Nephrol Dial Transplant (1992) 7. 362-364 © 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Case Report
A. L. Brown1, P. A. Corris2, T. Ashcroft3 and R. Wilkinson1 Departments of 'Nephrology, 2Chest Medicine and 'Pathology, Freeman Hospital, Newcastle upon Tyne, UK
Key words: azathioprine; interstitial pneumonitis; renal transplant
Introduction Many drugs may cause interstitial lung disease, most commonly cytotoxic agents such as bleomycin, methotrexate and mitomycin [1]. Interstitial pneumonitis has been reported in association with some antibacterial agents, anticonvulsants, analgesics, diuretics, and antiarrhythmics [2]. Despite the widespread use of azathioprine as an immunosuppressive agent there are only three reported cases of interstitial pneumonitis secondary to azathioprine therapy; one in a patient who had received a renal and pancreatic allograft [3], and two further cases in nontransplanted patients [4]. We report a case of interstitial pneumonitis associated with azathioprine treatment in a renal transplant recipient.
Case report A 58-year-old Caucasian man was admitted on 9 July 1990 with a 6-week history of malaise, a week's history of night sweats, and mild shortness of breath on exertion. He had developed end-stage renal failure
secondary to renovascular disease and hypertension and had commenced dialysis in 1982. He suffered a myocardial infarction in 1986. He underwent cadaveric renal transplantation from a CMV-negative donor on 8 August 1987; initial immunosuppression was with cyclosporin alone. He required three boluses of methylprednisolone starting on day 5 because of primary non-function. Renal biopsy on day 31 showed no evidence of rejection or cyclosporin toxicity. Plasma creatinine was stable at 170 umol/1 in October 1987, but by March 1990 had increased to 274 umol/1, in association with persistently high cyclosporin trough levels (300-500 ng/ml). Transplant biopsy on 24 April 1990 showed no evidence of chronic rejection, and a presumptive diagnosis of chronic cyclosporin toxicity was made. Cyclosporin was reduced and azathioprine 150 mg and prednisolone 25 mg per day commenced on 19 April 1990. Cyclosporin was stopped on 3 June 1990, when his creatinine had declined to 179 umol/1. His other medication consisted of allopurinol lOOmg/day, frusemide 40 mg/day, and aspirin 300 mg/day. He had stopped taking atenolol 50 mg/day and nifedipine retard 20 mg/day 2 days prior to admission because of dizziness on standing.
On admission on 9 July 1990, he looked pale and unwell, with a temperature of 39°C. He had limited perioral herpes simplex. Radial pulse was 100/min, and blood pressure was 120/70 mmHg lying, 85/50 mmHg standing. His jugular venous pressure was not visible. His chest was clinically clear. Correspondence and offprint requests to: Dr A. Brown, Department of 8.2 g/dl, of Nephrology, Freeman Hospital, Newcastle upon Tyne NE7 Investigations showed a haemoglobin white cell count of 2.8 xlO 9 /! (16% lymphocytes) 7DN, UK.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
Azathioprine-related interstitial pneumonitis in a renal transplant recipient
363
renal transplant recipient
and platelets of 368 x 109/l, following which azathioprine was stopped. Arterial blood gases showed him to be markedly hypoxic, with a pO 2 of 7.5 kPa (56.25 mmHg) and pCO 2 of 4.1 kPa (30.75 mmHg) on air. Chest radiograph showed some ill-defined shadowing at the left base. Blood, urine, and sputum cultures were negative. Paired sera for rising antibody titres to influenza A and B, adenovirus, Mycoplasma pneumoniae, Chlamydia and Legionella showed no evidence of infection with these agents. Cytomegalovirus IgG and IgM were negative. Bronchoscopy on 9 July 1990 was unremarkable; Pneumocystis carinii immunofluoresence and stains for acid-fast bacilli were negative. A scanty growth of S. aureus was obtained from lavage, so flucloxacillin was commenced. The patient's pyrexia and hypoxia persisted, and transbronchial biopsy was carried out on 11 July 1990. Histological examination showed multiple non-necrotizing interstitial histiocytic granulomata composed of histiocytes and some epithelioid cells, and similar cells were found in alveoli. There was also mild focal interstitial infiltration by lymphocytes and neutrophils (Fig. 1). Stains for P. carinii, fungi, acid-fast bacilli, and pyogenic bacteria were negative, and no nuclear inclusions of cytomegalovirus or Herpes simplex were seen. Bacterial, viral, and fungal cultures of biopsy material were all negative. Acyclovir 200 mg five times daily was started in view of his perioral herpes simplex, but he remained
unwell. By 16 July 1990, his WCC was 3.8, and pO 2 on air had improved to 8.7 kPa (65.25 mmHg). In view of the persistently negative cultures it was felt that azathioprine-induced pneumonitis was the likely diagnosis. Eight days after stopping azathioprine, the patient became apyrexial and was clinically improved. Results of serial spirometry are shown in Fig. 2. Cyclosporin was restarted and renal function remains stable with a serum creatinine of 191 umol/1 on 11 March 1991.
Serial Respiratory Function Tests 6" 5" o E. 4 O
u
1
• After brc^chid a!sr 0
5
10
15 20 25 Days after presentation
Fig. 2. Results of serial spirometry tests.
30
35
40
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
1. Transbronchial lung biopsy showing histiocytic granuli
A L. Brown et al.
364
Discussion
References 1. Twohig KJ, Matthay RA Pulmonary effects of cytotoxic agents other than bleomycin. Clin Chest Med 1990; 11(1): 31-54 2. Cooper JAD, White DA, Matthay RA. Drug-induced pulmonary disease Part 1- Cylotoxic drugs. Amer Rev Respir Dis 1986, 133. 321-340 3. Carmichael DJS, Hamilton DV, Evans DB, Stovin PGI, Calne RY. Interstitial pneumonitis secondary to aiathiopnne in a renal transplant patient. Thorax 1983; 38; 951-952 4. Lehne G, Lote K. Pulmonary toxicity of cytotoxic and immunosuppressive agents; a review. Ada Oncol 1990; 29: 113-121 5. Rubin G, Baume R, Vandenberg R. Azathioprine and acute restrictive lung disease. Ausi NZ J Med 1972; 3: 272-27'4 6. Weisenberger DD. Interstitial pneumonitis associated with azathioprine therapy. Amer J Clin Palhol 1978; 69: 181-185 Received for publication 10.6.91 Accepted 2.9.91
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
Despite the extensive use of azathioprine as antirejection therapy in renal transplantation, there is only one previously reported case of interstitial pneumonitis associated with azathioprine in a renal transplant recipient. Carmichael et al. [3] described an acute interstitial pneumonitis in a 38-year-old insulindependent diabetic patient who had received a pancreatic and renal allograft, and developed a swinging fever and dyspnoea 4 months after changing from cyclosporin to azathioprine 50 mg/day, in addition to prednisolone. She had perioral herpes simplex; chest radiographs revealed diffuse nodular shadowing, and she was hypoxic with a restrictive defect on spirometry and a reduced transfer factor. Extensive investigation failed to reveal any infection; lung biopsy showed mild interstitial infiltration with lymphocytes and plasma cells, and early alveolar wall fibrosis. Her fever and dyspnoea settled 6 days after stopping azathioprine; 2 months later her chest radiograph was normal and her transfer factor had improved. Two further reports describe azathioprine-induced pneumonitis in a 20-year-old man with ulcerative colitis [5] and a 24-year-old woman with membranoproliferative glomerulonephritis [6]. The first patient developed cough, dyspnoea and fever after 6 weeks treatment with azathioprine (100 mg/day). Chest radiography showed bilateral basal shadowing, and respiratory function tests showed reduced vital capacity, FEV], and transfer factor. Lung biopsy was not performed, and the changes resolved 2 days after stopping azathioprine. The second patient developed
cough, dyspnoea and fever after treatment with azathioprine (150 mg/day) for 2 years; she was hypoxic, with bilateral shadowing on chest radiographs. Open lung biopsy showed acute interstitial pneumonitis. These changes resolved within 2 weeks of stopping azathioprine. Our patient had biopsy changes of alveolar wall thickening and mild inflammation together with histiocytic granulomata. Extensive investigation failed to reveal any infection, and the similar clinical features to the previous reported cases make an interstitial pneumonitis secondary to azathioprine the likely diagnosis. This is obviously a rare complication of azathioprine therapy, but an important differential diagnosis to consider in the immunocompromised patient who develops interstitial pneumonitis which may otherwise be attributed to opportunistic infection.
Nephrology Dialysis Transplantation
Case Report
A. L. Brown1, P. A. Corris2, T. Ashcroft3 and R. Wilkinson1 Departments of 'Nephrology, 2Chest Medicine and 'Pathology, Freeman Hospital, Newcastle upon Tyne, UK
Key words: azathioprine; interstitial pneumonitis; renal transplant
Introduction Many drugs may cause interstitial lung disease, most commonly cytotoxic agents such as bleomycin, methotrexate and mitomycin [1]. Interstitial pneumonitis has been reported in association with some antibacterial agents, anticonvulsants, analgesics, diuretics, and antiarrhythmics [2]. Despite the widespread use of azathioprine as an immunosuppressive agent there are only three reported cases of interstitial pneumonitis secondary to azathioprine therapy; one in a patient who had received a renal and pancreatic allograft [3], and two further cases in nontransplanted patients [4]. We report a case of interstitial pneumonitis associated with azathioprine treatment in a renal transplant recipient.
Case report A 58-year-old Caucasian man was admitted on 9 July 1990 with a 6-week history of malaise, a week's history of night sweats, and mild shortness of breath on exertion. He had developed end-stage renal failure
secondary to renovascular disease and hypertension and had commenced dialysis in 1982. He suffered a myocardial infarction in 1986. He underwent cadaveric renal transplantation from a CMV-negative donor on 8 August 1987; initial immunosuppression was with cyclosporin alone. He required three boluses of methylprednisolone starting on day 5 because of primary non-function. Renal biopsy on day 31 showed no evidence of rejection or cyclosporin toxicity. Plasma creatinine was stable at 170 umol/1 in October 1987, but by March 1990 had increased to 274 umol/1, in association with persistently high cyclosporin trough levels (300-500 ng/ml). Transplant biopsy on 24 April 1990 showed no evidence of chronic rejection, and a presumptive diagnosis of chronic cyclosporin toxicity was made. Cyclosporin was reduced and azathioprine 150 mg and prednisolone 25 mg per day commenced on 19 April 1990. Cyclosporin was stopped on 3 June 1990, when his creatinine had declined to 179 umol/1. His other medication consisted of allopurinol lOOmg/day, frusemide 40 mg/day, and aspirin 300 mg/day. He had stopped taking atenolol 50 mg/day and nifedipine retard 20 mg/day 2 days prior to admission because of dizziness on standing.
On admission on 9 July 1990, he looked pale and unwell, with a temperature of 39°C. He had limited perioral herpes simplex. Radial pulse was 100/min, and blood pressure was 120/70 mmHg lying, 85/50 mmHg standing. His jugular venous pressure was not visible. His chest was clinically clear. Correspondence and offprint requests to: Dr A. Brown, Department of 8.2 g/dl, of Nephrology, Freeman Hospital, Newcastle upon Tyne NE7 Investigations showed a haemoglobin white cell count of 2.8 xlO 9 /! (16% lymphocytes) 7DN, UK.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
Azathioprine-related interstitial pneumonitis in a renal transplant recipient
363
renal transplant recipient
and platelets of 368 x 109/l, following which azathioprine was stopped. Arterial blood gases showed him to be markedly hypoxic, with a pO 2 of 7.5 kPa (56.25 mmHg) and pCO 2 of 4.1 kPa (30.75 mmHg) on air. Chest radiograph showed some ill-defined shadowing at the left base. Blood, urine, and sputum cultures were negative. Paired sera for rising antibody titres to influenza A and B, adenovirus, Mycoplasma pneumoniae, Chlamydia and Legionella showed no evidence of infection with these agents. Cytomegalovirus IgG and IgM were negative. Bronchoscopy on 9 July 1990 was unremarkable; Pneumocystis carinii immunofluoresence and stains for acid-fast bacilli were negative. A scanty growth of S. aureus was obtained from lavage, so flucloxacillin was commenced. The patient's pyrexia and hypoxia persisted, and transbronchial biopsy was carried out on 11 July 1990. Histological examination showed multiple non-necrotizing interstitial histiocytic granulomata composed of histiocytes and some epithelioid cells, and similar cells were found in alveoli. There was also mild focal interstitial infiltration by lymphocytes and neutrophils (Fig. 1). Stains for P. carinii, fungi, acid-fast bacilli, and pyogenic bacteria were negative, and no nuclear inclusions of cytomegalovirus or Herpes simplex were seen. Bacterial, viral, and fungal cultures of biopsy material were all negative. Acyclovir 200 mg five times daily was started in view of his perioral herpes simplex, but he remained
unwell. By 16 July 1990, his WCC was 3.8, and pO 2 on air had improved to 8.7 kPa (65.25 mmHg). In view of the persistently negative cultures it was felt that azathioprine-induced pneumonitis was the likely diagnosis. Eight days after stopping azathioprine, the patient became apyrexial and was clinically improved. Results of serial spirometry are shown in Fig. 2. Cyclosporin was restarted and renal function remains stable with a serum creatinine of 191 umol/1 on 11 March 1991.
Serial Respiratory Function Tests 6" 5" o E. 4 O
u
1
• After brc^chid a!sr 0
5
10
15 20 25 Days after presentation
Fig. 2. Results of serial spirometry tests.
30
35
40
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
1. Transbronchial lung biopsy showing histiocytic granuli
A L. Brown et al.
364
Discussion
References 1. Twohig KJ, Matthay RA Pulmonary effects of cytotoxic agents other than bleomycin. Clin Chest Med 1990; 11(1): 31-54 2. Cooper JAD, White DA, Matthay RA. Drug-induced pulmonary disease Part 1- Cylotoxic drugs. Amer Rev Respir Dis 1986, 133. 321-340 3. Carmichael DJS, Hamilton DV, Evans DB, Stovin PGI, Calne RY. Interstitial pneumonitis secondary to aiathiopnne in a renal transplant patient. Thorax 1983; 38; 951-952 4. Lehne G, Lote K. Pulmonary toxicity of cytotoxic and immunosuppressive agents; a review. Ada Oncol 1990; 29: 113-121 5. Rubin G, Baume R, Vandenberg R. Azathioprine and acute restrictive lung disease. Ausi NZ J Med 1972; 3: 272-27'4 6. Weisenberger DD. Interstitial pneumonitis associated with azathioprine therapy. Amer J Clin Palhol 1978; 69: 181-185 Received for publication 10.6.91 Accepted 2.9.91
Downloaded from https://academic.oup.com/ndt/article-abstract/7/4/362/1813226 by Midwestern University user on 25 January 2019
Despite the extensive use of azathioprine as antirejection therapy in renal transplantation, there is only one previously reported case of interstitial pneumonitis associated with azathioprine in a renal transplant recipient. Carmichael et al. [3] described an acute interstitial pneumonitis in a 38-year-old insulindependent diabetic patient who had received a pancreatic and renal allograft, and developed a swinging fever and dyspnoea 4 months after changing from cyclosporin to azathioprine 50 mg/day, in addition to prednisolone. She had perioral herpes simplex; chest radiographs revealed diffuse nodular shadowing, and she was hypoxic with a restrictive defect on spirometry and a reduced transfer factor. Extensive investigation failed to reveal any infection; lung biopsy showed mild interstitial infiltration with lymphocytes and plasma cells, and early alveolar wall fibrosis. Her fever and dyspnoea settled 6 days after stopping azathioprine; 2 months later her chest radiograph was normal and her transfer factor had improved. Two further reports describe azathioprine-induced pneumonitis in a 20-year-old man with ulcerative colitis [5] and a 24-year-old woman with membranoproliferative glomerulonephritis [6]. The first patient developed cough, dyspnoea and fever after 6 weeks treatment with azathioprine (100 mg/day). Chest radiography showed bilateral basal shadowing, and respiratory function tests showed reduced vital capacity, FEV], and transfer factor. Lung biopsy was not performed, and the changes resolved 2 days after stopping azathioprine. The second patient developed
cough, dyspnoea and fever after treatment with azathioprine (150 mg/day) for 2 years; she was hypoxic, with bilateral shadowing on chest radiographs. Open lung biopsy showed acute interstitial pneumonitis. These changes resolved within 2 weeks of stopping azathioprine. Our patient had biopsy changes of alveolar wall thickening and mild inflammation together with histiocytic granulomata. Extensive investigation failed to reveal any infection, and the similar clinical features to the previous reported cases make an interstitial pneumonitis secondary to azathioprine the likely diagnosis. This is obviously a rare complication of azathioprine therapy, but an important differential diagnosis to consider in the immunocompromised patient who develops interstitial pneumonitis which may otherwise be attributed to opportunistic infection.
