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Physiology of chronic lung allograft dysfunction: back to the future?

Chronic lung allograft dysfunction (CLAD) is, in one sense, a term without a true consensus definition, although its common usage in the field of lung transplantation implies a base understanding throughout the community that it describes a lung allograft that does not work (well) [1]. There appears to be general agreement that CLAD most commonly occurs in a time-dependent fashion after transplant and is a harbinger of a foreshortened survival [2]. However, different phenotypes have been described based on a combination of physiological and radiological features [3]. A restrictive ventilatory defect, with or without interstitial pulmonary infiltrates and/or pleural thickening, has the worst prognosis and is also associated with inferior results from attempts at salvage by retransplantation [4]. One curious feature of the natural history of CLAD is the chameleon-like property of morphing from one predominant phenotype to another [5]. Perhaps this bespeaks our simplistic understanding of the root causative mechanisms, but emphasises there is still much to learn about this dominant complication of lung transplantation, which is the major risk factor for death in those who survive the perioperative period. The article by Kneidinger et al. [6] in this issue of the European Respiratory Journal attempts to fine-tune our insight into CLAD phenotypes and provides valuable information regarding the prognostic value of gas trapping in CLAD. Once again, the precision of pulmonary physiology assessment as a longitudinal tool is shown to provide a useful guide to survival. In this way, repeated measures of a safe and noninvasive test can assist individual patient management by highlighting early trends. Whether effective therapies are currently available is another question, but at least some stratification of those individuals less likely to deteriorate can be carried out. One perennial problem in this type of long-term retrospective single-centre analysis is the potential for variable adherence to testing schedules and the relatively small number of patients in each group. In this case, 20 had restrictive physiology (defined by a 10% reduction in total lung capacity (TLC) from baseline) and 21 had gas trapping (defined as a residual volume/TLC ≥50%) at CLAD onset. Both of these phenotypes had inferior survival compared with other patients with CLAD who predominantly had bronchiolitis obliterans syndrome (BOS), as defined recently in the Journal [7]. Is this surprising? Although the finding of a poor outcome with gas trapping has not been widely reported previously after lung transplantation, it makes biological sense and resonates with conventional knowledge that accepts that gas trapping is associated with an increased risk of dynamic hyperinflation (an increase in TLC) and thereby an increase in mechanical load on the inspiratory muscles, reduced mechanical advantage and increased oxygen cost of breathing [8]. The result is impaired exercise performance and greater levels of dyspnoea. Ultimately, respiratory cachexia and hypercapnoeic respiratory failure develop, with death commonly from respiratory tract infection. Conversely, there is now a building body of evidence regarding the adverse prognosis of restrictive CLAD – whether associated with pleuroparenchymal disease or not. Upper lobe fibrosis was first described by Konen et al. [9] in 2003, and later, restrictive allograft syndrome (RAS) was described by Sato et al. [10], combining changes in TLC with computed tomography (CT) evidence to examine outcomes. A number of other authors have employed different physiological criteria of restriction, not always measuring lung volumes, and broadly found similar outcomes [11]. There are nuances of course, and while a case can be made for the expedience of measuring lung mechanics alone (spirometrically determined variables) to assess likelihood of the presence of a restrictive defect, it is refreshing to see the diligence of the current report, where full lung function testing was performed at least every 3 months using body plethysmography – recognised as the preferred laboratory tool for assessing lung volumes, as opposed to helium dilution, which may underestimate trapped gas and TLC. Phenotyping chronic lung allograft dysfunction using lung volume measurements allows stratification of outcomes http://ow.ly/CF0Q309hx9Q