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Azathioprine Hypersensitivity Mimicking Goodpasture's Syndrome
Azathioprine Hypersensitivity Mimicking Goodpasture's Syndrome M. Stetter, MD, M. Schmidli, MD, and R. Krapf, MD • Side effects due to azathioprine I(the nitroimidazole derivative of 6-mercaptopurine) can be classified as toxic (myelosuppression, hepatotoxicity) ~nd idiosyncratic (fever, rigors, arthralgias, pneumonitis, and gastrointestinal symptoms). While the toxic effects are due to 6-mercaptopurine, the hypersensitivity reactions are believed to be caused by the nitroimidazole moiety. A 21-year-old male patient developed end-stage renal failure due to antiglomerular basement membrane (AGBM) disease (rapidly progressive glomerulonephritis with linear immunoglobulin G deposits and positive circulating AGBM antibodies). The patient became dependent on continuous ambulatory peritoneal dialysis and, later, hemodialysis, and received two renal allografts at the ages of 23 and 27 years. He received three courses of azathioprine treatment: one course for AGBM glomerulonephritis and two courses for rejection episodes. Each course was followed within 4 to 7 days bYlsymptoms compatible with Goodpasture's syndrome, ie, high fever, rigors, arthralgias, diarrhea, myalgias, and pulmonary infiltrates with hemoptysis. All signs and symptoms always resolved completely on discontinuation of azathioprine. During the treatment for rejections, AGBM antibodies were not elevated, and during one episode AGBM disease in the lung (Goodpasture's syndrome) was excluded by open lung biopsy. Treatment of a subsequent rejection episode with 6-mercaptopurine was well tolerated. We conclude that azathioprine hypersensitivity can mimic the pulmonary manifestations of Goodpasture's syndrome. Hypersensitivity probably is due to the nitroimidazole mOiety of azathioprine. Thus, differential diagnosis of Goodpasture's syndrome (and probably of any "pulmonary renal syndrome") should include azathioprine hypersensitivity. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Azathioprine hypersensitivity; Goodpasture's syndrome; lung hemorrhage.
O
VER THE LAST 30 years, azathioprine (the nitroimidazole derivative of 6-mercaptopurine) has assumed a major role in immunosuppression. In contrast to toxic side effects (myelosuppression, hepatotoxicity), hypersensitivity reactions to azathioprine are rare. Hypersensitivity reactions comprise fever, rigors, arthralgias, pneumonitis, and gastrointestinal symptoms (for review, see refs 1 and 2). While the toxic effects are due to the active compound 6-mercaptopurine, the hypersensitivity reactions are believed to be caused by the nitroimidazole moiety.3 We report a case of antiglomerular basement membrane (AGBM) disease treated with azathioprine (once for glomerulonephritis and twice for rejection episodes after transplantation). Each administration of azathioprine was followed within 4 to 7 days by pulmonary and systemic signs and symptoms reminiscent of Goodpasture's syndrome. The subsequent, well-tolerated treatment with 6-mercaptopurine supports the From the Medizinische Klinik B, Kantonsspital, St Gallen, Switzerland. Received October 8, 1993; accepted in revised/orm December 14, 1993. Address reprint requests to R. Krapf, MD, Medizinische Klinik B, Kantonsspital, 9007 St Gallen, Switzerland. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0017$3.00/0
874
theory that azathioprine hypersensitivity mimicked Goodpasture's syndrome in this case. CASE REPORT A 21-year-old man was admitted on June 10, 1985, with a 2-week history of malaise, nausea, vomiting, and hematuria. His plasma urea and creatinine concentrations were 123 mgl dL and 14.5 mg/dL, respectively (creatinine clearance, 1.5 mL/min). In addition, normocytic, normochromic anemia (hemoglobin, 67 giL) was present. A renal biopsy showed a rapidly progressive glomerulonephritis characterized by intracapillary and extracapillary proliferations, fibrin deposits and, on immunofluorescence, linear immunoglobulin G (lgG) deposits along the glomerular basement membrane. The chest x-ray film was unremarkable (Fig I). Circulating AGBM antibodies were positive at a titer of I :512. The patient was diagnosed with AGBM-positive glomerulonephritis and treated with prednisolone 60 mg/d and azathioprine ISO mg/d orally as well as peritoneal dialysis (Table I). Seven days after the institution of azathioprine treatment, the patient developed high fever (39.3°C), rigors, arthralgias, myalgias, diarrhea, and pulmonary infiltrates with hemoptysis leading to acute respiratory failure, necessitating assisted ventilation (Fig 2). A diagnosis of Goodpasture's syndrome was made. Therefore, plasmapheresis (five consecutive phereses, 4,000 mL/d; replacement fluid: isotonic saline containing 2.5 giL albumin) was prescribed, and azathioprine was discontinued and replaced by cyclophosphamide (100 mg/d orally). All the signs and symptoms mentioned above resolved within 5 days. On January 29, 1987, the patient received a cadaveric allograft. The immunosuppressive regimen included cyclosporine and prednisone. One year and 6 months later, in July 1988, as well as in September 1990, graft biopsies performed for increases in serum creatinine (1988: 1.9 to 2.6 mg/dL; 1990: 3.05 to 8.1
American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 874-877
875
AZATHIOPRINE HYPERSENSITIVITY
were negative and no evidence of an infectious etiology was discernible. Azathioprine was discontinued; a rapid resolution of fever and all other symptoms occurred within 2 days. After this last episode a diagnosis of azathioprine hypersensitivity was made. Since this reaction is believed to be caused by the nitroimidazole moiety/ a subsequent rejection episode was treated with the addition of the active metabolite of azathioprine, 6-mercaptopurine (50 mgjd), to the cyclosporinejprednisone regimen. Treatment with 6-mercaptopurine for 48 days at a dose of 50 to 75 mgjd was tolerated without side effects. Due to ethical considerations, re-exposure to azathioprine was not attempted.
DISCUSSION
Fig 1. Chest x-ray film taken on admission. A rapidly progressive glomerulopathy was diagnosed at this time. mgjdL) showed moderate tubulointerstitial rejections, which were both treated with pulse dose methylprednisolone. During the second episode, azathioprine 25 mgjd orally was also given. Six days later, the patient was readmitted with generalized myalgias, arthralgias, an increase in temperature to 39.5°C, diarrhea, and hypoxia (Po2 = 51 mm Hg). An open lung biopsy showed lung hemorrhage, hemosiderin-loaded macrophages, and some IgM deposits (but no linear IgG deposits). Although the AGBM were not detectable in serum, a relapse of Goodpasture's syndrome was assumed. The patient again underwent plasmapheresis (five treatments of 4,000 mL each) and received cyclophosphamide (100 mgjd). Azathioprine was given for 25 days. Remarkably, 2 days after discontinuation of the drug, fever and myalgiasjarthralgias resolved (Tables I and 2). The pulmonary diffusion capacity remained decreased (40% of the age-adjusted normal value) after this episode. In June 1991, progressive loss in graft function necessitated hemodialysis. On November II, 1991, the patient received a second renal allograft complicated by an acute tubulointerstitial rejection despite perioperative treatment with anti thymocyte globulin. Pulse dose methylprednisolone (500 mgjd for 5 days) was ineffective. Therefore, a 12-day regimen of OKT3 (5 mgjd) was instituted. Renal function improved, and the plasma creatinine stabilized at 2.3 mgjdL. The additional immunosuppressive regimen consisted of cyclosporine and prednisone. Three months later, the cyclosporine dosage was reduced and azathioprine was instituted (50 mgjd) because of suspected cyclosporine toxicity (plasma creatinine, 1.7 to 2.5 mgjdL). Four days later, shaking chills, rigors, high fever (39.5°C), generalized muscle pain, arthralgias, anemia (hemoglobin 86 gjL), and thrombocytopenia developed acutely. Neither eosinophilia nor eosinophiluria was present. Once again, AGBMs
Azathioprine is the nitroimidazole derivative of 6-mercaptopurine. 4 The major side effects of azathioprine are toxic in nature, dose dependent, and usually reversible. Anorexia, nausea and vomiting, bone marrow depression, and hepatotoxicity 5 are the major toxic side effects. Hypersensitivity reactions to azathioprine (and/or its metabolites) have been previously recognized and comprise fever, rigors, arthralgias, myalgias, cutaneous reactions, headache, interstitial nephritis, hypotension, pancreatitis, dyspnea, cough, and pneumonitis. 1-3.6-9 The most striking feature of this case is the observation that the administration of azathioprine was followed under three occasions by pneumonitis complicated by pulmonary hemorrhage and severe constitutional symptoms (fever, rigors, arthralgias, myalgias, diarrhea). The reactions to the first administration (Table 1) could have been due to classical Goodpasture's syndrome, since it is well established that the pulmonary manifestations can follow the renal disease in this syndrome. Pulmonary AGBM disease was not excluded by biopsy. However, the nearly identical clinical course and pulmonary manifestations on two re-exposures to azathioprine and the negative open lung biopsy during a subsequent episode are strong evidence that azathioprine hypersensitivity was the cause of this complication. In addition, all three renal allograft biopsies did not show linear IgG deposits, thus excluding relapses of AGBM disease. The temporal relationship between administration of azathioprine and onset of lung hemorrhage and other symptoms suggests an idiosyncratic etiology (Table 2). The interval between azathioprine administration and clinical symptoms shortened progressively (from 7 to 4 days). In addition, no
STETTER , SCHMIDLI, AND KRAPF
876
Table 1. Case Report Date
Clinical Picture
Clinical Interpretation
6/10/85
End-stage renal failure, creatinine 14.5 mg/dL; biopsy: intracapillary and extracapillary proliferations with linear IgG deposits; AGBM antibodies: 1:512 Treatment: azathioprine (150 mg/d) and prednisolone (60 mg/d) Hemoptysis, fever, arthralgias, myalgias, lung hemorrhage; treatment: plasmapheresis, cyclophosphamide (100 mg/d); azathioprine was discontinued First renal allograft (cyclosporine A, prednisolone) Increased serum creatinine (1.9-2.6 mg/dL); graft biopsy: moderate tubulointerstitial rejection; treatment: methylprednisolone pulses (5 x 500 mg) Increased serum creatinine (3.1-8.1 mg/dL); graft biopsy: tubulointerstitial rejection; treatment: azathioprine (25 mg/d), methylprednisolone pulses (5 x 500 mg) Fever, arthralgias, myalgias, diarrhea, lung hemorrhage; open lung biopsy: hemorrhage, hemosiderin-loaded macrophages, no linear IgG deposits; treatment plasmapheresis, cyclophosphamide (100 mg/d), methylprednisolone pulses (5 x 500 mg); azathioprine was discontinued Second renal graft (cyclosprine, prenisolone) Increased serum creatinine (1.7-2.5 mg/dL); treatment: azathioprine (50 mg/d) Fever, rigors, arthralgias, myalgias, anemia, thrombocytopenia, pneumonitis (x-ray); azathioprine was discontinued Substitution of azathioprine by 6-mercaptopurine; tolerated without side effects
AGBM-positive, rapidly progressive glomerulonephritis
6/20/85 6/28/85
1/29/87 7/11/88
9/24/90
9/30/90
11/27/91 3/17/92 3/21/92 7/14/92
dose dependence was observed (25 to 150 mg/d were given) and all signs and symptoms resolved completely within a few days after discontinuation of azathioprine. We therefore conclude that pneumonitis complicated by lung hemorrhage represented an idiosyncratic reaction to azathioprine. ' ,9
Goodpasture's syndrome
Graft rejection
Graft rejection
Relapse of Goodpasture's syndrome?
Graft rejection Azathioprine hypersensitivity?
This case illustrates that azathioprine hypersensitivity can mimic the systemic and pulmonary manifestations of AGBM disease (ie, classical Goodpasture's syndrome). Thus, before making this diagnosis or considering other etiologies of the "pulmonary renal syndrome," physicians should also consider azathioprine hyper-
Table 2. Temporal Relationships Between Administration of Azathioprine and Disease Manifestations
Azathioprine
Duration 01 Symptoms
Signs and Symptoms
AGBM
6/201-7/1/85 (150 mg /d)
6/28/- 7f7185
Hemoptysis, fever, arthralgias, myalgias; chest x-ray : pulmonary infiltrates
15 : 12
9/24/- 10/21 /85 (25 mg/d)
9/301-10/23/90
Fever, arthralgias, myalgias, diarrhea, lung hemorrhage ; open lung biopsy: hemorrhage, hemosiderin-loaded macrophages, no linear IgG deposits
Negative
3/17/-3/21 /92 (50 mg /d)
3/21 /-3/24/92
Fever, rigors , arthralgias, myalgias, thrombocytopenia; suspected pneumonitis (x-ray)
Negative
NOTE. On the verticle rule, t = time, solid boxes denote time period of azathioprine administration, and shaded boxes denote time period of clinical illness.
877
AZATHIOPRINE HYPERSENSITIVITY
In conclusion, azathioprine hypersensitivity can mimic the pulmonary and systemic manifestations of Goodpasture's syndrome. Early recognition of these side effects may obviate expensive and potentially dangerous therapies, such as plasmapheresis. Finally, 6-mercaptopurine represents a valuable alternative to the compound drug azathioprine as the hypersensitivity may be due to the nitroimidazole moiety in azathioprine. In the appropriate clinical background, azathioprine hypersensitivity should be added to the list of etiologic considerations for "pulmonary renal syndrome."
REFERENCES
Fig 2. Chest x-ray film taken 7 day after the first treatment episode with azathioprine. The film discloses extensive, bilateral, reticulonodular, and alveolar infiltrates consistent with pneumonitis and alveolar hemorrhage.
sensItIvIty as an alternative explanation for pulmonary and systemic manifestations in patients with glomerulonephritis or renal transplant rejection. Our case further illustrates that azathioprine hypersensitivity was probably due to the nitroimidazole moiety of azathioprine as treatment with the active component, 6-mercaptopurine, was tolerated without side effects. 3
I. Saway A, Heck LW. Bonner JR, Kriklin JK: Azathioprine hypersensitivity. Am J Med 84:960-964, 1988 2. Dore P, Meurice Jc, Recart D, Patte F: Reaction d'hypersensibilite a I'azathioprine. Presse Med 21 : 1040-1041, 1992 3. Davis M, Eddleston A, Williams R: Hypersensitivity and jaundice due to azathioprine. Postgrad Med J 56:274-275, 1980 4. Elion G, Callahan S, Bieber S: A summary of investigations with 6( l-methyl-4-nitro-5-imidazolyl)thio purine. Cancer Chemother Rep 14:93-98, 1952 5. Calabresi P, Chobner BA: Chemotherapy of neoplastic diseases, in Gilman AG, Rail TW, Nies AS, Taylor P (eds): Gilman and Goodman's: The Pharmaceutical Basis of Therapeutics (ed 8). New York, NY, Pergamon, 1990, pp 12321236 6. DeSwarte RD: Drug allergy: An Overview. Clin Rev Allergy 4:143-169, 1986 7. Mosbech H, Anderson C: Hypersensitivity of azathioprine. Ugeskr Laeger 144:2424, 1982 8. King J, Laver M, Fairly K, Ames G: Sensitivity to azathioprine. Med J Aust 2:939-941 , 1972 9. Krowka M, Brever R, Kehoe T: Azathioprine-associated pulmonary dysfunction. Chest 36:35-39, 1983
O
VER THE LAST 30 years, azathioprine (the nitroimidazole derivative of 6-mercaptopurine) has assumed a major role in immunosuppression. In contrast to toxic side effects (myelosuppression, hepatotoxicity), hypersensitivity reactions to azathioprine are rare. Hypersensitivity reactions comprise fever, rigors, arthralgias, pneumonitis, and gastrointestinal symptoms (for review, see refs 1 and 2). While the toxic effects are due to the active compound 6-mercaptopurine, the hypersensitivity reactions are believed to be caused by the nitroimidazole moiety.3 We report a case of antiglomerular basement membrane (AGBM) disease treated with azathioprine (once for glomerulonephritis and twice for rejection episodes after transplantation). Each administration of azathioprine was followed within 4 to 7 days by pulmonary and systemic signs and symptoms reminiscent of Goodpasture's syndrome. The subsequent, well-tolerated treatment with 6-mercaptopurine supports the From the Medizinische Klinik B, Kantonsspital, St Gallen, Switzerland. Received October 8, 1993; accepted in revised/orm December 14, 1993. Address reprint requests to R. Krapf, MD, Medizinische Klinik B, Kantonsspital, 9007 St Gallen, Switzerland. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0017$3.00/0
874
theory that azathioprine hypersensitivity mimicked Goodpasture's syndrome in this case. CASE REPORT A 21-year-old man was admitted on June 10, 1985, with a 2-week history of malaise, nausea, vomiting, and hematuria. His plasma urea and creatinine concentrations were 123 mgl dL and 14.5 mg/dL, respectively (creatinine clearance, 1.5 mL/min). In addition, normocytic, normochromic anemia (hemoglobin, 67 giL) was present. A renal biopsy showed a rapidly progressive glomerulonephritis characterized by intracapillary and extracapillary proliferations, fibrin deposits and, on immunofluorescence, linear immunoglobulin G (lgG) deposits along the glomerular basement membrane. The chest x-ray film was unremarkable (Fig I). Circulating AGBM antibodies were positive at a titer of I :512. The patient was diagnosed with AGBM-positive glomerulonephritis and treated with prednisolone 60 mg/d and azathioprine ISO mg/d orally as well as peritoneal dialysis (Table I). Seven days after the institution of azathioprine treatment, the patient developed high fever (39.3°C), rigors, arthralgias, myalgias, diarrhea, and pulmonary infiltrates with hemoptysis leading to acute respiratory failure, necessitating assisted ventilation (Fig 2). A diagnosis of Goodpasture's syndrome was made. Therefore, plasmapheresis (five consecutive phereses, 4,000 mL/d; replacement fluid: isotonic saline containing 2.5 giL albumin) was prescribed, and azathioprine was discontinued and replaced by cyclophosphamide (100 mg/d orally). All the signs and symptoms mentioned above resolved within 5 days. On January 29, 1987, the patient received a cadaveric allograft. The immunosuppressive regimen included cyclosporine and prednisone. One year and 6 months later, in July 1988, as well as in September 1990, graft biopsies performed for increases in serum creatinine (1988: 1.9 to 2.6 mg/dL; 1990: 3.05 to 8.1
American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 874-877
875
AZATHIOPRINE HYPERSENSITIVITY
were negative and no evidence of an infectious etiology was discernible. Azathioprine was discontinued; a rapid resolution of fever and all other symptoms occurred within 2 days. After this last episode a diagnosis of azathioprine hypersensitivity was made. Since this reaction is believed to be caused by the nitroimidazole moiety/ a subsequent rejection episode was treated with the addition of the active metabolite of azathioprine, 6-mercaptopurine (50 mgjd), to the cyclosporinejprednisone regimen. Treatment with 6-mercaptopurine for 48 days at a dose of 50 to 75 mgjd was tolerated without side effects. Due to ethical considerations, re-exposure to azathioprine was not attempted.
DISCUSSION
Fig 1. Chest x-ray film taken on admission. A rapidly progressive glomerulopathy was diagnosed at this time. mgjdL) showed moderate tubulointerstitial rejections, which were both treated with pulse dose methylprednisolone. During the second episode, azathioprine 25 mgjd orally was also given. Six days later, the patient was readmitted with generalized myalgias, arthralgias, an increase in temperature to 39.5°C, diarrhea, and hypoxia (Po2 = 51 mm Hg). An open lung biopsy showed lung hemorrhage, hemosiderin-loaded macrophages, and some IgM deposits (but no linear IgG deposits). Although the AGBM were not detectable in serum, a relapse of Goodpasture's syndrome was assumed. The patient again underwent plasmapheresis (five treatments of 4,000 mL each) and received cyclophosphamide (100 mgjd). Azathioprine was given for 25 days. Remarkably, 2 days after discontinuation of the drug, fever and myalgiasjarthralgias resolved (Tables I and 2). The pulmonary diffusion capacity remained decreased (40% of the age-adjusted normal value) after this episode. In June 1991, progressive loss in graft function necessitated hemodialysis. On November II, 1991, the patient received a second renal allograft complicated by an acute tubulointerstitial rejection despite perioperative treatment with anti thymocyte globulin. Pulse dose methylprednisolone (500 mgjd for 5 days) was ineffective. Therefore, a 12-day regimen of OKT3 (5 mgjd) was instituted. Renal function improved, and the plasma creatinine stabilized at 2.3 mgjdL. The additional immunosuppressive regimen consisted of cyclosporine and prednisone. Three months later, the cyclosporine dosage was reduced and azathioprine was instituted (50 mgjd) because of suspected cyclosporine toxicity (plasma creatinine, 1.7 to 2.5 mgjdL). Four days later, shaking chills, rigors, high fever (39.5°C), generalized muscle pain, arthralgias, anemia (hemoglobin 86 gjL), and thrombocytopenia developed acutely. Neither eosinophilia nor eosinophiluria was present. Once again, AGBMs
Azathioprine is the nitroimidazole derivative of 6-mercaptopurine. 4 The major side effects of azathioprine are toxic in nature, dose dependent, and usually reversible. Anorexia, nausea and vomiting, bone marrow depression, and hepatotoxicity 5 are the major toxic side effects. Hypersensitivity reactions to azathioprine (and/or its metabolites) have been previously recognized and comprise fever, rigors, arthralgias, myalgias, cutaneous reactions, headache, interstitial nephritis, hypotension, pancreatitis, dyspnea, cough, and pneumonitis. 1-3.6-9 The most striking feature of this case is the observation that the administration of azathioprine was followed under three occasions by pneumonitis complicated by pulmonary hemorrhage and severe constitutional symptoms (fever, rigors, arthralgias, myalgias, diarrhea). The reactions to the first administration (Table 1) could have been due to classical Goodpasture's syndrome, since it is well established that the pulmonary manifestations can follow the renal disease in this syndrome. Pulmonary AGBM disease was not excluded by biopsy. However, the nearly identical clinical course and pulmonary manifestations on two re-exposures to azathioprine and the negative open lung biopsy during a subsequent episode are strong evidence that azathioprine hypersensitivity was the cause of this complication. In addition, all three renal allograft biopsies did not show linear IgG deposits, thus excluding relapses of AGBM disease. The temporal relationship between administration of azathioprine and onset of lung hemorrhage and other symptoms suggests an idiosyncratic etiology (Table 2). The interval between azathioprine administration and clinical symptoms shortened progressively (from 7 to 4 days). In addition, no
STETTER , SCHMIDLI, AND KRAPF
876
Table 1. Case Report Date
Clinical Picture
Clinical Interpretation
6/10/85
End-stage renal failure, creatinine 14.5 mg/dL; biopsy: intracapillary and extracapillary proliferations with linear IgG deposits; AGBM antibodies: 1:512 Treatment: azathioprine (150 mg/d) and prednisolone (60 mg/d) Hemoptysis, fever, arthralgias, myalgias, lung hemorrhage; treatment: plasmapheresis, cyclophosphamide (100 mg/d); azathioprine was discontinued First renal allograft (cyclosporine A, prednisolone) Increased serum creatinine (1.9-2.6 mg/dL); graft biopsy: moderate tubulointerstitial rejection; treatment: methylprednisolone pulses (5 x 500 mg) Increased serum creatinine (3.1-8.1 mg/dL); graft biopsy: tubulointerstitial rejection; treatment: azathioprine (25 mg/d), methylprednisolone pulses (5 x 500 mg) Fever, arthralgias, myalgias, diarrhea, lung hemorrhage; open lung biopsy: hemorrhage, hemosiderin-loaded macrophages, no linear IgG deposits; treatment plasmapheresis, cyclophosphamide (100 mg/d), methylprednisolone pulses (5 x 500 mg); azathioprine was discontinued Second renal graft (cyclosprine, prenisolone) Increased serum creatinine (1.7-2.5 mg/dL); treatment: azathioprine (50 mg/d) Fever, rigors, arthralgias, myalgias, anemia, thrombocytopenia, pneumonitis (x-ray); azathioprine was discontinued Substitution of azathioprine by 6-mercaptopurine; tolerated without side effects
AGBM-positive, rapidly progressive glomerulonephritis
6/20/85 6/28/85
1/29/87 7/11/88
9/24/90
9/30/90
11/27/91 3/17/92 3/21/92 7/14/92
dose dependence was observed (25 to 150 mg/d were given) and all signs and symptoms resolved completely within a few days after discontinuation of azathioprine. We therefore conclude that pneumonitis complicated by lung hemorrhage represented an idiosyncratic reaction to azathioprine. ' ,9
Goodpasture's syndrome
Graft rejection
Graft rejection
Relapse of Goodpasture's syndrome?
Graft rejection Azathioprine hypersensitivity?
This case illustrates that azathioprine hypersensitivity can mimic the systemic and pulmonary manifestations of AGBM disease (ie, classical Goodpasture's syndrome). Thus, before making this diagnosis or considering other etiologies of the "pulmonary renal syndrome," physicians should also consider azathioprine hyper-
Table 2. Temporal Relationships Between Administration of Azathioprine and Disease Manifestations
Azathioprine
Duration 01 Symptoms
Signs and Symptoms
AGBM
6/201-7/1/85 (150 mg /d)
6/28/- 7f7185
Hemoptysis, fever, arthralgias, myalgias; chest x-ray : pulmonary infiltrates
15 : 12
9/24/- 10/21 /85 (25 mg/d)
9/301-10/23/90
Fever, arthralgias, myalgias, diarrhea, lung hemorrhage ; open lung biopsy: hemorrhage, hemosiderin-loaded macrophages, no linear IgG deposits
Negative
3/17/-3/21 /92 (50 mg /d)
3/21 /-3/24/92
Fever, rigors , arthralgias, myalgias, thrombocytopenia; suspected pneumonitis (x-ray)
Negative
NOTE. On the verticle rule, t = time, solid boxes denote time period of azathioprine administration, and shaded boxes denote time period of clinical illness.
877
AZATHIOPRINE HYPERSENSITIVITY
In conclusion, azathioprine hypersensitivity can mimic the pulmonary and systemic manifestations of Goodpasture's syndrome. Early recognition of these side effects may obviate expensive and potentially dangerous therapies, such as plasmapheresis. Finally, 6-mercaptopurine represents a valuable alternative to the compound drug azathioprine as the hypersensitivity may be due to the nitroimidazole moiety in azathioprine. In the appropriate clinical background, azathioprine hypersensitivity should be added to the list of etiologic considerations for "pulmonary renal syndrome."
REFERENCES
Fig 2. Chest x-ray film taken 7 day after the first treatment episode with azathioprine. The film discloses extensive, bilateral, reticulonodular, and alveolar infiltrates consistent with pneumonitis and alveolar hemorrhage.
sensItIvIty as an alternative explanation for pulmonary and systemic manifestations in patients with glomerulonephritis or renal transplant rejection. Our case further illustrates that azathioprine hypersensitivity was probably due to the nitroimidazole moiety of azathioprine as treatment with the active component, 6-mercaptopurine, was tolerated without side effects. 3
I. Saway A, Heck LW. Bonner JR, Kriklin JK: Azathioprine hypersensitivity. Am J Med 84:960-964, 1988 2. Dore P, Meurice Jc, Recart D, Patte F: Reaction d'hypersensibilite a I'azathioprine. Presse Med 21 : 1040-1041, 1992 3. Davis M, Eddleston A, Williams R: Hypersensitivity and jaundice due to azathioprine. Postgrad Med J 56:274-275, 1980 4. Elion G, Callahan S, Bieber S: A summary of investigations with 6( l-methyl-4-nitro-5-imidazolyl)thio purine. Cancer Chemother Rep 14:93-98, 1952 5. Calabresi P, Chobner BA: Chemotherapy of neoplastic diseases, in Gilman AG, Rail TW, Nies AS, Taylor P (eds): Gilman and Goodman's: The Pharmaceutical Basis of Therapeutics (ed 8). New York, NY, Pergamon, 1990, pp 12321236 6. DeSwarte RD: Drug allergy: An Overview. Clin Rev Allergy 4:143-169, 1986 7. Mosbech H, Anderson C: Hypersensitivity of azathioprine. Ugeskr Laeger 144:2424, 1982 8. King J, Laver M, Fairly K, Ames G: Sensitivity to azathioprine. Med J Aust 2:939-941 , 1972 9. Krowka M, Brever R, Kehoe T: Azathioprine-associated pulmonary dysfunction. Chest 36:35-39, 1983