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Bleomycin-induced fatal hyperpyrexia
Bleomycin-Induced Fatal Hyperpyrexia
J. JACQUES MARGARET MURRAY Boston,
GARTER,
M.D.
L. MCLAUGHLIN, M. BERN,
M.D.
M.D.
Massachusetts
Bleomycin is a frequentiy used antitumor agent with adverse effects usually involving the lungs, skin, and bone marrow. An acute hyperpyrexic reaction has also been noted with this agent, usually after the initlal injection. Thus a test dose Is recommended before therapy is begun. A case of fulmlnant hyperpyrexla and death In a patient with lymphoma who had previously received multiple courses of bleomycin wlthout prior hyperpyrexla Is reported. Fever was associated with the patient’s lymphoma and may have effectively reduced the patlent’s “margln” for tolerating the addltlonal druginduced pyrexia. It is suggested that attempts be made to lower fevers before therapy with this agent is initlated. Bleomycin, a cytotoxic antitumor antibiotic, is active in a wide variety of neopiasms with significant adverse effects [l-3]. Toxic pulmonary reactions include an interstitial pneumonitis that can progress to pulmonary fibrosis and fatal respiratory insufficiency [4,5]. A reversible hypersensitivity pneumonitis responsive to steroid therapy has also been reported [6]. Cutaneous toxicity includes hyperpigmentation, alopecia, stomatitis, gangrene of the fingertips, and linear streaking of skin on the torso and extremities [3,7-lo]. Transient thrombocytopenia and leukopenia have also been noted [ 11,121. Mild pyrexia has been noted in 20 to 60 percent of patients treated with bleomycin [l-3]. A more uncommon acute fulminant reaction with profound hyperpyrexia, diaphoresis, hypotension, and sustained cardiorespiratory collapse is seen almost exclusively in the treatment of Hodgkin’s and non-Hodgkin’s lymphoma. It usually occurs after the first injection of bleomycin [ 1,3,13] and is uncommon after subsequent injections. We describe a case of fatal bleomycin-induced fulminant hyperpyrexia in a patient already febrile with lymphoma, who had previously received several injections of bleomycin without significant prior hyperpyrexia.
CASE REPORT
From the Department of Medicine, Hew England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Murray M. Bern, SecDepartment of Medicine, New tloncnkmaWcgy, EnglandDeaconessHospital, 185 Pilgrim Road, Boston, Massachusetts 02215. Manuscript accepted February 8, 1982.
The patient, an l&year-old woman, was found to have an anterior mediitinal mass 18 months earlier, during a routine Army radiographic examination. Diagnostic thoracotomy demonstrated that the mediastinal lymphadenopathy was due to mixed IymphocytWhistiocytic lymphoma. A liver biopsy specknen also demonstrated disease involvement. Study of bone marrow aspiration and biopsy specimens revealed no abnormalities. Postoperatively, a chemotherapeutic regimen was begun consisting of bleomycin (4.0 units/m*), doxorubicin (45 mg/m2), cyclophosphamide (600 mg/m*), and vincristine (1 .O mg/m*), each administered intravenously every three weeks; dexamethasone (6.0 mg/m*) was given orally daily for five days. After receiving the first course of chemotherapy, the patient experienced a fever of 38.3%
March 1983
The American Journal of Medlclne
Volume 74
523
BLEOMYCIN-INDUCED FATAL HYPERPYREXIA-CARTER
ET AL
(IOlOF), which was believed to be a reaction to the bleomycin. She was discharged and as an outpatient continued to receive the same chemotherapeutic regimen every three weeks without febrile reactions for a total of 10 courses. No further fever occurred. Alopecia and dose-dependent marrow suppression occurred as expected from the chemotherapy. Her disease entered and remained in remission for one year beyond therapy, as reflected by follow-up chest films, liver-spleen scans, sonograms, and bone marrow studies. However, one month before readmission, fever of 39.4’C (103OF) developed accompanied by nightsweats, headaches, earaches, and a nonproductive cough. An extensive fever evaluation, including chest radiography, multiple bacterial and fungal cultures of blood, urine, and sputum specimens, viral serologic studies, echocardiography, liver-spleen scanning, and bone marrow biopsy, were performed. Except for asymptomatic bacteruria, these studies had normal findings. The liver-spleen scan, when compared with one performed two months earlier, revealed a slight increase in spleen size with no other changes noted. With no definite source of fever found, the patient was discharged receiving trimethoprim/sulfamethoxazole for bacteruria and acetaminophen for fever. She was readmitted three weeks later because of persistent fever and new rigors. She was febrile to 39’C (102OF), and had sinus tachycardia of 150 beats per minute. There were no new physical findings. Specifically, there was no peripheral lymphadenopathy. Abnormal results of laboratory studies now included an alkaline phosphatase value of 516 mU/dl, lactic dehydrogenase value of 2,714 mU/dl, serum glutamic-oxaloacetic transaminase level of 641 mU/dl; and total bilirubin value of 11.8 mg/dl (8.1mg/dl direct). Multiple microbiologic studies of blood, urine, and sputum specimens again gave negative results. Abdominal sonography showed new defects in both the liver and spleen, with no retroperitoneal adenopathy. Intravenous pyelography showed no abnormalities. Liver biopsy confirmed the recurrence of her tumor and another course of chemotherapy was planned at the previously established doses. During the injections, the patient was resting comfortably with a temperature of 37.9’C (100.2’F). (All temperatures after the drug injections were determined rectally.) Thirty minutes after the injections, she complained of “chills,” with a temperature of 38.5’C (101.4°F), which was treated with oral antipyretics. Two hours later, she became confused, disoriented, was making purposeless chewing motions, and had a temperature greater than 41.6OC (107OF), exceeding the range of the thermometer being used. The blood pressure decreased to 80/50 mm Hg, and the pulse rate was 120 beats per minute. Rapid intravenous fluid replacement was initiated, and cooling was attempted with ice packs, alcohol sponges, iced gastric lavage, and a hypothermic mattress. She had a tonic-clonic seizure with urinary and fecal incontinence. This was controlled with intravenous diazepam. The fever began to respond to the therapy, decreasing to 40.8’C (1056OF). However, the patient’s sinus tachycardia quickened to 180 beats per minute and her hypotension persisted. Respiratory arrest ensued, which was managed by immediate endotracheal intubation. Intravenous hydrocortisone, fluids, and
524
March 1983
TheAmerican Journal of Medicine
vasopressor therapy were maintained. Her temperature returned to normal, and her blood pressure was maintained with vasopressors. However, the patient remained comatose. Electroencephalographic studies revealed minimal brain activity. Repeated bacteriologic cultures of blood and urine samples gave negative results. Laboratory studies performed eight hours after respiratory arrest demonstrated evidence of disseminated intravascular coagulation with a prothrombin time of 45 seconds (control 11.6 seconds), activated partial thromboplastin time that was greater than 200 seconds (normal 26 to 40 seconds), a platelet count of 16,000/mm3, a fibrinogen level of 20 mg/dl (normal, 150 to 310 mg/dl), increased fibrin degradation products, and schistocytes in the peripheral blood smear. The ccagulopathy was controlled with frozen plasma, cryoprecipitate, and heparin. However, despite rigorous support, her condition deteriorated, and she died two days later. Postmortem examination revealed acute necrosis of the brain, most severe in the thalami, hippocompi, mid-brain, pons, cerebellum, and medulla. Although consistent with hyperthermia, the extent of tissue necrosis with involvement of the brainstem more closely resembled a picture of brain death due to hypotension. Whether the brain death was the result of hyperthermia coupled with hypotension is unclear. Diffuse, bilateral interstitial pneumonitis was also noted and was thought to be an acquired infection secondary to mechanical ventilation. Postmortem blood cultures grew Klebsiella pneumoniae and Clostridium perfringens.
COMMENTS Acute hyperpyrexia after bleomycin therapy occurs almost exclusively in patients with lymphoma [l-3]. Although the pyrogenicity of bleomycin was once believed to result from contaminating endotoxins, animal studies suggest that this agent produces fever by liberating an endogenous pyrogen from host cells [ 141. Endogenous pyrogens produced by various types of host cells have been characterized [ 151. The precise mechanism by which drugs stimulate these host cells to produce their endogenous pyrogens remains to be elucidated [ 161. Unlike anesthesia-induced hyperthermia, which is postulated to result from the release of calcium from skeletal muscle cells leading to an uncoupling of oxidative phosphorylation and a fulminant rise in body temperature [ 171, endogenous pyrogens probably produce fever by direct interaction with receptors in the hypothalamic thermoregulatory center. Although fever is common in patients with Hodgkin’s and non-Hodgkin’s lymphomas, the reason these patients are more susceptible to bleomycin-induced idiosyncratic hyperpyrexia is unclear. Lymphoid tissue specimens containing Hodgkin’s disease can produce pyrogens when incubated in vitro, whereas lymphoid tissue samples from patients with nonmalignant disease create little or no pyrogenic reaction [ 181. This raises the possibility of an augmented release of endogenous
Volume 74
BLEOMYCIN-INDUCEDFATAL HYPERPYREXIA-CARTER ET AL
pyrogen from lymphomatous tissue after bleomycin therapy. In this case, the toxic response to bleomycin was superimposed on already established pyrexia due to the basic, underlying disease. Thus, the patient’s “margin” for tolerating additional fever was significantly narrowed. The patient described in this report had disseminated intravascular coagulation with typical laboratory findings. The development of disseminated intravascular coagulation in a patient with bleomycininduced hyperpyrexia has also recently been reported [ 131. Interestingly, disseminated intravascular coagulation can also occur during heat stroke [19]. In our case, it is unclear whether the disseminated intravascular coagulation was caused directly by the drug reaction itself, by endothelial damage, or by the hypotension that followed the drug reaction. Acute fulminant reactions to bleomycin are rare, but the associated mortality is high. An initial test dose is recommended by the manufacturer. This case is an example of an acute reaction occurring in a patient who had previously received 10 full doses of bleomycin, totaling more than 60 units, with only one prior minor
2. 3.
4.
5.
6. 7.
a. 9.
Blum RH, Carter DK, Agre K: A clinical review of bleomytin-a new antineoplastic agent. Cancer 1973; 31: 903-914. Crooke ST. Bradner WT: Bleomycin, a review. J Med 1976; 7: 333-428. Yagoda A, Mukherji B, Young C, et al: Bleomycin, an antitumor antibiotic: clinical experience in 274 patients. Ann Intern rvted 1972; 77: 861-870. Luna MA, Bedrossian CWM, Lichtiger B, et al: Interstitial pneumonitis associated with bleomycin therapy. Am J Clin Path01 1972; 58: 501-510. lacovino JR, Leitner J, Abbas AK, et al: Fatal pulmonary reaction from low doses of bleomycin: an idiosyncratic tissue response. JAMA 1976; 235: 1253-1255. Holoye PY, Luna MA, MacKay B, et al: Bleomycin hypersensitivity pneumonitis. Ann Intern Med 1976; 66: 47-49. Cohen IS. Mosher MB. O’Keefe EJ, et al: Cutaneous toxicity of bleomycin therapy. Arch Dermatol 1973; 107: 553. Werner Y, Tornberg B: Cutaneous side effects of bleomycin therapy. Acta Derm Venereol (Stockholm) 1976; 56: 155-158. Lowitz BB: Streaking with bleomycin (letter). N Engl J Med 1975: 292: 1300-1301.
febrile reaction. Inasmuch as she received a combination of chemotherapy, it is conceivable, although unlikely, that the reaction could have been due to one of the other agents. Premeditation with oral antipyretics is usually of little or no benefit in preventing febrile reactions with bleomycin, although it may lessen the severity of such reactions [ 11. The occurrence of these reactions is unpredictable, and therapy is generally supportive, directed toward lowering body temperature and maintaining blood pressure. Parenteral diphenhydramine and chlorpromazine have also been employed with variable results [ 1,3,13]. The intent of this case report is to alert physicians to the potential for fulminant hyperpyrexia in patients with lymphoma who are treated with bleomycin after previously uncomplicated therapy with this agent. It is also our intent to propose that patients already febrile should not be given bleomycin until the fever is suppressed, either with antipyretic agents or with alternative antitumor regimens. This approach may improve the margin for tolerating a drug-induced fever should one occur.
10.
11.
12.
13. 14.
15. 16. 17. la.
19.
March 1983
Perrot H, Ortonne JP: Hyperpigmentation after bleomycin therapy: ultrastructural study. Arch Dermatol Res 1976; 261: 245-252. Robert F, Omura GA, Gams RA: Hematologic toxicity from bleomycin in advanced cancer patients. Ala J Med Sci 1976; 13: 380-383. Hilgard P, Hossfeld DK: Transient bleomycin-induced thrombocytopenia: a clinical study. Eur J Cancer Clin Oncol 1976; 14: 1261-1264. Ma DDF, lsbister JP: Cytotoxic-inducedfulminant hyperpyrexia. Cancer 1980; 45: 2249-225 1. Dinarello CA, Ward SB. Wolff SM: Pyrogenic properties of bleomycin (NSC-125006). Cancer Chemother Rep 1973; 57: 393-398. Atkins E, Bode1 P: Fever. N Engl J Med 1972; 266: 27-34. Dinarello CA, Wolff SM: Pathogenesis of fever in man. N Engl J Med 1976; 296: 607-612. Stephen CR: Malignant hyperpyrexia. Annu Rev Med 1977; 28: 153-157. Bode1 P: Pyrogen release in vitro by lymphoid tissues from patients with Hodgkin’s disease. Yale J Biol Med 1974; 47: 101-112. Simon HB: Extreme pyrexia. JAMA 1976; 236: 2419-2421.
The American
Journal
of Medicine
Volume 74
525
J. JACQUES MARGARET MURRAY Boston,
GARTER,
M.D.
L. MCLAUGHLIN, M. BERN,
M.D.
M.D.
Massachusetts
Bleomycin is a frequentiy used antitumor agent with adverse effects usually involving the lungs, skin, and bone marrow. An acute hyperpyrexic reaction has also been noted with this agent, usually after the initlal injection. Thus a test dose Is recommended before therapy is begun. A case of fulmlnant hyperpyrexla and death In a patient with lymphoma who had previously received multiple courses of bleomycin wlthout prior hyperpyrexla Is reported. Fever was associated with the patient’s lymphoma and may have effectively reduced the patlent’s “margln” for tolerating the addltlonal druginduced pyrexia. It is suggested that attempts be made to lower fevers before therapy with this agent is initlated. Bleomycin, a cytotoxic antitumor antibiotic, is active in a wide variety of neopiasms with significant adverse effects [l-3]. Toxic pulmonary reactions include an interstitial pneumonitis that can progress to pulmonary fibrosis and fatal respiratory insufficiency [4,5]. A reversible hypersensitivity pneumonitis responsive to steroid therapy has also been reported [6]. Cutaneous toxicity includes hyperpigmentation, alopecia, stomatitis, gangrene of the fingertips, and linear streaking of skin on the torso and extremities [3,7-lo]. Transient thrombocytopenia and leukopenia have also been noted [ 11,121. Mild pyrexia has been noted in 20 to 60 percent of patients treated with bleomycin [l-3]. A more uncommon acute fulminant reaction with profound hyperpyrexia, diaphoresis, hypotension, and sustained cardiorespiratory collapse is seen almost exclusively in the treatment of Hodgkin’s and non-Hodgkin’s lymphoma. It usually occurs after the first injection of bleomycin [ 1,3,13] and is uncommon after subsequent injections. We describe a case of fatal bleomycin-induced fulminant hyperpyrexia in a patient already febrile with lymphoma, who had previously received several injections of bleomycin without significant prior hyperpyrexia.
CASE REPORT
From the Department of Medicine, Hew England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Murray M. Bern, SecDepartment of Medicine, New tloncnkmaWcgy, EnglandDeaconessHospital, 185 Pilgrim Road, Boston, Massachusetts 02215. Manuscript accepted February 8, 1982.
The patient, an l&year-old woman, was found to have an anterior mediitinal mass 18 months earlier, during a routine Army radiographic examination. Diagnostic thoracotomy demonstrated that the mediastinal lymphadenopathy was due to mixed IymphocytWhistiocytic lymphoma. A liver biopsy specknen also demonstrated disease involvement. Study of bone marrow aspiration and biopsy specimens revealed no abnormalities. Postoperatively, a chemotherapeutic regimen was begun consisting of bleomycin (4.0 units/m*), doxorubicin (45 mg/m2), cyclophosphamide (600 mg/m*), and vincristine (1 .O mg/m*), each administered intravenously every three weeks; dexamethasone (6.0 mg/m*) was given orally daily for five days. After receiving the first course of chemotherapy, the patient experienced a fever of 38.3%
March 1983
The American Journal of Medlclne
Volume 74
523
BLEOMYCIN-INDUCED FATAL HYPERPYREXIA-CARTER
ET AL
(IOlOF), which was believed to be a reaction to the bleomycin. She was discharged and as an outpatient continued to receive the same chemotherapeutic regimen every three weeks without febrile reactions for a total of 10 courses. No further fever occurred. Alopecia and dose-dependent marrow suppression occurred as expected from the chemotherapy. Her disease entered and remained in remission for one year beyond therapy, as reflected by follow-up chest films, liver-spleen scans, sonograms, and bone marrow studies. However, one month before readmission, fever of 39.4’C (103OF) developed accompanied by nightsweats, headaches, earaches, and a nonproductive cough. An extensive fever evaluation, including chest radiography, multiple bacterial and fungal cultures of blood, urine, and sputum specimens, viral serologic studies, echocardiography, liver-spleen scanning, and bone marrow biopsy, were performed. Except for asymptomatic bacteruria, these studies had normal findings. The liver-spleen scan, when compared with one performed two months earlier, revealed a slight increase in spleen size with no other changes noted. With no definite source of fever found, the patient was discharged receiving trimethoprim/sulfamethoxazole for bacteruria and acetaminophen for fever. She was readmitted three weeks later because of persistent fever and new rigors. She was febrile to 39’C (102OF), and had sinus tachycardia of 150 beats per minute. There were no new physical findings. Specifically, there was no peripheral lymphadenopathy. Abnormal results of laboratory studies now included an alkaline phosphatase value of 516 mU/dl, lactic dehydrogenase value of 2,714 mU/dl, serum glutamic-oxaloacetic transaminase level of 641 mU/dl; and total bilirubin value of 11.8 mg/dl (8.1mg/dl direct). Multiple microbiologic studies of blood, urine, and sputum specimens again gave negative results. Abdominal sonography showed new defects in both the liver and spleen, with no retroperitoneal adenopathy. Intravenous pyelography showed no abnormalities. Liver biopsy confirmed the recurrence of her tumor and another course of chemotherapy was planned at the previously established doses. During the injections, the patient was resting comfortably with a temperature of 37.9’C (100.2’F). (All temperatures after the drug injections were determined rectally.) Thirty minutes after the injections, she complained of “chills,” with a temperature of 38.5’C (101.4°F), which was treated with oral antipyretics. Two hours later, she became confused, disoriented, was making purposeless chewing motions, and had a temperature greater than 41.6OC (107OF), exceeding the range of the thermometer being used. The blood pressure decreased to 80/50 mm Hg, and the pulse rate was 120 beats per minute. Rapid intravenous fluid replacement was initiated, and cooling was attempted with ice packs, alcohol sponges, iced gastric lavage, and a hypothermic mattress. She had a tonic-clonic seizure with urinary and fecal incontinence. This was controlled with intravenous diazepam. The fever began to respond to the therapy, decreasing to 40.8’C (1056OF). However, the patient’s sinus tachycardia quickened to 180 beats per minute and her hypotension persisted. Respiratory arrest ensued, which was managed by immediate endotracheal intubation. Intravenous hydrocortisone, fluids, and
524
March 1983
TheAmerican Journal of Medicine
vasopressor therapy were maintained. Her temperature returned to normal, and her blood pressure was maintained with vasopressors. However, the patient remained comatose. Electroencephalographic studies revealed minimal brain activity. Repeated bacteriologic cultures of blood and urine samples gave negative results. Laboratory studies performed eight hours after respiratory arrest demonstrated evidence of disseminated intravascular coagulation with a prothrombin time of 45 seconds (control 11.6 seconds), activated partial thromboplastin time that was greater than 200 seconds (normal 26 to 40 seconds), a platelet count of 16,000/mm3, a fibrinogen level of 20 mg/dl (normal, 150 to 310 mg/dl), increased fibrin degradation products, and schistocytes in the peripheral blood smear. The ccagulopathy was controlled with frozen plasma, cryoprecipitate, and heparin. However, despite rigorous support, her condition deteriorated, and she died two days later. Postmortem examination revealed acute necrosis of the brain, most severe in the thalami, hippocompi, mid-brain, pons, cerebellum, and medulla. Although consistent with hyperthermia, the extent of tissue necrosis with involvement of the brainstem more closely resembled a picture of brain death due to hypotension. Whether the brain death was the result of hyperthermia coupled with hypotension is unclear. Diffuse, bilateral interstitial pneumonitis was also noted and was thought to be an acquired infection secondary to mechanical ventilation. Postmortem blood cultures grew Klebsiella pneumoniae and Clostridium perfringens.
COMMENTS Acute hyperpyrexia after bleomycin therapy occurs almost exclusively in patients with lymphoma [l-3]. Although the pyrogenicity of bleomycin was once believed to result from contaminating endotoxins, animal studies suggest that this agent produces fever by liberating an endogenous pyrogen from host cells [ 141. Endogenous pyrogens produced by various types of host cells have been characterized [ 151. The precise mechanism by which drugs stimulate these host cells to produce their endogenous pyrogens remains to be elucidated [ 161. Unlike anesthesia-induced hyperthermia, which is postulated to result from the release of calcium from skeletal muscle cells leading to an uncoupling of oxidative phosphorylation and a fulminant rise in body temperature [ 171, endogenous pyrogens probably produce fever by direct interaction with receptors in the hypothalamic thermoregulatory center. Although fever is common in patients with Hodgkin’s and non-Hodgkin’s lymphomas, the reason these patients are more susceptible to bleomycin-induced idiosyncratic hyperpyrexia is unclear. Lymphoid tissue specimens containing Hodgkin’s disease can produce pyrogens when incubated in vitro, whereas lymphoid tissue samples from patients with nonmalignant disease create little or no pyrogenic reaction [ 181. This raises the possibility of an augmented release of endogenous
Volume 74
BLEOMYCIN-INDUCEDFATAL HYPERPYREXIA-CARTER ET AL
pyrogen from lymphomatous tissue after bleomycin therapy. In this case, the toxic response to bleomycin was superimposed on already established pyrexia due to the basic, underlying disease. Thus, the patient’s “margin” for tolerating additional fever was significantly narrowed. The patient described in this report had disseminated intravascular coagulation with typical laboratory findings. The development of disseminated intravascular coagulation in a patient with bleomycininduced hyperpyrexia has also recently been reported [ 131. Interestingly, disseminated intravascular coagulation can also occur during heat stroke [19]. In our case, it is unclear whether the disseminated intravascular coagulation was caused directly by the drug reaction itself, by endothelial damage, or by the hypotension that followed the drug reaction. Acute fulminant reactions to bleomycin are rare, but the associated mortality is high. An initial test dose is recommended by the manufacturer. This case is an example of an acute reaction occurring in a patient who had previously received 10 full doses of bleomycin, totaling more than 60 units, with only one prior minor
2. 3.
4.
5.
6. 7.
a. 9.
Blum RH, Carter DK, Agre K: A clinical review of bleomytin-a new antineoplastic agent. Cancer 1973; 31: 903-914. Crooke ST. Bradner WT: Bleomycin, a review. J Med 1976; 7: 333-428. Yagoda A, Mukherji B, Young C, et al: Bleomycin, an antitumor antibiotic: clinical experience in 274 patients. Ann Intern rvted 1972; 77: 861-870. Luna MA, Bedrossian CWM, Lichtiger B, et al: Interstitial pneumonitis associated with bleomycin therapy. Am J Clin Path01 1972; 58: 501-510. lacovino JR, Leitner J, Abbas AK, et al: Fatal pulmonary reaction from low doses of bleomycin: an idiosyncratic tissue response. JAMA 1976; 235: 1253-1255. Holoye PY, Luna MA, MacKay B, et al: Bleomycin hypersensitivity pneumonitis. Ann Intern Med 1976; 66: 47-49. Cohen IS. Mosher MB. O’Keefe EJ, et al: Cutaneous toxicity of bleomycin therapy. Arch Dermatol 1973; 107: 553. Werner Y, Tornberg B: Cutaneous side effects of bleomycin therapy. Acta Derm Venereol (Stockholm) 1976; 56: 155-158. Lowitz BB: Streaking with bleomycin (letter). N Engl J Med 1975: 292: 1300-1301.
febrile reaction. Inasmuch as she received a combination of chemotherapy, it is conceivable, although unlikely, that the reaction could have been due to one of the other agents. Premeditation with oral antipyretics is usually of little or no benefit in preventing febrile reactions with bleomycin, although it may lessen the severity of such reactions [ 11. The occurrence of these reactions is unpredictable, and therapy is generally supportive, directed toward lowering body temperature and maintaining blood pressure. Parenteral diphenhydramine and chlorpromazine have also been employed with variable results [ 1,3,13]. The intent of this case report is to alert physicians to the potential for fulminant hyperpyrexia in patients with lymphoma who are treated with bleomycin after previously uncomplicated therapy with this agent. It is also our intent to propose that patients already febrile should not be given bleomycin until the fever is suppressed, either with antipyretic agents or with alternative antitumor regimens. This approach may improve the margin for tolerating a drug-induced fever should one occur.
10.
11.
12.
13. 14.
15. 16. 17. la.
19.
March 1983
Perrot H, Ortonne JP: Hyperpigmentation after bleomycin therapy: ultrastructural study. Arch Dermatol Res 1976; 261: 245-252. Robert F, Omura GA, Gams RA: Hematologic toxicity from bleomycin in advanced cancer patients. Ala J Med Sci 1976; 13: 380-383. Hilgard P, Hossfeld DK: Transient bleomycin-induced thrombocytopenia: a clinical study. Eur J Cancer Clin Oncol 1976; 14: 1261-1264. Ma DDF, lsbister JP: Cytotoxic-inducedfulminant hyperpyrexia. Cancer 1980; 45: 2249-225 1. Dinarello CA, Ward SB. Wolff SM: Pyrogenic properties of bleomycin (NSC-125006). Cancer Chemother Rep 1973; 57: 393-398. Atkins E, Bode1 P: Fever. N Engl J Med 1972; 266: 27-34. Dinarello CA, Wolff SM: Pathogenesis of fever in man. N Engl J Med 1976; 296: 607-612. Stephen CR: Malignant hyperpyrexia. Annu Rev Med 1977; 28: 153-157. Bode1 P: Pyrogen release in vitro by lymphoid tissues from patients with Hodgkin’s disease. Yale J Biol Med 1974; 47: 101-112. Simon HB: Extreme pyrexia. JAMA 1976; 236: 2419-2421.
The American
Journal
of Medicine
Volume 74
525