Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome―A consensus report from the Pulmonary Council of the ISHLT

Since the inception of lung transplantation (LTx), serial pulmonary function testing (PFT) has been the primary method of quantifying the physiologic performance of the allograft. The spirometric indices have since been the standard benchmark to detect the emergence of chronic allograft dysfunction (CLAD). Historic descriptions of physiologic and histologic findings in the first heart‒lung transplant (HLTx) recipients formed the basis for our initial understanding of chronic dysfunction of the pulmonary allograft. In 1984, Burke et al described 14 long-term survivors of combined HLTx, 5 of whom developed airflow limitation.1Burke CM Theodore J Dawkins KD et al.Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation.Chest. 1984; 86: 824-829Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar The authors noted that 3 of the latter patients also developed a superimposed progressive restrictive ventilatory defect. In 1985, Yousem et al described the histopathologic features in these HLTx recipients based on analysis of 2 open lung biopsies, 2 autopsies, and 1 explant.2Yousem SA Burke CM Billingham ME Pathologic pulmonary alterations in long-term human heart-lung transplantation.Hum Pathol. 1985; 16: 911-923Crossref PubMed Scopus (172) Google Scholar Morphologically, the allografts showed extensive bronchiolitis obliterans (BO) and interstitial and pleural fibrosis, with both arterial and venous vasculopathy. In a prescient statement, Yousem opined that BO may prove to be a significant complication of HLTx. In 1988, Glanville et al examined 12 HLTx patients with a non-progressive restrictive ventilatory defect and concluded that a stable restrictive defect post-HLTx was determined primarily by chest wall mechanics.3Glanville AR Theodore J Harvey J Robin ED Elastic behavior of the transplanted lung. Exponential analysis of static pressure-volume relationships.Am Rev Respir Dis. 1988; 137: 308-312Crossref PubMed Scopus (21) Google Scholar Patients with progressive restrictive physiology were not examined in that study. In 1993, the International Society for Heart and Lung Transplantation (ISHLT) established an ad-hoc working group that published a working formulation to describe chronic dysfunction of the allograft. The group concluded that a decline in the forced expiratory volume in 1 second (FEV1) was the most reliable and consistent indicator of allograft dysfunction after other identifiable causes were excluded.4Cooper JD Billingham M Egan T et al.A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar The acronym BOS (bronchiolitis obliterans syndrome) was introduced to describe such dysfunction, but the previously described restrictive physiology related to parenchymal with or without pleural fibrosis was not included in the syndrome. The BOS update published by Estenne et al in 2002 did not include a definition for restrictive mechanics either.5Estenne M Maurer JR Boehler A et al.Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria.J Heart Lung Transplant. 2002; 21: 297-310Abstract Full Text Full Text PDF PubMed Scopus (1145) Google Scholar By the time Meyer et al published their clinical practice guideline on the diagnosis and management of BOS in 2014, recognition of the clinical importance of a restrictive defect was emerging.6Meyer KC Raghu G Verleden GM et al.An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (365) Google Scholar Indeed, in 2005, Pakhale et al described 13 LTx patients, out of a cohort of 686, who developed radiographic findings of upper lobe fibrosis.7Pakhale SS Hadjiliadis D Howell DN et al.Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.J Heart Lung Transplant. 2005; 24: 1260-1268Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Pulmonary function tests demonstrated predominantly a progressive restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of BO, organizing pneumonia (OP), and aspiration. Nine patients died at a median follow-up of 2,310 (range 266–3,740) days, 8 due to respiratory failure. The authors concluded that upper lobe fibrosis was a novel presentation of CLAD, which could be differentiated from BOS on the basis of physiologic and radiologic findings. One year later, Martinu et al described pathologic changes in 12 patients undergoing retransplantation for BOS and found a wide range of pathologic processes of potential clinical significance, including severe pulmonary fibrosis (n = 2).8Martinu T Howell DN Davis RD Steele MP Palmer SM Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients.Chest. 2006; 129: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar They concluded that “end-stage” BOS displayed significant histologic heterogeneity, which may contribute to variability of treatment responses. Recognizing the emerging evidence for a diversity of phenotypes, and possibly endotypes of allograft dysfunction after LTx, the acronym CLAD was first introduced in 2010 by Glanville as an umbrella term to include both obstructive and restrictive phenotypes.9Glanville AR Bronchoscopic monitoring after lung transplantation.Semin Respir Crit Care Med. 2010; 31: 208-221Crossref PubMed Scopus (58) Google Scholar A seminal report by Sato et al in 2011, introduced the term restrictive allograft syndrome (RAS).10Woodrow JP Shlobin OA Barnett SD Burton N Nathan SD Comparison of bronchiolitis obliterans syndrome to other forms of chronic lung allograft dysfunction after lung transplantation.J Heart Lung Transplant. 2010; 29: 1159-1164Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 11Sato M Waddell TK Wagnetz U et al.Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30: 735-742Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar In the series, RAS was diagnosed in 30% of bilateral LTx patients with CLAD. The diagnosis was based on finding a restrictive ventilatory defect, defined as FEV1 ≤80% and total lung capacity (TLC) ≤90% of baseline values. Many patients with RAS had radiographic findings of interstitial or ground-glass opacities, of whom 41% had upper zone involvement. Patients with RAS had an inferior median survival from diagnosis compared to patients with BOS.12Sato M Hwang DM Ohmori-Matsuda K et al.Revisiting the pathologic finding of diffuse alveolar damage after lung transplantation.J Heart Lung Transplant. 2012; 31: 354-363Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 13Sato M Hwang DM Waddell TK Singer LG Keshavjee S Progression pattern of restrictive allograft syndrome after lung transplantation.J Heart Lung Transplant. 2013; 32: 23-30Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 14Ofek E Sato M Saito T et al.Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis.Mod Pathol. 2013; 26: 350-356Crossref PubMed Scopus (170) Google Scholar A slightly earlier publication by Woodrow et al showed that single LTx patients were less likely to be categorized by either phenotype using the radiographic and spirometry criteria proposed by Sato. Building on the these findings, a broader global vision of chronic allograft dysfunction was constructed using the collection of physiologic evidence of phenotypes and their associated outcomes.15Glanville AR CLAD: does the emperor have new clothes?.Am J Transplant. 2014; 14: 2681-2682Crossref PubMed Scopus (4) Google Scholar, 16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar In 2014, a definition of CLAD was proposed to define a persistent decrease in FEV1 and/or forced vital capacity (FVC) of at least 20% with respect to baseline (defined as the mean of the best 2 measurements after LTx, obtained at least 3 weeks apart).17Verleden GM Raghu G Meyer KC Glanville AR Corris P A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar At that time, a number of known causes of allograft dysfunction were included under the umbrella of CLAD, in keeping with the common usage meaning. However, the most recent consensus definition of CLAD now excludes acute onset of treatable causes of graft dysfunction but recognizes that these episodes are risk factors for the eventual development of CLAD.18Verleden GM Glanville AR Lease ED et al.Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar To best understand how RAS fits in with the revised definition of CLAD, it is strongly advised to read the current RAS article in conjunction with the CLAD consensus article. In this article, we provide a consensus standardized definition of RAS for use across centers; provide a state-of-the-art literature review supporting the development of the definition; and describe in detail the current understanding of clinical, physiologic, radiologic, and histologic manifestations of RAS. In addition, we discuss available data on risk factors and treatment approaches to RAS and identify key research priorities for future consideration in areas where critical data are still lacking. We propose that RAS (formerly also termed r[restrictive]CLAD) is defined as the restrictive phenotype of CLAD, which is defined in the CLAD consensus document (Table 1).18Verleden GM Glanville AR Lease ED et al.Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar The restrictive phenotype of CLAD is defined physiologically by:1.A persistent ≥20% decline in FEV1 compared with the reference or baseline value, which is computed as the mean of the best 2 post-operative FEV1 measurements (taken ≥3 weeks apart).2.A concomitant ≥10% decline in TLC, compared with the reference or baseline value, which is computed as the mean of the 2 TLC measurements taken at the time of, or very near to, the best 2 post-operative FEV1 measurements.3.The presence of persistent opacities on chest imaging. In the current definition, once the patient qualifies for CLAD,18Verleden GM Glanville AR Lease ED et al.Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar we propose that an additional essential requirement for RAS diagnosis is the presence of parenchymal with or without pleural-based opacities, on high-resolution (HR) chest CT scan (preferred) or on chest X-ray (CXR) if HRCT is unavailable.Table 1Definition of Restrictive Allograft SyndromeCriterion1Persistent ≥20% decline in FEV1, compared with baseline2Concomitant ≥10% decline in TLC, compared with baseline3Persistent opacities on chest imagingCLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second; TLC, total lung capacity. Once CLAD is diagnosed,18Verleden GM Glanville AR Lease ED et al.Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar phenotype should be determined. Restrictive allograft syndrome (RAS) is defined by the combination of all 3 of the criteria listed. Post-operative FEV1 baseline is computed as the mean of the best 2 post-operative FEV1 values, at least 3 weeks apart. The post-operative TLC baseline is computed as the mean of 2 post-operative TLC values taken at the time of or very near to the best 2 post-operative FEV1 measurements, at least 3 weeks apart. Consistent with the definition of CLAD, the date of RAS onset is defined as the date at which the first value of FEV1 ≤80% of baseline is recorded, when subsequent values also fall below the threshold. Open table in a new tab CLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second; TLC, total lung capacity. Once CLAD is diagnosed,18Verleden GM Glanville AR Lease ED et al.Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 493-503Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar phenotype should be determined. Restrictive allograft syndrome (RAS) is defined by the combination of all 3 of the criteria listed. Post-operative FEV1 baseline is computed as the mean of the best 2 post-operative FEV1 values, at least 3 weeks apart. The post-operative TLC baseline is computed as the mean of 2 post-operative TLC values taken at the time of or very near to the best 2 post-operative FEV1 measurements, at least 3 weeks apart. Consistent with the definition of CLAD, the date of RAS onset is defined as the date at which the first value of FEV1 ≤80% of baseline is recorded, when subsequent values also fall below the threshold. If restrictive physiology and CXR/CT opacities persist after 3 months despite appropriate therapeutic efforts, the diagnosis of CLAD with the phenotype of RAS is confirmed. Note that this definition applies to de-novo RAS. Where RAS develops after BOS has been established (mixed phenotype CLAD), the baseline for TLC should be taken as the last TLC measured in BOS to minimize the effect that gas trapping may have on calculation of the FVC. If a restrictive defect is implied by changes in spirometry, as discussed in what follows, then an appellation of “probable” RAS can be applied, if facilities to measure TLC are not available. Plethysmography is the preferred means to measure TLC to further define the emergence of a restrictive ventilatory defect, but serial TLC monitoring is not routinely performed in most LTx centers. Moreover, diagnostic criteria for pulmonary restriction may be obscured in single LTx recipients due to the dual effects of allograft dysfunction and mechanics of the native lung. A number of studies have assessed alternative methodologies of making a RAS diagnosis. The first study, detailed in what follows, examined the FEV1/FVC ratio (assuming it will remain stable or increase in a restrictive ventilatory defect), and the second study examined the FVC at CLAD onset relative to the FVC baseline.16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar, 19Verleden GM Vos R Verleden SE et al.Survival determinants in lung transplant patients with chronic allograft dysfunction.Transplantation. 2011; 92: 703-708Crossref PubMed Scopus (92) Google Scholar A subsequent report combined the FVC loss criterion with computed tomography (CT) findings of pleural or parenchymal fibrosis, and validated the utility of FVC loss in predicting the outcome of CLAD, both in bilateral and single LTx recipients.20DerHovanessian A Todd JL Zhang A et al.Validation and refinement of chronic lung allograft dysfunction phenotypes in bilateral and single lung recipients.Ann Am Thorac Soc. 2016; 13: 627-635Crossref PubMed Scopus (38) Google Scholar A single-center retrospective study showed that loss of >10% TLC with respect to baseline, or air trapping (defined as residual volume [RV]/TLC ≥50%), was associated with inferior survival.21Glanville AR Physiology of chronic lung allograft dysfunction: back to the future?.Eur Respir J. 2017; 49Crossref PubMed Scopus (3) Google Scholar, 22Kneidinger N Milger K Janitza S et al.Lung volumes predict survival in patients with chronic lung allograft dysfunction.Eur Respir J. 2017; 491601315Crossref PubMed Scopus (0) Google Scholar Severity of the restrictive ventilatory defect and the extent of CT changes were associated with poorer survival in the study by Suhling et al, as was FVC loss at CLAD onset, a predictor also confirmed by Verleden et al.23Suhling H Dettmer S Greer M et al.Phenotyping chronic lung allograft dysfunction using body plethysmography and computed tomography.Am J Transplant. 2016; 6: 3163-3170Crossref Scopus (36) Google Scholar, 24Verleden SE de Jong PA Ruttens D et al.Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation.J Heart Lung Transplant. 2014; 33: 270-277Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar It appears some RAS patients may present with a mixed phenotype ab initio, whereas others may demonstrate a shift from the original phenotype (usually BOS) to a mixed phenotype over time. Taken together, and acknowledging the slight differences between each set of diagnostic criteria, studies to date have confirmed 18% to 30% of all CLAD patients have a restrictive ventilatory defect at diagnosis with CT findings of parenchymal with or without pleural fibrosis. Universally, a diagnosis of RAS portends a worse prognosis than BOS.16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar, 25Verleden SE Ruttens D Vandermeulen E et al.Predictors of survival in restrictive chronic lung allograft dysfunction after lung transplantation.J Heart Lung Transplant. 2016; 35: 1078-1084Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In one series of 53 patients with RAS, predictors of decreased survival included the presence of lower lobe dominant or diffuse infiltrates on CT scan, increased bronchoalveolar lavage (BAL) neutrophilia or eosinophilia, the presence of a discernible trigger, and a history of lymphocytic bronchiolitis (LB).25Verleden SE Ruttens D Vandermeulen E et al.Predictors of survival in restrictive chronic lung allograft dysfunction after lung transplantation.J Heart Lung Transplant. 2016; 35: 1078-1084Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Patients with RAS report shortness of breath (either insidious or acute onset), fever, non-productive cough, pleurisy, chest tightness, and weight loss. Signs of RAS may include coarse crackles or bronchial breath sounds on auscultation in combination with hypoxemia and impaired exercise capacity.13Sato M Hwang DM Waddell TK Singer LG Keshavjee S Progression pattern of restrictive allograft syndrome after lung transplantation.J Heart Lung Transplant. 2013; 32: 23-30Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar The natural history and prognosis of RAS is highly variable, although 3 general patterns of progression have been described:1.A subset of patients present with acute hypoxemic respiratory failure, akin to adult respiratory distress syndrome, which leads to rapid deterioration and death or retransplant. The Leuven and Hannover group described 21 LTx recipients with acute late-onset allograft failure characterized by bilateral radiographic opacities and severe hypoxemia. Explanted lungs revealed acute fibrinoid organizing pneumonia (AFOP), organizing pneumonia (OP), and diffuse alveolar damage (DAD), but also identified BO. All patients who survived to discharge without retransplantation (n = 2, 9%) subsequently developed RAS.26Verleden SE Gottlieb J Dubbeldam A et al."White-out" after lung transplantation: a multicenter cohort description of late acute graft failure.Am J Transplant. 2017; 17: 1905-1911Crossref PubMed Scopus (9) Google Scholar2.Another subset of patients are characterized by a less fulminant course and a “stair-step” pattern of lung function decline and disease progression. Sato et al13Sato M Hwang DM Waddell TK Singer LG Keshavjee S Progression pattern of restrictive allograft syndrome after lung transplantation.J Heart Lung Transplant. 2013; 32: 23-30Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar described 25 patients with this pattern of RAS progression distinguished by recurrent episodes of acute-onset hypoxemia, hospital admission, and/or mechanical ventilation. These exacerbations were followed by intervals of relative clinical stability. During these intervals, pulmonary function improved, remained stable, or continued to decline. Radiographically, ground-glass opacities and/or consolidation predominated during acute exacerbations and subsequently evolved to progressive changes compatible with fibrosis. None of the patients fully recovered, and the mean ± SD time from the initial acute exacerbation to death or retransplant was 558 ± 441 days (range 104 to 1,612 days, median 457 days).3.A third subset of patients present with radiographic changes and a gradually progressive decline in lung function. In a smaller study, Pakhale et al7Pakhale SS Hadjiliadis D Howell DN et al.Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.J Heart Lung Transplant. 2005; 24: 1260-1268Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar described 13 patients with a predominance of upper lobe fibrosis and a slow but steady decline in TLC, which, over time, resulted in a better prognosis compared with the type 1 or type 2 patients just described. In the initial description of RAS, Sato et al examined serial post-transplant lung volume measurements by plethysmography in 468 bilateral LTx recipients, 156 of whom developed chronic graft dysfunction as defined by a sustained impairment in FEV1.11Sato M Waddell TK Wagnetz U et al.Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30: 735-742Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar A threshold decline in TLC to ≤90% of the baseline value demonstrated the best operating characteristics for correctly classifying an irreversible loss.11Sato M Waddell TK Wagnetz U et al.Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30: 735-742Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar Thirty percent of the CLAD cohort had a sustained decline in TLC to ≤90% of the baseline TLC. Furthermore, these patients had distinct radiographic and histologic findings, including upper lung zone opacities compatible with fibrosis on imaging and features of DAD on pathology.11Sato M Waddell TK Wagnetz U et al.Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30: 735-742Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar This observation was confirmed by Verleden et al, who evaluated the impact of a ≥10% TLC decline on survival in 71 lung recipients, including 23 single LTx recipients.19Verleden GM Vos R Verleden SE et al.Survival determinants in lung transplant patients with chronic allograft dysfunction.Transplantation. 2011; 92: 703-708Crossref PubMed Scopus (92) Google Scholar This initial report prompted other centers to provide independent validation and refinement of physiologic criteria. Two studies, in particular, have added to our understanding of TLC changes in association with CLAD. Suhling et al reported 89 patients with CLAD, as defined by persistent loss of FEV1; 28% of their cohort developed RAS, defined as TLC ≤90% of the baseline value. In the study, patients with TLC loss to ≤80% had the shortest graft survival.23Suhling H Dettmer S Greer M et al.Phenotyping chronic lung allograft dysfunction using body plethysmography and computed tomography.Am J Transplant. 2016; 6: 3163-3170Crossref Scopus (36) Google Scholar However, before CLAD onset, 52 patients (58%) exhibited an FEV1/FVC ratio of <0.7, increasing to 0.76 (85%) at CLAD diagnosis and 0.85 (95%) at last follow-up. These data indicate a proportion of patients display a mixed restrictive and obstructive phenotype at CLAD onset, which could impact survival. Kneidinger et al confirmed that a decline in TLC to ≤90% of baseline was adversely associated with survival after onset of graft dysfunction in bilateral LTx recipients.27Kneidinger N Milger K Janitza S et al.Lung volumes predict survival in patients with chronic lung allograft dysfunction.Eur Respir J. 2017; 49Crossref Scopus (30) Google Scholar Moreover, the TLC/TLCbaseline ratio, when modeled as a continuous rather than categorical variable, was also associated with a higher hazard for death.27Kneidinger N Milger K Janitza S et al.Lung volumes predict survival in patients with chronic lung allograft dysfunction.Eur Respir J. 2017; 49Crossref Scopus (30) Google Scholar Although TLC remains the primary criterion for the diagnosis of a restrictive ventilatory defect, TLC monitoring is not always obtained as part of standard post-transplant care. Also, some patients are unable to undergo body plethysmography. In the absence of utilizing the TLC, a restrictive disorder can be identified from spirometry if the FVC is reduced from baseline and the ratio of FEV1/FVC is elevated or increasing from baseline.28Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis. 1991; 144: 1202-1218Crossref PubMed Scopus (2574) Google Scholar Todd et al performed a retrospective clinical trial in 216 bilateral LTx recipients with CLAD to determine whether the spirometric pattern present at the time of CLAD onset could be utilized to meaningfully determine survival.16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar FVC loss was determined by FVCCLAD/FVCbest <0.8 at CLAD onset, where FVCbest was the average of the 2 FVC measurements that paired with the 2 best post-LTx FEV1 values used to determine the FEV1 baseline.16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar Within this cohort, 30% of patients met spirometric criteria for FVC loss, the majority of whom simultaneously demonstrated interstitial opacities on CT. Patients who had measured decreases in FVC at onset of CLAD had significantly worse survival compared with those who had preserved FVC (median survival 309 vs 1,070 days).16Todd JL Jain R Pavlisko EN et al.Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.Am J Respir Crit Care Med. 2014; 189: 159-166Crossref PubMed Scopus (62) Google Scholar The true overlap of patients identified by FVC loss and those meeting criteria for RAS, as defined by TLC loss, could not be described due to the lack of formal lung volumes in the study. A declining FVC could also be attributable to air trapping and hyperinflation, which are the hallmarks of airflow limitation.22Kneidinger N Milger K Janitza S et al.Lung volumes predict survival in patients with chronic lung allograft dysfunction.Eur Respir J. 2017; 491601315Crossref PubMed Scopus (0) Google Scholar, 29Suhling H de Wall C Rademacher J et al.Low exercise tolerance correlates with reduced inspiratory capacity and respiratory muscle function in recipients with advanced chronic lung allograft dysfunction.Transplantation. 2013; 95: 1045-1050Crossref PubMed Scopus (5) Google Scholar Subsequent studies have validated the association of FVC loss with poor survival after the onset of CLAD in independent cohorts of bilateral LTx recipients, and also extended these observations for the first time to a multicenter cohort of single LTx recipients.20DerHovanessian A Todd JL Zhang A et al.Validation and refinement of chronic lung allograft dysfunction phenotypes in bilateral and single lung recipients.Ann Am Thorac Soc. 2016; 13: 627-635Crossref PubMed Scopus (38) Google Scholar, 30Belloli EA Wang X Murray S et al.Longitudinal forced vital capacity monitoring as a prognostic adjunct after lung transplantation.Am J Respir Crit Care Med. 2015; 192: 209-218Crossref PubMed Scopus (38) Google Scholar Together, these studies support the idea that, whenever TLC data are not available, a decline in FVC at CLAD diagnosis is a useful clinical tool to identify LTx patients at risk for poor clinical outcomes at the onset of CLAD and during follow-up. However, it should be clear that not all these patients have RAS. These data identify a population in whom further evaluation with formal lung volumes by plethysmography and HRCT may provide additional valuable information to definitely phenotype such patients. Single LTx recipients are an important target group for further detailed examination given the risk of