Prophylactic azithromycin for chronic lung allograft dysfunction following lung transplantation: a systematic review and meta-analysis

Abstract

Background: Azithromycin (AZI) has proven effective in improving pulmonary function and survival in certain patients with established chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx), but its prophylactic effects on CLAD remain controversial. This study aimed to assess the outcomes of prophylactic AZI for CLAD following LTx.

Methods: A systematic review was conducted based on PubMed, Embase and Cochrane Library. All included studies reported the primary or secondary outcomes in the prophylactic azithromycin (pAZI) and control groups. The CLAD onset, disease-free survival and overall survival (OS) data were pooled using fixed-effect or random-effect models. Sensitivity analysis was employed to evaluate the robustness of the pooled results, while a funnel plot was utilized to assess the publication bias.

Results: Six eligible studies involving 1,251 LTx recipients were included. The pooled analysis revealed a lower risk of CLAD onset in the pAZI group compared to the control group [relative risk (RR) 0.64, 95% confidence interval (CI): 0.51-0.81, P<0.001]. Moreover, the pAZI group exhibited superiority in the 3-year [hazard ratio (HR) 0.57, 95% CI: 0.39-0.83, P=0.003] and 5-year CLAD-free survival (HR 0.61, 95% CI: 0.43-0.86, P=0.005); but this superiority was not observed in the 3-year (HR 0.69, 95% CI: 0.31-1.54, P=0.36) and 5-year OS (HR 0.59, 95% CI: 0.30-1.14, P=0.12).

Conclusions: Prophylactic AZI may reduce the risk of CLAD onset and improve 3- and 5-year CLAD-free survival, providing supporting evidence for its application in LTx community. More high-quality and well-designed studies are warranted to determine the prophylactic effects of AZI on CLAD and its phenotypes following LTx.

Keywords: Azithromycin (AZI); chronic lung allograft dysfunction (CLAD); lung transplantation (LTx); prophylaxis; treatment.

Figure 1

Flow chart of the study inclusion and exclusion for this systematic review and meta-analysis. CLAD, chronic lung allograft dysfunction; LTx, lung transplantation.

Figure 2

Forest plots of the prophylactic effects of azithromycin on the risk of CLAD onset. (A) The overall risk of CLAD onset, (B) the medium- to long-term risk of CLAD onset. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel method.

Figure 3

Forest plots of the prophylactic effects of azithromycin on the CLAD-free survival. (A) 3-year CLAD-free survival, (B) 5-year CLAD-free survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; SE, standard error.

Figure 4

Forest plots of the prophylactic effects of azithromycin on the overall survival. (A) 3-year overall survival, (B) 5-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; SE, standard error.

Figure 5

Forest plots of the prophylactic effects of azithromycin on CLAD based on the latest definition. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 5-year CLAD-free survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.

Figure 6

Forest plots of the prophylactic effects of azithromycin on CLAD and overall survival based on the relatively long-term AZI duration. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 3-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.

Figure 7

Forest plots of the prophylactic effects of azithromycin on CLAD and overall survival based on RCT studies. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 3-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; RCT, randomized controlled trial; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.