Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment―A consensus report from the Pulmonary Council of the ISHLT

The outcomes of transplantation vary widely by organ. Lung transplantation (LTx) has rather poor long-term outcome, with a current median post-transplant survival of 6.0 years.1Opelz G Döhler B Ruhenstroth A et al.The Collaborative Transplant Study Registry.Transplant Rev. 2013; 27: 43-45Crossref Scopus (72) Google Scholar, 2Chambers DC Yusen RD Cherikh WS et al.The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult lung and heart‒lung transplantation report—2017; Focus theme: Allograft ischemic time.J Heart Lung Transplant. 2017; 36: 1047-1059Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar Survival after organ transplantation is limited by both graft-related and non‒graft-related factors. Allograft failure remains the leading cause of morbidity and mortality across all organ groups and is the major cause of death, accounting for >40% of deaths beyond the first year post-LTx.1Opelz G Döhler B Ruhenstroth A et al.The Collaborative Transplant Study Registry.Transplant Rev. 2013; 27: 43-45Crossref Scopus (72) Google Scholar, 2Chambers DC Yusen RD Cherikh WS et al.The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult lung and heart‒lung transplantation report—2017; Focus theme: Allograft ischemic time.J Heart Lung Transplant. 2017; 36: 1047-1059Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar Our understanding of the patterns and pathophysiology of lung allograft dysfunction has evolved over time. Relatively early in the history of LTx, the lung transplant community, through the International Society for Heart and Lung Transplantation (ISHLT), recognized the need to develop a standard approach to classification of persistent allograft dysfunction. In 1993, Cooper et al3Cooper 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.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar introduced the first definition of “bronchiolitis obliterans syndrome” (BOS) as the key manifestation of lung allograft dysfunction. BOS, a clinical syndrome, based on spirometry, was suggested to be the clinical correlate of bronchiolitis obliterans (BO), thought to be the pathologic hallmark of chronic rejection.3Cooper 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.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar BOS was identified as a persistent decline in forced expiratory volume in 1 second (FEV1) of ≥20%, compared with the reference FEV1, defined as the mean of the 2 best post-operative FEV1 measurements taken at least 3 weeks apart3Cooper 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.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar and after exclusion of other known pulmonary and extrapulmonary causes of FEV1 decline. Since the original report by Cooper et al, a revised definition by Estenne et al has been published, incorporating a new stage, “BOS 0-p,” characterized by a 10% to 20% drop in FEV1, signifying potential BOS.4Estenne 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 (1146) Google Scholar The intention of this new stage was to trigger early investigations and therapy with the hope of preventing further allograft dysfunction. More recently, a consensus guideline on the diagnosis and treatment of BOS was published that evaluated the existing literature and used the GRADE system to demonstrate the lack of evidence for most therapies for BOS.5Meyer KC Raghu G Verleden GM et al.ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (366) Google Scholar It has become apparent that the diagnosis of BOS requires further refinement. Some patients who had been diagnosed with BOS proved to have reversible allograft dysfunction after specific treatments, such as management of gastroesophageal reflux6Palmer SM Miralles AP Howell DN Brazer SR Tapson VF Davis RD Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation.Chest. 2000; 118: 1214-1217Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar and addition of a neomacrolide antibiotic, usually azithromycin.7Gerhardt SG McDyer JF Girgis RE Conte JV Yang SC Orens JB Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study.Am J Respir Crit Care Med. 2003; 168: 121-125Crossref PubMed Scopus (299) Google Scholar, 8Verleden GM Dupont LJ Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.Transplantation. 2004; 77: 1465-1467Crossref PubMed Scopus (147) Google Scholar In addition, different patterns of lung function decline have been described in the last decade. Sato et al identified a progressive decline in pulmonary function, which was restrictive in nature rather than obstructive, and was accompanied by pleural changes and/or interstitial fibrosis on imaging studies.9Pakhale 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 (77) Google Scholar This led to the introduction of the term “restrictive allograft syndrome” (RAS), which was initially described as a chronic, persistent restrictive decline in pulmonary function (decline in total lung capacity of at least 10% compared with the mean of the 2 best post-operative values) in the context of a decline in FEV1 of ≥20%, often with persistent opacities on computed tomography (CT) scan of the chest.10Sato 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 (335) Google Scholar As a consequence of these and other observations supporting the heterogeneity within BOS, the term chronic lung allograft dysfunction (CLAD), first introduced by Glanville,11Glanville AR Bronchoscopic monitoring after lung transplantation.Semin Respir Crit Care Med. 2010; 31: 208-221Crossref PubMed Scopus (58) Google Scholar has been proposed as an umbrella term to describe the clinical manifestations of a range of pathologic processes in the airway and parenchymal compartments of the lung allograft that lead to a significant and persistent deterioration in lung function (with or without chest radiologic changes) and occur >3 months after LTx.12Verleden 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 (395) Google Scholar, 13Glanville AR CLAD: does the emperor have new clothes?.Am J Transplant. 2014; 14: 2681-2682Crossref PubMed Scopus (4) Google Scholar The lack of a consensus definition of CLAD and how it relates to BOS has been problematic. Factors including the varied timing and reproducibility of spirometry and the frequent presence of potentially reversible conditions, such as infection, pleural effusion, or acute rejection, that subsequently fail to improve with treatment may result in lack of agreement about the presence and timing of onset of CLAD.14Kapila A Baz MA Valentine VG et al.Reliability of diagnostic criteria for bronchiolitis obliterans syndrome after lung transplantation: a survey.J Heart Lung Transplant. 2015; 34: 65-74Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Furthermore, some authors have used the term CLAD as a synonym for BOS, or a combination of BOS and RAS, whereas others proposed to use CLAD for every possible post-transplant decline in FEV1.12Verleden 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 (395) Google Scholar As a consequence, the Pulmonary Council of the ISHLT assembled a group of experts to create a robust description for the term CLAD that would encompass its definition, etiology, phenotypes, pathology, treatment, and outcome. It was acknowledged that the lack of literature available on this specific topic mandated the generation of a consensus report based on expert opinion. The primary aim of this consensus report is to standardize the nomenclature of CLAD and its clinical phenotypes to facilitate collaboration among centers investigating the pathogenesis, prevention, and treatment of CLAD. CLAD is defined as a substantial and persistent decline (≥20%) in measured FEV1 value from the reference (baseline) value. The baseline value is computed as the mean of the best 2 post-operative FEV1 measurements (taken >3 weeks apart). CLAD can present either as a predominantly obstructive ventilatory pattern, a restrictive pattern, or a mixed obstructive and restrictive pattern that is not explained by other conditions as outlined in Table 1 or as a combination of these.11Glanville AR Bronchoscopic monitoring after lung transplantation.Semin Respir Crit Care Med. 2010; 31: 208-221Crossref PubMed Scopus (58) Google Scholar, 12Verleden 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 (395) Google Scholar, 15Levine DJ Glanville AR Aboyoun C et al.Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2016; 35: 397-406Abstract Full Text Full Text PDF PubMed Scopus (221) Google ScholarTable 1Processes and Diseases That May Lead to Chronic Loss of Allograft Function and Are Not Included in Current Definition of CLADA. Factors where recalculation/resetting of the FEV1 reference value may be valid (if FEV1 remains stable for at least 6 months): 1. Decreasing lung function due to the normal aging process. 2. Surgical factors. • Transplant lung resection, chest-wall surgery, phrenic nerve damage. 3. Mechanical factors. • Persistent pleural effusion. • Persistent lung edema due to significant kidney/heart/liver failure. • Airway stenosis. • Myopathy, neuropathy, and Parkinson disease. • Weight gain. • Native lung hyperinflation after single-lung transplant. 4. Localized infection with chronic scarring. • Abscess/empyema/mycetoma.B. Factors that cannot be differentiated easily from CLAD and do not ever allow recalculation/resetting of the FEV1 reference value: 1. Any from (A) above where there is not a period of at least 6 months of stability. 2. Infiltration with tumor. 3. Infiltration of the allograft with proven disease recurrence from the underlying transplant indication (e.g., LAM, sarcoidosis, etc.). 4. Drug or other induced pulmonary toxicity (e.g., sirolimus, methotrexate, amiodarone, radiotherapy). 5. Pulmonary arterial strictures or emboli. 6. Acute/subacute generalized infection. 7. Acute/subacute cellular or antibody-mediated rejection. 8. Acute/subacute effects of aspiration.C. Failing to reach normal predicted lung function (i.e., low FEV1 reference value such that FEV1 is ≤ 80% of the recipient predicted value). This situation may include an age difference between donor and recipient where older donor lungs are implanted or when an intra-operative allograft reduction surgery/lobectomy is performed.CLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second; LAM, lymphangioleiomyomatosis. Open table in a new tab CLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second; LAM, lymphangioleiomyomatosis. The critical level of change in lung function is a ≥20% fall from baseline FEV1 with or without a change in forced vital capacity (FVC), to qualify for “possible” CLAD, although it is accepted that most centers will trigger a series of investigations at a ≥10% threshold for "potential" CLAD (Figure 1), recognizing that this threshold falls outside the normal day-to-day variability of FEV1.16Glanville AR Physiology of chronic lung allograft dysfunction: back to the future?.Eur Respir J. 2017; 49Google Scholar Prompt investigations should be performed to exclude the causes that may respond to intervention (Table 1). If lung function parameters remain impaired on a second reading at least 3 weeks after the first ≥20% fall from baseline and after adequate treatment of secondary causes such as infection, acute cellular/antibody-mediated rejection, or airway stenosis has been implemented, then a diagnosis of “probable” CLAD can be made. CLAD staging (as proposed in Table 2) and clinical sub-typing into phenotypes (Table 3) should be performed at this stage to stratify potential investigations and therapies, including entry into clinical trials if available. It was the consensus of the writing group to no longer use the classical BOS staging but to change to a CLAD staging (from CLAD 0 to 4), which seems more appropriate now that different phenotypes of allograft dysfunction have been described. CLAD Stage 3 was adapted (>35% to 50%) and a Stage 4 (≤35%) was introduced to better reflect differences in prognosis and to allow further clinical studies with specific CLAD stages. Moreover, it was also decided to no longer include a Stage 0-p, which was only introduced into the BOS staging system to trigger further investigations. Instead, it is now advised to start investigations whenever the FEV1 declines by ≥10% from baseline. CLAD is “confirmed” if the physiologic abnormalities (i.e., FEV1 decline of ≥20%) persist for 3 months after the first value is taken (Figure 1). Further investigation to exclude any treatable causes or complications of therapy may be warranted at any stage. Infection, acute rejection (cellular or antibody-mediated), and aspiration are all relevant factors to consider when diagnosing the definitive presence and timing of the onset of CLAD. These entities are all known risk factors for acute allograft injury and subsequent CLAD. For a diagnosis of CLAD in the setting of recent infection, rejection, or aspiration, clinically appropriate therapies must be completed, and we would advise a prolonged course (at least 8 weeks) of neomacrolide therapy (usually azithromycin) in patients not already on such therapy. Although these therapies should have clinically “eliminated” the acute insult, if the allograft function fails to recover or continues to deteriorate beyond 3 months, then CLAD can be confirmed (definite CLAD).5Meyer KC Raghu G Verleden GM et al.ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (366) Google Scholar The date of onset of CLAD is defined as the date at which the first value of FEV1 ≤80% of baseline is recorded.4Estenne 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 (1146) Google Scholar, 5Meyer KC Raghu G Verleden GM et al.ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (366) Google Scholar By definition, if lung function returns to >80% of baseline after therapy, then the diagnosis of CLAD is not sustained (Figure 2A). These time intervals are unavoidably arbitrary and experience-based, as no hard evidence supports a time threshold for determination of when physiologic changes become permanent.Table 2CLAD StagingStageSpirometryCLAD 0Current FEV1 >80% FEV1 baselineCLAD 1Current FEV1 >65‒80% FEV1 baselineCLAD 2Current FEV1 >50‒65% FEV1 baselineCLAD 3Current FEV1 >35‒50% FEV1 baselineCLAD 4Current FEV1 ≤35% FEV1 baselineCLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second. Once CLAD is diagnosed, staging is performed according to the decline in FEV1, compared with baseline. The date of onset of CLAD is defined as the date at which the first value of FEV1 ≤80% of baseline was recorded when subsequent values taken at least 3 weeks (and for definite CLAD up to 3 months) apart also fell below the threshold. The same principle holds for each stage. Open table in a new tab Table 3Basic Phenotypes of Chronic Lung Allograft DysfunctionObstructionaObstruction is defined by a fall in FEV1 (as described in the text) and associated with other indices of airflow limitation (FEV1/FVC ratio <0.70). (FEV1/FVC <0.7)RestrictionbRestriction is properly defined as a ≥10% reduction in baseline TLC. (TLC decline ≥10% from baseline)CT opacitiescRefers to parenchymal opacities and/or increasing pleural thickening consistent with a diagnosis of pulmonary and/or pleural fibrosis and likely to cause a restrictive physiology, rather than the airway-based changes consistent with bronchiectasis. Although the 2 (opacities and bronchiectasis) may coexist, in some cases, the presence of bronchiectasis may reflect traction changes on airways due to fibrotic parenchymal opacities.BOSYesNoNoRASNoYesYesMixeddBy definition, all cases that transition from a BOS phenotype to an RAS phenotype and vice-versa, will meet these criteria, which is in accord with histopathologic findings at explant/post-mortem.YesYesYesUndefinedeUndefined means definite CLAD, but with 2 possible combinations of variables, making it difficult to categorize in the upper panels (BOS, RAS, or mixed phenotype).YesNoYesYesYesNoBOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; CT, computed tomography; FEV1, forced expiratory volume in 1 second; RAS, restrictive allograft syndrome; FVC, forced vital capacity; RAS, restrictive allograft syndrome; TLC, total lung capacity.a Obstruction is defined by a fall in FEV1 (as described in the text) and associated with other indices of airflow limitation (FEV1/FVC ratio <0.70).b Restriction is properly defined as a ≥10% reduction in baseline TLC.c Refers to parenchymal opacities and/or increasing pleural thickening consistent with a diagnosis of pulmonary and/or pleural fibrosis and likely to cause a restrictive physiology, rather than the airway-based changes consistent with bronchiectasis. Although the 2 (opacities and bronchiectasis) may coexist, in some cases, the presence of bronchiectasis may reflect traction changes on airways due to fibrotic parenchymal opacities.d By definition, all cases that transition from a BOS phenotype to an RAS phenotype and vice-versa, will meet these criteria, which is in accord with histopathologic findings at explant/post-mortem.e Undefined means definite CLAD, but with 2 possible combinations of variables, making it difficult to categorize in the upper panels (BOS, RAS, or mixed phenotype). Open table in a new tab Figure 2Case studies. (A) In 1997, this patient underwent a heart‒lung transplant for complex Eisenmenger syndrome, and had several biopsy-proven acute cellular rejection episodes, which were treated with courses of intravenous steroids and intravenous anti-thymocyte globulins, and a shift from cyclosporine to tacrolimus and azathioprine to mycophenolate mofetil. Her FEV1 decreased gradually from 2.92 liters to 1.88 liters, and she was diagnosed with CLAD Stage 2 (FEV1 decline to 64% of baseline), phenotype BOS (obstructive and no CT opacities). At that time (in 2002), azithromycin was added (red arrow) and FEV1 normalized within 2 months. CLAD could no longer be sustained, so it is unlikely that her FEV1 decline before azithromycin was due to development of BO (BOS). Later, she had another gradual decline in FEV1, which was considered CLAD (initial BOS phenotype), but subsequently demonstrated a mixed phenotype with TLC decline (12%) and persistent pleuroparenchymal opacities on chest CT scan. (B) In 2011, this patient underwent a re-do bilateral lung transplant because of end-stage BOS. In 2014, after late biopsy-proven acute rejection, he developed rapidly declining obstructive spirometry, diagnosed as CLAD Stage 3, phenotype BOS. After initiation of extracorporeal photophoresis, FEV1 increased from 2.12 liters to a maximum of 2.70 liters, after which it remained stable at around 2.35 liters. This patient showed partial reversibility (+27%), with a subsequent new decline, although the patient has remained in CLAD Stage 2, phenotype BOS, illustrating that a reversible (possibly inflammatory) part of CLAD (BOS) was effectively treated, even though BO itself is not reversible. (C) In 1996, the patient underwent a bilateral lung transplantation for pulmonary arterial hypertension. The best post-operative FEV1 was 3.9 liters (100% predicted). Current FEV1 is 3.1 liters (98% predicted). Although there was an FEV1 decline of 0.8 liter (corresponding to a 20.5% decline), this is not considered CLAD, as the percent predicted has remained almost identical; thus, this may be considered a natural FEV1 decline over the course of 22 years. (D) In 2000, this patient underwent bilateral lung transplant for idiopathic pulmonary fibrosis. Her weight increased by 25 kg over the next 5 years, but then remained stable. At the same time, her FEV1 and FVC decreased by 20% compared with baseline. This was initially considered CLAD Stage 1, with restrictive pulmonary function (TLC decline 11%), but there were no opacities on chest CT scan (hence not qualifying for RAS). After she underwent a gastric bypass procedure (red arrow), resulting in a weight loss of 30 kg, pulmonary function again normalized. The patient did not have CLAD because her restrictive pulmonary function decline was due to weight gain, and CLAD score was restored to 0 with substantial weight loss. CLAD, chronic lung allograft dysfunction; CT, computerized tomography; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RAS, restrictive allograft syndrome; TLC, total lung capacity.View Large Image Figure ViewerDownload Hi-res image Download (PPT) CLAD, chronic lung allograft dysfunction; FEV1, forced expiratory volume in 1 second. Once CLAD is diagnosed, staging is performed according to the decline in FEV1, compared with baseline. The date of onset of CLAD is defined as the date at which the first value of FEV1 ≤80% of baseline was recorded when subsequent values taken at least 3 weeks (and for definite CLAD up to 3 months) apart also fell below the threshold. The same principle holds for each stage. BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; CT, computed tomography; FEV1, forced expiratory volume in 1 second; RAS, restrictive allograft syndrome; FVC, forced vital capacity; RAS, restrictive allograft syndrome; TLC, total lung capacity. We do not recommend passive waiting to achieve a confirmed diagnosis of CLAD. Rather, active investigations and therapies should be employed and graft function monitored frequently. Every opportunity should be sought for a useful therapeutic intervention. Reassessment is a valuable tool to confirm staging and phenotype at 3 months and comparison should be made with initial staging and phenotype at CLAD onset, which occasionally may evolve quickly (e.g., from BOS to RAS). In some circumstances, CLAD may be partly reversible upon treatment (Figure 2B), suggesting that the observed graft dysfunction was partly due to inflammation, and not only to airway or parenchymal/pleural fibrosis, which are thought to cause permanent damage.17Sato 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 An acutely reversible condition, such as acute infection and even acute rejection, may exist in conjunction with developing early CLAD. These 2 conditions are not mutually exclusive, and it is the net sum of persistent effects after a full course of therapy that determines whether a firm diagnosis of CLAD can be established. The most common manifestation of CLAD is the development of airflow limitation, caused by BO, which will continue to be termed BOS. The diagnostic criteria remain largely as previously elaborated.4Estenne 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 (1146) Google Scholar, 5Meyer KC Raghu G Verleden GM et al.ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503Crossref PubMed Scopus (366) Google Scholar Briefly, obstruction is defined by a fall in FEV1 ≥20% (compared with baseline) and associated with other indices of airflow limitation (Table 3), without persistent radiologic pulmonary opacities (as defined in what follows). Up to 30% of patients with CLAD develop a restrictive defect.10Sato 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 (335) Google Scholar, 18Verleden 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 In the presence of persistent radiologic pulmonary opacities, this will continue to be called “restrictive allograft syndrome” (RAS) (Table 3). RAS (previously called restrictive [R]-CLAD) is defined physiologically by: (1) a persistent ≥20% decline in FEV1 (± FVC) compared with the reference or baseline value; (2) a decrease in total lung capacity (TLC) to ≤90% compared with baseline, defined as the average of the 2 measurements obtained at the same time as or very near to the best 2 post-operative FEV1 measurements; and (3) the presence of persistent opacities on chest imaging (chest X-ray [CXR] and/or computed tomography [CT]). Restriction should be diagnosed by a ≥10% decline in TLC relative to baseline. The potential role of an FVC decline ≥20% from baseline as a surrogate marker for restriction20Todd 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 is addressed further in the RAS consensus report.21Glanville AR Verleden GM Todd J et al.Chronic lung allograft dysfunction: definition and update of restrictive allograft syndrome―a consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019; 38: 483-492Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar If, despite appropriate therapeutic efforts, both features (restrictive physiology and CXR/CT opacities) persist after 3 months, then the diagnosis of definite CLAD with the phenotype of RAS is confirmed. Given the uncertainty inherent in relying solely on spirometry to diagnose a restrictive ventilatory defect, we strongly recommend measuring TLC by body plethysmography to confirm a suspected diagnosis in all cases unless specific contraindications exist. In this regard, obtaining a baseline TLC at 3 and 6 months post-transplant in addition to a high-resolution CT (HRCT) at 6 months will provide a clinically useful baseline. FEV1/FVC ratio per definition increases to >0.7 with a restrictive process, but such changes are difficult to interpret in some situations. For instance, FVC may be falsely reduced due to an increased residual volume (RV), rather pointing to obstruction. Also, after single-LTx for chronic obstructive pulmonary syndrome (COPD), or in the presence of anastomotic stenosis after bilateral LTx, the FEV1/FVC ratio may remain <0.7, even if RAS, and hence restriction develops. In that case, TLC decline may be the only indication for restriction in the pulmonary function testing. Another pitfall in the interpretation of the FEV1/FVC ratio is when the BOS phenotype moves into the mixed phenotype. In these patients, usually the FEV1/FVC ratio will also remain <0.7, but it may increase from the value at the last BOS spirometry. In that situation, development of persistent opacities on chest imaging and the associated decline in TLC of ≥10% may be the best indicators of a mixed phenotype development. Chest CT may reveal opacities (ground glass, consolidation, small linear and reticular) that can be multilobar and/or show increasing pleural thickening consistent with a diagnosis of pulmonary and/or pleural fibrosis. This should be the prob