Bronchiolitis Obliterans and Organizing Pneumonia in Renal Transplant Recipients

Bronchiolitis obliterans and organizing pneumonia (BOOP) is a recently defined clinicopathologic entity (1). Its pathologic features are characterized by polypoid tufts of organizing connective tissue in bronchioles that may extend to alveolar ducts and alveoli. Clinically, BOOP presents usually with cough and dyspnea of <3 months in association with fever and malaise. A chest x-ray and computerized tomography (CT) scan typically show patchy bilateral infiltrates. Most cases are idiopathic, but BOOP has been associated with drug exposure, collagen vascular diseases, infection, and organ transplantation (5). Rapamycin is a new potent immunosuppressive agent being used with increasing frequency in clinical transplantation. We report here the first known association of BOOP with rapamycin in two renal transplant recipients. The first patient is a 57-year-old male kidney transplant recipient with stable renal function (serum creatinine 160 μmol/l) taking Neoral® (cyclosporine) and prednisone immunosuppressive therapy. Neoral® was replaced with rapamycin at a dose of 5 mg/day 16 months after transplantation in an attempt to improve posttransplant diabetes mellitus. He was also taking diltiazem and vitamin E. Two months, later the patient developed malaise, cough, dyspnea, fever, and weight loss. A chest x-ray and CT (Fig. 1A) Figure 1: (A) CT scan of the chest (patient 1) showing bilateral patchy air space infiltrates, (B) Open lung biopsy (hematoxylin & eosin × 100) showing cellular proliferation of organizing connective tissue filling several terminal and respiratory bronchioles with interstitial changes in surrounding lung tissue.showed bilateral patchy air space infiltration. Bronchial washings were negative for bacterial, fungal, mycobacterial, and viral cultures. Pneumocystis carinii (PC) immunofluorescence (IF), mycoplasma, and chlamydia serologic tests were negative. The symptoms progressed despite empirical antibiotics and a thoracoscopic lung biopsy was performed. All cultures and PC IF were negative. The lung pathologic features were consistent with BOOP, with obliteration of respiratory bronchiolar lumina by organizing connective tissue extending to alveolar ducts and alveoli (Fig. 1B). Rapamycin was discontinued with subsequent dramatic subjective improvement in the patient’s symptoms. Prednisone 50 mg/day was given for 10 days, and symptoms resolved completely within 1 week of therapy. The chest x-ray was normal within 8 weeks. He continues taking Neoral® and prednisone 5 mg/day, without any recurrence 26 months later. The second patient is a 62-year-old male kidney transplant recipient taking Neoral® and prednisone immunosuppressive therapy. Neoral® was discontinued and rapamycin was started at 5 mg/day at 43 months after transplantation for biopsy proven chronic transplant nephropathy. His other medications were ranitidine and diltiazem. Three weeks later, the patient presented with fatigue, anorexia, fever, and productive cough. Sputum culture, urine Legionella antigen, and serologic tests for chlamydia, mycoplasma, and viral pathogens were negative. A 2-week course of empiric antibiotics was without benefit. A chest x-ray and CT showed bilateral patchy peripheral air space disease consistent with BOOP. Because of our experience with the first patient, the rapamycin dose was decreased to 2.5 mg/day. The cough and fever disappeared completely; the patient’s appetite and fatigue improved significantly within 2 weeks. The air space disease pattern on the chest x-ray improved significantly but did not disappear completely. The patient is well 19 months later. BOOP is a relatively new clinicopathologic entity and has been reported in association with many drugs (5) as well as with bone marrow transplantation (6). As well, BOOP has been reported in a single renal transplantation case (7). A 26-year-old man taking prednisone and cyclosporine developed BOOP after an episode of pneumonia, which initially responded to empiric antibiotics. The patient responded rapidly to an increase in prednisone dose. Rapamycin is a new immunosuppressive drug with macrolide structure that is being used with increased frequency in kidney transplantation. In both our patients, typical symptoms of BOOP appeared between 21 and 60 days after initiation of rapamycin. No other new drugs were introduced at that time. Extensive investigation for infection was negative, and empiric antibiotics were of no benefit. CT appearance was characteristic for BOOP in both patients, and in the first patient, the diagnosis was confirmed pathologically. Both patients improved rapidly after discontinuation or reduction of rapamycin. These observations suggest a possible temporal relationship between rapamycin and BOOP. BOOP could, thus, be caused by a direct toxic effect of rapamycin on the lung. Unfortunately, little is known about the therapeutic blood level of this immunosuppressive drug in humans, and we did not have such data available in our patients. In addition to drug toxicity, rapamycin as a potent immunosuppressive agent could have promoted an opportunistic infection. Neither patient received antibiotic prophylaxis for PC pneumonia, because its incidence is extremely low in our program. The lack of evidence for a pathogen on microbiologic, serologic, and pathologic tests as well as lack of response to empiric antibiotics makes this possibility less likely. The potential association between rapamycin and BOOP should be kept in mind, especially with wider use of rapamycin. To our knowledge, this is the first report of such an association. Kamran Mahalati Multi-Organ Transplant Program Division of Urology Queen Elizabeth II Health Sciences Centre Dalhousie University Halifax, Nova Scotia, Canada Donogh M. Murphy Division of Anatomical Pathology Department of Pathology Queen Elizabeth II Health Sciences Centre Dalhousie University Halifax, Nova Scotia, Canada Michael L. West1