Are we near to an effective drug treatment for bronchiolitis obliterans?

Lung transplantation remains the only effective therapeutic option for well-selected patients with end-stage (cardio) pulmonary diseases such as emphysema, cystic fibrosis, lung fibrosis and pulmonary arterial hypertension. Although the results have improved lately, the long-term survival is still far behind other organ transplantations. This is mainly due to the development of chronic lung allograft dysfunction (CLAD), with bronchiolitis obliterans (BO) being the most frequent manifestation and restrictive CLAD or restrictive allograft syndrome (RAS) being a rather novel distinct entity, with a worse survival. Although the pathology of BO has been well described, this is not an obvious diagnosis after lung transplantation, because of the low sensitivity of transbronchial biopsies to detect BO. As a consequence, BO syndrome (BOS), the clinical correlate of BO, characterized by a progressive and obstructive decline in FEV1, has been introduced and is used worldwide to describe patients affected by this condition. BOS is the major long-term problem after lung transplantation, occurring in some 50% of patients within 5 years after the transplant procedure and causing up to 30% of late mortality between 3 and 5 years after transplantation. Its treatment remains very difficult, although recent advances have certainly improved the survival after diagnosis of BOS. We will here review the current therapeutic options to try to prevent BOS on the one hand and to treat BOS on the other hand.

Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection.

Chronic lung allograft rejection is the single most important cause of death in lung transplant recipients after the first postoperative year, resulting in a 5-year survival rate of approximately 50%, which is far behind that of other solid organ transplantations. Spirometry is routinely used as a clinical marker for assessing pulmonary allograft function and diagnosing chronic lung allograft rejection after lung transplantation (LTx). As such, a progressive obstructive decline in pulmonary allograft function (forced expiratory volume in 1 sec [FEV1]) in absence of all other causes (currently defined as bronchiolitis obliterans syndrome [BOS]) is considered to reflect the evolution of chronic lung allograft rejection. BOS has a 5-year prevalence of approximately 45% and is thought to be the final common endpoint of various alloimmunologic and nonalloimmunologic injuries to the pulmonary allograft, triggering different innate and adaptive immune responses. Most preventive and therapeutic strategies for this complex process have thus far been largely unsuccessful. However, the introduction of the neomacrolide antibiotic azithromycin (AZI) in the field of LTx as of 2003 made it clear that some patients with established BOS might in fact benefit from such therapy due to its various antiinflammatory and immunomodulatory properties, as summarized in this review. Particularly in patients with an increased bronchoalveolar lavage neutrophilia (i.e., 15%-20% or more), AZI treatment could result in an increase in FEV1 of at least 10%. More recently, it has become clear that prophylactic therapy with AZI actually may prevent BOS and improve FEV1 after LTx, most likely through its interactions with the innate immune system. However, one should always be aware of possible adverse effects related to AZI when implementing this drug as prophylactic or long-term treatment. Even so, AZI therapy after LTx can generally be considered as safe.