Perspective
Restrictive chronic lung allograft dysfunction: Where are we now?

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Chronic lung allograft dysfunction (CLAD) remains a frequent and troublesome complication after lung transplantation. Apart from bronchiolitis obliterans syndrome (BOS), a restrictive phenotype of CLAD (rCLAD) has recently been recognized, which occurs in approximately 30% of CLAD patients. The main characteristics of rCLAD include a restrictive pulmonary function pattern with a persistent decline in lung function (FEV1, FVC and TLC), persistent parenchymal infiltrates and (sub)pleural thickening on chest CT scan, as well as pleuroparenchymal fibroelastosis and obliterative bronchiolitis on histopathologic examination. Once diagnosed, median survival is only 6 to 18 months compared with 3 to 5 years with BOS. In this perspective we review the historic evidence for rCLAD and describe the different diagnostic criteria and prognosis. Furthermore, we elaborate on the typical radiologic and histopathologic presentations of rCLAD and highlight risk factors and mechanisms. Last, we summarize some opportunities for further research including the urgent need for adequate therapy. In this perspective we not only assess the current knowledge, but also clarify the existing gaps in understanding this increasingly recognized complication after lung transplantation.

Section snippets

History

In 1984, Burke et al were the first to describe the presence of obliterative bronchiolitis (OB) in patients with a ventilatory defect after heart-lung transplantation. OB is a fibroproliferative obliteration of the small airways and, in subsequent decades, it was considered to be the hallmark of chronic rejection. However, these patients did not show a typical, purely obstructive, ventilatory defect and suffered at least partially from restrictive physiology as a decrease in total lung capacity

Diagnosing rCLAD

There is currently no internationally approved definition for rCLAD, but several groups attempted to discriminate a form of rCLAD by using different diagnostic criteria. Woodrow et al made a distinction within CLAD patients (single and double LTx) based on the presence of pleuroparenchymal infiltrates on chest computed tomography (CT) scan and the pattern of decline in forced vital capacity (FVC). First, they made a distinction between “non-specific” CLAD (pleuro-parenchymal infiltrates

Prevalence and prognosis of rCLAD

Woodrow et al undertook an important study investigating non-specific CLAD patients using a combination of imaging and spirometry.11 Patients with persistent pleuroparenchymal infiltrates on CT were denominated “non-specific” CLAD (35%), whereas “specific” CLAD patients (no pleuroparenchymal infiltrates) were divided into restrictive BOS (28%) and obstructive BOS (37%) patients. There was no survival difference, however, between “non-specific” and “specific” CLAD patients and no difference

Radiology of rCLAD

All reports on rCLAD demonstrated radiologic alterations of interstitial lung disease.12, 13, 14 Typical characteristics included (traction-)bronchiectasis, central and peripheral consolidation, pleural thickening and volume loss, with most patients showing an upper lobe-dominant fibrotic pattern.12, 14 One surprising finding was that half of the rCLAD patients already demonstrated parenchymal alterations on chest CT scan before CLAD onset. This demonstrates that patients with persistent

Pathology of rCLAD

Histopathologic analysis of explanted lungs and open lung biopsies of patients with rCLAD revealed pleuroparenchymal fibroelastosis, characterized by hypocellular collagen deposition with thickening of the septa.20 This collagen accumulation was mainly situated in the sub-pleural space, but centrilobular and paraseptal collagen distribution was also observed. A sharp demarcation between “healthy” and diseased zones was present. Remarkably, almost all specimens also showed OB lesions, indicating

Risk factors and mechanism

The risk factors and mechanisms of rCLAD remain mostly elusive as no comprehensive studies have been performed to date. Females were more predisposed to develop rCLAD in the study by Todd et al,14 but no other studies have confirmed their findings. Similarly, patients developing rCLAD were also younger in the study by Verleden et al and tended to be younger in the study by Sato et al,12, 13 but this was not confirmed in other studies.14, 16 Similarly, cytomegalovirus mismatch seemed to

Treatment

Pirfenidone is an anti-fibrotic drug and, in some countries, has been approved as the first treatment option for idiopathic pulmonary fibrosis.28 Recently, a case report demonstrated the potential of pirfenidone for slowing the evolution of rCLAD.19 Another drug that could be beneficial is alemtuzumab (Campath-1H), which is an antagonist of CD52, a protein expressed on B-cells, lymphocytes, dendritic cells and monocytes. This drug was found to improve interstitial changes and lung function in 4

Phenotyping CLAD: Near the end or just starting?

There is a clear need for studies confirming the prognosis of rCLAD, as well as internationally approved diagnostic criteria for rCLAD. This would spur the initiation of multicenter trials to investigate risk factors and mechanisms in more depth. In addition, there is a need for studies comparing spirometric evolution (FEV1, FVC, FEV1/FVC and TLC) with radiology and pathology to establish the degree of overlap between the different diagnostic criteria for rCLAD. Indeed, we are only in the phase

Disclosure statement

The authors have no conflicts of interest to disclose. This study was supported by the Research Foundation Flanders (12G8715N to S.E.V.; KAN2014 1.5.139.14 to R.V.; G.0723.10, G.0679.12 and G.0679.12 to G.M.V.) and Onderzoeksfonds KU Leuven (OT/10/050 to G.M.V.).

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