Progression pattern of restrictive allograft syndrome after lung transplantation

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1 FEATURED ARTICLES Progression pattern of restrictive allograft syndrome after lung transplantation Masaaki Sato, MD, PhD, a,b David M. Hwang, MD, PhD, a Thomas K. Waddell, MD, MSc, a Lianne G. Singer, MD, a and Shaf Keshavjee, MD, MSc a From the a Toronto Lung Transplant Program, University Health Network, University of Toronto, Ontario, Canada; and the b Department of Thoracic Surgery, Kyoto University, Kyoto, Japan. KEYWORDS: chronic rejection; chronic lung allograft dysfunction; restrictive allograft syndrome; diffuse alveolar damage; bronchiolitis obliterans syndrome BACKGROUND: Restrictive allograft syndrome (RAS) is a novel form of chronic lung allograft dysfunction after lung transplantation. RAS is characterized by restrictive physiology and peripheral lung fibrosis. The purpose of the study is to analyze progression patterns of RAS. METHODS: Clinical information, pulmonary function test results and radiographic findings were reviewed for 25 RAS patients who received bilateral lung or heart lung transplantation between January 2004 and December RESULTS: Average time from transplantation to RAS onset was (mean SD) days; RAS onset to end of observation (death or re-transplantation) was days. RAS patients had 1 to 4 episodes of acute exacerbation ( episodes/patient) that accompanied acute respiratory deterioration or distress, a sudden drop in pulmonary function, evidence of diffuse alveolar damage (DAD) on biopsies, and patchy or diffuse ground-glass opacities (GGO) with occasional consolidation on computed tomography scan. Patients were most frequently managed by high-dose steroid in combination with empirical antibiotics, with uncertain efficacy. Acute exacerbation was followed by an interval during which resolution of GGO and progression of consolidation, interstitial reticular shadows and traction bronchiectasis were frequently observed. The interval between episodes of acute exacerbation was days. In 21 patients, the last episode of acute exacerbation led to death or urgent retransplantation. CONCLUSIONS: RAS shows a stair-step pattern of progression. Acute lung injury represented by DAD and GGO is followed by an interval period during which graft fibrosis often progresses. J Heart Lung Transplant 2013;32:23 30 r 2013 International Society for Heart and Lung Transplantation. All rights reserved. Restrictive allograft syndrome (RAS) is a novel form of chronic lung allograft dysfunction (CLAD) after lung transplantation. 1 In contrast to bronchiolitis obliterans syndrome (BOS), which is characterized by small airway fibrosis and obstructive physiology, RAS is characterized by peripheral lung fibrosis and restrictive physiology. 1 In our recent study, RAS accounted for 25% to 35% of CLAD, 1 Reprint requests: Shaf Keshavjee, MD, MSc, Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth Street, 9N947, Toronto, ON M5G 2C4, Canada. Telephone: Fax: address: dr.shaf.keshavjee@uhn.on.ca /$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved. and the survival of RAS patients after CLAD onset was significantly shorter than that of BOS (median survival 541 days vs 1,421 days). 1 Such wide prevalence and negative clinical impact of RAS have recently been confirmed by the Leuven investigators. 2 A practical problem in the management of RAS patients is uncertainty in making the clinical diagnosis. We defined RAS as a form of CLAD that accompanies irreversible restrictive physiologic changes based on pulmonary function tests (PFTs). 1,3 Although the diagnostic criteria were useful in a retrospective study, they do not seem very helpful in prospective patient management. A patient

2 24 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 developing RAS is often too sick to undergo PFT 3 and, even if such testing can be performed, it is nearly impossible to determine whether the PFT decline can be reversed in a timely manner. Moreover, given the novelty of RAS as a diagnostic category, a detailed clinical course of RAS has not been well described. Thus, even if the diagnosis of RAS were to be made, it would be difficult for lung transplant physicians to predict what would happen next for the patient. Given such difficulties in diagnosis and management of RAS, more detailed descriptions of RAS are needed. In particular, radiologic characterization of RAS may be a valuable aid for lung transplant physicians. RAS is characterized by multiple radiographic abnormalities, including ground-glass opacities (GGO), interstitial reticular shadows and interlobular septal thickening. 1 However, our previous study was limited in that only the latest computed tomography (CT) scan was evaluated; hence, the CT scans evaluated were mostly those of terminal-stage RAS patients. Understanding the progression patterns of radiographic abnormalities in RAS and their association with clinical information would be helpful for lung transplant physicians. The purpose of the present study is to characterize progression pattern of RAS. We have demonstrated here that RAS shows a stair-step pattern of progression. Acute lung injury represented by diffuse alveolar damage (DAD) and GGO is followed by an interval period during which graft fibrosis often progresses. Methods Definition of CLAD and RAS CLAD and RAS were defined as described previously. 1 In brief, baseline forced expiratory volume in 1 second (FEV 1 ) was defined according to criteria recommended by the International Society for Heart and Lung Transplantation, 4 and then the baseline values of other PFT parameters were taken as the average of the parameters measured at the time of the best FEV 1 measurements. CLAD was defined as an irreversible drop of FEV 1 to o80% of baseline. RAS was defined as a condition in which restrictive physiology, defined by an irreversible decline in total lung capacity (TLC) to o90% of the baseline, coexists with CLAD. Acute exacerbation Acute exacerbation was defined as a sudden-onset or aggravation of respiratory distress that necessitated increased oxygen supplementation, hospital admission or mechanical ventilation. The first date when the symptomatic deterioration was recorded was defined as onset date of the episode of acute exacerbation. Symptoms (dry or productive cough and fever), results of sputum culture and bronchoalveolar lavage, biopsies (transbronchial or open lung biopsies) and treatment (changes or augmentation of immunosuppression, anti-microbial medication) at the time of acute exacerbation were reviewed in patient charts. Findings in chest CT reports were reviewed in patient charts; at the same time, chest CT scans were reviewed at 3 levels (aortic arch, tracheal bifurcation and inferior pulmonary vein). Appearance or aggravation of GGO, consolidation, interstitial reticular shadow and traction bronchiectasis were recorded. GGO was further classified into patchy (seen in fewer than 2 lobes) or diffuse. Intervals between episodes of acute exacerbation The first change in the slope of FEV 1 after the initiation of acute exacerbation was taken as the end of the acute exacerbation episode (Figure 1). Clinical courses after an episode of acute exacerbation were classified based on post-exacerbation FEV 1 changes (Figure 1). These included: complete recovery recovery of pulmonary function (FEV 1 ) close to the level of preexacerbation over time (480% from the end of acute exacerbation); partial recovery recovery of pulmonary function (FEV 1 ) after acute exacerbation 420%, but not to the level before acute exacerbation (o80%); stable disease stable FEV 1 after acute exacerbation (improvement or decline o20% to the end of acute exacerbation); and progressive disease a progressive decline in FEV 1 after acute exacerbation (decline 420% after the episode of acute exacerbation). Results Patient demographics of the 25 RAS cases examined are shown in Table 1. Among them, 3 patients initially showed BOS phenotype and then developed RAS. Although the number of patients with cystic fibrosis was relatively large Patients Among the 302 patients who received bilateral lung or heart lung transplantation in the Toronto Lung Transplant Program from January 1, 2004 to June 30, 2009 and survived 43 months with sufficient follow-up data, including measurements of TLC, 89 developed CLAD by April 30, Of these, 27 patients (30.3%) showed a RAS phenotype. Monthly spirometry was recommended for at least the first 2 years after transplant, with testing every 1 to 3 months thereafter. TLC was measured using plethysmography at least every 3 months in the first year, every 6 months in the second year, and annually thereafter. Detailed clinical information, including symptoms at the time of acute exacerbation, treatment conducted, and pathologic, radiologic and microbiologic results were available from 25 patients and studied further. Figure 1 Acute exacerbation and definition of clinical course during the period of study. The first change in the slope of FEV 1 after the initiation of acute exacerbation was taken as the end of the acute exacerbation episode. Clinical courses after an episode of acute exacerbation were classified based on post-exacerbation FEV 1 changes.

3 Sato et al. RAS Progression Pattern 25 Table 1 Patient Demographics Number of patients 25 Follow-up period, 1, (269 4,308) days (range) Time to RAS onset, (133 2,744) days (range) Recipient age at transplant, (15 66) years (range) Donor age at transplant, (16 69) year (range) Recipient gender M 12 (48%) F 13 (52%) Donor gender M 15 (60.0%) F 10 (40.0%) Original diagnosis CF 9 (36.0%) COPD 6 (24.0%) IPF 4 (16.0%) Bronchiectasis 2 (8.0%) PAH 2 (8.0%) Others 2 (8.0%) Transplant type Bilateral lung 22 (88.0%) Heart-lung 3 (12.0%) CMV matching D þ R þ 8 (32.0%) D þ R 8 (32.0%) D R þ 6 (24.0%) D R 3 (12.0%) CF, cystic fibrosis; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; PAH, pulmonary arterial hypertension. in this study, the original diagnosis was not significantly different among BOS, RAS and non-clad patients in our previous study using a larger cohort. 1 In all RAS cases analyzed, patients had at least 1 episode of acute exacerbation. None of the patients showed a steady gradual decline in pulmonary function, as described previously in BOS patients. 5 In total, 62 episodes of acute exacerbation were recorded, with 1 to 4 episodes per patient (mean SD: ). Time period from transplantation to the first episode of acute exacerbation was days (range 120 to 2,744 days, median 416 days). Time between episodes of acute exacerbation was days (range 34 to 687 days, median 161 days). Repeated exacerbation did not appear to change intervals between episodes of exacerbation (time between first to second episodes: days [range 34 to 687 days, median 181 days]; second to third episodes: days [range 76 to 683 days, median 146 days]; third to fourth episodes: days [range 92 to 348 days, median 321 days]). Time from the initial episode of acute exacerbation to death or retransplantation was days (range 104 to 1,612 days, median 457 days). Symptoms of acute exacerbation included shortness of breath or respiratory distress in all 62 of the episodes; fever Figure 2 Changes in CT scan findings at the time of acute exacerbation. CT scans at the time of acute exacerbation were available and compared with those before acute exacerbation in 43 episodes of 23 patients. Acute exacerbation typically showed GGO, more often diffuse than patchy. Appearance or aggravation of consolidation was also a relatively common finding, whereas appearance or aggravation of interstitial reticular shadow or traction bronchiectasis was observed less frequently at the time of acute exacerbation. was seen in 13 episodes and cough in 41 episodes, including dry cough in 28 and productive cough in 13. Lung biopsies were taken during 26 episodes in 21 patients, DAD was detected in 22 episodes of 19 patients, organizing pneumonia in 1 episode, and Grade A1 rejection was observed in 2 episodes of 2 patients. Infectious microorganisms were detected in 11 episodes of 8 patients; Pseudomonas aerginosa was detected in 4 episodes of 4 patients; Haemophilus influenzae, Klebsiella pneumoniae, Serratia marcescens, herpes simplex virus (HSV), cytomegalovirus (CMV), methicillin-sensitive Staphylococcus aureus, Aspergillus and Scedosporium species were each detected in 1 episode; Serratia and Scedosporium were detected at the same time in 1 episode; and Pseudomonas and Aspergillus were detected concurrently 1 episode. Among the 62 episodes of acute exacerbation, CT scans were available for comparison with those before acute exacerbation in 43 episodes. Acute exacerbations typically showed GGO. Appearance or aggravation of consolidation was also a relatively common finding, whereas interstitial reticular shadows or traction bronchiectasis were observed less frequently (Figure 2). These changes were usually bilateral but very often asymmetric. The management strategy that was taken most frequently in acute exacerbation was high-dose steroid with or without steroid pulse for 39 episodes in 24 patients. Immunosuppression regimens were modified in 5 episodes (cyclosporine to tacrolimus in 4 patients; azathioprine to mycophenolate mofetil in 1 patient). Thymoglobulin was used in 2 episodes and plasmapheresis was conducted in 3 episodes to treat existing donor-specific antibody. Azithromycin was initiated at the time of acute exacerbation in 8 episodes, whereas azithromycin had already been initiated in 23 episodes. Anti-bacterial antibiotics were given in 47 episodes, anti-fungal treatment in 8 episodes and

4 26 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 first exacerbation, PFT showed a decline over time, whereas, after the second episode, PFT showed partial recovery. On CT scan, there were diffuse bilateral GGO and consolidation at the time of exacerbation. GGO resolved to some extent during intervals between episodes of acute exacerbation, whereas consolidation and interstitial reticular shadow extended over time. The third episode resulted in the patient s death due to respiratory failure at 905 days after transplantation. Case 2 Figure 3 Changes in CT scan findings during intervals between acute exacerbations. During 25 acute exacerbation intervals in 18 patients, GGO usually showed improvement on CT scan, whereas other characteristics (interstitial reticular shadow, consolidation and traction bronchiectasis) tended to worsen. Not applicable (n/a) indicates that the type of abnormality did not exist before the interval and did not appear during the interval. anti-viral treatment in 15 episodes (14 anti-cmv, 1 acyclovir for HSV). After acute exacerbation, none of the RAS patients showed complete recovery of FEV 1. During intervals between episodes of acute exacerbation, partial recovery was observed in 12 intervals, stable disease in 10 intervals and progressive disease in 15 intervals. Different progression patterns were observed even in a single patient. Among 37 intervals between episodes of acute exacerbation, 25 series of CT scans were available for comparison with those of prior acute exacerbation. During intervals, CT scans typically showed improvement or disappearance of GGO, whereas other radiographic abnormalities, including interstitial reticular shadow, traction bronchiectasis and consolidation, tended to show aggravation (Figure 3). These changes were usually bilateral but were often asymmetric. To summarize, typical RAS patients had multiple episodes of acute exacerbation that were characterized by respiratory symptoms, DAD on biopsy and diffuse GGO on CT scan, with or without consolidation. High-dose steroid was the treatment of choice in combination with antibiotics in most episodes; however, the efficacy of the treatment was inconclusive. During intervals between episodes of acute exacerbation, pulmonary function may improve, remain stable or continue to decline; CT scan shows improvement in GGO whereas other radiologic abnormalities, such as interstitial reticular shadow, traction bronchiectasis and consolidation, may progress. Clinical data of 3 representative cases of RAS are shown in Figures 4, 5 and 6. Case 1 A 62-year-old man received cadaveric bilateral lung transplantation for chronic obstructive pulmonary disease (COPD) (Figure 4). Although his early post-transplant course was uneventful, he had 3 episodes of acute exacerbation. After the A 28-year-old man with cystic fibrosis received cadaveric bilateral lung transplantation (Figure 5). His post-transplant recovery was excellent except for complications of supraventricular tachycardia and intracardiac thrombus formation. His chest remained clear until he had an initial episode of acute exacerbation, accompanied by extensive bilateral GGO, bilateral pneumothoraces and pneumomediastinum (Figure 5C). Although PFT indicated temporary recovery and the radiographic abnormalities resolved to some extent, he had 3 subsequent episodes of acute exacerbation and eventually died of respiratory failure at 1,623 days after transplantation. Case 3 A 52-year-old man received bilateral lung transplantation for idiopathic pulmonary fibrosis (Figure 6). His clinical course was excellent until the first episode of acute exacerbation, approximately 1 year after transplantation. His general condition, PFTs and CT scans showed gradual improvement over the next 16 months, when he had a second episode of acute exacerbation. He died 868 days after transplantation due to respiratory failure. Discussion In this study we have documented the progression pattern of RAS. In general, patients suffer multiple episodes of acute exacerbation (a stair-step progression pattern) characterized by GGO, with or without consolidation and interstitial shadow on CT scan, and histologic features of DAD on biopsies. Although some episodes of acute exacerbation were associated with acute rejection or infection, there was no uniform explanation for acute exacerbation. After acute exacerbations, patients typically underwent periods of relative stability ranging from partial recovery to gradually progressive disease. During these intervals, GGO typically improved while other parenchymal changes (interstitial shadow, consolidation and traction bronchiectasis) tended to progress. Interestingly, episodes of acute exacerbation in RAS patients shared multiple features with acute respiratory distress syndrome (ARDS) in pathologic and radiographic findings. DAD, which was commonly found in RAS patients, 3 is essentially the pathologic counterpart of acute lung injury or ARDS. 6 Moreover, in CT scans, GGO and intense parenchymal opacification are the most common findings in the acute phase of ARDS. 7 GGO was more

5 Sato et al. RAS Progression Pattern 27 Figure 4 A representative case of RAS after lung transplantation: Case 1. (A) Post-transplant PFT changes of a 62-year-old man who received cadaveric bilateral lung transplantation for COPD. (B) (G) Chest CT scan of the same patient. (B) Post-transplant day 179, when the patient was stable. (C) Post-transplant day 361, when the patient was stabilized to some extent but still undergoing continuous functional deterioration. (D) Post-transplant day 760, when the patient was recovering from the second exacerbation. (E) Post-transplant day 284, when the patient underwent the first episode of acute exacerbation. DAD was detected in a transbronchial biopsy. Steroid pulse with empirical antibiotics treatment was conducted. Cyclosporine was switched to tacrolimus. (F) Post-transplant day 468, when the patient had the second episode of acute exacerbation. Once again, DAD was detected in a transbronchial biopsy. Azithromycin was initiated. (G) Post-transplant day 889, when the patient had the third episode of acute exacerbation. Arrows: time-point at which the CT scan was taken; white arrows: acute exacerbation. CsA, cyclosporine; FK, FK 506 (tacrolimus). frequently seen in the ventral (i.e., non-dependent) areas, whereas areas of intense parenchymal opacification or consolidation were more common in the dorsal areas in the supine position (i.e., gravity-dependent areas). 7 The CT findings in acute exacerbations of RAS were consistent with these findings. Findings in CT scans during intervals between episodes of acute exacerbation were also similar to those of ARDS in the sub-acute to chronic phase. The most common abnormality on CT in survivors of ARDS is reported to be a reticular pattern seen in 85% of patients at follow-up, whereas GGO usually resolves to some extent. 7 Traction bronchiectasis and loss of lung volume are also common findings in chronic ARDS patients, suggesting progressive fibrosis after an acute, inflammatory, exudative phase of ARDS. 8 Similar to ARDS, the cause of RAS remains unclear and is likely to be multifactorial. Although acute rejection and infection were demonstrated in the acute phase of RAS in some cases, it was not clear whether treatment such as augmented immunosuppression was effective in stabilization of patients, as none of the RAS patients recovered their pulmonary function after acute episodes despite such treatments, and the relative stabilization after an acute episode could simply reflect the natural history of the syndrome. We have recently demonstrated that detection of late new-onset DAD in transbronchial biopsies in patients who eventually developed RAS was

6 28 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 Figure 5 A representative case of RAS after lung transplantation: Case 2. (A) Post-transplant PFT changes in a 28-year-old man with cystic fibrosis who received cadaveric bilateral lung transplantation. (B) (G) Chest CT scan of the same patient. (B) Post-transplant day 215, when the patient was stable. (C) Post-transplant day 535, when the patient was recovering from the first episode of acute exacerbation. After steroid pulse and increased prednisone, function partially recovered with clearance of GGO, although interlobular septal thickening, interstitial reticular shadow and consolidation remained. (D) Post-transplant day 1,131, when the patient was recovering from the second exacerbation. Although his condition was relatively stable for 2 years after the second episode, the patient s CT scan showed gradual increases in interlobular septal thickening, interstitial reticular shadow and consolidation. He was listed for retransplantation. (E) Posttransplant day 374, when the patient underwent the first episode of acute exacerbation. CT scan showed extensive bilateral GGO, bilateral pneumothorax and pneumomediastinum. Transbronchial biopsies demonstrated DAD without evident rejection or infection. (F) Posttransplant day 817, when the patient had the second episode of acute exacerbation. CT scan showed reappearance of diffuse GGO with worsening interstitial shadows. (G) Post-transplant day 1,333, when the patient had the third episode of acute exacerbation. FEV 1 declined further. CT scan showed further volume loss in the transplanted lungs, extensive GGO, and worsening consolidation and interlobular septal thickening. Arrows: time-point at which CT scan was taken; white arrows: acute exacerbation. associated with acute rejection in 8 of 28 patients (7 with Grade A1 and 1 with Grade A2 rejection), whereas pathogenic microorganisms were detected in the concurrent bronchoalveolar lavage in 6 of 28 patients. 3 Although it is practically impossible to determine whether infection was the cause of DAD, at least infection was not as overwhelming as to directly explain the condition. In these cases, infection or rejection was appropriately treated and progression to graft dysfunction was not directly attributed to the development of RAS. Besides, an episode of aspiration was not documented as a cause of DAD in these cases, although the effect of reflux was not systemically examined. It is possible that, similar to ARDS, an insult to the lung allograft, such as infection, rejection or something else, leads to acute, uncontrollable inflammation followed by fibrosis. We have recently demonstrated that activation of stromal resident cells, such as epithelial cells and fibroblasts, is important in the pathogenesis of CLAD. 9 Regardless of the causal inflammatory stimuli, the vicious cycle of immuneresponsive cells and activated stromal resident cells through cytokines, chemokines and adhesion molecules 10 may

7 Sato et al. RAS Progression Pattern 29 Figure 6 Representative case of RAS after lung transplantation: Case 3. (A) Post-transplant PFT changes in a 52-year-old man who received bilateral lung transplantation for IPF. (B) (G) Chest CT scans of the same patient. (B) Post-transplant day 280, when the patient was stable. (C) 401 days post-transplant. (D) Post-transplant day 853, when the patient had the second episode of acute exacerbation. CT scan showed diffuse bilateral GGO, interstitial septal thickening and consolidation. (E) Post-transplant day 364, when the patient underwent the first episode of acute exacerbation. CT scan showed extensive GGO, reticular shadow, confluent airspace opacities and architectural distortion. Transbronchial biopsies showed DAD without rejection or infection. His general condition and PFTs and CT scans showed gradual improvement over the next 16 months. (F) 735 days post-transplant. (G) 883 days post-transplant. Although CT scan showed mild improvement in GGO 1 month later, his condition continued to deteriorate, and he died about 1 month after the second episode of acute exacerbation. Arrows: time-point at which the CT scan was taken; white arrows: acute exacerbation. lead to irreversible tissue organization and fibrosis namely, irreversible graft dysfunction. If so, an appropriate therapeutic target of RAS or CLAD in general should not simply be the cause (i.e., rejection or infection) but instead the final common pathway (i.e., uncontrollable inflammation and subsequent fibrosis). Although RAS is similar to ARDS in many aspects, an important unique feature of RAS is the stair-step progression pattern. It is unclear why lung transplant recipients are so vulnerable to the ARDS-like acute exacerbation and repeat such episodes. One possibility is that, unlike general ARDS patients, RAS patients (i.e., lung transplant recipients) are on the subtle balance between infection and rejection under immunosuppression, making patients highly susceptible to insults resulting from either rejection or infection. Another possibility is that the stem-cell population (epithelial progenitors) may be depleted over time in lung transplant recipients and this could contribute to vulnerability to damage or irreversible damage after an injury. 11 Further investigation is necessary to elucidate the mechanisms whereby RAS patients repeat such ARDS-like episodes. This is the key clinical feature of RAS explaining its poor prognosis when compared with BOS. Our study is limited primarily by its descriptive nature; however, recognition of the progression pattern of RAS is highly important to lung transplant physicians. The most

8 30 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 common scenario in RAS is that, at the time of patient deterioration, management is aimed at an unknown, unusual condition that appears to be different from either typical infection or rejection. We assume many experienced lung transplant physicians have faced similar conditions. This is now not such an unknown condition but is recognized as RAS. Another limitation of this work and our previous studies 1,3 is inclusion of only bilateral lung transplant recipients. Although we recognize a condition similar to RAS in single-lung transplant recipients, hyperinflation of contralateral COPD native lung or volume loss of contralateral idiopathic pulmonary fibrosis (IPF) lung is likely to confound the result of TLC measurements. Further investigation is necessary to establish objective diagnostic criteria applicable to single-lung transplant recipients. By applying the clinical characteristics described in this study, RAS-like cases could be identified among single-lung transplant patients. Although the prognosis is poor, the mechanism is still largely unclear, and the diagnostic criteria need to be refined further, characterization of RAS is an important initial step toward effective treatment in the future. Disclosure statement The authors have no conflicts of interest to disclose. References 1. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic allograft dysfunction after lung transplantation. J Heart Lung Transplant 2011;30: Verleden GM, Vos R, Verleden SE, et al. Survival determinants in lung transplant patients with chronic allograft dysfunction. Transplantation 2011;92: Sato 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: Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21: Jackson CH, Sharples LD, McNeil K, et al. Acute and chronic onset of bronchiolitis obliterans syndrome (BOS): are they different entities? J Heart Lung Transplant 2002;21: Castro CY. ARDS and diffuse alveolar damage: a pathologist s perspective. Semin Thorac Cardiovasc Surg 2006;18: Desai SR, Wells AU, Rubens MB, et al. Acute respiratory distress syndrome: CT abnormalities at long-term follow-up. Radiology 1999;210: Desai SR. Acute respiratory distress syndrome: imaging of the injured lung. Clin Radiol 2002;57: Sato M, Hirayama S, Matsuda Y, et al. Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction. Transplantation 2011;91: Sato M, Keshavjee S. Bronchiolitis obliterans syndrome: alloimmunedependent and -independent injury with aberrant tissue remodeling. Semin Thorac Cardiovasc Surg 2008;20: Gilpin SE, Lung KC, Sato M, et al. Altered progenitor cell and cytokine profiles in bronchiolitis obliterans syndrome. J Heart Lung Transplant 2012;31:222-8.