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Late infections after blood progenitor cell transplantation in patients with multiple myeloma
CORRESPONDENCE LATE INFECTIONS AFTER BLOOD PROGENITOR CELL TRANSPLANTATION IN PATIENTS WITH MULTIPLE MYELOMA To the Editor: Single and tandem high-dose cytoreductive therapy with autologous stem cell transplantation is increasingly used for treating multiple myeloma. Although no cure has been documented, high-dose therapy combined with transplantation improves the response rate, event-free survival, and overall survival in these patients (1,2). In their article on infections after high-dose therapy and autologous stem cell transplantation in patients with lymphoproliferative malignancies, Ketterer et al (3) reported that total body irradiation, fludarabine, and a diagnosis of multiple myeloma were associated with an increased risk of late infections after autologous stem cell transplantation. We retrospectively analyzed infectious complications (including those that occurred a year or more after autologous stem cell transplantation) and risk factors in a cohort of patients with multiple myeloma who underwent autologous stem cell transplantation at our institution. Our findings that varicella zoster viral (VZV) infection and pneumonia were the most frequently observed infections corroborate those of Ketterer et al. Sixteen patients with multiple myeloma were included (9 women; median age 52 years, range 30 to 60). Twelve patients received tandem autografts and high-dose therapy consisting of melphalan at the first autologous stem cell transplantation, and melphalan followed by total body irradiation at the second transplantation. Patients who underwent a single autologous stem cell transplantation were given cyclophosphamide, etoposide, and total body irradiation 䉷2001 by Excerpta Medica, Inc. All rights reserved.
Table 1. Late Infectious Complications in Relation to Time Intervals Varicella zoster Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1
2 x x
Pneumonia 3
1
2
x
x S.p
Bacteremia 3
1
2
3
x S.p x x
x x S.p
x
x
x S.p
x x x
x
x
x
x
x S.p
x
x
x S.p
x S.p x
Time intervals: 1 ⫽ 30 –100 days posttransplant; 2 ⫽ 100 –365 days posttransplant; 3 ⫽ ⱖ1 year posttransplant; x ⫽ patients affected; S.p ⫽ infections caused by Streptococcus pneumoniae.
(n ⫽ 3) or melphalan alone (n ⫽ l). All patients undergoing tandem transplantation received a CD34⫹ selected graft on the second occasion. The average dose of reinfused CD34⫹ cells was 3.7 ⫻ 106/kg body weight, and all but 3 patients received ⬎2.5 ⫻ 106/kg body weight CD34⫹ cells. Patients received prophylaxis for Pneumocystis carinii pneumonia for 3 months after autologous stem cell transplantation, but no antiviral prophylaxis. Infectious complications from day 30 after transplantation until relapse or progression of the underlying disease or death were registered. The median follow-up time was 660 days (range 330 to 1,305). Thirteen patients (75%) developed a total of 46 infectious episodes. Six patients had 8 episodes of VZV infection (6 herpes zoster and 2 varicella). Three patients had septicemia and 7 had pneumonia; Streptococcus pneumoniae was the causative agent in 6 of these 10 infections. Three patients died during a nonprogressive phase of the underlying disease. One patient developed angioimmunoblastic lymphadenopathy af-
ter autologous stem cell transplantation and died of S. pneumoniae pneumonia. Another died of encephalitis caused by an unknown pathogen, and the third patient died of pneumonitis related to total body irradiation. Ketterer et al (3) reported a lower incidence of late infectious complications than we did. This is consistent with their findings that a diagnosis of multiple myeloma and total body irradiation are associated with an increased risk of late infections. Pneumonia and bacteremia occurred more than 2 years after transplant, whereas all VZV infections developed within 12 months after transplant (Table 1). In our patients, age, type of highdose treatment, or time to T and B cell reconstitution were not associated with a risk of developing infectious complications after autologous stem cell transplantation. The addition of total body irradiation to melphalan in patients who receive tandem autografts does not lead to increased complete remission rates. Instead, the survival of patients receiving total body irradiation as 0002-9343/01/$–see front matter 329
Letters to the Editor
part of the conditioning therapy is inferior to that of patients treated with melphalan alone (4). At our hospital, responding patients under the age of 60 with multiple myeloma receive melphalan 200 mg/m2 as the preparative regimen for first and second autologous stem cell transplantation. Treatment with single and tandem autologous stem cell transplantation predisposes patients to viral and bacterial infections for a long time. We believe that a nontotal body irradiation preparative regimen is to be preferred, and patients should receive long-term anti-viral prophylaxis as well as pneumococcal vaccination. Gammaglobulin administration should be considered for certain patients. Hlif Steingrimsdottir, MD Astrid Gruber, MD, PhD Mats Kalin, MD, PhD Magnus Bjo¨rkholm, MD, PhD Department of Medicine Karolinska Hospital and Institutet Stockholm, Sweden 1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomised trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996; 335:91–97. 2. Johnsen H, Bjo¨rkstrand B, Carlson K, et al. Outcome for patients with leukemia, multiple myeloma and lymphoma who relapse after high dose therapy and autologous stem cell support. Leuk Lymphoma. 1996;24:81– 91. 3. Ketterer N, Espinousse D, Chomarat M, et al. Infections following peripheral blood progenitor cell transplantation for lymphoprolipherative malignancies: etiology and potential risk factors. Am J Med. 1999;106: 191–197. 4. Desikan KR, Tricot G, Dhodapkar M, et al. Melphalan plus total body irradiation (MEL-total body irradiation) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. Bone Marrow Transplant. 2000;25:483– 487.
330
March 2001
HYPERSENSITIVITY SYNDROME ASSOCIATED WITH AZITHROMYCIN To the Editor: A 79-year-old man with a history of hypertension and cerebrovascular disease was hospitalized with progressive mental status change, functional decline, and oliguria. He had completed a 5-day outpatient course of oral azithromycin (Zithromax, 500 mg initially, then 250 mg daily), prescribed for bronchitis 10 days before admission. His other chronic medications were atenolol, benazepril, clonidine, and aspirin. On examination, the patient was thin, febrile, and obtunded, and had generalized erythroderma and dry oral mucosa. His pulmonary examination was unremarkable. An abdominal examination revealed no hepatomegaly, and a neurologic examination showed no new neurologic deficits and no signs of meningeal irritation. Laboratory studies yielded the following serum levels: white cell count 14 ⫻ 109/L (33% eosinophils); blood urea nitrogen 139 mg/dL and creatinine 4.9 mg/dL (from 25 mg/dL and 1.1 mg/dL, respectively, 10 days previously); aspartate aminotransferase 229 U/L, alanine aminotransferase 210 U/L, and alkaline phosphatase 1,512 U/L. Serologic testing for hepatitis A, B, and C was negative. Urinalysis showed 2 to 5 WBCs, 1⫹ albumin, few hyaline casts, and a negative Hansel’s stain. Abdominal ultrasound showed normal liver structure, nondilated biliary ducts, and no hydronephrosis. With intravenous hydration only, the patient’s fever decreased and his urinary output and renal and hepatic function returned to normal over the next 4 days. His mental status improved significantly. The skin rash was followed by extensive desquamation. The constellation of fever, mental
THE AMERICAN JOURNAL OF MEDICINE威
Volume 110
status change, rash, oliguric acute renal failure, and hepatitis in our patient suggested a hypersensitivity syndrome most likely related to azithromycin, given the temporal relationship between the exposure to the drug and the development of symptoms. To our knowledge, no other cases of hypersensitivity syndrome have been reported with azithromycin. Macrolides have been in clinical use for 40 years, and reports of major side effects have been rare (1). Hepatotoxicity is mostly associated with the erythromycins and manifests as hypersensitivity-mediated hepatocellular necrosis. A hypersensitivity syndrome with interstitial nephritis, thrombocytopenia, hepatitis, and high amylase levels was associated with clarithromycin (2). Allergic reactions to macrolides are rare, even when administered topically (1). Contact dermatitis, urticaria, toxic epidermal necrolysis, fixed drug eruptions, and interstitial nephritis have been described mainly with erythromycin (1). Azithromycin is very well tolerated in all age groups. It has excellent tissue penetration with a uniform long elimination half-life; effective tissue concentrations are therefore maintained for several days after the drug is discontinued. In a population of 3,995 (aged 2 to 94 years) who received azithromycin for infections of the respiratory tract, skin or skin structures (1.5 g over 5 days), urethritis or cervicitis (1 g as a single dose), the overall incidence of side effects was 12%, the most common of which were associated with gastrointestinal dismotility (3). Transient elevation in aminotransferases (3), neutrophilia (3), immune-mediated intrahepatic cholestasis (4), skin rashes (1), and ototoxicity (5) have also been described. Azithromycin remains one of the best tolerated macrolides; neverthe-
Table 1. Late Infectious Complications in Relation to Time Intervals Varicella zoster Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1
2 x x
Pneumonia 3
1
2
x
x S.p
Bacteremia 3
1
2
3
x S.p x x
x x S.p
x
x
x S.p
x x x
x
x
x
x
x S.p
x
x
x S.p
x S.p x
Time intervals: 1 ⫽ 30 –100 days posttransplant; 2 ⫽ 100 –365 days posttransplant; 3 ⫽ ⱖ1 year posttransplant; x ⫽ patients affected; S.p ⫽ infections caused by Streptococcus pneumoniae.
(n ⫽ 3) or melphalan alone (n ⫽ l). All patients undergoing tandem transplantation received a CD34⫹ selected graft on the second occasion. The average dose of reinfused CD34⫹ cells was 3.7 ⫻ 106/kg body weight, and all but 3 patients received ⬎2.5 ⫻ 106/kg body weight CD34⫹ cells. Patients received prophylaxis for Pneumocystis carinii pneumonia for 3 months after autologous stem cell transplantation, but no antiviral prophylaxis. Infectious complications from day 30 after transplantation until relapse or progression of the underlying disease or death were registered. The median follow-up time was 660 days (range 330 to 1,305). Thirteen patients (75%) developed a total of 46 infectious episodes. Six patients had 8 episodes of VZV infection (6 herpes zoster and 2 varicella). Three patients had septicemia and 7 had pneumonia; Streptococcus pneumoniae was the causative agent in 6 of these 10 infections. Three patients died during a nonprogressive phase of the underlying disease. One patient developed angioimmunoblastic lymphadenopathy af-
ter autologous stem cell transplantation and died of S. pneumoniae pneumonia. Another died of encephalitis caused by an unknown pathogen, and the third patient died of pneumonitis related to total body irradiation. Ketterer et al (3) reported a lower incidence of late infectious complications than we did. This is consistent with their findings that a diagnosis of multiple myeloma and total body irradiation are associated with an increased risk of late infections. Pneumonia and bacteremia occurred more than 2 years after transplant, whereas all VZV infections developed within 12 months after transplant (Table 1). In our patients, age, type of highdose treatment, or time to T and B cell reconstitution were not associated with a risk of developing infectious complications after autologous stem cell transplantation. The addition of total body irradiation to melphalan in patients who receive tandem autografts does not lead to increased complete remission rates. Instead, the survival of patients receiving total body irradiation as 0002-9343/01/$–see front matter 329
Letters to the Editor
part of the conditioning therapy is inferior to that of patients treated with melphalan alone (4). At our hospital, responding patients under the age of 60 with multiple myeloma receive melphalan 200 mg/m2 as the preparative regimen for first and second autologous stem cell transplantation. Treatment with single and tandem autologous stem cell transplantation predisposes patients to viral and bacterial infections for a long time. We believe that a nontotal body irradiation preparative regimen is to be preferred, and patients should receive long-term anti-viral prophylaxis as well as pneumococcal vaccination. Gammaglobulin administration should be considered for certain patients. Hlif Steingrimsdottir, MD Astrid Gruber, MD, PhD Mats Kalin, MD, PhD Magnus Bjo¨rkholm, MD, PhD Department of Medicine Karolinska Hospital and Institutet Stockholm, Sweden 1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomised trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996; 335:91–97. 2. Johnsen H, Bjo¨rkstrand B, Carlson K, et al. Outcome for patients with leukemia, multiple myeloma and lymphoma who relapse after high dose therapy and autologous stem cell support. Leuk Lymphoma. 1996;24:81– 91. 3. Ketterer N, Espinousse D, Chomarat M, et al. Infections following peripheral blood progenitor cell transplantation for lymphoprolipherative malignancies: etiology and potential risk factors. Am J Med. 1999;106: 191–197. 4. Desikan KR, Tricot G, Dhodapkar M, et al. Melphalan plus total body irradiation (MEL-total body irradiation) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. Bone Marrow Transplant. 2000;25:483– 487.
330
March 2001
HYPERSENSITIVITY SYNDROME ASSOCIATED WITH AZITHROMYCIN To the Editor: A 79-year-old man with a history of hypertension and cerebrovascular disease was hospitalized with progressive mental status change, functional decline, and oliguria. He had completed a 5-day outpatient course of oral azithromycin (Zithromax, 500 mg initially, then 250 mg daily), prescribed for bronchitis 10 days before admission. His other chronic medications were atenolol, benazepril, clonidine, and aspirin. On examination, the patient was thin, febrile, and obtunded, and had generalized erythroderma and dry oral mucosa. His pulmonary examination was unremarkable. An abdominal examination revealed no hepatomegaly, and a neurologic examination showed no new neurologic deficits and no signs of meningeal irritation. Laboratory studies yielded the following serum levels: white cell count 14 ⫻ 109/L (33% eosinophils); blood urea nitrogen 139 mg/dL and creatinine 4.9 mg/dL (from 25 mg/dL and 1.1 mg/dL, respectively, 10 days previously); aspartate aminotransferase 229 U/L, alanine aminotransferase 210 U/L, and alkaline phosphatase 1,512 U/L. Serologic testing for hepatitis A, B, and C was negative. Urinalysis showed 2 to 5 WBCs, 1⫹ albumin, few hyaline casts, and a negative Hansel’s stain. Abdominal ultrasound showed normal liver structure, nondilated biliary ducts, and no hydronephrosis. With intravenous hydration only, the patient’s fever decreased and his urinary output and renal and hepatic function returned to normal over the next 4 days. His mental status improved significantly. The skin rash was followed by extensive desquamation. The constellation of fever, mental
THE AMERICAN JOURNAL OF MEDICINE威
Volume 110
status change, rash, oliguric acute renal failure, and hepatitis in our patient suggested a hypersensitivity syndrome most likely related to azithromycin, given the temporal relationship between the exposure to the drug and the development of symptoms. To our knowledge, no other cases of hypersensitivity syndrome have been reported with azithromycin. Macrolides have been in clinical use for 40 years, and reports of major side effects have been rare (1). Hepatotoxicity is mostly associated with the erythromycins and manifests as hypersensitivity-mediated hepatocellular necrosis. A hypersensitivity syndrome with interstitial nephritis, thrombocytopenia, hepatitis, and high amylase levels was associated with clarithromycin (2). Allergic reactions to macrolides are rare, even when administered topically (1). Contact dermatitis, urticaria, toxic epidermal necrolysis, fixed drug eruptions, and interstitial nephritis have been described mainly with erythromycin (1). Azithromycin is very well tolerated in all age groups. It has excellent tissue penetration with a uniform long elimination half-life; effective tissue concentrations are therefore maintained for several days after the drug is discontinued. In a population of 3,995 (aged 2 to 94 years) who received azithromycin for infections of the respiratory tract, skin or skin structures (1.5 g over 5 days), urethritis or cervicitis (1 g as a single dose), the overall incidence of side effects was 12%, the most common of which were associated with gastrointestinal dismotility (3). Transient elevation in aminotransferases (3), neutrophilia (3), immune-mediated intrahepatic cholestasis (4), skin rashes (1), and ototoxicity (5) have also been described. Azithromycin remains one of the best tolerated macrolides; neverthe-