Original article: Clinical research SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2016; 33; 242-246 © Mattioli 1885 Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis Naoyuki Kuse, Shinji Abe, Hiroki Hayashi, Koichiro Kamio, Yoshinobu Saito, Jiro Usuki, Arata Azuma, Shoji Kudoh, Akihiko Gemma Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Abstract. Background and objective: There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long- term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. Methods: A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. Results: AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Conclusion: Our results indicate the potential beneficial efficacy of macro- lide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF. (Sarcoidosis Vasc Diffuse Lung Dis 2016; 33: 242-246) Key words: idiopathic pulmonary fibrosis (IPF), acute exacerbation (AE), macrolides Introduction cent several clinical trials suggest that pharmacologi- cal treatment may prevent the progression or AE in Idiopathic pulmonary fibrosis (IPF) is a chronic IPF (3-9). progressive interstitial pneumonia with a poor prog- Macrolides have both antibacterial and anti- nosis. The median survival of patients with IPF varies inflammatory activity (10-12). It has been suggested from 2 to 4 years after diagnosis and the major cause that the anti-inflammatory activity is not related to of death is respiratory failure due to IPF progression the antibacterial action because the anti-inflamma- called “acute exacerbation (AE)” (1, 2). While there tory effect is seen at low concentrations, below the are no proven effective therapies for IPF to date, re- minimal inhibitory concentration for airway bacte- ria (10). Macrolides are now used for long term in Received: 20 December 2014 conditions such as cystic fibrosis to reduce airway Accepted after revision: 29 September 2015 inflammation (13, 14). Correspondence: Shinji Abe Department of Pulmonary Medicine and Oncology, In the present study, we retrospectively evaluat- Graduate School of Medicine, Nippon Medical School, ed whether long-term macrolide therapy reduce the Tokyo, Japan frequency of AE in IPF patients. We also evaluated 1-1-5 Sendagi Bunkyo-ku Tokyo Japan 113-8603 Tel/Fax +81-3-5685-3075 the survival rate of IPF patients after the conven- Email: [email protected] tional treatment with or without macrolides. Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis 243 Patients and Methods period. The survival rates after treatment with or without macrolides were compared by the log rank Patients test and Kaplan-Meier survival curves were plotted. In all cases, statistically significance was defined as p We carried out a retrospective analysis of all values < 0.05. All statistical analyses were performed IPF patients who were admitted to Nippon Medical with Stat View 5.0 for Windows. School Hospital between January 2003 and Decem- ber 2008. Excluded patients were those who could no be controlled during the follow-up period. The diag- Results nosis of IPF was based on the criteria of the Ameri- can thoracic Society/European Respiratory Society Baseline characteristics of the 52 patients (10 (ATS/ERS) international consensus statement (2): female) with IPF are shown in Table 1. All pa- 1) exclusion of other unknown causes of intersti- tients were satisfied IPF diagnostic criteria of ATS/ tial lung diseases such as domestic and occupational ERS (2). Twenty-nine IPF patients (7 female) were environmental exposures, connective tissue disease, treated by conventional agents plus macrolides with and drug toxicities; 2) the presence of a UIP pattern a mean age of 67.2±6.3 years, and macrolide agents on high-resolution (HR) chest CT in patients not were as follows: clarithromycin (200-400 mg/day, subjected to surgical lung biopsy; 3) specific combi- n=27) and erythromycin (400 mg/day, n=2). Twenty- nations of HRCT and usual interstitial pneumonia three IPF patients (3 female) were treated by con- (UIP) pattern in patients subjected to surgical lung ventional agents with a mean age of 69.1± 7.35 years. biopsy. Acute exacerbation (AE) of IPF was defined Diagnosis of UIP was made by surgical lung biopsy as described previously (9, 15): exacerbation of dys- in three of 29 patients in macrolide and two of 23 pa- pnea within one month, newly developing diffuse tients in non-macrolide group, respectively. There are pulmonary opacities on chest radiographs, decrease no differences between two groups except the value in arterial oxygen tension (PaO2) of more than 10 of serum LDH. Due to chronic respiratory failure, Torr under similar conditions, and absence of heart twenty of 29 patients (69.0%) with macrolide and failure or an identified infectious agent. A total of 52 thirteen of 23 patients (56.6%) without macrolide IPF patients were included in the study. Consecutive were receiving long-term oxygen therapy. 29 IPF patients were treated by conventional agents AE was observed in one case and two cases each with macrolides (erythromycin or clarithromycin). in macrolide group and in non-macrolide group dur- Comparable number of 23 IPF patients without ing 12 months, which was not significantly different. macrolides pertaining to age, serum KL-6, pulmo- On the other hand, during 36 months AE was ob- nary function tests, and conventional therapy during served in 4 cases (13.8%) and 8 cases (34.8%) each the same period were also included. We retrospec- in macrolide group and in non-macrolide group, re- tively analyzed the frequency of acute exacerbation spectively. AE free survival rate of macrolide group and the survival of each group. Informed consent was was significantly better than that of non-macrolide obtained from all patients and the study protocol was group (logrank p=0.027) (Fig. 1) during 36 months. approved by the local ethics committee at Nippon Survival rate of IPF patients with macrolide therapy Medical School. was significantly better than that of IPF patients without macrolide therapy (p=0.047) during 60 Statistical analysis months (Fig. 2). Data are summarized using mean ± SD. Pa- tient demographics were compared between those Discussion patients receiving macrolides or not, using the two- sample unpaired t-test and Chi-square test. For This is the first retrospective study that suggested survival analysis, time zero is defined as the index the beneficial effects of long-term macrolide therapy visit, which was the date the patient was first seen at for reducing exacerbation frequency and mortality in Nippon Medical School Hospital during the study patients with IPF. 244 N. Kuse, S. Abe, H. Hayashi, et al. Table 1. Characteristics of patients Fig. 1. ��������������������������������������������������������Comparison of acute exacerbation free survival rates be- Fig. 2. Comparison of survival rates between the macrolide group tween the macrolide group (blue line, n=29) and the non-macro- (blue line, n=29 ) and the non-macrolide group (green line, n=23 ). lide group (green line, n=23). (Kaplan-Meier method) (Kaplan-Meier method) The incidence of AE in IPF patients has re- explained by differences in AE criteria. In the pres- ported to be varied. In a series of 74 IPF patients, ent study with the revised AE criteria (9, 15), the Kondoh et al. reported the one, two and three year one, two and three-year incidence of AE in IPF pa- incidence of AE was 8.6%, 12.6%, 23.9%, respec- tients with macrolide therapy was 3.4%, 4.8% and tively (16). Of 461 IPF patients followed up for 22.9 13.8%, respectively. This result suggested that long- months, the one and two year incidence of AE was term macrolide combined with conventional therapy 14.2% and 20.7% (17). In another study of 147 pa- could reduce the incidence of AE in IPF patients. tients with biopsy-proven IPF, the one and two-year This study also showed the significant improvement frequency of AE in was 8.5% and 9.6% (18). The of overall survival in IPF patients with macrolide differences of AE incidence in these studies may be therapy followed up for 60 months. Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis 245 To date he exact pathogenesis of AE in IPF ments for IPF were variable in the present therapy. patients remains unclear. Histological findings from IPF treatments combined with macrolides could af- lung specimens from IPF patients with AE show fect the incidence of AE and survival. We need to diffuse alveolar damage (DAD), which was also evaluate the clinical efficacy of macrolides for IPF observed in patients with acute lung injury (ALI)/ patients in a randomized control study. acute respiratory distress syndrome (ARDS) (18, In conclusion, the present study suggests the 19). Broncho- alveolar lavage in both IPF patients beneficial effect of long-term macrolide therapy on with AE and patients with ALI/ARDS revealed a AE and survival in IPF patients. Further studies are predominant neutrophilia.