Azithromycin Reverses Airflow Obstruction in
Established Bronchiolitis Obliterans Syndrome

Bryan Yates, Desmond M. Murphy, Ian A. Forrest, Chris Ward, Robert M. Rutherford, Andrew J. Fisher,
James L. Lordan, John H. Dark, and Paul A. Corris

William Leech Centre for Lung Research, The Freeman Hospital, High Heaton, Newcastle upon Tyne, United Kingdom Introduction: A recent pilot study noted clinical benefit of macrolide
airflow limitation, progressive dyspnea, and ultimately, prema- therapy in the management of six lung transplant recipients with
ture death (1, 10, 11). International Registry data shows a 50% bronchiolitis obliterans syndrome (BOS), a condition previously
prevalence of BOS at 5 years after transplant. This is associated regarded as irreversible. Objective: To examine the effect of low-
with a reduction in quality of life and increased morbidity and dose macrolides on lung function in lung allograft recipients with
mortality, limiting 7-year mean survival to only 31% (12).
established BOS and to assess whether this benefit is sustained.
The current classification of BOS is based on changes in Methods: We retrospectively evaluated the effect of azithromycin
(250 mg alternate days) on clinical status and lung function in 20

FEV1, with the maximum post-transplant FEV1 being assigned allograft recipients with established BOS, confirmed by decline in
a 100% predicted value (the mean of the two best postoperative 1 or FEF25–75; consistent high-resolution computed tomography
1 values with at least 3 weeks between the measurements).
findings; and exclusion of acute rejection, infection, or anastomatic
Patients experiencing a persistent decline in FEV1 (i.e., two con- complications. Azithromycin was introduced at mean 82 months
secutive measurements within 3–6 weeks) in the absence of acute after transplantation. BOS staging at initiation of treatment was
rejection, infection, or bronchial anastomosis complications are BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were
grouped into stages. Additionally, a reduction in FEF25–75 is used on maintenance immunosuppression comprising cell-cycle inhibi-
tor, oral corticosteroids, and calcineurin inhibitor. Results: There
Current strategies in the management of BOS have ranged was a significant increase in FEV1 of median 110 ml (range, Ϫ70 to
from switching immunosuppressive regimens, augmenting with 730 ml) between baseline and 3 months of azithromycin therapy
ϭ 0.002). This improvement was sustained beyond 3 months in
corticosteroids, and initiating cytolytic therapy. These have had the majority of patients, who had initially benefited from azithro-
little or no impact on the progression of the condition. Although mycin (up to 11 months follow up). Conclusions: This case series
we have recently demonstrated that total lymphoid irradiation confirms the benefit of azithromycin in not only halting, but re-
(TLI) significantly reduces the rate of decline in graft function versing the declining lung function seen in patients with BOS. This
associated with BOS, it fails to halt its progression and may benefit appears to be maintained over time. Low-dose macrolides
have significant morbidity (14). Significantly, data from ex vivo offer a new and exciting therapeutic strategy for the treatment of
experiments indicate that many of the traditional agents used progressive BOS, and further clinical and translational mechanistic
may upregulate proinflammatory cytokines and growth factors, studies are required.
with a potentially detrimental effect on allografts (15–19).
Keywords: lung; macrolide; transplantation
There has been recent interest in the potential role of macro- lide antibiotics in the management of BOS. Macrolides have Lung transplantation has evolved to become an accepted strat- demonstrated antiinflammatory properties in other respiratory egy in the management of advanced disease in selected patients conditions such as asthma, cystic fibrosis, and diffuse panbronchi- (1). Unfortunately, although there has been considerable improve- olitis (15–26). Notably, in a recent pilot study, Gerhardt and co- ment in early outcomes after lung transplantation as a result workers described a significant, short-term improvement (mean of advances in surgical techniques and better perioperative man- follow-up of 14 weeks) in lung function in six lung transplant agement, long-term survival remains limited by the development recipients with BOS who were treated with azithromycin (27).
of bronchiolitis obliterans syndrome (BOS).
These promising data have been confirmed by Verleden and The histologic lesion of BOS is obliterative bronchiolitis colleagues in eight further subjects with short-term follow-up (OB). This is characterized by epithelial cell activation as a (28). In this article we examine the effect of low-dose mainte- result of alloimmune and nonalloimmune mechanisms. An early nance azithromycin therapy in 20 patients with BOS, followed feature is peribronchiolar leukocyte infiltration leading to an for up to 48 weeks. This study has previously been partially pre- abnormal, exaggerated repair response, fibroproliferation, andeventual obliteration of the small airways (2–9). This leads to sented at The International Society for Heart and Lung Trans- deteriorating graft function that is characterized by the develop- plantation and The American Thoracic Society annual meetings, ment of progressive, irreversible small airway narrowing, fixed with publication in abstract form (29, 30).
Study Subjects
(Received in original form November 18, 2004; accepted in final form June 15, 2005) Twenty lung transplant recipients with a diagnosis of BOS (n ϭ 18) or This research was funded by the Newcastle upon Tyne Hospitals Special Trustees, BOS0-p (n ϭ 2) were placed on maintenance azithromycin. A diagnosis European Respiratory Society Fellowships (D.M.M., C.W.), Medical ResearchCouncil Fellowship (I.A.F.), and the McPhail Trust (J.L.L.).
of BOS was assigned on the basis of the International Society for Heartand Lung Transplantation criteria (13). Patients displayed no clinical Correspondence and requests for reprints should be addressed to Paul A. Corris, evidence of infection, acute rejection, or other cause for their deteriora- The William Leech Centre for Lung Research, The Freeman Hospital, High Heaton,Newcastle upon Tyne, NE7 7DN, UK. E-mail: [email protected] tion in lung function. All patients meeting these criteria for BOS wereconsecutively treated with azithromycin. The data presented in this Am J Respir Crit Care Med
Vol 172. pp 772–775, 2005
Originally Published in Press as DOI: 10.1164/rccm.200411-1537OC on June 23, 2005
paper were retrospectively collected and are presented in a case series Internet address: www.atsjournals.org
Yates, Murphy, Forrest, et al.: Macrolide Therapy in BOS Treatment Regimen
transplants, and three heart-lung transplants. The mean age at All patients were treated with oral azithromycin at a dose of 250 mg transplantation was 38 (range, 17–59 years), with an average alternate days from the time of BOS diagnosis to preparation of this manuscript. Patients were regularly evaluated at clinic with pulmonary number of acute rejection episodes (Grade A2 or greater) was function testing to assess response. Liver function was monitored at regular intervals without any adverse effect of therapy. All patients BOS stages at initiation of treatment were BOS 3 (n ϭ 10), remained on immunosuppressive therapy comprising a calcineurin in- BOS 2 (n ϭ 2), BOS 1 (n ϭ 6), and BOS0-p (n ϭ 2). Mean hibitor (cyclosporin or tacrolimus), oral corticosteroids, and a purine follow-up at time of manuscript preparation has been 6.25 months antagonist (azathioprine or mycophenolate mofetil). The standard im- (range, 3–11 months). There was a significant but variable im- munosuppression regimen used at our facility is a triple therapy ap- proach of cyclosporin, prednisolone, and azathioprine. In this study two patients were on tacrolimus and one on mycophenolate. Azithro- between baseline and after 3 months of azithromycin therapy mycin was commenced at varying time points. Immunosuppressant lev- (Figure 1, p ϭ 0.002). This improvement was sustained beyond els were not affected by azithromycin therapy in our patient cohort.
3 months in 12 of 17 patients (up to 11 months follow-up). Figure During the treatment phase, one patient required antibiotic treatment 1 shows percentage change in FEV1 from baseline.
for infection (Patient 15, Table 1) and one patient was switched tomycophenolate (Patient 17, Table 1). Mean follow-up is 6.25 months DISCUSSION
We have confirmed the recent studies of Gerhardt and coworkers Statistical Analysis
(27) and Verleden and colleagues (28), and have shown that Patients had variable times of follow-up, and spirometry was performed azithromycin therapy can successfully treat BOS, a condition at various time points. Analysis was performed using nonparametric refractory to previous clinical management. We have extended methods (Minitab, release 14 for Windows; State College, PA) and the current literature by performing our study in a bigger patient post-treatment data grouped into 3-month blocks and compared with baseline values. Baseline refers to spirometry measurements performed These findings are remarkable in that they offer hope in at the initiation of treatment. Spirometry measurements were per- arresting the progression of BOS. There was median gain in lung formed at 3 (2–4 months), 6 (5–7 months), and 9 (8–10) months.
function of 110 ml for the group, and in one patient a 730-mlincrease was observed. There were no side effects of therapy reported by our patients, and no patient has discontinued therapy Patient characteristics and responses are shown in Table 1 and to date. This benefit profile is unprecedented in our program.
Figure 1. Our study population consisted of 10 males and 10 The mechanism of action of macrolides in BOS is not known, females. The underlying diagnoses were cystic fibrosis (n ϭ 6), but is not likely to be due to a direct microbicidal action, because of the low doses used. Similar dosing regimens demonstrate chiectesis (n ϭ 2), sarcoidosis (n ϭ 2), pulmonary hypertension clinical improvement, efficacy, improved lung function, and anti- (n ϭ 2), and retransplantation for obliterative bronchiolitis (n ϭ inflammatory properties in patients with asthma, cystic fibrosis, 2). There were nine bilateral lung transplants, eight single lung and panbronchiolitis (20–26). Several mechanisms have been TABLE 1. CHARACTERISTICS OF STUDY PATIENTS
Definition of abbreviations: BLT ϭ bilateral lung transplant; HLT ϭ heart-lung transplant; LSLT ϭ left single lung transplant; RSLT ϭ right single lung transplant.
Age at transplant refers to the patient’s age in years, diagnosis refers to the patients diagnosis/indication for transplantation, maximum FEV1 refers to the maximum measured post-transplant FEV1, acute rejection episodes refers to the number of acuterejection episodes of grade A2 or greater before the diagnosis of bronchiolitis obliterans syndrome (BOS), baseline FEV1 refers tothe FEV1 at the commencement of azithromycin, and BOS score refers to the BOS score assigned according to the InternationalSociety of Heart and Lung Transplantation guidelines (37).
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Figure 1. Change in FEV1 over time. Each symbol represents an individ-
Reticular basement membrane thickening in airways of lung transplant ual patient, and the broken line indicates the pattern of change in their recipients is not affected by inhaled corticosteroids. Clin Exp Allergy 1 over time in months. The change in FEV1 is represented as a 8. DiGiovine B, Lynch JP III, Martinez FJ, Flint A, Whyte RI, Iannettoni 1 at the time azithromycin was commenced.
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does not have a financial relationship with a commercial entity that has an interest 19. Zhang JG, Walmsley MW, Moy JV, Cunningham AC, Talbot D, Dark in the subject of this manuscript; I.A.F. does not have a financial relationship with JH, Kirby JA. Differential effects of cyclosporin A and tacrolimus a commercial entity that has an interest in the subject of this manuscript; C.W.
on the production of TGF-beta: implications for the development of does not have a financial relationship with a commercial entity that has an interest obliterative bronchiolitis after lung transplantation. Transpl Int 1998;11: in the subject of this manuscript; R.M.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; 20. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin A.J.F. does not have a financial relationship with a commercial entity that has an in children with cystic fibrosis: a randomised, placebo-controlled cross- interest in the subject of this manuscript; J.L.L. does not have a financial relation-ship with a commercial entity that has an interest in the subject of this manuscript; over trial. Lancet 2002;360:978–984.
J.H.D. does not have a financial relationship with a commercial entity that has an 21. Everard ML, Sly P, Brenan S, Ryan G. Macrolide antibiotics in diffuse interest in the subject of this manuscript; P.A.C. has received grant funding of panbronchiolitis and in cystic fibrosis. Eur Respir J 1997;10:2926.
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