Azithromycin in lung transplantation: revisiting its dual role from prophylaxis to therapy

Extract

We read with great interest the recent article by Gottlieb et al. [1], which described the clinical landscape of chronic lung allograft dysfunction (CLAD) after lung transplantation across 44 centres in 20 European countries. In this survey, 72% of respondents reported initiating prophylactic azithromycin (pAZI), while 82% initiated therapeutic azithromycin (tAZI) to mitigate CLAD risk and preserve pulmonary function. Over the past two decades, the clinical roles of azithromycin in CLAD have been widely investigated, and have evolved in accordance with the latest definition from the International Society for Heart and Lung Transplantation (ISHLT) [2–4].

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Azithromycin has already demonstrated promise in both the prophylaxis and therapy of CLAD, thereby warranting further comprehensive investigations into its dual effect in this evolving era https://bit.ly/45Y4FLw

To the Editor:

We read with great interest the recent article by Gottlieb et al. [1], which described the clinical landscape of chronic lung allograft dysfunction (CLAD) after lung transplantation across 44 centres in 20 European countries. In this survey, 72% of respondents reported initiating prophylactic azithromycin (pAZI), while 82% initiated therapeutic azithromycin (tAZI) to mitigate CLAD risk and preserve pulmonary function. Over the past two decades, the clinical roles of azithromycin in CLAD have been widely investigated, and have evolved in accordance with the latest definition from the International Society for Heart and Lung Transplantation (ISHLT) [2–4]. Despite the increasing use of azithromycin, several concerns regarding its prophylactic and therapeutic effects on CLAD remain to be elucidated.

First, pulse azithromycin primarily targets the inflammatory injury preceding definitive CLAD, but has limited effect on the existing irreversible pathological variations. In earlier clinical experience, azithromycin was demonstrated to halt, or even reverse, the decline in pulmonary function among recipients with CLAD, particularly those with neutrophil-driven airway inflammation, known as the neutrophilic reversible allograft dysfunction (NRAD) phenotype [3, 5]. This outcome was largely attributable to an earlier and less mature definition of CLAD (particularly bronchiolitis obliterans syndrome), which referred to a substantial and persistent decline in forced expiratory volume in 1 s (FEV₁) from the reference baseline with a 3-week threshold, whereas the updated definition extended it to 3 months [2, 6]. The previous shorter window inevitably captured cases with residual reversibility, many of which would now be classified as probable CLAD under the latest diagnostic framework. Accordingly, the clinical therapeutic role of azithromycin should be repositioned as an adjunctive treatment for emerging or residual airway inflammation, to fully exclude alternative diagnoses, rather than as a therapy for established CLAD [1]. Gottlieb et al. [1] adopted the diagnostic framework introduced in 2014, increasing the sensitivity and warning signals of detecting CLAD to some extent [6]. Further investigations are warranted into the therapeutic effects of azithromycin on CLAD and its phenotypes in the modern era.

In addition, identifying the optimal window for pAZI initiation may contribute to reducing the onset of CLAD. Theoretically, early pAZI initiation could attenuate neutrophil-driven airway inflammation, delaying potential epithelial injury and matrix remodelling. However, a notable proportion of recipients eventually developed CLAD despite receiving adequate pAZI, which may be partially caused by variations in initiation timing and duration in different transplant centres. Kapnadak et al. [7] documented significant heterogeneity in both the timing and duration of azithromycin in the international transplant community, and even within individual centres. A great majority of respondents initiated pAZI after recognised CLAD risk events (e.g. FEV₁ decline, lymphocytic bronchiolitis or bronchoalveolar lavage neutrophilia), whereas only 29% reported initiating pAZI during initial transplant hospitalisation [7]. Cristeto Porras et al. [8] observed that initiating pAZI within the first 3 weeks conferred a modest benefit over later initiation, but their study did not evaluate how long pAZI should be maintained. Whether earlier and longer pAZI exposure pose an absolute benefit requires more exploration, along with careful assessment of potential adverse effects such as antimicrobial resistance, QT-interval prolongation and gastrointestinal intolerance [9]. Based on the extensive experience reflected in the study by Gottlieb et al. [1], further high-quality and large-scale studies would be highly valuable in developing evidence-based recommendations for pAZI practice.

Furthermore, for recipients who experience substantial FEV₁ decline despite long-term pAZI, the value of an azithromycin trial (≥8 weeks) prior to definite CLAD remains open to further discussion. Based on stepwise diagnostic framework of CLAD, a prolonged course of azithromycin trial is recommended to exclude other explainable reasons [2]. Given the prior exposure to adequate pAZI, an additional trial could potentially delay the diagnosis and intervention of definite CLAD, particularly in recipients with rapidly deteriorating FEV₁. Nevertheless, it remains essential to thoroughly investigate and treat every other reversible injury at each step of the CLAD diagnostic process [2].

Given the inherent challenge of reversing the natural course of CLAD, greater emphasis should be placed on research into prophylactic strategies in current clinical practice, while parallel efforts continue to focus on developing more effective therapeutic options. Azithromycin has already demonstrated promise in both the prophylaxis and therapy of CLAD, thereby warranting further comprehensive investigations into its dual effect in this evolving era. We congratulate Gottlieb and their colleagues on their outstanding survey, which provides contemporary real-world data for moving CLAD management forward.