Bleomycin Hypersensitivity Pneumonitis PAUL Y. HOLOYE, M.D.; MARIO A. LUNA, M.D.; BRUCE MacKAY, M.D.; and CARLOS W. M. BEDROSSIAN, M.D.; Houston, Texas
Three patients developed radiologic and functional pulmonary changes after bleomycin therapy similar to ones previously associated with administration of this drug. However, biopsy specimens showed a pattern consistent with hypersensitivity pneumonitis rather than the interstitial pneumonia usually reported in bleomycin pulmonary toxicity. There was a patchy eosinophilic infiltrate surrounding small airways and distal air spaces, but no immune deposits were noted by ultrastructure or immunofluorescence using conventional techniques and a specific antibody against bleomycin. Two of the patients had peripheral eosinophilia of 1 2 % and 1 6 % . All three patients showed considerable improvement on chest roentgenogram after corticosteroid treatment. Our findings are consistent with the view that bleomycin hypersensitivity pneumonitis has a different pathogenesis than bleomycin interstitial pneumonitis. Its recognition as a separate entity seems warranted because of the favorable response to steroid therapy.
B L E O M Y C I N S U L F A T E has become one of the most useful agents in cancer chemotherapy because of its efficacy in treating a number of tumors and lack of myelosuppression. The drug is active against testicular tumors (1) and squamous cell carcinomas of the cervix (2), penis (3), esophagus (4), and head and neck area (5), as well as Hodgkin's and non-Hodgkin's lymphomas (6). However, bleomycin has an unusual and potentially lethal pulmonary side effect manifested by interstitial fibrosis (7), thought to be a direct toxicity, which increases in incidence with escalating dosage, age of the patient (5), and prior radiotherapy (8). Morphologic studies show an interstitial pneumonia of the usual type with ultrastructural evidence of alveolar epithelial damage (9). We report here the cases of three patients who, while receiving bleomycin, developed radiologic and functional changes similar to the usual bleomycin interstitial pneumonitis. However, lung biopsies showed a pattern of hypersensitivity reaction. Treatment with steroids led to a rapid and complete clearing of the radiologic and functional abnormalities. • F r o m the D e p a r t m e n t s of Internal Medicine a n d Anatomical Pathology, T h e University of Texas System Cancer Center, M . D . Anderson Hospital and T u m o r Institute, and the Department of Pathology and Laboratory Medicine, T h e University of Texas Medical School; Houston, Texas.
Annals of Internal Medicine 88:47-49, 1978
Downloaded from https://annals.org by Tulane University user on 01/12/2019
Case Reports CASE 1
A 17-year-old white boy had an orchiectomy for a choriocarcinoma in the right testicle in May 1973. At physical examination a periumbilical mass was found. Pulmonary functions were normal, and the patient denied any history of allergy. He received two courses of doxorubicin, vincristine, and bleomycin; the cumulative dose of bleomycin was 180 mg. In August 1973, a chest roentgenogram showed bilateral basilar interstitial infiltrates, although spirometry was almost normal and no rales were heard at auscultation (Figure 1, left). A routine complete blood count showed 1 6 % eosinophils. A percutaneous needle biopsy was done, after which the patient received isoniazid, pyridoxine, prednisone, and additional bleomycin. In November 1973 the chest roentgenogram showed that the interstitial infiltrates had cleared. Laparotomy with excision of a residual mass was done in December. T h e patient is now free of disease and asymptomatic. CASE 2
A 20-year-old Mexican man discovered a painless swelling of his left testicle in November 1974. By April 1975, abdominal and thoracic metastases were noted. Malignant teratoma, embryonal carcinoma, and choriocarcinoma were found at orchiectomy. Chest roentgenogram showed a large mass in the right upper part of the mediastinum. Chemotherapy consisting of vinblastine sulfate (0.4 mg/body weight) and bleomycin (30 units per day for 5 days by continuous infusion) was given in May and repeated in July and September 1975. Before the last course, the mediastinal mass had disappeared, but new densities had appeared in both midlung and lower-lung fields with small, bilateral pleural effusions. Pulmonary auscultation was normal. Another regimen of bleomycin, Cytoxan® (cyclophosphamide), Oncovin (vincristine), methotrexate, and 5-/luorouracil (B-comF) was given in December 1975 and January 1976. In March 1976, after a cumulative bleomycin dose of 1000 mg, the pulmonary infiltrates had increased (Figure 1, middle), and forced vital capacity (FVC) had dropped from 3.99 to 2.48 litres, but the blood gas values remained normal. A routine complete blood count showed 1 2 % eosinophils. An open lung biopsy was done on 19 March 1976. Administration of prednisone was started on 25 March 1976, and infiltrates had completely resolved by 23 April 1976. Additional bleomycin has been administered with prednisone protection without recurrence of pulmonary symptoms or signs. CASE 3
A 25-year-old white man was found to have a teratocarcinoma and embryonal carcinoma of the left testicle on 5 May 1976. Roentgenogram examination showed bilateral pulmonary metastasis and partial obstruction of the right ureter by enlarged para-aortic nodes. He received a combination of vinblastine sulfate and bleomycin (5 days of continuous infusions) on 27 May, 16 June, and 3 August 1975. Rapid reduction of the tumor masses with no deterioration of pulmonary functions was observed. On 13 August 1976 the patient had an anaphylatic reaction to carbenicillin, which necessitated Solu-Medrol® and amino© 1 9 7 8 American College of Physicians
47
Figure 1 . Chest roentgenograms in three patients who received bleomycin: Case 1, left, Case 2, middle; bilateral, diffuse, interstitial pulmonary infiltrates that cleared after therapy with prednisone.
phylline administration. The steroids were withdrawn a few days after discharge. He returned to the hospital on 10 September 1976 and complained of tachypnea at rest and dyspnea on exertion. The FVC had decreased from 3.45 to 1.79 litres, and arterial blood gas values were Po2, 65 mm Hg, Pco2, 39 mm Hg, and oxygen saturation, 92%. No rales were heard at auscultation. Chest roentgenogram showed diffuse bibasilar interstitial and alveolar infiltrates (Figure 1, right). Open lung biopsy was done on 19 September, after which therapy with prednisone, 20 mg four times a day, was started. In December, chest roentgenogram showed almost complete resolution of the infiltrates, and the FVC had increased to 2.37 litres. The patient is now asymptomatic. Pathology
Biopsy specimens in these three cases showed similar characteristics by light microscopy using routine hematoxylin-eosin staining as well as periodic acid-Schiff and the Masson trichrome stains. A patchy eosinophilic infiltrate affected the distal air spaces with little or no involvement of more proximal airways. Focal areas of interstitial fibrosis were present, but there was no involvement of large airways or evidence of vasculitis. Bronchio-
Case 3, right. All films show
lar squamous metaplasia of the distal air spaces was noticed along with a prominent eosinophilic infiltrate of the alveolar walls (Figure 2, left). Under electron microscopy, using staining with lead citrate and uranyl acetate, the striking feature was the absence of immune deposits in either epithelial or endothelial basement membranes. The focal hyperplasia of type II alveolar epithelial cells was marked in some of the sections examined, but no intrinsic alterations of type I alveolar epithelial cells were observed. These hyperplastic type II cells lacked the bizarre shapes and the extrusion of lamellar bodies usually noted in cases of bleomycin-induced interstitial pneumonias (Figure 2, middle). In concurrence with the patchy involvement noted by light microscopy, some of the electron micrographs showed minimal alterations, and the number of eosinophils observed varied from one area to another. Eosinophils were present within the capillaries and in the interstitial space of the alveolar septa, which contained immature fibroblasts and collagen. As in classic cases of bleomycin-induced interstitial pneumonitis, no disruption
Figure 2. Morphologic findings in a patient (Case 2). Left. Light microscopy of biopsy specimen showing widening of alveolar septa and infiltration by eosinophils (original magnification, x 1 6 0 ; hematoxilin and eosin). Middle. Electron micrograph showing alveolar epithelial hyperplasia. Note large number of granular pneumonocytes (type II cells) with prominent lamellar bodies (original magnification, x 4 2 0 0 ; lead citrate and uranyl acetate). Right. Electron micrograph of interstitial space. Note intact capillary in upper right and eosinophil interspersed amid collagen fibrils (original magnification, x 6 0 0 0 ; lead citrate and uranyl acetate).
48
January 1978
• Annals of Internal Medicine • Volume 88 • Number
Downloaded from https://annals.org by Tulane University user on 01/12/2019
1
of the capillary endothelium was noted within the boundaries of the alveolar walls (Figure 2, right). Deposits of IgG, IgA, IgM, fibrinogen, and complement were not detected in the pulmonary tissue by immunofluorescence techniques, and the presence of bleomycin could not be detected with a "sandwich" technique using various dilutions of an antibody raised against this drug in the rabbit and rabbit antiserum (10). Discussion
Bleomycin sulfate (Blenoxane®) is a mixture of at least 13 large polypeptides, derived from the fermentation of Streptomyces verticillus (11). Blum, Carter, and Agre (5) have reviewed experiences with bleomycin in the United States. Among 808 patients, 86 (10.7%) developed pulmonary toxicity of variable severity, and seven deaths occurred (1%). The prevalence increased when the total dose was greater than 450 mg and the patient was older than 70 years. Since the treatment of bleomycin pulmonary toxicity has been unsatisfactory, management consists of prevention and early diagnosis through frequent auscultation, pulmonary function studies, and chest roentgenograms (12). More recently, Bedrossian and Corey (13) reported abnormal sputum cytologies of patients on low-dose bleomycin. Luna and colleagues (7) described morphologic changes consisting of "diffuse alveolar damage" progressing to "usual interstitial pneumonia" with minimal or no inflammatory reaction. The changes described in our three patients are different and appear to be a hypersensitivity reaction. Interstitial fibrosis was patchy and not as pronounced as in classic bleomycin interstitial pneumonitis. Ultrastructural studies of classic bleomycin pulmonary toxicity failed to show eosinophils within the alveolar walls (9). Electron microscopy in our cases showed numerous eosinophils as described in Loeffler's pneumonitis (14). The absence of IgG, IgA, and IgM in the lung tissue of two patients is an indication against types II and III immunologic reactions (15). However, it does not rule out that a type I (IgE dependent) or a type IV (cell-mediated delayed hypersensitivity) immunologic reaction is involved, but the latter is less likely because no granulomas were noted in the tissues. Recognition of clinical features of this drug reaction might allow its diagnosis before lung biopsy. Auscultation failed to reveal the dry, end-inspiratory rales typical of interstitial pulmonary fibrosis. A leukocyte count differential in the first two patients showed mild eosinophilia, suggestive of drug hypersensitivity reaction. The toxicity that we report here is probably unusual, as Luna and associates (7) did not describe it in 37 cancer patients treated with bleomycin, 12 of whom developed interstitial pneumonia. DeLena and colleagues (16) found the usual pattern of interstitial pneumonia in seven patients and Yagoda and co-workers (12) in four. Likewise, none of the individual case reports (17, 18) showed a
hypersensitivity pneumonitis similar to the one induced by methotrexate or nitrofurantoin (19). In addition, a recent experimental study supported a direct type of effect in bleomycin pulmonary toxicity without eosinophilic infiltrates (20). Biopsy-proven bleomycin interstitial pneumonitis seldom responds to prednisone treatment. The consensus is that steroids are effective only when the fibrosis is not advanced. In contrast, bleomycin hypersensitivity pneumonitis responded promptly in our three cases with normalization of the radiologic changes and functional abnormalities. It is suggested, therefore, that this entity be recognized because of its good prognostic implication. ACKNOWLEDGMENTS: The authors thank Drs. Alan Broughton and James Strong for providing the antibody for the immunofluorescence study of the biopsies. Received 31 May 1977; revision accepted 2 September 1977. • Requests for reprints should be addressed to Carlos W.M. Bedrossian, M.D.; Department of Pathology and Laboratory Medicine, The University of Texas Medical School, P.O. Box 20708; Houston, TX 77030.
References 1. SAMUELS ML, H O L O Y E PY, JOHNSON DE: Bleomycin
2. 3. 4. 5. 6.
combination
chemotherapy in the management of testicular neoplasia. Cancer 36:318-326, 1975 SUZUKI M, W A T A N A B E M: Effects of bleomycin on gynecological carcinoma. Gann Monograph No. 19:221-230, 1976 ISHIKAWA T, N A K U N A J: Bleomycin treatment of the tumors of penis and scrotum. / Urol 102:699-707, 1969 NABEYA J: The use of bleomycin in the treatment of carcinoma of the esophagus. Gann Monograph No. 19:177-186, 1976 BLUM R H , CARTER SK, A G R E K: A clinical review of bleomycin—a new antineoplastic agent. Cancer 31:903-914, 1973 YAGODA A, KRAKOFF IH: Observations on the use of bleomycin in the treatment of malignant lymphoma in the U.S.A. Gann Monograph No. 19:255-268, 1976
7. L U N A MA, BEDROSSIAN CWM, LICHTIGER B, SALEM A: Interstitial
pneumonitis associated with bleomycin therapy. Am J Clin 58:501-510, 1972
8. SAMUELS ML, JOHNSON DE, H O L O Y E PY, L A N Z O T I VJ: Large-dose
bleomycin therapy and pulmonary toxicity. A possible note of prior radiotherapy. JAMA 235:1117-1120, 1976 9. BEDROSSIAN CWM, L U N A MA, M A C K A Y B, LICHTIGER B: Ultrastruc-
ture of pulmonary bleomycin toxicity. Cancer 32:44-51, 1973 10. BROUGHTON A, STRONG JE: Radioimmunoassay of bleomycin. Cancer Res 36:1418-1421, 1976 11. M U R A O K A Y, T A K I T A T, M A E D A K, U M E Z A W A H: The chemistry of
bleomycin. VI. Selective cleavage of bleomycin A2 by N-bromosuccinimide. / Antibiot (Tokyo) 25:185-186, 1972 12. Y A G O D A A, M U K H E R J I B, Y O U N G C, ETCUBANAS E, L A M O N T E C,
SMITH JR, T A N CTC, KRAKOFF IH: Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 77:861-870, 1972 13. BEDROSSIAN CWM, COREY BJ: Abnormal sputum cytopathology during chemotherapy with bleomycin (abstract). Acta Cytol (Baltimore) 20:586, 1976 14. BEDROSSIAN CWM, G R E E N B E R G SD, W I L L I A M S LJ J R : Ultrastructure
of the lung in Loeffler's pneumonia. Am J Med 58:438-443, 1975 15. M C C O M B S RP: Diseases due to immunologic reactions in the lungs. N EnglJ Med 286:1186-1194, 1245-1252, 1972 16. D E L E N A M, G U Z Z O N A, M O N F A R D I N I S, BONADONNA G: Clinical,
radiologic, and histopathologic studies on pulmonary toxicity induced by treatment with bleomycin. Cancer Chemother Rep 56:343-356, 1972 17. P E R E Z - G U E R R A F, H A R K L E R O A D LE, W A L S H RE, CONSTANZI JJ:
Acute bleomycin lung. Am Rev Respir Dis 106:909-913, 1972 18. KROUS H F , HAMLIN WB: Pulmonary toxicity due to bleomycin. Report of a case. Arch Pathol 95:407-410, 1973 19. ROSENOW EC III: The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, 1972 20. BEDROSSIAN CWM, G R E E N B E R G SD, Y A W N DH, O ' N E A L RM: Ex-
perimentally induced bleomycin sulfate pulmonary toxicity: histopathologic and ultrastructural study in the pheasant. Arch Pathol 101:248254, 1977
Holoye et al. • Bleomycin Hypersensitivity Pneumonitis
Downloaded from https://annals.org by Tulane University user on 01/12/2019
Pathol
49
Three patients developed radiologic and functional pulmonary changes after bleomycin therapy similar to ones previously associated with administration of this drug. However, biopsy specimens showed a pattern consistent with hypersensitivity pneumonitis rather than the interstitial pneumonia usually reported in bleomycin pulmonary toxicity. There was a patchy eosinophilic infiltrate surrounding small airways and distal air spaces, but no immune deposits were noted by ultrastructure or immunofluorescence using conventional techniques and a specific antibody against bleomycin. Two of the patients had peripheral eosinophilia of 1 2 % and 1 6 % . All three patients showed considerable improvement on chest roentgenogram after corticosteroid treatment. Our findings are consistent with the view that bleomycin hypersensitivity pneumonitis has a different pathogenesis than bleomycin interstitial pneumonitis. Its recognition as a separate entity seems warranted because of the favorable response to steroid therapy.
B L E O M Y C I N S U L F A T E has become one of the most useful agents in cancer chemotherapy because of its efficacy in treating a number of tumors and lack of myelosuppression. The drug is active against testicular tumors (1) and squamous cell carcinomas of the cervix (2), penis (3), esophagus (4), and head and neck area (5), as well as Hodgkin's and non-Hodgkin's lymphomas (6). However, bleomycin has an unusual and potentially lethal pulmonary side effect manifested by interstitial fibrosis (7), thought to be a direct toxicity, which increases in incidence with escalating dosage, age of the patient (5), and prior radiotherapy (8). Morphologic studies show an interstitial pneumonia of the usual type with ultrastructural evidence of alveolar epithelial damage (9). We report here the cases of three patients who, while receiving bleomycin, developed radiologic and functional changes similar to the usual bleomycin interstitial pneumonitis. However, lung biopsies showed a pattern of hypersensitivity reaction. Treatment with steroids led to a rapid and complete clearing of the radiologic and functional abnormalities. • F r o m the D e p a r t m e n t s of Internal Medicine a n d Anatomical Pathology, T h e University of Texas System Cancer Center, M . D . Anderson Hospital and T u m o r Institute, and the Department of Pathology and Laboratory Medicine, T h e University of Texas Medical School; Houston, Texas.
Annals of Internal Medicine 88:47-49, 1978
Downloaded from https://annals.org by Tulane University user on 01/12/2019
Case Reports CASE 1
A 17-year-old white boy had an orchiectomy for a choriocarcinoma in the right testicle in May 1973. At physical examination a periumbilical mass was found. Pulmonary functions were normal, and the patient denied any history of allergy. He received two courses of doxorubicin, vincristine, and bleomycin; the cumulative dose of bleomycin was 180 mg. In August 1973, a chest roentgenogram showed bilateral basilar interstitial infiltrates, although spirometry was almost normal and no rales were heard at auscultation (Figure 1, left). A routine complete blood count showed 1 6 % eosinophils. A percutaneous needle biopsy was done, after which the patient received isoniazid, pyridoxine, prednisone, and additional bleomycin. In November 1973 the chest roentgenogram showed that the interstitial infiltrates had cleared. Laparotomy with excision of a residual mass was done in December. T h e patient is now free of disease and asymptomatic. CASE 2
A 20-year-old Mexican man discovered a painless swelling of his left testicle in November 1974. By April 1975, abdominal and thoracic metastases were noted. Malignant teratoma, embryonal carcinoma, and choriocarcinoma were found at orchiectomy. Chest roentgenogram showed a large mass in the right upper part of the mediastinum. Chemotherapy consisting of vinblastine sulfate (0.4 mg/body weight) and bleomycin (30 units per day for 5 days by continuous infusion) was given in May and repeated in July and September 1975. Before the last course, the mediastinal mass had disappeared, but new densities had appeared in both midlung and lower-lung fields with small, bilateral pleural effusions. Pulmonary auscultation was normal. Another regimen of bleomycin, Cytoxan® (cyclophosphamide), Oncovin (vincristine), methotrexate, and 5-/luorouracil (B-comF) was given in December 1975 and January 1976. In March 1976, after a cumulative bleomycin dose of 1000 mg, the pulmonary infiltrates had increased (Figure 1, middle), and forced vital capacity (FVC) had dropped from 3.99 to 2.48 litres, but the blood gas values remained normal. A routine complete blood count showed 1 2 % eosinophils. An open lung biopsy was done on 19 March 1976. Administration of prednisone was started on 25 March 1976, and infiltrates had completely resolved by 23 April 1976. Additional bleomycin has been administered with prednisone protection without recurrence of pulmonary symptoms or signs. CASE 3
A 25-year-old white man was found to have a teratocarcinoma and embryonal carcinoma of the left testicle on 5 May 1976. Roentgenogram examination showed bilateral pulmonary metastasis and partial obstruction of the right ureter by enlarged para-aortic nodes. He received a combination of vinblastine sulfate and bleomycin (5 days of continuous infusions) on 27 May, 16 June, and 3 August 1975. Rapid reduction of the tumor masses with no deterioration of pulmonary functions was observed. On 13 August 1976 the patient had an anaphylatic reaction to carbenicillin, which necessitated Solu-Medrol® and amino© 1 9 7 8 American College of Physicians
47
Figure 1 . Chest roentgenograms in three patients who received bleomycin: Case 1, left, Case 2, middle; bilateral, diffuse, interstitial pulmonary infiltrates that cleared after therapy with prednisone.
phylline administration. The steroids were withdrawn a few days after discharge. He returned to the hospital on 10 September 1976 and complained of tachypnea at rest and dyspnea on exertion. The FVC had decreased from 3.45 to 1.79 litres, and arterial blood gas values were Po2, 65 mm Hg, Pco2, 39 mm Hg, and oxygen saturation, 92%. No rales were heard at auscultation. Chest roentgenogram showed diffuse bibasilar interstitial and alveolar infiltrates (Figure 1, right). Open lung biopsy was done on 19 September, after which therapy with prednisone, 20 mg four times a day, was started. In December, chest roentgenogram showed almost complete resolution of the infiltrates, and the FVC had increased to 2.37 litres. The patient is now asymptomatic. Pathology
Biopsy specimens in these three cases showed similar characteristics by light microscopy using routine hematoxylin-eosin staining as well as periodic acid-Schiff and the Masson trichrome stains. A patchy eosinophilic infiltrate affected the distal air spaces with little or no involvement of more proximal airways. Focal areas of interstitial fibrosis were present, but there was no involvement of large airways or evidence of vasculitis. Bronchio-
Case 3, right. All films show
lar squamous metaplasia of the distal air spaces was noticed along with a prominent eosinophilic infiltrate of the alveolar walls (Figure 2, left). Under electron microscopy, using staining with lead citrate and uranyl acetate, the striking feature was the absence of immune deposits in either epithelial or endothelial basement membranes. The focal hyperplasia of type II alveolar epithelial cells was marked in some of the sections examined, but no intrinsic alterations of type I alveolar epithelial cells were observed. These hyperplastic type II cells lacked the bizarre shapes and the extrusion of lamellar bodies usually noted in cases of bleomycin-induced interstitial pneumonias (Figure 2, middle). In concurrence with the patchy involvement noted by light microscopy, some of the electron micrographs showed minimal alterations, and the number of eosinophils observed varied from one area to another. Eosinophils were present within the capillaries and in the interstitial space of the alveolar septa, which contained immature fibroblasts and collagen. As in classic cases of bleomycin-induced interstitial pneumonitis, no disruption
Figure 2. Morphologic findings in a patient (Case 2). Left. Light microscopy of biopsy specimen showing widening of alveolar septa and infiltration by eosinophils (original magnification, x 1 6 0 ; hematoxilin and eosin). Middle. Electron micrograph showing alveolar epithelial hyperplasia. Note large number of granular pneumonocytes (type II cells) with prominent lamellar bodies (original magnification, x 4 2 0 0 ; lead citrate and uranyl acetate). Right. Electron micrograph of interstitial space. Note intact capillary in upper right and eosinophil interspersed amid collagen fibrils (original magnification, x 6 0 0 0 ; lead citrate and uranyl acetate).
48
January 1978
• Annals of Internal Medicine • Volume 88 • Number
Downloaded from https://annals.org by Tulane University user on 01/12/2019
1
of the capillary endothelium was noted within the boundaries of the alveolar walls (Figure 2, right). Deposits of IgG, IgA, IgM, fibrinogen, and complement were not detected in the pulmonary tissue by immunofluorescence techniques, and the presence of bleomycin could not be detected with a "sandwich" technique using various dilutions of an antibody raised against this drug in the rabbit and rabbit antiserum (10). Discussion
Bleomycin sulfate (Blenoxane®) is a mixture of at least 13 large polypeptides, derived from the fermentation of Streptomyces verticillus (11). Blum, Carter, and Agre (5) have reviewed experiences with bleomycin in the United States. Among 808 patients, 86 (10.7%) developed pulmonary toxicity of variable severity, and seven deaths occurred (1%). The prevalence increased when the total dose was greater than 450 mg and the patient was older than 70 years. Since the treatment of bleomycin pulmonary toxicity has been unsatisfactory, management consists of prevention and early diagnosis through frequent auscultation, pulmonary function studies, and chest roentgenograms (12). More recently, Bedrossian and Corey (13) reported abnormal sputum cytologies of patients on low-dose bleomycin. Luna and colleagues (7) described morphologic changes consisting of "diffuse alveolar damage" progressing to "usual interstitial pneumonia" with minimal or no inflammatory reaction. The changes described in our three patients are different and appear to be a hypersensitivity reaction. Interstitial fibrosis was patchy and not as pronounced as in classic bleomycin interstitial pneumonitis. Ultrastructural studies of classic bleomycin pulmonary toxicity failed to show eosinophils within the alveolar walls (9). Electron microscopy in our cases showed numerous eosinophils as described in Loeffler's pneumonitis (14). The absence of IgG, IgA, and IgM in the lung tissue of two patients is an indication against types II and III immunologic reactions (15). However, it does not rule out that a type I (IgE dependent) or a type IV (cell-mediated delayed hypersensitivity) immunologic reaction is involved, but the latter is less likely because no granulomas were noted in the tissues. Recognition of clinical features of this drug reaction might allow its diagnosis before lung biopsy. Auscultation failed to reveal the dry, end-inspiratory rales typical of interstitial pulmonary fibrosis. A leukocyte count differential in the first two patients showed mild eosinophilia, suggestive of drug hypersensitivity reaction. The toxicity that we report here is probably unusual, as Luna and associates (7) did not describe it in 37 cancer patients treated with bleomycin, 12 of whom developed interstitial pneumonia. DeLena and colleagues (16) found the usual pattern of interstitial pneumonia in seven patients and Yagoda and co-workers (12) in four. Likewise, none of the individual case reports (17, 18) showed a
hypersensitivity pneumonitis similar to the one induced by methotrexate or nitrofurantoin (19). In addition, a recent experimental study supported a direct type of effect in bleomycin pulmonary toxicity without eosinophilic infiltrates (20). Biopsy-proven bleomycin interstitial pneumonitis seldom responds to prednisone treatment. The consensus is that steroids are effective only when the fibrosis is not advanced. In contrast, bleomycin hypersensitivity pneumonitis responded promptly in our three cases with normalization of the radiologic changes and functional abnormalities. It is suggested, therefore, that this entity be recognized because of its good prognostic implication. ACKNOWLEDGMENTS: The authors thank Drs. Alan Broughton and James Strong for providing the antibody for the immunofluorescence study of the biopsies. Received 31 May 1977; revision accepted 2 September 1977. • Requests for reprints should be addressed to Carlos W.M. Bedrossian, M.D.; Department of Pathology and Laboratory Medicine, The University of Texas Medical School, P.O. Box 20708; Houston, TX 77030.
References 1. SAMUELS ML, H O L O Y E PY, JOHNSON DE: Bleomycin
2. 3. 4. 5. 6.
combination
chemotherapy in the management of testicular neoplasia. Cancer 36:318-326, 1975 SUZUKI M, W A T A N A B E M: Effects of bleomycin on gynecological carcinoma. Gann Monograph No. 19:221-230, 1976 ISHIKAWA T, N A K U N A J: Bleomycin treatment of the tumors of penis and scrotum. / Urol 102:699-707, 1969 NABEYA J: The use of bleomycin in the treatment of carcinoma of the esophagus. Gann Monograph No. 19:177-186, 1976 BLUM R H , CARTER SK, A G R E K: A clinical review of bleomycin—a new antineoplastic agent. Cancer 31:903-914, 1973 YAGODA A, KRAKOFF IH: Observations on the use of bleomycin in the treatment of malignant lymphoma in the U.S.A. Gann Monograph No. 19:255-268, 1976
7. L U N A MA, BEDROSSIAN CWM, LICHTIGER B, SALEM A: Interstitial
pneumonitis associated with bleomycin therapy. Am J Clin 58:501-510, 1972
8. SAMUELS ML, JOHNSON DE, H O L O Y E PY, L A N Z O T I VJ: Large-dose
bleomycin therapy and pulmonary toxicity. A possible note of prior radiotherapy. JAMA 235:1117-1120, 1976 9. BEDROSSIAN CWM, L U N A MA, M A C K A Y B, LICHTIGER B: Ultrastruc-
ture of pulmonary bleomycin toxicity. Cancer 32:44-51, 1973 10. BROUGHTON A, STRONG JE: Radioimmunoassay of bleomycin. Cancer Res 36:1418-1421, 1976 11. M U R A O K A Y, T A K I T A T, M A E D A K, U M E Z A W A H: The chemistry of
bleomycin. VI. Selective cleavage of bleomycin A2 by N-bromosuccinimide. / Antibiot (Tokyo) 25:185-186, 1972 12. Y A G O D A A, M U K H E R J I B, Y O U N G C, ETCUBANAS E, L A M O N T E C,
SMITH JR, T A N CTC, KRAKOFF IH: Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 77:861-870, 1972 13. BEDROSSIAN CWM, COREY BJ: Abnormal sputum cytopathology during chemotherapy with bleomycin (abstract). Acta Cytol (Baltimore) 20:586, 1976 14. BEDROSSIAN CWM, G R E E N B E R G SD, W I L L I A M S LJ J R : Ultrastructure
of the lung in Loeffler's pneumonia. Am J Med 58:438-443, 1975 15. M C C O M B S RP: Diseases due to immunologic reactions in the lungs. N EnglJ Med 286:1186-1194, 1245-1252, 1972 16. D E L E N A M, G U Z Z O N A, M O N F A R D I N I S, BONADONNA G: Clinical,
radiologic, and histopathologic studies on pulmonary toxicity induced by treatment with bleomycin. Cancer Chemother Rep 56:343-356, 1972 17. P E R E Z - G U E R R A F, H A R K L E R O A D LE, W A L S H RE, CONSTANZI JJ:
Acute bleomycin lung. Am Rev Respir Dis 106:909-913, 1972 18. KROUS H F , HAMLIN WB: Pulmonary toxicity due to bleomycin. Report of a case. Arch Pathol 95:407-410, 1973 19. ROSENOW EC III: The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, 1972 20. BEDROSSIAN CWM, G R E E N B E R G SD, Y A W N DH, O ' N E A L RM: Ex-
perimentally induced bleomycin sulfate pulmonary toxicity: histopathologic and ultrastructural study in the pheasant. Arch Pathol 101:248254, 1977
Holoye et al. • Bleomycin Hypersensitivity Pneumonitis
Downloaded from https://annals.org by Tulane University user on 01/12/2019
Pathol
49
