the fevers and cytopenias resolved.
Hemophagocytic syndrome is an uncommon condition with many origins. It is characterized by a proliferation of histiocytes with phagocytosis of formed elements of blood. Clinical manifestations include signs and symptoms of immune activation and decreased peripheral blood cell counts. This condition is often underdiagnosed because clinicians are unfamiliar with it. Mayo Clin Proc. 2002;77:287-290 CLL = chronic lymphocytic leukemia; HPS = hemophagocytic syndrome
H
Multiple bacterial and fungal blood cultures and serologic tests for fungi (including Histoplasma) and viruses were performed, the results of which were negative. A bone marrow biopsy specimen demonstrated that the CLL was in complete remission; special stains and microbiologic cultures of the bone marrow were negative. The patient also underwent transesophageal echocardiography, which did not show any evidence of infective endocarditis. Imaging of his lungs with a computed tomographic scan demonstrated a lung nodule. A biopsy specimen of this lung nodule revealed multiple noncaseating granulomatous lesions containing argyrophilic organisms that were morphologically consistent with Histoplasma species. The patient’s blood cell counts began to decline, and an additional bone marrow biopsy was performed (2 weeks after the first). The biopsy specimen revealed noncaseating granulomas and an interstitial histiocytic infiltrate with intense hemophagocytosis (Figure 1). Silver staining of the bone marrow sections confirmed the presence of organisms suggestive of Histoplasma species (Figure 2). Immunostaining of paraffin sections with antibodies to CD68 highlighted the histiocytic cytoplasm and accentuated the degree of hemophagocytosis (Figure 3). There was no morphologic or immunophenotypic evidence of CLL in the biopsy specimen. Antifungal therapy with intravenous amphotericin B was initiated. The patient’s fever resolved promptly. Two weeks later, he was switched to oral itraconazole therapy. At a 2-month follow-up examination, he was symptom free. His symptoms and the cytopenias had resolved. A
emophagocytic syndrome (HPS) is a nonmalignant syndrome characterized by an expansion of the monocyte-macrophage population and intense hemophagocytosis. It can occur de novo, but more often occurs in the setting of another disorder, usually an infection or a malignancy. Therapy is dictated by the underlying diagnosis. Herein, we present a case of hemophagocytosis in a patient with a disseminated Histoplasma infection and B-cell chronic lymphocytic leukemia (CLL). REPORT OF A CASE The patient was a 68-year-old man with B-cell CLL. He had been observed for 8 years during which he did not undergo therapy or exhibit any symptoms of HPS. He then developed progressive anemia and was treated with a combination of cyclophosphamide (600 mg/m2 on day 1) and fludarabine phosphate (20 mg/m2 on days 1-5) administered every 4 weeks. After 3 cycles, he developed spiking fevers and therapy was halted. He was hospitalized and treated empirically with broad-spectrum antibiotics. His physical examination results were nonfocal with no evidence of lymphadenopathy, hepatomegaly, splenomegaly, or rash. An extensive work-up for neutropenic fevers was performed. His laboratory data are presented in Table 1.
From the Division of Hematology and Internal Medicine (R.D.R., R.L.P.) and Department of Laboratory Medicine and Pathology (W.G.M.), Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Robert L. Phyliky, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:287-290
287
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
288
Hemophagocytosis in CLL and Histoplasmosis
Mayo Clin Proc, March 2002, Vol 77
Table 1. Results of Laboratory Testing* Test
Admission
2-mo follow-up
Reference range
White blood cell count (×109/L) ANC ALC AMC Hemoglobin (g/dL) Platelets (×109/L) Sedimentation rate (mm/1 h) Ferritin (µg/L) Alkaline phosphatase (U/L) AST (U/L) ALT (U/L) Activated partial thromboplastin time (s) Prothrombin time (s)
1.3 9.88 0.156 0.104 7.5 62 22 1142 1035 37 74
4.0 2.16 0.440 NA 11.3 228 27 ND ND ND ND
3.5-10.5 1.7-7.0 0.9-2.9 0.3-0.9 13.5-17.5 150-450 0-22 20-300 119-309 12-31 10-45
30 12.1
ND ND
21-33 8.4-12
*ALC = absolute lymphocyte count; ALT = alanine aminotransferase; AMC = absolute monocyte count; ANC = absolute neutrophil count; AST = aspartate aminotransferase; NA = not applicable; ND = not done.
DISCUSSION Hemophagocytic syndrome is an uncommon nonneoplastic disorder of the mononuclear phagocytic system. It can occur as a primary idiopathic syndrome but more commonly is secondary to a neoplastic, infectious, or autoimmune process. Clinically, HPS is characterized by signs and symptoms of immune activation, such as fever, organ dysfunction (hepatosplenomegaly, abnormal liver function test results, and neurologic dysfunction), and depressed peripheral blood cell counts. Biopsy specimens of involved
organs and bone marrow reveal a generalized histiocytic expansion with marked hemophagocytosis by these histiocytes. Patients are usually very sick and have a high mortality, which is a reflection on the severity of the underlying disorder. The pathogenesis of this syndrome is related to uncontrolled activation of the cellular immune system. Evidence suggests that patients have an inability to down-regulate immune activation set off by a trigger, usually an infection.1,2 The initiating factor is T-lymphocyte activation, which sets off an immune cascade, with a significant elevation of various cytokines (tumor necrosis factor α, interferon γ, interleukin 2, interleukin 6, prostaglandin F2α,
Figure 1. Bone marrow biopsy specimen stained with hematoxylineosin (original magnification, ×400) demonstrating an intense histiocytic infiltrate with hemophagocytosis. The arrows point to histiocytes with abundant cytoplasm engorged with red blood cells.
Figure 2. Bone marrow biopsy specimen stained with GrocottGomori methenamine–silver nitrate stain with eosin counterstain (original magnification, ×600) demonstrating argyrophilic organisms consistent with Histoplasma species.
subsequent bone marrow biopsy was not performed in view of the good clinical response.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 2002, Vol 77
and prostaglandin E2). This leads to a proliferation of the monocyte-macrophage system and its activation as evidenced by an increased ability to spontaneously reduce nitroblue tetazolium. It is not known why only a subset of patients develop this syndrome in response to these triggers. The diagnosis of HPS is based on clinical criteria proposed by Henter et al.3 Criteria include the presence of fever, organomegaly, cytopenias, hypertriglyceridemia, and pathologic evidence of hemophagocytosis. The diagnosis of primary idiopathic HPS requires the absence of a malignancy on the biopsy specimen or evidence of other secondary causes of the syndrome. Primary HPS appears to have a hereditary (autosomal recessive) basis. There is a history of consanguinity in some families, and certain ethnic groups seem to be predisposed to the condition.4 It occurs in infants who present with a clinical picture reminiscent of acute leukemia. Even though this is not a neoplastic process, most patients do poorly and die after a short illness. The primary defect seems to be an inability to shut off an exuberant immune response to a childhood infection. In the absence of a positive family history, a virus-associated HPS has to be considered among the differential diagnoses. Therapy with cytotoxic drugs, such as etoposide, leads to remission, but problems with toxic effects and relapses remain. Other options include cyclosporine, methotrexate, and allogeneic bone marrow transplantation.5,6 Secondary HPS occurs in the setting of another neoplastic, autoimmune, or infectious disease.1,7 The more common causes are listed in Table 2. Secondary HPS is much more common than the primary variant and can occur in all age groups. This diagnosis should prompt a search for the primary disease, if not already known. The prognosis and therapy of patients with HPS depend on the primary diagnosis. Certain subsets of patients merit special mention. Adult patients with HPS associated with Epstein-Barr virus infections carry an especially poor prognosis without therapy. They respond to cytotoxic chemotherapy as for high-grade lymphomas. Other therapies that have been successfully used in adults with Epstein-Barr virus and HPS include etoposide, cyclosporine, prednisone, intravenous immunoglobulin, and allogeneic bone marrow transplantation.8,9 Lupus-associated HPS is another special category and should be treated with corticosteroids. A review of the literature reveals only 6 other cases of histoplasmosis-associated HPS.10-13 Although the association of HPS with high-grade lymphomas is well established,14,15 there are no published reports, to our knowledge, of an association with B-cell CLL. This patient responded
Hemophagocytosis in CLL and Histoplasmosis
289
Figure 3. Immunohistochemical staining of the bone marrow biopsy specimen with anti-CD68 antibody (KP-1 with hematoxylin counterstain, original magnification, ×600), which highlights the mononuclear cell population. The intense hemophagocytosis is well demonstrated here.
to chemotherapy with a complete remission and had no pathologic evidence of CLL at the time of the diagnosis of HPS. We believe that the immunosuppression caused by chemotherapy was the underlying cause for disseminated histoplasmosis and hence the HPS. Interestingly, the patient developed this syndrome after being treated with fludarabine, which is a potent inhibitor of monocytes and T cells, both of which play important roles in the pathogenesis of HPS.
Table 2. Conditions Associated With Hemophagocytic Syndromes* Viruses Herpesviruses (Epstein-Barr virus, cytomegalovirus) Human immunodeficiency virus Bacteria Bacterial sepsis (eg, Pneumococcus) Mycobacteria Fungi Aspergillus species Cryptococcus neoformans Histoplasma capsulatum Pneumocystis carinii Parasites Babesia microti Plasmodium falciparum Malignancy Non-Hodgkin lymphoma (T and B cell) Acute leukemia Autoimmune disorders Systemic lupus erythematosus Hereditary Primary hemophagocytic syndrome *For a complete list, see Fisman.1
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
290
Hemophagocytosis in CLL and Histoplasmosis
CONCLUSION Hemophagocytic syndrome is an uncommon condition associated with cytopenias and immune activation. This diagnosis should be considered in patients with unexplained cytopenias in the setting of disseminated infections, malignancies, or autoimmune disorders.
Mayo Clin Proc, March 2002, Vol 77
7.
8.
9.
REFERENCES 1. 2.
3.
4. 5.
6.
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6:601-608. Lay J-D, Tsao C-J, Chen J-Y, Kadin ME, Su I-J. Upregulation of tumor necrosis factor-α gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus–infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest. 1997; 100:1969-1979. Henter JI, Elinder G, Ost A, FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. 1991;18:29-33. Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992;9:63-74. Arico M, Janka G, Fischer A, et al, FHL Study Group of the Histiocyte Society. Hemophagocytic lymphohistiocytosis: report of 122 children from the International Registry. Leukemia. 1996;10:197-203. Stephan JL, Donadieu J, Ledeist F, Blanche S, Griscelli C, Fischer A. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood. 1993;82:2319-2323.
10.
11.
12.
13.
14.
15.
Wong KF, Chan JK. Reactive hemophagocytic syndrome—a clinicopathologic study of 40 patients in an Oriental population. Am J Med. 1992;93:177-180. Tsuda H, Shirono K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colony-stimulating factor. Br J Haematol. 1996; 93:572-575. Imashuku S, Naya M, Yamori M, et al. Bone marrow transplantation for Epstein-Barr virus-related clonal T cell proliferation associated with hemophagocytosis [letter]. Bone Marrow Transplant. 1997;19:1059-1060. Reiner AP, Spivak JL. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore). 1988;67:369-388. Keller FG, Kurtzberg J. Disseminated histoplasmosis: a cause of infection-associated hemophagocytic syndrome. Am J Pediatr Hematol Oncol. 1994;16:368-371. Kumar N, Jain S, Singh ZN. Disseminated histoplasmosis with reactive hemophagocytosis: aspiration cytology findings in two cases. Diagn Cytopathol. 2000;23:422-424. Koduri PR, Chundi V, DeMarais P, Mizock BA, Patel AR, Weinstein RA. Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis. 1995;21:1463-1465. Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol. 2000;79:378-388. Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma. 2000;38:121130.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 2002, Vol 77
287
Case Report
Hemophagocytosis in a Patient With Chronic Lymphocytic Leukemia and Histoplasmosis RAVI D. RAO, MD; WILLIAM G. MORICE, MD, PHD; AND ROBERT L. PHYLIKY, MD We present a case of hemophagocytosis in the setting of a disseminated Histoplasma infection in a patient with B-cell chronic lymphocytic leukemia (CLL). A 68-year-old man with CLL presented with progressive pancytopenia and fevers after therapy with cyclophosphamide and fludarabine phosphate. Extensive evaluation for a source of infection revealed a pulmonary nodule. A biopsy specimen taken from the nodule showed granulomas containing Histoplasma organisms. A bone marrow biopsy specimen demonstrated disseminated histoplasmosis and intense hemophagocytosis. Antifungal therapy with amphotericin B was initiated, and the fevers and cytopenias resolved.
Hemophagocytic syndrome is an uncommon condition with many origins. It is characterized by a proliferation of histiocytes with phagocytosis of formed elements of blood. Clinical manifestations include signs and symptoms of immune activation and decreased peripheral blood cell counts. This condition is often underdiagnosed because clinicians are unfamiliar with it. Mayo Clin Proc. 2002;77:287-290 CLL = chronic lymphocytic leukemia; HPS = hemophagocytic syndrome
H
Multiple bacterial and fungal blood cultures and serologic tests for fungi (including Histoplasma) and viruses were performed, the results of which were negative. A bone marrow biopsy specimen demonstrated that the CLL was in complete remission; special stains and microbiologic cultures of the bone marrow were negative. The patient also underwent transesophageal echocardiography, which did not show any evidence of infective endocarditis. Imaging of his lungs with a computed tomographic scan demonstrated a lung nodule. A biopsy specimen of this lung nodule revealed multiple noncaseating granulomatous lesions containing argyrophilic organisms that were morphologically consistent with Histoplasma species. The patient’s blood cell counts began to decline, and an additional bone marrow biopsy was performed (2 weeks after the first). The biopsy specimen revealed noncaseating granulomas and an interstitial histiocytic infiltrate with intense hemophagocytosis (Figure 1). Silver staining of the bone marrow sections confirmed the presence of organisms suggestive of Histoplasma species (Figure 2). Immunostaining of paraffin sections with antibodies to CD68 highlighted the histiocytic cytoplasm and accentuated the degree of hemophagocytosis (Figure 3). There was no morphologic or immunophenotypic evidence of CLL in the biopsy specimen. Antifungal therapy with intravenous amphotericin B was initiated. The patient’s fever resolved promptly. Two weeks later, he was switched to oral itraconazole therapy. At a 2-month follow-up examination, he was symptom free. His symptoms and the cytopenias had resolved. A
emophagocytic syndrome (HPS) is a nonmalignant syndrome characterized by an expansion of the monocyte-macrophage population and intense hemophagocytosis. It can occur de novo, but more often occurs in the setting of another disorder, usually an infection or a malignancy. Therapy is dictated by the underlying diagnosis. Herein, we present a case of hemophagocytosis in a patient with a disseminated Histoplasma infection and B-cell chronic lymphocytic leukemia (CLL). REPORT OF A CASE The patient was a 68-year-old man with B-cell CLL. He had been observed for 8 years during which he did not undergo therapy or exhibit any symptoms of HPS. He then developed progressive anemia and was treated with a combination of cyclophosphamide (600 mg/m2 on day 1) and fludarabine phosphate (20 mg/m2 on days 1-5) administered every 4 weeks. After 3 cycles, he developed spiking fevers and therapy was halted. He was hospitalized and treated empirically with broad-spectrum antibiotics. His physical examination results were nonfocal with no evidence of lymphadenopathy, hepatomegaly, splenomegaly, or rash. An extensive work-up for neutropenic fevers was performed. His laboratory data are presented in Table 1.
From the Division of Hematology and Internal Medicine (R.D.R., R.L.P.) and Department of Laboratory Medicine and Pathology (W.G.M.), Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Robert L. Phyliky, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:287-290
287
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
288
Hemophagocytosis in CLL and Histoplasmosis
Mayo Clin Proc, March 2002, Vol 77
Table 1. Results of Laboratory Testing* Test
Admission
2-mo follow-up
Reference range
White blood cell count (×109/L) ANC ALC AMC Hemoglobin (g/dL) Platelets (×109/L) Sedimentation rate (mm/1 h) Ferritin (µg/L) Alkaline phosphatase (U/L) AST (U/L) ALT (U/L) Activated partial thromboplastin time (s) Prothrombin time (s)
1.3 9.88 0.156 0.104 7.5 62 22 1142 1035 37 74
4.0 2.16 0.440 NA 11.3 228 27 ND ND ND ND
3.5-10.5 1.7-7.0 0.9-2.9 0.3-0.9 13.5-17.5 150-450 0-22 20-300 119-309 12-31 10-45
30 12.1
ND ND
21-33 8.4-12
*ALC = absolute lymphocyte count; ALT = alanine aminotransferase; AMC = absolute monocyte count; ANC = absolute neutrophil count; AST = aspartate aminotransferase; NA = not applicable; ND = not done.
DISCUSSION Hemophagocytic syndrome is an uncommon nonneoplastic disorder of the mononuclear phagocytic system. It can occur as a primary idiopathic syndrome but more commonly is secondary to a neoplastic, infectious, or autoimmune process. Clinically, HPS is characterized by signs and symptoms of immune activation, such as fever, organ dysfunction (hepatosplenomegaly, abnormal liver function test results, and neurologic dysfunction), and depressed peripheral blood cell counts. Biopsy specimens of involved
organs and bone marrow reveal a generalized histiocytic expansion with marked hemophagocytosis by these histiocytes. Patients are usually very sick and have a high mortality, which is a reflection on the severity of the underlying disorder. The pathogenesis of this syndrome is related to uncontrolled activation of the cellular immune system. Evidence suggests that patients have an inability to down-regulate immune activation set off by a trigger, usually an infection.1,2 The initiating factor is T-lymphocyte activation, which sets off an immune cascade, with a significant elevation of various cytokines (tumor necrosis factor α, interferon γ, interleukin 2, interleukin 6, prostaglandin F2α,
Figure 1. Bone marrow biopsy specimen stained with hematoxylineosin (original magnification, ×400) demonstrating an intense histiocytic infiltrate with hemophagocytosis. The arrows point to histiocytes with abundant cytoplasm engorged with red blood cells.
Figure 2. Bone marrow biopsy specimen stained with GrocottGomori methenamine–silver nitrate stain with eosin counterstain (original magnification, ×600) demonstrating argyrophilic organisms consistent with Histoplasma species.
subsequent bone marrow biopsy was not performed in view of the good clinical response.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 2002, Vol 77
and prostaglandin E2). This leads to a proliferation of the monocyte-macrophage system and its activation as evidenced by an increased ability to spontaneously reduce nitroblue tetazolium. It is not known why only a subset of patients develop this syndrome in response to these triggers. The diagnosis of HPS is based on clinical criteria proposed by Henter et al.3 Criteria include the presence of fever, organomegaly, cytopenias, hypertriglyceridemia, and pathologic evidence of hemophagocytosis. The diagnosis of primary idiopathic HPS requires the absence of a malignancy on the biopsy specimen or evidence of other secondary causes of the syndrome. Primary HPS appears to have a hereditary (autosomal recessive) basis. There is a history of consanguinity in some families, and certain ethnic groups seem to be predisposed to the condition.4 It occurs in infants who present with a clinical picture reminiscent of acute leukemia. Even though this is not a neoplastic process, most patients do poorly and die after a short illness. The primary defect seems to be an inability to shut off an exuberant immune response to a childhood infection. In the absence of a positive family history, a virus-associated HPS has to be considered among the differential diagnoses. Therapy with cytotoxic drugs, such as etoposide, leads to remission, but problems with toxic effects and relapses remain. Other options include cyclosporine, methotrexate, and allogeneic bone marrow transplantation.5,6 Secondary HPS occurs in the setting of another neoplastic, autoimmune, or infectious disease.1,7 The more common causes are listed in Table 2. Secondary HPS is much more common than the primary variant and can occur in all age groups. This diagnosis should prompt a search for the primary disease, if not already known. The prognosis and therapy of patients with HPS depend on the primary diagnosis. Certain subsets of patients merit special mention. Adult patients with HPS associated with Epstein-Barr virus infections carry an especially poor prognosis without therapy. They respond to cytotoxic chemotherapy as for high-grade lymphomas. Other therapies that have been successfully used in adults with Epstein-Barr virus and HPS include etoposide, cyclosporine, prednisone, intravenous immunoglobulin, and allogeneic bone marrow transplantation.8,9 Lupus-associated HPS is another special category and should be treated with corticosteroids. A review of the literature reveals only 6 other cases of histoplasmosis-associated HPS.10-13 Although the association of HPS with high-grade lymphomas is well established,14,15 there are no published reports, to our knowledge, of an association with B-cell CLL. This patient responded
Hemophagocytosis in CLL and Histoplasmosis
289
Figure 3. Immunohistochemical staining of the bone marrow biopsy specimen with anti-CD68 antibody (KP-1 with hematoxylin counterstain, original magnification, ×600), which highlights the mononuclear cell population. The intense hemophagocytosis is well demonstrated here.
to chemotherapy with a complete remission and had no pathologic evidence of CLL at the time of the diagnosis of HPS. We believe that the immunosuppression caused by chemotherapy was the underlying cause for disseminated histoplasmosis and hence the HPS. Interestingly, the patient developed this syndrome after being treated with fludarabine, which is a potent inhibitor of monocytes and T cells, both of which play important roles in the pathogenesis of HPS.
Table 2. Conditions Associated With Hemophagocytic Syndromes* Viruses Herpesviruses (Epstein-Barr virus, cytomegalovirus) Human immunodeficiency virus Bacteria Bacterial sepsis (eg, Pneumococcus) Mycobacteria Fungi Aspergillus species Cryptococcus neoformans Histoplasma capsulatum Pneumocystis carinii Parasites Babesia microti Plasmodium falciparum Malignancy Non-Hodgkin lymphoma (T and B cell) Acute leukemia Autoimmune disorders Systemic lupus erythematosus Hereditary Primary hemophagocytic syndrome *For a complete list, see Fisman.1
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
290
Hemophagocytosis in CLL and Histoplasmosis
CONCLUSION Hemophagocytic syndrome is an uncommon condition associated with cytopenias and immune activation. This diagnosis should be considered in patients with unexplained cytopenias in the setting of disseminated infections, malignancies, or autoimmune disorders.
Mayo Clin Proc, March 2002, Vol 77
7.
8.
9.
REFERENCES 1. 2.
3.
4. 5.
6.
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6:601-608. Lay J-D, Tsao C-J, Chen J-Y, Kadin ME, Su I-J. Upregulation of tumor necrosis factor-α gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus–infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest. 1997; 100:1969-1979. Henter JI, Elinder G, Ost A, FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. 1991;18:29-33. Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992;9:63-74. Arico M, Janka G, Fischer A, et al, FHL Study Group of the Histiocyte Society. Hemophagocytic lymphohistiocytosis: report of 122 children from the International Registry. Leukemia. 1996;10:197-203. Stephan JL, Donadieu J, Ledeist F, Blanche S, Griscelli C, Fischer A. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood. 1993;82:2319-2323.
10.
11.
12.
13.
14.
15.
Wong KF, Chan JK. Reactive hemophagocytic syndrome—a clinicopathologic study of 40 patients in an Oriental population. Am J Med. 1992;93:177-180. Tsuda H, Shirono K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colony-stimulating factor. Br J Haematol. 1996; 93:572-575. Imashuku S, Naya M, Yamori M, et al. Bone marrow transplantation for Epstein-Barr virus-related clonal T cell proliferation associated with hemophagocytosis [letter]. Bone Marrow Transplant. 1997;19:1059-1060. Reiner AP, Spivak JL. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore). 1988;67:369-388. Keller FG, Kurtzberg J. Disseminated histoplasmosis: a cause of infection-associated hemophagocytic syndrome. Am J Pediatr Hematol Oncol. 1994;16:368-371. Kumar N, Jain S, Singh ZN. Disseminated histoplasmosis with reactive hemophagocytosis: aspiration cytology findings in two cases. Diagn Cytopathol. 2000;23:422-424. Koduri PR, Chundi V, DeMarais P, Mizock BA, Patel AR, Weinstein RA. Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis. 1995;21:1463-1465. Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol. 2000;79:378-388. Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma. 2000;38:121130.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.