Long-Term Azithromycin Use for Treatment of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients

Long-Term Azithromycin Use for Treatment of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients

THE BEAUTY OF BREVITY Long-Term Azithromycin Use for Treatment of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients David Shitrit, MD,a...

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THE BEAUTY OF BREVITY

Long-Term Azithromycin Use for Treatment of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients David Shitrit, MD,a Daniele Bendayan, MD,a Sahar Gidon, MD,b Milton Saute, MD,b Ilana Bakal, RN,a and Mordechai R. Kramer, MDa Short-term improvement in lung function was observed in 5 of 6 lung transplant recipients with bronchiolitis obliterans syndrome (BOS) who were treated with oral azithromycin. We assessed the long-term effect (mean duration 10 months) of treatment with oral azthromycin in 11 lung transplant recipients with BOS. Mean forced expiratory volume in 1 second (FEV1) was 40 ⫾ 9% at initiation of azithromycin treatment, 39 ⫾ 10% after 1 month, 39 ⫾ 12% after 4 months, 38 ⫾ 10% after 7 months and 38 ⫾ 10% after 10 months, respectively (statistically non-significant for all data). We conclude that long-term administration with oral azithromycin does not reverse BOS in lung transplant recipients, but may slow progression of the disease. J Heart Lung Transplant 2005;24:1440 – 43. Copyright © 2005 by the International Society for Heart and Lung Transplantation.

Lung transplantation (LTx) has emerged as a valuable therapeutic option for patients with end-stage pulmonary disease.1 Although short-term survival is improved with transplantation, long-term survival is limited by the development of bronchiolitis obliterans syndrome (BOS). Studies have shown that BOS occurs in 40% to 70% of recipients by 5 years after transplantation.2,3 Alloimmunologic injury directed against endothelial and epithelial structures have been thought to mediate BOS, but non-allimmunologic inflammatory conditions, including bacterial and viral infections, may also play a role.4 Moreover, previous studies have shown that neutrophilia is present in BAL fluid after diagnosis of BOS.5 In addition, many transplant recipients have recurrent infections that potentially worsen chronic rejection. Thus, new therapeutic strategies are needed to improve long-term outcome in LTx. In a recent pilot study, the addition of oral azithromycin therapy was found to improve lung function in 5 of 6 transplant recipients, suggesting a possible antiinflammatory role for macrolides in BOS.6 However, the follow-up period was short (13.7 weeks), and no data were provided on the presence of gastroesophageal reflux disease (GERD), a potential risk factor for BOS.7 To shed more light on this issue, we designed an

From the aPulmonary Institute and bDepartment of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Received June 2, 2004; revised July 22, 2004; accepted August 15, 2004. Reprint requests: Mordechai R. Kramer, MD, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petach Tikva, 49100 Israel. Telephone: ⫹972-3-9377221. Fax: ⫹972-3-9242091. E-mail: davids3@ clalit.org.il Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.08.006

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open-label pilot study to examine the effect of longterm maintenance therapy with oral azithromycin in lung transplant recipients with BOS. PATIENTS AND METHODS Study Subjects Eleven lung transplant recipients with deteriorating allograft function were enrolled in an open-label pilot trial of maintenance oral azithromycin. All patients had clinical BOS Stage 1a or higher, which was unresponsive to augmented immunosuppression. The diagnosis of BOS was based on criteria of the International Society for Heart and Lung Transplantation—specifically, a decline of ⱖ20% in forced expiratory volume in 1 second (FEV1) from the maximum post-transplant value, in the absence of acute infection or acute rejection.3 Acute infection was defined as a positive blood or sputum culture in the presence of fever, new pulmonary infiltrate or new-onset symptoms, including cough, shortness of breath and increased sputum production. Use of 24-hour pH monitoring and gastroscopy identified GERD. Treatment Regimen Oral azithromycin was administered to all patients at a dose of 250 mg, 3 times per week. Spirometry was performed to evaluate FEV1 at each follow-up visit (every 4 weeks) at the transplant clinic. The follow-up period began at the start of azithromycin therapy and continued to the time of article preparation. Ten patients were started on therapy at the same timepoints, and 1 was started later. Each patient continued to receive baseline immunosuppression therapy, as listed in Table 1. Immunosuppression before 1998 included a combination of prednisone, azathioprine and cyclosporine (CsA). Patients operated upon after November 1998 were treated with

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Table 1. Clinical Characteristics of Lung Transplant Recipients With BOS No. 1 2 3 4 5 6 7 8 9 10 11

Gender/ age (y) M/51 F/43 F/52 M/47 M/60 M/59 M/40 M/45 M/58 M/66 M/67

Disease IPF Bronchiectasis IPF IPF Emphysema IPF PPH IPF IPF Emphysema IPF

LTx Rt SLT BLT Rt SLT HLT Lt SLT Lt SLT HLT Rt SLT Lt SLT Rt SLT Rt SLT

Time since LTx 7 35 32 13 9 43 54 38 39 55 36

BOS stage 2a 2a 2a 2a 1a 1a 1a 2a 1a 2a 3a

IS regimen MTX/MMF/CS FK/MMF/CS FK/MMF MTX/FK/CS FK/MMF/CS FK/MMF/CS MTX/CS/FK FK/MMF/CS FK/CsA/CS RAPA/CsA/MMF/CS FK/MTX/CS

Pseudomonas culture ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹

GERD ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹

Follow-up (months) 10 10 10 10 10 10 10 10 10 10 5

BOS, bronchiolitis obliterans syndrome; BLT, bilateral lung transplantation; CS, corticosteroids; CsA, cyclosporine; FK, tacrolimus; GERD, gastrointestinal reflux disease; HLT, heart–lung transplantation; IPF, interstitial lung disease; IS, immunosuppression; Lt, left; LTx, lung transplantation; MMF, mycophenolate mofetil; MTX, methotrexate; PPH, primary pulmonary hypertension; RAPA, rapamycin; Rt, right; SLT, single-lung transplantation.

prednisone, mycophenolate mofetil (MMF) and tacrolimus (FK). In cases of rejection without improvement after pulses of prednisolone, we added OKT3 as a rescue therapy and/or methotrexate and/or rapamycin (sirolimus). All medications clinically indicated during the study period were continued as well. The institutional human subjects review board approved the study protocols. Statistical Analysis A 2-tailed, paired t-test was used to compare the absolute and percent of predicted FEV1 values before and after azithromycin treatment to the most recent FEV1 value. p ⬍ 0.05 was considered statistically significant. The Statistical Package for Social Sciences (SPSS Corporation) was used for all statistical analyses. RESULTS Clinical Characteristics shows the demographic and clinical characteristics of the study population. The mean time from LTx to initiation of azithromycin was 33 ⫾ 17 months (range 7 to 55 months). One patient had BOS Stage 3a, 6 patients had Stage 2a and 4 had Stage 1a. In 9 patients, respiratory colonization with Pseudomonas aeruginosa was documented before initiation of macrolide therapy. Two patients had GERD and were being treated with high-dose protonpump inhibitors. Six patients were treated with pulse steroids during the study period, without significant improvement in lung function. Lung Function During Azithromycin Treatment Mean duration of follow-up was 10 months in all patients, except 1 (5 months) who started treatment at a later timepoint. At the last follow-up visit, all 11 patients demonstrated stable lung function, as assessed

by serial measurements of FEV1, without significant improvement compared with their baseline values at the start of azithromycin therapy. Individual serial FEV1 values are shown in Figure 1, beginning with the pre-transplant FEV1, the highest post-transplant FEV1, the value at 3 and 6 months before onset of macrolide therapy, at initiation of azithromycin treatment, and at all timepoints during follow-up. Mean FEV1 was 40 ⫾ 9% at the start of azithromycin treatment, 39 ⫾ 10% after 1 month, 39 ⫾ 12% after 4 months, 38 ⫾ 10% after 7 months and 38 ⫾ 10% after 10 months (p ⫽ NS for all data). FEV1 improved in 2 patients (Patients 1 and 3) after 4 months, but both returned to basal lung function levels during long-term follow-up (Figure 1). No significant decline in lung function was noted at the 2 patients with GERD compared with the other patients.

Figure 1. Forced expiratory flow volume in 1 second (FEV1) during the study period in 11 transplant recipients with bronchiolitis obliterans syndrome who were treated with azithromycin.

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DISCUSSION This study demonstrates that long-term administration of oral azithromycin for the treatment of BOS has no effect on lung function. We found no improvement in FEV1 after a mean follow-up of 10 months. However, several studies have suggested that macrolide antibiotics may possess anti-inflammatory properties in patients with diffuse panbronchiolitis and asthma.8 –10 Wolter et al11 assessed the effect of long-term treatment with azithromycin in adults with cystic fibrosis and found that it significantly improved quality of life, decreased the number of respiratory exacerbations, and reduced the rate of decline in lung function. Other studies demonstrated a reduction in inflammatory mediators, including interleukin (IL)-8, tumor necrosis factor-␣ and IL-1␤ in patients receiving macrolide therapy.12,13 IL-8 is perhaps the best-studied inflammatory mediator that appears to be inhibited by macrolide antibiotics. As levels of IL-8 and transforming growth factor-␤ are apparently high in the bronchoalveolar fluid of patients with BOS,14 macrolide treatment may be expected to lead to at least some improvement. Our study showed no improvement with the use of azithromycin therapy. However, we found that patients did not have further significant deterioration over the 10-month study period. Therefore, we conclude that long-term administration of oral azithromycin does not reverse BOS in lung transplant recipients, but may slow progression of the disease. Recently, Gerhardt et al6 reported findings in lung transplant recipients treated with maintenance azithromycin for a mean of 13.7 weeks. They found that addition of azithromycin resulted in statistically significant improvement in lung function in 5 of 6 individuals, as measured by serial FEV1. However, 5 of the patients had positive respiratory cultures, 4 for Pseudomonas and 1 for Streptococcus pneumoniae. Pseudomonas infections are a common and well-recognized complication of LTx, and both in vivo and in vitro studies have demonstrated a potential role for macrolides in their treatment.15–17 Therefore, the reported improvement in patients after azithomycin therapy may have been attributable to alleviation of the bacterial infection and not the bronchiolitis. Furthermore, the study was limited by its short follow-up period (only 13.7 weeks), lack of placebo control, small sample size, and lack of data on the presence of suspected GERD. Our study, although further limited by a lack of a placebo control group and small sample size, has 2 important advantages: First, 9 of the 11 patients in our series did not have clinical GERD, so that our findings could be related to the direct effect of azithromycin on BOS. Second, we followed the patients for a long time period (10 months). We found no long-term improve-

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ment in lung function despite the high incidence of Pseudomonas colonization (9 of 11 patients). A possible explanation for the differences between our findings and the previous report by Gerhardt et al could be the underlying disease of the patients. Four of the 6 patients in their report had bronchiectasis or cystic fibrosis. Therefore, their lung function could be improved after macrolide treatment. In contrast, only 1 patient in our study had bronchiectasis, all others had emphysema or pulmonary fibrosis. Thus, we conclude that, until a large-scale, randomized, placebo-controlled clinical study is conducted, long-term azithromycin therapy may not reverse BOS in lung transplant recipients, but may slow progression of the disease. REFERENCES 1. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart–lung transplantation. Ann Thorac Surg 1995;60:1845–53. 2. Vereden G. Chronic allograft rejection (obliterative bronchiolitis). Semin Respir Crit Care Med 2001;22:551–7. 3. Estenne M, Hertz M. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002;166: 440 – 4. 4. Esteene M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310. 5. Whitford HM, Orside B, Pais M, et al. Features of bronchoalveolar lavage (BAL) in lung transplant recipients who later develop BOS. J Heart Lung Transplant 2001;20:176. 6. Gerhardt AG, McDyar JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2003;168:121–5. 7. Palmer SM, Miralles AP, Howell DN, et al. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest 2000;118:1214 –7. 8. Zeiger RS, Schatz M, Sperling W, et al. Efficacy of troleandomycin in outpatients with severe, corticosteroiddependent asthma. J Immunol 1980;66:438 – 46. 9. Kudoh S, Azuma A, Yamamato M, et al. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998;157:1829 –32. 10. Ekici A, Ekici M, Erdemoglu AK. Effect of azithromycin on the severity of bronchial hypersensitiveness in patients with mild asthma. Asthma 2002;39:181–5. 11. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomized trial. Thorax 2002;57:212– 6. 12. Culic O, Erakovic V, Cepelak I, et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol 2002;450:277– 89. 13. Suzuki H, Asada Y, Ikeda K. Inhibitory effect of erythromycin on IL-8 secretion from exudative cells in the nasal discharge of patients with chronic sinusitis. Laryngoscope 1999;109:407–10.

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14. Elssner A, Jaumann F, Dobmann S, et al. Elevated levels of IL-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant 2000;70:362–7. 15. Nagino K, Kobayashi H. Influence of macrolides on mucoid alginate biosynthethic enzyme from Pseudomonas aeroginosa. Clin Microbiol Infect 1997;3:342–9.

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16. Ichimiya T, Takeoka K, Hiramatsu K, et al. The influence of azithromycin on the biofilm formation of Pseudomonas aeroginosa in vitro. Chemotherapy 1996;42:186 –91. 17. Yamasaki T, Ichimiya T, Hirari K, et al. Effect of antimicrobial agents on the palliation of Pseudomonas aeruginosa and adherence to mouse tracheal epithelium. J Chemother 1997;9:32–7.