Chronic allograft dysfunction, with progressive loss of pulmonary function and finally graft loss, was originally described in 1969 by Derom et al. in the first long-term survivor following (single-sided) lung transplantation (LTx) [1,2]. With a growing number of (heart-)LTxs performed thereafter, late allograft dysfunction was increasingly recognized as a major problem hampering long-term outcome, which is currently still the case [3▪,4,5]. Histopathological postmortem examination revealed small airways fibrosis and luminal obliteration, called obliterative bronchiolitis . Clinically, this pathologic finding was associated with persistent loss of allograft function, as demonstrated by a decline in posttransplant forced expiratory volume in 1 s (FEV1). As such, in 1993, the term bronchiolitis obliterans syndrome (BOS) was adopted to identify this syndrome of late-onset (i.e. after the first three postoperative months), persistent loss of allograft function, which could not be explained by other, potentially reversible complications, such as acute rejection, infection or bronchial suture problems . At least 20% decline in FEV1 from the best postoperative baseline, assessed by two measurements with a 3 or more weeks interval, was considered to be critical for BOS diagnosis and further staging of disease severity: BOS grade 1 was defined as FEV1 decline between 66 and 80% of baseline, BOS grade 2 as FEV1 51–65% of baseline and BOS grade 3 as FEV1 50% or less of baseline . Later, BOS grade 0p (‘potential BOS’) was added (FEV1 81–90% and/or an FEF25–75 value of ≤75% of baseline) because a 20% FEV1 decline might be too insensitive to detect an early decline in allograft function due to early obliterative bronchiolitis, which might thus delay appropriate diagnostic and therapeutic actions .
During the past decades, BOS was generally equated with the term chronic rejection. However, various therapeutic and prophylactic interventions, including intensified or novel immunosuppressives, demonstrated little or no effect on BOS prevalence or on the FEV1 decline in these patients [9,10]. At most, a temporary stabilization or a decrease in the rate of decline in FEV1 could be obtained, as was seen with total lymphoid irradiation [11,12] or extracorporeal photopheresis (ECP) [13–18]. Recently, however, it became clear that some patients with supposed BOS may respond to treatment with macrolides (particularly azithromycin), which in some 40% of these patients resulted in at least 10% improvement in FEV1 after 3–6 months of treatment . This is mainly attributable to attenuation of airway and systemic inflammation . A placebo-controlled trial in patients with BOS confirmed that azithromycin was superior to placebo regarding improvement in FEV1 in established BOS . Therefore, clinical practice guidelines nowadays recommend initiating azithromycin in all patients with suspected BOS [22▪▪,23▪▪]. So-called ‘responders’ to azithromycin, mostly patients with elevated bronchoalveolar lavage (BAL) neutrophilia at diagnosis, were initially classified as ‘neutrophilic-reversible allograft dysfunction’, nowadays renamed to ‘azithromycin responsive allograft dysfunction’ (ARAD). The latter entity is currently no longer regarded to reflect BOS, characterized by a persistent decline in FEV1, but rather as a confounding factor that needs to be excluded by azithromycin treatment before BOS can actually be diagnosed [22▪▪–24▪▪]. In addition, some LTx recipients may develop a restrictive form of allograft dysfunction distinct from BOS [25▪,26]. The latter condition was initially termed restrictive allograft syndrome (RAS), characterized by a restrictive pulmonary function decline [i.e. decrease in FEV1, forced vital capacity (FVC) and total lung capacity (TLC)], persistent parenchymal infiltrates and subpleural thickening on chest computed tomography (CT) scan, as well as pleuroparenchymal fibroelastosis and obliterative bronchiolitis on histopathology. Median survival after diagnosis in RAS is limited to 6–18 months versus 3–5 years in BOS [26,27].
Given these new insights, the acronym CLAD was introduced as an overarching term to cover different phenotypes of chronic lung allograft dysfunction [24▪▪], including obstructive CLAD (BOS), restrictive CLAD (RAS) and dysfunction due to causes not related to chronic rejection. In general, CLAD related to chronic rejection affects up to 50% of LTx recipients after 5 years [3▪]. Approximately 70% of CLAD is attributable to BOS, 30% to RAS and only a small number to nonrejection-related causes [25▪]. Of the patients with supposed BOS, some 30–40% will respond to azithromycin (ARAD) and 60–70% will not . Some 30% of ARAD patients will later develop azithromycin-nonresponsive CLAD, mainly BOS [24▪▪]. Some patients will evolve from BOS to RAS in a later stage. Other nonrejection-related conditions, including both allograft-related and extra-allograft-related disorders, may also cause CLAD. A schematic overview of the shift in the terminology of chronic rejection following LTx is given in Fig. 1. Careful evaluation for these factors should always be performed before diagnosing an LTx recipient with chronic rejection, being BOS or RAS [22▪▪–24▪▪]. In the present review, we will highlight the most recent insights of the past year and current controversies regarding this new CLAD terminology, with specific attention for obstructive and restrictive CLAD.
CHRONIC LUNG ALLOGRAFT DYSFUNCTION: A PARADIGM SHIFT
Patients may have more than one reason for a persistent declining graft function, for example obliterative bronchiolitis manifested as BOS, with concurrent chronic graft infection or ongoing airway colonization. Adequate treatment of the latter may halt or even improve the pulmonary function decline. Next, in case of single-sided LTx, problems with the native lung may lead to a decrease in pulmonary function, such as hyperinflation with compression of the transplanted lung [28,29] or progressive fibrosis. Third, some patients may postoperatively never achieve a ‘normal’ baseline after double LTx and are diagnosed with an early (i.e. within the first postoperative 6–12 months) obstructive, and thus suboptimal pulmonary function according to their calculated predicted values . The same is true after single-sided LTx, in which case postoperative FEV1 should be at least 50% predicted, to be considered normal. This early suboptimal pulmonary function may probably be because of preoperative or perioperative allograft injury, or preexisting mild emphysematous or interstitial changes in the donor lung. There is controversy whether this condition should also be regarded as CLAD [24▪▪]. Indeed, it is still not clear whether the term CLAD should be used in case the allograft not achieves its predicted normal function, or only in case of a new onset, persistent decline in pulmonary function from this, yet suboptimal, baseline lung function [24▪▪].
From acute to chronic lung allograft dysfunction
Some of the factors causing acute lung allograft dysfunction are a risk factor for later CLAD. One of such conditions may be ARAD. Indeed, despite an initial ≥ 10% improvement in FEV1 with azithromycin, some 30% of ARAD patients will later develop CLAD (mostly BOS) [24▪▪]. As lymphocytic bronchitis/bronchiolitis, generally regarded as acute airway rejection and a significant risk factor for later BOS, and ARAD are both characterized by interleukin-17+ T-cell-mediated interleukin-8/CXCL-8-induced neutrophilic airway inflammation attenuatable by azithromycin [31,32], both disorders probably reflect a spectrum of the same condition. Nevertheless, in some ARAD patients, FEV1 will not fully recover to its prior baseline, suggesting that these patients are likely to have additional (mild) BOS because of the presence of irreversible obliterative bronchiolitis lesions [24▪▪]. Acute pulmonary infections may also predispose to later CLAD (mainly BOS), as seen with community-acquired respiratory viral infections, such as human metapneumovirus , respiratory syncytial virus  and influenza . This was previously also shown with cytomegalovirus , whose risk now has drastically decreased because of the general use of postoperative prophylaxis. Similarly, bacterial infections and allograft colonization with Pseudomonas aeruginosa and fungal infections with Aspergillus species  have been associated with later CLAD (mainly BOS). Recent evidence also suggests that lymphocytic bronchiolitis is associated with daily (acute) changes in air pollution  and that chronic exposure to traffic-related air pollution is associated with CLAD (mainly BOS) [40,41]. Another risk factor for CLAD (mainly BOS) is gastroesophageal reflux disease with silent aspiration .
As such, all of these factors probably have the same common mechanism: nonalloimmune triggers causing acute/chronic epithelial injury and innate immune stimulation [43,44], resulting in activation of fibrotic repair mechanisms and the adaptive immune system; and ultimately small airways obstruction. Pathologically, this appears as ‘constrictive’ bronchiolitis, also called obliterative bronchiolitis or bronchiolitis obliterans, characterized by peribronchiolar fibrosis with extrinsic narrowing and obliteration of the bronchiolar lumen, or, less commonly, as ‘proliferative’ bronchiolitis, previously sometimes called bronchiolitis obliterans organizing pneumonia, characterized by intraluminal plugs of proliferating myofibroblasts within alveolar ducts and spaces with varying degrees of bronchiolar involvement [45,46]. Until now, it remains unclear how the interstitial changes seen in RAS exactly fit in this ‘injury–repair’ hypothesis. Although histopathological analysis of RAS patients demonstrated obliterative bronchiolitis lesions in almost all cases – thus suggesting at least a partial etiologic and mechanistic overlap with BOS – typically, parenchymal alterations were also present, pointing to involvement of the alveolar or pleural compartment. Indeed, pleuroparenchymal fibroelastosis, characterized by hypocellular collagen deposition, mainly in the subpleural space and to a lesser extent with centrilobular or paraseptal distribution, septal thickening and diffuse alveolar damage in adjacent areas is typically present in RAS [25▪]. Also, a novel entity called acute fibrinoid-organizing pneumonia (AFOP) was identified, which is a form of acute lung injury e causa ignota, characterized by peribronchiolar and alveolar fibrin deposition with little or no concomitant inflammation [25▪,47]. There is scarce evidence that AFOP may be related with viral infection, such as influenza A/H1N1 . AFOP patients generally present with an acute or semiacute onset, nonobstructive pulmonary function defect and bilateral infiltrates, mainly ground-glass changes with interlobular septal thickening, consolidation or peripheral fibrosis [25▪,47,48]. Further investigation is needed to assess whether AFOP may be an early or acute presentation of RAS, yet given the clear clinical similarities, there is likely extensive overlap between both the entities [25▪].
From exogenous to inherited risk factors
Inherited risk factors also contribute to CLAD, besides exogenous risk factors related to the lungs’ continuous exposure to the external milieu. Genetic variables may either be donor or recipient related [49–51]. Single-nucleotide polymorphisms in oxidant stress genes and acute-phase proteins are associated with primary graft dysfunction, and thus possibly also with CLAD, although this has not yet been formally investigated [51–54]. An overview of the genetic variants associated with CLAD is given in Table 1[51,55–57]. Taken together, these genetic variants mostly affect the innate immune system, hereby altering or attenuating immune responses to injury and/or increasing susceptibility for allograft infections and/or airway inflammation, finally leading to CLAD. None of the identified genetic factors, however, have currently been implemented in risk assessment strategies, and this will probably not change shortly. Therefore, the search for other, diagnostic or predictive, biomarkers of CLAD continues.
From diagnostic to predictive biomarkers
Significantly different cytokine, chemokine and growth factor expression is present in BOS and RAS, pointing to clear mechanistic differences in the airway microenvironment [58,59]. Indeed, biologic profiling demonstrated distinct expression patterns of several alveolar alarmins in BAL fluid in RAS compared with BOS . Similar findings were seen for BAL eosinophils, interleukin-6, interferon-gamma-inducible protein 10/chemokine (C-X-C motif) ligand 10 and interferon-inducible T-cell alpha chemokine/CXCL11 in RAS , whereas in BOS, higher BAL neutrophils, defensins, increased levels of tissue inhibitor of metalloproteinase-1 and 2 and total matrix metalloproteinase-2/3/7/8/9 were present [59,61,62]. Despite a growing number of differentially expressed proteins in RAS and BOS being documented, none of these, however, can currently be used as a tool for early and/or rapid CLAD diagnosis or phenotyping given their nonspecificity.
There is mounting evidence for involvement of alloimmune factors, such as donor-specific antibodies (DSAs), mostly antihuman leukocyte antigen (HLA) but also non-HLA antibodies, in CLAD onset and prognosis. Indeed, several studies now have shown that DSA are associated with development, timing and severity of BOS [63,64]. As such, it is now clear that allograft expression of specific HLA epitopes may also play a role in CLAD. For instance, early graft HLA-G expression post-LTx has been associated with long-term graft acceptance . On the contrary, BAL-soluble HLA-G concentration, which is expressed by bronchial and alveolar epithelial cells or alveolar macrophages, was related to acute (A grade) rejection and the presence of BOS . Whether, as seen in BOS, anti-HLA or nonanti-HLA antibodies (for instance to self-antigens K-α-1-tubulin and collagen V) play a role in the parenchymal fibrosis in RAS currently remains unknown.
Similarly, the search continues for specific predictive biomarkers for timely CLAD diagnosis and phenotyping. However, neither profiling of circulating blood mononuclear cells  nor local cell number or profile in transbronchial allograft biopsies  can accurately predict later CLAD for the moment, which is also true for specific BAL proteins or cellular profiles.
From standard X-ray to microimaging and functional imaging
Given the low specificity to detect small airways disease and early interstitial changes using conventional imaging techniques [69–71], novel imaging techniques have been introduced to assess CLAD. One of these is the so-called microCT, which allows ex-vivo scanning of allograft tissue specimens at very high resolution. MicroCT has confirmed that the constrictive bronchiolitis in end-stage BOS mainly affects conducting airways in a segmental pattern, while sparing larger airways as well as terminal bronchioles and the alveolar surface . These findings were corroborated by histologic reconstruction of the bronchiolar lesions in BOS . In RAS, conversely, microCT demonstrated even more pronounced destruction of both preterminal and terminal bronchioles. In addition, the interstitial compartments are expanded and alveolar airspaces demonstrate accumulation of fibrous connective tissue .
Another novel technique is MRI, in which measurement of oxygen transfer function may serve as an early marker for detection of CLAD (mainly BOS) . In RAS, 18F-fluorodeoxyglucose positron emission tomography imaging may detect subpleural hypermetabolic activity, possibly indicating active fibroproliferation and pleuroparenchymal remodelling; yet again, this needs further confirmation .
FROM SPIROMETRY TO FULL PULMONARY FUNCTION, LONGITUDINAL ANALYSIS AND VENTILATION DISTRIBUTION
CLAD, by definition, is currently diagnosed as a persistent decline in FEV1 of at least 20% compared with the two best postoperative values, in absence of other causes [24▪▪]. After a trial with azithromycin and if there is no subsequent improvement in FEV1, further differentiation into BOS or RAS should be performed using TLC and/or FEV1/FVC ratio and/or FVC and CT scan findings [24▪▪,25▪]. However, spirometry is relatively insensitive to nonspecific changes within the small airways. Pathological changes may perhaps be better assessed using ventilation distribution or heterogeneity [77–80]. Indeed, single or multiple-breath nitrogen washout testing, which reflects structural changes in acinar and conductive lung zones, could detect early inhomogeneity of ventilation distribution in LTx recipients with obliterative bronchiolitis and worsening ventilation heterogeneity seems to correlate with worse BOS stage. Furthermore, considerable interobserver variability exists when using spirometry in diagnosing presence and time of BOS onset . As for RAS, this has currently not been demonstrated, yet the same finding will probably be true, especially because there currently is no internationally approved definition for RAS. As such, several groups attempted to define RAS by using different diagnostic criteria, such as a decline in FVC of at least 20% from best baseline, FEV1/FVC ratio above 0.70, FVC/FVCbest below 0.80 (with FVCbest being the highest FVC post-LTx) or a decline in TLC of at least 10% versus baseline [24▪▪,25▪]. A standardized, multimodal approach, using radiologic, histopathological and functional evaluation of the allograft is likely necessary to diagnose and phenotype CLAD consistently in the future. Longitudinal monitoring of other pulmonary function parameters, may provide additional information, as is seen with longitudinal FVC monitoring. Indeed, a recent study demonstrated that a concurrent FEV1 and FVC decline identifies LTx recipients with rapid deterioration and was a clinical predictor of poor survival. Subsequent FVC decline in LTx recipients with an initial isolated FEV1 decline identifies disease progression and indicates poor prognosis compared to patients with stable FVC during follow-up .
FROM ONE FITS ALL TO PERSONALIZED TREATMENT
With the introduction of azithromycin, it has become clear that patients do not equally benefit from specific therapies and that personalized treatment is most likely the most effective approach in CLAD. However, available therapies have not been proven to result in significant benefit in neither BOS nor RAS [22▪▪–24▪▪,25▪,83]. In BOS, current guidelines recommend not to use sustained administration of high-dose corticosteroids because of their harmful side-effects and ineffectiveness. On the contrary, conversion of cyclosporine to tacrolimus, a trial of azithromycin for a minimum duration of 3 months, fundoplication of the gastroesophageal junction in case of documented gastroesophageal reflux or retransplantation in selected cases is recommended [22▪▪,23▪▪]. For RAS, no formal treatment guidelines exist. In these cases, treatment is currently experimental; case reports have demonstrated some beneficial effects (i.e. mild improvement of interstitial changes and lung function) with pirfenidone or alemtuzumab [25▪]. Retransplantation is probably not a good approach in RAS, as a recent multicenter study demonstrated worse outcome for patients with RAS compared with BOS following retransplantation, that is 3-year survival of 34% after retransplantation for RAS compared with 68% in BOS. Moreover, patients with RAS seem to redevelop CLAD earlier and were more likely to redevelop RAS following retransplantation .
ECP has emerged as a promising second-line treatment for CLAD, especially for BOS. Available data suggest that around two-thirds of patients may demonstrate either slowing or cessation of disease progression after treatment with ECP. Phenotyping CLAD predicts response to ECP, as most beneficial effects are seen in BOS patients with a progressive decline in FEV1 and increased BAL neutrophilia, whereas ‘rapid decliners,’ BOS patients with normal BAL neutrophilia and RAS patients have worse outcomes with ECP [13–18]. Interestingly, besides its known immunomodulatory effect on regulatory T cells, ECP reduces the levels of circulating DSA, antibodies to lung-associated self-antigens and circulating levels of several proinflammatory cytokines that are known to contribute in BOS development .
Perhaps ex-vivo lung perfusion (EVLP) may also prove to be beneficial in reducing CLAD . During EVLP, the lung is kept normothermic and metabolically active in the period between donation and transplantation, which allows for graft reconditioning and reassessment. Immune modulatory benefits of EVLP could arise from several aspects, including reduced inflammation and early innate immune activation because of normothermic conditions compared with cold static preservation, and the use of a leukocytes filter that decreases the load of donor inflammatory cells within the graft. The long-term impact of EVLP for CLAD prevalence and onset, however, remains to be elucidated.
Prevention of CLAD is an important therapeutic approach. Yet, data from randomized trials regarding preventive strategies for CLAD are scarce. As such, compared with cyclosporine, de-novo tacrolimus use was found to be associated with a significantly reduced risk for BOS grade 1 or above at 3 years following LTx . Another multicenter study investigating enteric-coated mycophenolate sodium versus delayed-onset everolimus, in combination with cyclosporine and corticosteroids, on the other hand, could not demonstrate any benefit of either scheme in preventing BOS at 3 years following LTx . Azithromycin prophylaxis, given in addition to standard immunosuppression, might also prevent BOS, yet this was only demonstrated in a single-centre study . Whether preventive ECP treatment in the early pretransplant and/or posttransplant period may be able to reduce the rate of CLAD remains to be investigated, yet promising results with this approach are seen for steroid-refractory acute graft versus host disease after allogeneic haematopoietic cell transplantation [89,90], although the results for chronic graft versus host disease may be less beneficial .
In summary, the term CLAD was recently introduced as an overarching term covering different phenotypes of chronic lung allograft dysfunction, including obstructive CLAD (BOS) and restrictive CLAD (RAS). Clearly, different pathophysiological mechanisms are involved in these clinically distinct phenotypes of chronic rejection, as is reflected by differences in histology, allograft function and imaging. However, at present, no biomarker can accurately predict later onset or phenotype of CLAD. Therefore, the search continues for specific predictive biomarkers, pulmonary function parameters and imaging techniques for timely CLAD diagnosis and phenotyping. Also, not all CLAD patients equally benefit from specific therapies. Therefore, personalized or targeted therapy is probably the most effective approach for treatment and prevention of CLAD.
Financial support and sponsorship
R.V. is a Senior Research Fellow of the Research Foundation Flanders (FWO) (KAN2014 188.8.131.52; 1803516N). S.E.V. is supported by the FWO (12G 8715N). G.M.V. is supported by the FWO (G.0723.10, G.0679.12 and G.0679.12).
Conflicts of interest
The manuscript includes description of unlabelled/investigational use of products/devices, including azithromycin, campath-H1 and ECP.
There are no conflicts of interest.
The authors of this manuscript have no conflicts of interest to disclose regarding the current review.
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