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Hereditary hemorrhagic telangiectasia, idiopathic thrombocytopenic purpura, and chronic lymphocytic leukemia treated with rituximab
Letters to the Editor
nal aortography confirmed an arteriovenous fistula between the aorta and the inferior vena cava through the renal vein (Figure). The patient showed progressive clinical improvement after closure of the fistula in May 2002 (Table). Renal function normalized postsurgery, a phenomenon that has been reported elsewhere (6). Despite the high risk of left ventricular decompensation during endovascular repair of the fistula because of the acute increase in cardiac afterload, the patient’s heart failure did not worsen. There may be a delay of 5 days to 12 years between the traumatic event and the surgical repair of the arteriovenous fistula (7). Cardiac decompensation occurs in about 75% of patients. Because of shunting of blood from a high-resistance arterial circuit to a low-resistance venous system, elevated jugular venous pressure, tachycardia, and widened pulse pressure are common clinical signs. The increased cardiac preload, together with decreased afterload, lead to a compensatory increase in cardiac output and, possibly, heart failure. The lowered arterial blood pressure in conjunction with the increased venous blood pressure lead to a lowered renal pressure, which may explain the renal impairment. Primary symptoms of an aortocaval fistula include edema of the lower legs, venous stasis, heart failure, and abdominal bruit (8). Aortocaval fistula should therefore be considered in patients with penetrating trauma injuries, for whom a bruit is heard at the site of injury and who have signs of cardiac failure. Diagnosis, which may be confirmed by aortography (9), should be followed by early surgical intervention. Dahir Ramos de Andrade Ju´ nior, PhD Carla Almeida Wood, MD Joel Tedesco, MD Departamento de Clı´nica Me´dica, School of Medicine University of Sa˜o Paulo Sa˜o Paulo, Brazil 700
December 1, 2002
1. Semiz E, Sancaktar O, Yalcinkaya S, et al. Thoracic aortocaval fistula due to gunshot wound. Thorac Cardiovasc Surg. 1996;44: 261–263. 2. Duong C, Atkinson N. Review of aortoiliac aneurysms with spontaneous large vein fistula. Aust N Z J Surg. 2001;71:52–55. 3. Lanne T, Bergquist D. Aortocaval fistula associated with ruptured abdominal aortic aneurysms. Eur J Surg. 1992;158:457–465. 4. Burke AM, Jamieson GG. Aortocaval fistula associated with ruptured aortic aneurysm. Br J Surg. 1983;70:431–433. 5. Reckless JPD, McColl I, Taylor GW. Aortocaval fistulae: an uncommon complication of abdominal aortic aneurysms. Br J Surg. 1972;59:461–465. 6. Brunkwall J, Lanne T, Bergentz SE. Acute renal impairment due to a primary aortocaval fistula is normalised after a successful operation. Eur J Vasc Endovasc Surg. 1999; 17:191–196. 7. Machiedo GW, Jain KM, Swan KG, et al. Traumatic aorto-caval fistula. J Trauma. 1983;23:243–246. 8. Magee HR, Mellick AS. Aortocaval fistula as a complication of leaking aortic aneurysm. Br J Surg. 1977;64:239 –241. 9. Cook AM, Dyet JF, Mann SL. Case report: ultrasonic and comparative angiographic appearances of a spontaneous aorto-caval fistula. Clin Radiol. 1990;41:286 –288.
HEREDITARY HEMORRHAGIC TELANGIECTASIA, IDIOPATHIC THROMBOCYTOPENIC PURPURA, AND CHRONIC LYMPHOCYTIC LEUKEMIA TREATED WITH RITUXIMAB To the Editor: We report a case of refractory idiopathic thrombocytopenic purpura (ITP) associated with chronic lymphocytic leukemia (CLL) in a patient known to have hereditary hemorrhagic telangiectasia since childhood. Severe epistaxis occurred when her platelet count fell below 30 ⫻ 109/L. Treatment with rituximab led to complete remission of both ITP and CLL and cessation of epistaxis. A 71-year-old woman was referred because of lymphocytosis and anemia following a 2-month period of fatigue
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113
in 1997. Her past medical problems included hereditary hemorrhagic telangiectasia for which she had had laser surgeries for recurrent epistaxis. Lymphocyte count was 15 ⫻ 109/L (normal, 1 to 4 ⫻ 109/L), and histological examination showed smudge cells consistent with CLL. Flow cytometry showed a monoclonal Blymphocyte population with CD19⫹, CD5⫹, CD23⫹, CD79B⫹, and surface immunoglobulin ⫹, which was also consistent with CLL. Her platelet count was 245 ⫻ 109/L. Two weeks later, she noticed petechial lesions on her legs. A complete blood count showed a platelet count of 2 ⫻ 109/L. A bone marrow biopsy specimen showed lymphoproliferative involvement consistent with CLL with erythroid and megakaryocytic hyperplasia. Drug-related thrombocytopenia was ruled out. Idiopathic thrombocytopenic purpura–associated CLL was diagnosed. For 9 months, she received oral steroids, anti-D, and vincristine, which improved her condition slightly. She underwent a splenectomy that ameliorated her platelet count temporarily. She later had several hospital admissions for severe epistaxis and gastrointestinal bleeding, during which she received several transfusions of packed red blood cells. She took several therapeutic agents in various combinations, including vincristine, intravenous immunoglobulin, and cyclophosphamide (Figure). Her platelet count varied between 2 and 90 ⫻ 109/L. Rituximab (375 mg/m2), cytoxan, vincristine, and prednisone were administered weekly for 4 weeks. Four more doses of rituximab were given weekly with no adjunctive treatment. Platelet counts rose to 300 ⫻ 109/L and remained stable after 19 months of follow-up. Her lymphocytosis is stable at 1 ⫻ 109/L, and she has had a complete remission of her CLL and ITP. Idiopathic thrombocytopenic purpura occurs in 2% to 3% of patients with CLL (1,2). Pathogenesis is associated with both abnormal produc-
Letters to the Editor
Figure. Platelet counts rise after rituximab therapy.
tion of antibodies and T-cell dysfunction (3). It is unclear if hereditary hemorrhagic telangiectasia is also related, because there are no reports of an association of the three entities. In our patient, thrombocytopenia was more of a clinical problem because of the patient’s hemorrhagic telangiectasia. Rituximab is an anti-CD20 monoclonal antibody that is approved for the treatment of B-cell non-Hodgkin’s lymphoma. It also seems to have a beneficial effect in patients with CLL. Several reports have described partial remissions and tolerable toxicity even at higher doses (4,5). In patients with refractory ITP, there is no proven algorithm for standard care (6), but rituximab has shown some utility (7,8). There are no data about the use of rituximab in combined ITP and CLL, but our case suggests a favorable outcome.
ACKNOWLEDGMENT The authors thank Mr Karl Witton for his contribution with this article. Toni Choueiri, MD Alan E. Lichtin, MD The Cleveland Clinic Foundation Cleveland, Ohio
1. Duhrsen U, Augner W, Swingers T, et al. Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myleproliferative diseases. Br J Haematol. 1987;67:235–239. 2. Haubenstock A, Zalusky R. Autoimmune hyperthyroidism and thrombocytopenia developing in a patient with chronic lymphocytic leukemia. Am J Hematol. 1985;19: 281–283. 3. George JN, El-Harake MA, Aster RH. Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In: Beutler E, Lichtman M, Coller BC, et al, eds. Williams Hematology, Vol 5. New York: McGraw-Hill; 1995:1315–1355. 4. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165–2170. 5. Nguyen DT, Amess JA, Doughty H, et al. IDEC-C2B8 anti-CD 20 (rituximab) immunotherapy in patients with low-grade nonHodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol. 1999;62:76 –82. 6. George JN, Koujouri K, Perdue JJ, Vesely SK. Management of patients with chronic refractory idiopathic thrombocytopenic purpura. Semin Hematol. 2000;37:290 –298. 7. Perotta A, Sunneberg T, Scott J, et al. Rituxan in the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Blood. 1999;94:14. 8. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic December 1, 2002
idiopathic thrombocytopenic Blood. 2001;98:952–957.
purpura.
DIABETIC KETOACIDOSIS ASSOCIATED WITH ORAL SALBUTAMOL OVERDOSE To the Editor: Salbutamol, an adrenergic 2 receptor agonist, is used mainly as a solution for inhalation in patients with asthma and as a continuous infusion for the treatment of premature labor. Salbutamol overdose is associated with cardiovascular, neuromuscular, and metabolic manifestations. Most cases of overdose have involved continuous infusion. Thus far, diabetic ketoacidosis has been reported in three cases of salbutamol overdose (1–3), all involving continuous infusion. We report a case of oral salbutamol overdose with diabetic ketoacidosis. A 28-year-old woman with asthma had ingested 100 mg of salbutamol BP solution in a suicide attempt. One and a half hours after ingestion, she complained of chest pain, generalized tremors, and palpitations. About 4 hours later, she arrived at the emer-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 701
nal aortography confirmed an arteriovenous fistula between the aorta and the inferior vena cava through the renal vein (Figure). The patient showed progressive clinical improvement after closure of the fistula in May 2002 (Table). Renal function normalized postsurgery, a phenomenon that has been reported elsewhere (6). Despite the high risk of left ventricular decompensation during endovascular repair of the fistula because of the acute increase in cardiac afterload, the patient’s heart failure did not worsen. There may be a delay of 5 days to 12 years between the traumatic event and the surgical repair of the arteriovenous fistula (7). Cardiac decompensation occurs in about 75% of patients. Because of shunting of blood from a high-resistance arterial circuit to a low-resistance venous system, elevated jugular venous pressure, tachycardia, and widened pulse pressure are common clinical signs. The increased cardiac preload, together with decreased afterload, lead to a compensatory increase in cardiac output and, possibly, heart failure. The lowered arterial blood pressure in conjunction with the increased venous blood pressure lead to a lowered renal pressure, which may explain the renal impairment. Primary symptoms of an aortocaval fistula include edema of the lower legs, venous stasis, heart failure, and abdominal bruit (8). Aortocaval fistula should therefore be considered in patients with penetrating trauma injuries, for whom a bruit is heard at the site of injury and who have signs of cardiac failure. Diagnosis, which may be confirmed by aortography (9), should be followed by early surgical intervention. Dahir Ramos de Andrade Ju´ nior, PhD Carla Almeida Wood, MD Joel Tedesco, MD Departamento de Clı´nica Me´dica, School of Medicine University of Sa˜o Paulo Sa˜o Paulo, Brazil 700
December 1, 2002
1. Semiz E, Sancaktar O, Yalcinkaya S, et al. Thoracic aortocaval fistula due to gunshot wound. Thorac Cardiovasc Surg. 1996;44: 261–263. 2. Duong C, Atkinson N. Review of aortoiliac aneurysms with spontaneous large vein fistula. Aust N Z J Surg. 2001;71:52–55. 3. Lanne T, Bergquist D. Aortocaval fistula associated with ruptured abdominal aortic aneurysms. Eur J Surg. 1992;158:457–465. 4. Burke AM, Jamieson GG. Aortocaval fistula associated with ruptured aortic aneurysm. Br J Surg. 1983;70:431–433. 5. Reckless JPD, McColl I, Taylor GW. Aortocaval fistulae: an uncommon complication of abdominal aortic aneurysms. Br J Surg. 1972;59:461–465. 6. Brunkwall J, Lanne T, Bergentz SE. Acute renal impairment due to a primary aortocaval fistula is normalised after a successful operation. Eur J Vasc Endovasc Surg. 1999; 17:191–196. 7. Machiedo GW, Jain KM, Swan KG, et al. Traumatic aorto-caval fistula. J Trauma. 1983;23:243–246. 8. Magee HR, Mellick AS. Aortocaval fistula as a complication of leaking aortic aneurysm. Br J Surg. 1977;64:239 –241. 9. Cook AM, Dyet JF, Mann SL. Case report: ultrasonic and comparative angiographic appearances of a spontaneous aorto-caval fistula. Clin Radiol. 1990;41:286 –288.
HEREDITARY HEMORRHAGIC TELANGIECTASIA, IDIOPATHIC THROMBOCYTOPENIC PURPURA, AND CHRONIC LYMPHOCYTIC LEUKEMIA TREATED WITH RITUXIMAB To the Editor: We report a case of refractory idiopathic thrombocytopenic purpura (ITP) associated with chronic lymphocytic leukemia (CLL) in a patient known to have hereditary hemorrhagic telangiectasia since childhood. Severe epistaxis occurred when her platelet count fell below 30 ⫻ 109/L. Treatment with rituximab led to complete remission of both ITP and CLL and cessation of epistaxis. A 71-year-old woman was referred because of lymphocytosis and anemia following a 2-month period of fatigue
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113
in 1997. Her past medical problems included hereditary hemorrhagic telangiectasia for which she had had laser surgeries for recurrent epistaxis. Lymphocyte count was 15 ⫻ 109/L (normal, 1 to 4 ⫻ 109/L), and histological examination showed smudge cells consistent with CLL. Flow cytometry showed a monoclonal Blymphocyte population with CD19⫹, CD5⫹, CD23⫹, CD79B⫹, and surface immunoglobulin ⫹, which was also consistent with CLL. Her platelet count was 245 ⫻ 109/L. Two weeks later, she noticed petechial lesions on her legs. A complete blood count showed a platelet count of 2 ⫻ 109/L. A bone marrow biopsy specimen showed lymphoproliferative involvement consistent with CLL with erythroid and megakaryocytic hyperplasia. Drug-related thrombocytopenia was ruled out. Idiopathic thrombocytopenic purpura–associated CLL was diagnosed. For 9 months, she received oral steroids, anti-D, and vincristine, which improved her condition slightly. She underwent a splenectomy that ameliorated her platelet count temporarily. She later had several hospital admissions for severe epistaxis and gastrointestinal bleeding, during which she received several transfusions of packed red blood cells. She took several therapeutic agents in various combinations, including vincristine, intravenous immunoglobulin, and cyclophosphamide (Figure). Her platelet count varied between 2 and 90 ⫻ 109/L. Rituximab (375 mg/m2), cytoxan, vincristine, and prednisone were administered weekly for 4 weeks. Four more doses of rituximab were given weekly with no adjunctive treatment. Platelet counts rose to 300 ⫻ 109/L and remained stable after 19 months of follow-up. Her lymphocytosis is stable at 1 ⫻ 109/L, and she has had a complete remission of her CLL and ITP. Idiopathic thrombocytopenic purpura occurs in 2% to 3% of patients with CLL (1,2). Pathogenesis is associated with both abnormal produc-
Letters to the Editor
Figure. Platelet counts rise after rituximab therapy.
tion of antibodies and T-cell dysfunction (3). It is unclear if hereditary hemorrhagic telangiectasia is also related, because there are no reports of an association of the three entities. In our patient, thrombocytopenia was more of a clinical problem because of the patient’s hemorrhagic telangiectasia. Rituximab is an anti-CD20 monoclonal antibody that is approved for the treatment of B-cell non-Hodgkin’s lymphoma. It also seems to have a beneficial effect in patients with CLL. Several reports have described partial remissions and tolerable toxicity even at higher doses (4,5). In patients with refractory ITP, there is no proven algorithm for standard care (6), but rituximab has shown some utility (7,8). There are no data about the use of rituximab in combined ITP and CLL, but our case suggests a favorable outcome.
ACKNOWLEDGMENT The authors thank Mr Karl Witton for his contribution with this article. Toni Choueiri, MD Alan E. Lichtin, MD The Cleveland Clinic Foundation Cleveland, Ohio
1. Duhrsen U, Augner W, Swingers T, et al. Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myleproliferative diseases. Br J Haematol. 1987;67:235–239. 2. Haubenstock A, Zalusky R. Autoimmune hyperthyroidism and thrombocytopenia developing in a patient with chronic lymphocytic leukemia. Am J Hematol. 1985;19: 281–283. 3. George JN, El-Harake MA, Aster RH. Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In: Beutler E, Lichtman M, Coller BC, et al, eds. Williams Hematology, Vol 5. New York: McGraw-Hill; 1995:1315–1355. 4. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165–2170. 5. Nguyen DT, Amess JA, Doughty H, et al. IDEC-C2B8 anti-CD 20 (rituximab) immunotherapy in patients with low-grade nonHodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol. 1999;62:76 –82. 6. George JN, Koujouri K, Perdue JJ, Vesely SK. Management of patients with chronic refractory idiopathic thrombocytopenic purpura. Semin Hematol. 2000;37:290 –298. 7. Perotta A, Sunneberg T, Scott J, et al. Rituxan in the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Blood. 1999;94:14. 8. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic December 1, 2002
idiopathic thrombocytopenic Blood. 2001;98:952–957.
purpura.
DIABETIC KETOACIDOSIS ASSOCIATED WITH ORAL SALBUTAMOL OVERDOSE To the Editor: Salbutamol, an adrenergic 2 receptor agonist, is used mainly as a solution for inhalation in patients with asthma and as a continuous infusion for the treatment of premature labor. Salbutamol overdose is associated with cardiovascular, neuromuscular, and metabolic manifestations. Most cases of overdose have involved continuous infusion. Thus far, diabetic ketoacidosis has been reported in three cases of salbutamol overdose (1–3), all involving continuous infusion. We report a case of oral salbutamol overdose with diabetic ketoacidosis. A 28-year-old woman with asthma had ingested 100 mg of salbutamol BP solution in a suicide attempt. One and a half hours after ingestion, she complained of chest pain, generalized tremors, and palpitations. About 4 hours later, she arrived at the emer-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 701