Chronic Lung Allograft Dysfunction Onset Research Articles

Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation.

Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restrictionon PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

The Association Between Frailty and Chronic Lung Allograft Dysfunction After Lung Transplantation.

After lung transplantation, both frailty and chronic lung allograft dysfunction (CLAD) commonly develop, and when they do, are associated with poorer outcomes. Given their potential shared mechanisms, we sought to explore the temporal relationship between frailty and CLAD onset. In a single center, we prospectively measured frailty by the short physical performance battery (SPPB) repeatedly after transplant. Because of the nature of the relationship between frailty and CLAD is unknown, we tested the association between frailty, modeled as a time-dependent predictor, and CLAD development as well as CLAD development, modeled as a time-dependent predictor, and frailty development. To do so, we used Cox proportional cause-specific hazards and conditional logistic regression models adjusted for age, sex, race, diagnosis, cytomegalovirus serostatus, posttransplant body mass index, and acute cellular rejection episodes as time-dependent covariates. We tested SPPB frailty as a binary (≤9 points) and continuous predictor (12-point scale); as an outcome, we defined frailty as SPPB ≤9. The 231 participants were a mean age of 55.7 y (SD 12.1). After adjusting for covariates, the development of frailty within 3 y after lung transplant was associated with cause-specific CLAD risk (adjusted cause-specific hazard ratio: 1.76; 95% confidence interval [CI], 1.05-2.92 when defining frailty as SPPB ≤9 and adjusted cause-specific hazard ratio: 1.10, 95% CI, 1.03-1.18 per 1-point worsening in SPPB). CLAD onset did not appear to be a risk factor for subsequent frailty (odds ratio, 4.0; 95% CI, 0.4-197.0). Studying the mechanisms underlying frailty and CLAD could provide new insights into the pathobiology of both and potential targets for intervention.

Risk of Bronchial Complications After Lung Transplantation With Respiratory Corynebacteria. Results From a Monocenter Retrospective Cohort Study.

Corynebacterium spp. are associated with respiratory infections in immunocompromised hosts. A link with bronchial complications after lung transplantation (LTx) has been suggested. We aimed to assess the link between respiratory sampling of Corynebacterium spp. and significant bronchial complication (SBC) after LTx. We performed a single center retrospective study. Inclusion of LTx recipients with at least one respiratory Corynebacterium spp. sample (July 2014 to December 2018). Subjects were matched to unexposed LTx recipients. Primary outcome was SBC occurrence after Corynebacterium spp. isolation. Secondary outcomes were Corynebacterium spp. persistent sampling, chronic lung allograft dysfunction (CLAD) onset and all-cause mortality. Fifty-nine patients with Corynebacterium spp. sampling with 59 without isolation were included. Corynebacterium spp. identification was not associated with SBC occurrence (32.4% vs. 21.6%, p = 0.342). Previous SBC was associated with further isolation of Corynebacterium spp. (OR 3.94, 95% CI [1.72-9.05]). Previous SBC and corticosteroids pulses in the last 3months were the only factors associated with increased risk of Corynebacterium spp. isolation in multivariate analysis. Corynebacterium spp. sampling was significantly associated with CLAD onset (27.1% vs. 6.9%, p = 0.021). Corynebacterium spp. isolation was not associated with SBC but with higher risk of CLAD. Whether CLAD evolution is affected by Corynebacterium spp. eradication remains to be investigated.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

Quantitative Image Analysis at Chronic Lung Allograft Dysfunction Onset Predicts Mortality.

Background.Chronic lung allograft dysfunction (CLAD) phenotype determines prognosis and may have therapeutic implications. Despite the clarity achieved by recent consensus statement definitions, their reliance on radiologic interpretation introduces subjectivity. The Center for Computer Vision and Imaging Biomarkers at the University of California, Los Angeles (UCLA) has established protocols for chest high-resolution computed tomography (HRCT)-based computer-aided quantification of both interstitial disease and air-trapping. We applied quantitative image analysis (QIA) at CLAD onset to demonstrate radiographic phenotypes with clinical implications.Methods.We studied 47 first bilateral lung transplant recipients at UCLA with chest HRCT performed within 90 d of CLAD onset and 47 no-CLAD control HRCTs. QIA determined the proportion of lung volume affected by interstitial disease and air-trapping in total lung capacity and residual volume images, respectively. We compared QIA scores between no-CLAD and CLAD, and between phenotypes. We also assigned radiographic phenotypes based solely on QIA, and compared their survival outcomes.Results.CLAD onset HRCTs had more lung affected by the interstitial disease (P = 0.003) than no-CLAD controls. Bronchiolitis obliterans syndrome (BOS) cases had lower scores for interstitial disease as compared with probable restrictive allograft syndrome (RAS) (P < 0.0001) and mixed CLAD (P = 0.02) phenotypes. BOS cases had more air-trapping than probable RAS (P < 0.0001). Among phenotypes assigned by QIA, the relative risk of death was greatest for mixed (relative risk [RR] 11.81), followed by RAS (RR 6.27) and BOS (RR 3.15).Conclusions.Chest HRCT QIA at CLAD onset appears promising as a method for precise determination of CLAD phenotypes with survival implications.

Chronic lung allograft dysfunction is associated with an early increase of circulating cytotoxic CD4+CD57+ILT2+ T cells, selectively inhibited by the immune check-point HLA-G

Survival after lung transplantation (LTx) still remains limited by chronic lung allograft dysfunction (CLAD), thought to represent a form of chronic rejection. We investigated whether the immune checkpoint HLA-G/ILT2 expressed by peripheral T-cell subpopulations could predict CLAD.We used data for 150 LTx recipients from COLT (Cohort-For-Lung-Transplantation) cohort with ≥1 available blood sample at 1-, 6-, or 12-months post-Tx. Analysis of T cells by flow cytometry focused on the ILT2 receptor of HLA-G and other markers (CD57, CD25, CD127). T-cell subset analyses compared stable patients and those with CLAD at 3 years post-LTx.With data for 78 stable and 72 CLAD patients, among 21 T-cell subsets expressing ILT2, only CD4+CD57+ILT2+ T cells were associated with outcome. At 1-month post-Tx, low proportion of CD4+CD57+ILT2+ T cells was associated with reduced 3-year incidence of CLAD (CD4+CD57+ILT2+ T cells ≤ first IQR [25%] vs > first IQR, log-rank test, p = 0.028). Furthermore, the incidence of CLAD was higher with >2.6- vs ≤2.6-fold increased proportion of CD4+CD57+ILT2+ T cells over the first year post-LTx (3-year freedom frequencies: 27% [95%CI: 8-50] vs 64% [95%CI: 48-77] (log-rank test, p = 0.014). On multivariable analysis, increased proportion of CD4+CD57+ILT2+ T cells over the first year predicted CLAD (hazard ratio 1.25; 95%CI: 1.09-1.44; p = 0.001). Focusing on CD4+CD57+ILT2+ T cells, we demonstrated ex vivo that they are cytotoxic CD4+ T cells, selectively inhibited by HLA-G.Our data suggest that an early increase of CD4+CD57+ILT2+ T cells after LTx may be associated with CLAD onset.

The Percentage of Low Attenuation Area on Computed Tomography to Detect Chronic Lung Allograft Dysfunction After Bilateral Lung Transplantation

<h3>Purpose</h3> Lung emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). To evaluate the severity of lung emphysema, the percentage of low attenuation area (LAA%) of the bilateral lungs calculated on computed tomography has been shown to be a useful index. This study aimed to investigate whether the LAA% was associated with the development of CLAD after bilateral LT. <h3>Methods</h3> We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT from May 2008 to August 2015. The LAA% on computed tomography were calculated and compared between the CLAD group (N = 30) and the non-CLAD group (N = 45) from 2 years before to 4 years after the diagnosis of CLAD. The LAA% at 5 years after bilateral LT was designated as the control value in the non-CLAD group. The Pearson product-moment correlation coefficient was calculated between the LAA% and the percent baseline values of the forced expiratory volume in 1 s (FEV1), the forced vital capacity (FVC), and the total lung capacity (TLC) at the diagnosis of CLAD after bilateral LT. <h3>Results</h3> The median observation period after LT was 3277 (380-7691) days. The LAA% in the CLAD group was significantly higher than that in the non-CLAD group from even 2 years before the diagnosis of CLAD to 2 years after the diagnosis of CLAD (P < 0.05) (Figure 1). The difference in the LAA% between the CLAD group and the non-CLAD group tended to increase after the onset of CLAD. Furthermore, the LAA% was significantly correlated with the percent baseline values of the FEV1, the FVC, and the TLC (FEV1, r = -0.36, P = 0.0031; FVC, r = -0.27, P = 0.027; TLC, r = -0.40, P < 0.001) (Figure 2). <h3>Conclusion</h3> The LAA% was associated with the development of CLAD and increased after the diagnosis of CLAD. Moreover, the LAA% was associated with declines in the FEV1, FVC and TLC at the time of CLAD diagnosis. The LAA% appears to have the potential to predict CLAD after bilateral LT.

Oxygenated Hemoglobin Predicts Outcome in Patients with Chronic Lung Allograft Dysfunction

Background: Long-term outcome of lung transplantation (LTx) recipients is limited by chronic lung allograft dysfunction (CLAD). In this setting of new onset respiratory failure, the amount of oxygenated hemoglobin (OxyHem; hemoglobin (Hb) concentration × fractional oxygen saturation) may provide valuable information. Objective: We hypothesized that OxyHem predicts survival of LTx recipients at the onset of CLAD. Methods: Data from 292 LTx recipients with CLAD were analyzed. After excluding patients with missing data or supplemental oxygen, the final population comprised 218 patients. The relationship between survival upon CLAD and OxyHem was analyzed by Cox regression analyses and ROC curves. Results: Among the 218 patients (102 males, 116 females), 128 (58.7%) died, median survival time after CLAD onset being 1,156 days. Survival was significantly associated with type of transplantation, time to CLAD, CLAD stage at onset, and OxyHem, which was superior to Hb or oxygen saturation. The risk for death after CLAD increased by 14% per reduction of OxyHem by 1 g/dL, and values below 11 g/dL corresponded to an 80% increase in mortality risk. Conclusion: Thus, OxyHem was identified as an independent predictor of mortality after CLAD onset. Whether it is useful in supporting therapeutic decisions and potentially home monitoring in the surveillance of lung transplant recipients has to be studied further.

Significance of phenotype change after chronic lung allograft dysfunction onset.

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR=4.00, CI 2.74-5.83, P<0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P<0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.

Chronic lung allograft dysfunction subtype analysis by computed tomography volumetry.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation. Of the two subtypes, restrictive allograft syndrome (RAS) is characterized by a larger lung volume decrease and worse prognosis than bronchiolitis obliterans syndrome (BOS). We used computed tomography (CT) volumetry to classify CLAD subtypes and determined their clinical impact. Adult primary lung transplants performed 2003-2015 (n=167) were retrospectively evaluated for CLAD and subclassified with CT volumetry. Lung volume decrease of<15% from baseline resulted in BOSCT-vol and ≥15% resulted in RASCT-vol diagnosis. Clinical impact of CLAD subtypes was defined, and the prognostic value of different lung function, radiological, and lung volume parameters present at the time of CLAD diagnosis were compared. CLAD affected 43% of patients and was classified with CT volumetry as BOSCT-vol in 89% and RASCT-vol in 11%. Median graft survival estimate in RASCT-vol was significantly decreased compared to BOSCT-vol (1.6vs. 9.7 years, P=.038). At CLAD onset, RASCT-vol diagnosis (P=.05), increased lung density (P=.007), and more severe FEV1 (P=.004) decline from baseline, increased graft loss risk in multivariate analysis. CT volumetry serves to identify lung transplant patients with a poor clinical outcome but should be validated in prospective trials.

Diffusing capacity of the lung for carbon monoxide: association with long-term outcomes after lung transplantation in a 20-year longitudinal study.

The diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (D LCOcor) measures gas movement across the alveolar-capillary interface. We hypothesised that D LCOcor is a sensitive measure of injurious allograft processes disrupting this interface. To determine the prognostic significance of the D LCOcor trajectory on chronic lung allograft dysfunction (CLAD) and survival. A retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or more D LCOcor measurements. Low baseline D LCOcor was defined as the failure to achieve a D LCOcor >75% predicted. Drops in D LCOcor were defined as >15% below recent baseline. 1259 out of 1492 lung transplant recipients were included. The median (range) time to peak D LCOcor was 354 (181-737) days and the mean±sd D LCOcor was 80.2±21.2% pred. Multivariable analysis demonstrated that low baseline D LCOcor was significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27-2.20; p<0.001). Low baseline D LCOcor was not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. Any D LCOcor declines ≥15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predicted D LCOcor values at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01). Low baseline D LCOcor and post-transplant declines in D LCOcor were significantly associated with survival, independent of spirometric measurements. We propose that D LCOcor testing may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring of D LCOcor after lung transplantation to identify patients at risk of poor outcomes.

Risk Assessment of Chronic Lung Allograft Dysfunction Phenotypes after Living-Donor Lobar Lung Transplantation According to the 2019 ISHLT Classification System

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is known as one of the major fatal disorders in the long-term phase after lung transplantation. Because CLAD is a heterogeneous disease, proper classification of phenotypes is important to understand each pathogenesis. In this study, we retrospectively evaluated the impact of new 2019 ISHLT classification system on living-donor lobar lung transplantation (LDLLT). <h3>Methods</h3> Between 1998 and 2019, a total of 96 patients underwent LDLLT at our hospital, and 73 patients who underwent bilateral LDLLT were included in this study. CLAD after bilateral LDLLT were diagnosed and classified according to the ISHLT consensus report in 2019. <h3>Results</h3> The median follow-up time was 10.3 years. A total of 27 (37.0%) patients were diagnosed as CLAD, including bronchiolitis obliterans syndrome (BOS) (n = 8, 29.6%), restrictive allograft syndrome (RAS) (n = 11, 40.7%), mixed (n = 1, 3.7%), undefined (n = 2, 7.4%), and unclassified (n = 5, 18.5%). CLAD developed in the unilateral lung in 26 patients. Five-year survival of the patients developing CLAD after LDLLT was 84.1%, whereas 5-year survival of the patients after CLAD onset was 58.4%. Survival after CLAD onset was worse in the patients with RAS (p=0.008) and undefined (p=0.003) than those with BOS. Though survival after CLAD onset did not differ between the patients with or without CT opacities (p=0.40), the patients with restriction on pulmonary function test had significantly worse survival than those without restriction (Figure, p=0.001). <h3>Conclusion</h3> While the patients with BOS had better prognosis, the presence of restriction on pulmonary function test could predict worse prognosis of the CLAD patients after bilateral LDLLT.

Non HLA Antibodies in Serum Prior to the Onset of Chronic Lung Allograft Dysfunction

PurposeNon-human leukocyte antigen (HLA) antibodies have been associated with chronic lung allograft dysfunction (CLAD). Whether they predate CLAD is unclear. We hypothesized that patients destined to develop CLAD might develop non-HLA antibodies prior to CLAD onset.MethodsIn a single centre retrospective study, we examined 100 consecutive crossmatch negative recipients of a bilateral lung transplant between 1 January 2013 and 31 December 2014. Using a two-colour fluorescent antigen microarray with 152 unique antigens, we measured IgG and IgM autoantibodies in pre-transplant and six months post-transplant serum samples. Log2-transformed mean fluorescent intensities (MFIs) were determined for each antigen. CLAD was determined using published definitions. Significance analysis of microarrays (SAM) was used to analyze differences in antigen reactivity with a false discovery rate of 0.05. Paired and unpaired analyses were used to examine differences within and between recipients who developed CLAD within 5 years and recipients who remained CLAD free at 5 years post-transplant.ResultsSerum samples were available for 96 recipients - 35 (36.5%) developed CLAD and 61 remained CLAD-free within 5 years. Total IgM and IgG reactivity decreased in most patients post-transplant (Fig 1A), although IgM levels were stable in patients developing CLAD. Three IgM autoantibodies - including anti-club cell secretory protein (CCSP, Fig 1B) - increased in most patients post-transplant; this increase was of greater magnitude in patients later developing CLAD. Patients destined to develop CLAD also had an increase in IgG fluorescence directed at human core histones (Fig 1C).ConclusionOur results suggest that there may be important differences in non-HLA antibody reactivity that appear before the onset of CLAD. These observations, which require validation in further studies, may also indicate a specific role for non-HLA antibodies directed at club cell secretory protein and nuclear antigens in CLAD development. Non-human leukocyte antigen (HLA) antibodies have been associated with chronic lung allograft dysfunction (CLAD). Whether they predate CLAD is unclear. We hypothesized that patients destined to develop CLAD might develop non-HLA antibodies prior to CLAD onset. In a single centre retrospective study, we examined 100 consecutive crossmatch negative recipients of a bilateral lung transplant between 1 January 2013 and 31 December 2014. Using a two-colour fluorescent antigen microarray with 152 unique antigens, we measured IgG and IgM autoantibodies in pre-transplant and six months post-transplant serum samples. Log2-transformed mean fluorescent intensities (MFIs) were determined for each antigen. CLAD was determined using published definitions. Significance analysis of microarrays (SAM) was used to analyze differences in antigen reactivity with a false discovery rate of 0.05. Paired and unpaired analyses were used to examine differences within and between recipients who developed CLAD within 5 years and recipients who remained CLAD free at 5 years post-transplant. Serum samples were available for 96 recipients - 35 (36.5%) developed CLAD and 61 remained CLAD-free within 5 years. Total IgM and IgG reactivity decreased in most patients post-transplant (Fig 1A), although IgM levels were stable in patients developing CLAD. Three IgM autoantibodies - including anti-club cell secretory protein (CCSP, Fig 1B) - increased in most patients post-transplant; this increase was of greater magnitude in patients later developing CLAD. Patients destined to develop CLAD also had an increase in IgG fluorescence directed at human core histones (Fig 1C). Our results suggest that there may be important differences in non-HLA antibody reactivity that appear before the onset of CLAD. These observations, which require validation in further studies, may also indicate a specific role for non-HLA antibodies directed at club cell secretory protein and nuclear antigens in CLAD development.

Longitudinal lung function measurements in single lung transplant recipients with chronic lung allograft dysfunction

Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) recipients is challenging. The aim of this study was to assess the diagnostic and prognostic value of longitudinal lung function tests in SLTX recipients with CLAD. A total of 295 SLTX recipients were analyzed and stratified according to native lung physiology. In addition to spirometry, measurements of static lung volumes and lung capacities were used to phenotype patients and to assess their prognostic value. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n = 71). Of 224 lung transplant recipients, 105 (46.9%) developed CLAD. Time to CLAD onset (hazard ratio [HR]: 0.82, 95% CI: 0.74-0.90; p < 0.001), severity of CLAD at onset (HR: 0.97, 95% CI: 0.94-0.99; p = 0.009), and progression after onset of CLAD (HR: 1.03, 95% CI: 1.00-1.05; p = 0.023) were associated with outcome. Phenotypes at onset were bronchiolitis obliterans syndrome (BOS) (59.1%), restrictive allograft syndrome (RAS) (12.4%), mixed phenotype (6.7%), and undefined phenotype (21.9%). Survival estimates differed significantly between phenotypes (p = 0.004), with RAS and mixed phenotype being associated with the worst survival, followed by BOS and undefined phenotype. Finally, a higher hazard for mortality was noticed for RAS (HR: 2.34, 95% CI: 0.99-5.52; p = 0.054) and mixed phenotype (HR: 3.30, 95% CI: 1.20-9.11; p = 0.021) while controlling for time to CLAD onset and severity of CLAD at onset. Phenotyping CLAD in SLTX remains challenging with a high number of patients with an undefined phenotype despite comprehensive lung function testing. However, phenotyping is of prognostic value. Furthermore, early, severe, and progressive CLADs are associated with worse survival.

Fibroproliferation in chronic lung allograft dysfunction: Association of mesenchymal cells in bronchoalveolar lavage with phenotypes and survival

Chronic lung allograft dysfunction (CLAD), the primary cause of poor outcome after lung transplantation, arises from fibrotic remodeling of the allograft and presents as diverse clinical phenotypes with variable courses. Here, we investigate whether bronchoalveolar lavage (BAL) mesenchymal cell activity at CLAD onset can inform regarding disease phenotype, progression, and survival. Mesenchymal cell colony-forming units (CFUs) were measured in BAL obtained at CLAD onset (n = 77) and CLAD-free time post-transplant matched controls (n = 77). CFU counts were compared using Wilcoxon's rank-sum test. Cox proportional hazards and restricted means models were utilized to investigate post-CLAD survival. Higher mesenchymal CFU counts were noted in BAL at the time of CLAD onset than in CLAD-free controls. Patients with restrictive allograft syndrome had higher BAL mesenchymal CFU count at CLAD onset than patients with bronchiolitis obliterans syndrome (p = 0.011). Patients with high mesenchymal CFU counts (≥10) at CLAD onset had worse outcomes than those with low (<10) CFU counts, with shorter average survival (2.64 years vs 4.25 years; p = 0.027) and shorter progression-free survival, defined as time to developing either CLAD Stage 3 or death (0.97 years vs 2.70 years; p < 0.001). High CFU count remained predictive of decreased overall survival and progression-free survival after accounting for the CLAD phenotype and other clinical factors in multivariable analysis. Fulminant fibroproliferation with higher mesenchymal CFU counts in BAL is noted in restrictive allograft syndrome and is independently associated with poor survival after CLAD onset.

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system

Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan-Meier and Cox proportional hazards models. Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17-3.93; p = 0.014) and similar survival to RAS or mixed phenotype. The new ISHLT CLAD phenotype classification is informative with regards to post-CLAD outcomes. Chest imaging demonstrating persistent parenchymal or pleural fibrosis may be used for risk-stratification of patients who do not match the major CLAD phenotypes.

Significance of Phenotype Change Post CLAD-Onset on Allograft Survival

Previous studies suggest Chronic Lung Allograft Dysfunction (CLAD) subtypes with RAS-like opacities (RLO) (i.e. persistent parenchymal or pleural fibrosis) at CLAD onset to have worse survival. However, the significance of transitions between CLAD subtypes remains obscure. This was a single center, retrospective cohort study of consecutive adult, first bilateral lung transplants from 2010-2015. Patients with CLAD were classified into ISHLT phenotypes BOS, RAS, Mixed, undefined and some remained unclassified. We defined phenotype transition as a change of at least one of three determinants: obstruction, restriction or RLO. Association of phenotype transition with time to death or retransplant starting at CLAD onset or transition date was assessed using Cox PH models. Multivariable models included age and CMV mismatch. Of 173 patients with CLAD, 108 patients with no RLO and 28 with RLO at CLAD onset did not change phenotype. 37 patients (21.3%) had a phenotype transition at a median time of 329 days (IQR 166-591) post CLAD onset. 15 patients without RLO (12 BOS, 2 undefined, 1 unclassified) developed RLO and changed phenotype to RAS (1), mixed (7), or undefined (7). 22 patients had a phenotype transition owing to a change in the ventilatory defect pattern (10 with RLO and 12 without RLO). Patients who developed RLO after CLAD onset had a non-significant trend towards worse survival from CLAD onset (HR=1.29, p=0.7) and also from transition date (HR=3.45, p=0.1) compared to patients who transitioned to a phenotype without RLO (Fig 1A), probably due to small number of patients. Survival after RLO emergence did not differ between patients with RLO at CLAD onset and patients who developed RLO post CLAD onset (HR=1.69, p=0.17 (Fig 1B). Our study shows that phenotype transition is a relatively common phenomenon, although a transition to RAS-like opacities occurred in only 9% of CLAD patients. The poor survival from emergence of RAS-like opacities appears to be similar regardless of timing relative to CLAD onset.

Azithromycin Prophylaxis after Lung Transplantation is Associated with Improved Survival and Graft Function

Azithromycin prophylaxis (AP) has been shown in a clinical trial to reduce the cumulative incidence of death or chronic lung allograft dysfunction (CLAD) onset in lung transplant recipients. However, there has been a lack of follow-up data on the long-term efficacy of this strategy in larger cohorts. Our program began using AP in 2010. Our objective was to evaluate the association between AP survival as well as CLAD and baseline lung allograft dysfunction (BLAD). We hypothesized that patients receiving AP would show equivalent survival and but reduced rates of CLAD and BLAD. We studied all double lung transplant recipients transplanted in our program between 2004-2016. We defined AP as any use of azithromycin prior to CLAD onset. The primary endpoint was death or retransplantation. We defined CLAD status, grade and subtype according to the 2019 ISHLT consensus criteria and BLAD in accordance with our previous published definition. We analyzed survival using proportional hazards regression with AP as a time-varying covariate, adjusting for recipient age, gender, transplant type, underlying diagnosis, year of transplant and induction. We used logistic regression to assess the relationship between AP and baseline allograft dysfunction (BLAD), defined as a failure to achieve both FEV1 and FVC ≥80% predicted on 2 consecutive tests ≥3 weeks apart. 445 patients were included and 344 (77%) were given AP with median time to azithromycin of 51 days [25th-75th quartile 20-211]. Patients receiving AP were more likely to receive induction with IL-2 receptor antagonists (57% vs. 35%; p<0.001) and had shorter mechanical ventilation (54 [29-150] vs. 96 [48-245] hours; p<0.001) and hospital stay (23 [18-36] days vs. 29 [19-44] days; p=0.016). AP was associated with improved survival (hazard ratio [HR] 0.60 [95% confidence interval [CI] 0.44-0.84]; p=0.002) in our adjusted model, as well as a reduced risk of CLAD onset (HR 0.64 [95% CI 0.44-0.94]; p=0.025) and reduced risk for BLAD (odds ratio 0.55 [95% CI 0.35-0.86]; p=0.009) in unadjusted models. Azithromycin prophylaxis is associated with improved survival after lung transplantation, possibly through improved baseline function and a reduced CLAD risk. This corroborates prior trial results, and suggest AP implementation would be beneficial for lung transplant recipients.

Transition from BOS to RAS Impairs Prognosis after Lung Transplantation - CLAD Subtype Analysis by CT-Volumetry

Chronic lung allograft dysfunction (CLAD) is the most important reason for poor patient survival after lung transplantation. Of the two CLAD subtypes, restrictive allograft syndrome (RAS) has worse prognosis than bronchiolitis obliterans syndrome (BOS), but only limited information is available on the incidence and clinical effect of CLAD subtype change after CLAD onset. We set out to characterize CLAD subtype development by computed tomography (CT) volumetry after CLAD onset. 167 adult patients who underwent de novo lung transplantation in a nationwide transplant centre between 2003-2015 were retrospectively analyzed. CLAD subtype was determined by CT volumetry at CLAD onset. Lung volume decrease of <15% from baseline resulted in BOS and >15% in RAS classification. Patients were re-classified to BOS->RAS or RAS->BOS if persistent lung volume change was detected, and no other specific reasons for lung volume change were present. Radiologic findings of air trapping and fibrosis were linked to lung volume change. Seventy-one (43%) patients were diagnosed with CLAD which was classified as BOS in 63 (89%) and RAS in 8 (11%) patients. After CLAD onset, 6 (9.5%) of BOS patients were re-classified as BOS->RAS, and one (12.5%) RAS patient was re-classified as RAS->BOS whereas other patients remained in their original CLAD subtype. Class change from BOS to RAS occurred at a median of 515.5 days after CLAD onset. Recipient (Figure A, p= 0.002) and graft survival (Figure B, p= 0.003) after CLAD diagnosis was impaired in BOS->RAS group compared to patients remaining in the BOS category. Radiological evidence of both air trapping and fibrosis was seen in 83% of BOS->RAS patients, and fibrotic changes preceded the subtype change in 67% of patients. A significant proportion of BOS patients transform to RAS after CLAD diagnosis, which has an adverse effect on recipient and graft survival.

Prevalence and Prognosis of Updated Phenotypes of Chronic Lung Allograft Dysfunction

The recently updated ISHLT chronic lung allograft dysfunction (CLAD) consensus report establishes four CLAD phenotypes. The proportion of patients who meet criteria for these phenotypes and their respective survival have not been described. We retrospectively determined the CLAD phenotype at the time of CLAD onset for all patients who received a bilateral lung transplant at the University of Michigan based on the presence of obstruction (FEV1/FVC <70%), restriction (TLC <90% of post-transplant baseline, when TLC data was not available FVC <80% of post-transplant baseline), and radiographic opacities (CT scan with parenchymal opacities or pleural thickening). Survival analyses were performed using Cox proportional hazards and presented as Kaplan Meier curves. Among 327 eligible patients, 142 (43.4%) developed a definitive FEV1 decline not attributable to another cause, consistent with CLAD. At CLAD onset, 46 (32.4%) patients had BOS, 22 (15.5%) patients had undefined CLAD, 12 (8.5%) had RAS, 8 (5.6%) patients had mixed CLAD; 54 (38.0%) patients could not be classified as any CLAD phenotype as defined by ISHLT guidelines (Figure, panel A). Compared to patients with BOS, patients with undefined CLAD, RAS, and mixed CLAD all had shorter survival after CLAD onset (p<0.001, p=0.007 & p<0.001, respectively), but these were not significantly different from each other (Figure, panel B). Patients with undefined CLAD, RAS, and mixed CLAD, as defined by the updated ISHLT guidelines, have worse survival than patients with BOS. A substantial portion of patients with CLAD could not be categorized into a defined phenotype.