Diagnosis Of Chronic Lung Allograft Dysfunction Research Articles

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.

Influence of azithromycin and allograft rejection on the post–lung transplant microbiota

Alterations in the lung microbiota may drive disease development and progression in patients with chronic respiratory diseases. Following lung transplantation (LTx), azithromycin is used to both treat and prevent chronic lung allograft dysfunction (CLAD). The objective of this study was to determine the association between azithromycin use, CLAD, acute rejection, airway inflammation, and bacterial microbiota composition and structure after LTx. Bronchoalveolar lavage samples (n = 219) from 69 LTx recipients (azithromycin, n = 32; placebo, n = 37) from a previously conducted randomized placebo-controlled trial with azithromycin were analyzed. Samples were collected at discharge, 1, and 2 years following randomization and at CLAD diagnosis. Bacterial microbial community composition and structure was determined using 16S ribosomal RNA gene sequencing and associated with clinically important variables. At discharge and following 1 and 2 years of azithromycin therapy, no clear differences in microbial community composition or overall diversity were observed. Moreover, no changes in microbiota composition were observed in CLAD phenotypes. However, acute rejection was associated with a reduction in community diversity (p = 0.0009). Significant correlations were observed between microbiota composition, overall diversity, and levels of inflammatory cytokines in bronchoalveolar lavage, particularly CXCL8. Chronic azithromycin usage did not disturb the bacterial microbiota. However, acute rejection episodes were associated with bacterial dysbiosis.

Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.

Single nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was one-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased one-year survival [rs7311358 HR 7.76 (1.37–44.04), p=0.021; rs4149117 HR 7.28 (1.27–41.78), p=0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01(1.06–3.81), p=0.031; rs7311358 GG699/G699A: OR 2.18(1.13–4.21) p=0.019] and lower survival through three years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p=0.048, rs7311358 p=0.023). For the MPA patients, Cox regression modelling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

Identification and Characterization of Patients With a Mixed Phenotype of CLAD

Purpose Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), have been identified as main phenotypes of chronic lung allograft dysfunction (CLAD), however patients can change phenotype. We aimed to describe incidence, prognosis, radiology, pulmonary function and pathology in this mixed group of CLAD. Methods We retrospectively assessed the chest CT-scans of all double lung patients transplanted between 2001 and 2015 with a FEV1 decline >20% of baseline. The diagnosis of RAS was made using a decline in TLC>10% compared to baseline or a decline in FVC>20% compared to baseline. A mixed group of CLAD was defined as patients developing a TLC or FVC decline with persistent CT opacities after initial CLAD diagnosis (without TLC or FVC drop) or vice versa. Results 44% of the patients developed CLAD (268/608) of which 77 developed persistent CT opacities (29%). 45 patients were immediately diagnosed with RAS. We found twenty-seven patients with a mixed phenotype of CLAD (25 BOS to RAS, 2 RAS to BOS). In 5 patients persistent pleuroparenchymal opacities were found without an additional decrease in FVC or TLC. The median time between CLAD and mixed diagnosis was 2Y (IQR 0.9-4.8Y). Median survival after CLAD diagnosis was longer in the mixed group compared to the RAS group (4.3Y vs 1.17, p=0.0052), however survival after the appearance of opacities was similar in both groups (p=0.39). We found significantly more emphysema patients in the mixed group (p=0.0062), with a lower FEV1 (p Conclusion We demonstrated that 35% of patients showed a mixed phenotype of CLAD, which showed difference in survival, demographics, pulmonary function, radiology and pathology compared to RAS patients.

Decreased Club Cell Secretory Protein in Bronchoalveolar Lavage is Associated with Chronic Lung Allograft Dysfunction (CLAD) but Not with CLAD Phenotypes

Purpose Chronic lung allograft dysfunction (CLAD) remains the main impediment to long-term survival after lung transplantation. Club cell secretory protein (CCSP), is an abundant protein secreted from non-ciliated bronchial epithelial cells with both antioxidative and anti-inflammatory properties. BAL CCSP levels were previously shown to be lower in patients who later developed CLAD. We aimed to examine whether levels of CCSP in BAL obtained early after CLAD diagnosis are associated with the major CLAD subtypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Methods Among all adult, first, bilateral, lung transplants, between 2004-2013, CLAD status was retrospectively determined as a sustained irreversible drop in FEV1, and patients were classified into BOS and RAS (based on 10% reduction in TLC), and long-term (>4 years) CLAD-free. First BAL available after CLAD diagnosis not associated with concurrent infection or acute rejection was chosen for this study. Protein levels were measured by ELISA. Log transformed CCSP levels were compared using linear regression models. Association of CCSP levels with post-CLAD survival was assessed using Cox PH models. Results BALs were obtained from 26 patients with established CLAD (10 RAS, 16 BOS) and 19 CLAD-free controls. CCSP levels were significantly lower in CLAD compared to CLAD-free controls (P=0.019) but did not differ between CLAD subgroups RAS and BOS (P=0.57). CCSP level was not associated with post-CLAD survival (HR 1.05, CI (0.72, 1.56), P=0.78). Conclusion We confirm that BAL CCSP levels are reduced in lung transplant recipients with CLAD. However, CCSP levels do not differ between BOS and RAS, possibly since airways are similarly affected in both conditions. Further investigation of other types of epithelial injury may provide insight into the pathogenesis of CLAD and its subtypes.

Differences in Onset of Chronic Lung Allograft Dysfunction between Living Donor and Cadaveric Lung Transplantation

Purpose Similar to the case after cadaveric lung transplantation (CLT), chronic lung allograft dysfunction (CLAD) is a major obstacle to long-term survival after living-donor lobar lung transplantation (LDLLT). However, after the concept of restrictive allograft syndrome (RAS) was introduced, little information has been available about the differences in the phenotypes of CLAD between LDLLT and CLT, especially in relation to the long-term outcomes of CLAD. In the present study, we compared the impact of CLAD on the long-term outcomes after bilateral LDLLT vs. bilateral CLT. Methods This study was a retrospective review of patients who underwent bilateral lung transplantation (LT) at Okayama University Hospital between October 1998 and August 2016. A total of 97 adult patients who underwent bilateral LT, including 51 recipients of bilateral LDLLT and 46 recipients of bilateral CLT, were included in this study. We assessed the preoperative and operative patient characteristics, and the postoperative outcomes. Results CLAD-free survival and overall survival after LDLLT were similar to those after CLT (p = 0.57 and p = 0.11). CLAD and RAS, but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (1807 ± 1402 vs. 689 ± 584 days, p = 0.015 and 2343 ± 1307 vs. 820 ± 460 days, p = 0.035) (Fig. 1a). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006) (Fig. 1b). However, after the diagnosis of CLAD, CLAD, irrespective of the phenotype, after LDLLT had a similar impact on the survival as CLAD after CLT (Fig. 1c). Conclusion CLAD, especially RAS, appears to develop later after LDLLT than after CLT. CLAD after LDLLT seems to have a lower impact on the overall survival, but a similar impact on the survival after the diagnosis of CLAD, as CLAD after CLT.

Early Shift of Lung Perfusion to the Unilateral Lung Predicts the Development of Unilateral Chronic Lung Allograft Dysfunction after Bilateral Living-Donor Lobar Lung Transplantation

Purpose In the diagnosis of chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT), lung ventilation scintigraphy using 133 Xe has been shown to be useful. However, the supply of 133 Xe has been discontinued worldwide in 2016 and a new diagnostic tool is required for CLAD after LDLLT. Generally, because CLAD has been shown to develop predominantly on one side after bilateral LDLLT, lung perfusion scintigraphy (LPS) could show a perfusion shift to the unilateral healthy lung ( Figure 1A ). Nevertheless, the usefulness of LPS in the diagnosis of CLAD after LDLLT is unknown. Methods We conducted a single-center retrospective cohort study of 58 recipients who underwent bilateral LDLLT at Okayama University Hospital between October 1998 and June 2016. The unilateral shift values in LPS were calculated, and compared between the CLAD group (N=27) and the non-CLAD group (N=31) from 5 years before the CLAD onset to 5 years after the CLAD onset. Results The median time to the CLAD onset was 2176 days (326-4763 days). The unilateral shift values in LPS of the CLAD group were significantly higher than those of the non-CLAD group during 5 years before the CLAD onset (P Figure 1B ). An ROC analysis of the performance of the unilateral shift value in LPS as a marker of CLAD yielded an AUC of 0.79 (sensitivity=0.54 and specificity=1.00 at a unilateral shift threshold level of 8.6%). The unilateral shift values in LPS were significantly correlated with the results of the forced expiratory volume in 1 second (P = 0.036, r = - 0.322) ( Figure 1C ). Conclusion In the patients with unilateral CLAD after bilateral LDLLT, LPS showed the unilateral perfusion shift to the healthy lung even during 5 years before the CLAD onset. LPS might have a potential to diagnose unilateral CLAD early after bilateral LDLLT.

Complement (C3a) Levels are Increased in the Bronchoalveolar Lavage Fluid of Patient with All Chronic Lung Allograft Dysfunction Phenotypes

Purpose Humoral immunity and complement activation are thought to play a role in the pathogenesis of chronic lung allograft dysfunction (CLAD). Here we investigate C3a levels in the bronchoalveolar lavage (BAL) fluid from patients with bronchiolitis obliterans syndrome (BOS) and restrictive chronic lung allograft dysfunction (rCLAD). Methods Spirometry and bronchoscopy were obtained per protocol on lung transplant recipients at the University of Michigan. C3a was quantified using ELISA and analyzed as ng/mL of BAL fluid. Patients with an isolated FEV1 decline to ≤80% post-transplant baseline were analyzed as BOS and patients with a concurrent FVC decline at time of FEV1 decline were analyzed as rCLAD. Results We included 86 samples in our analysis: 23 were collected prior to CLAD diagnosis (mean 921 days, range 91-4111), 39 were collected near CLAD onset (range 56 days before to 90 days after lung function decline), and 28 were collected after CLAD diagnosis (mean 1073 days, range 376-2962). Prior to CLAD onset, the average C3a level was 2.55±4.28 ng/ mL, however this increased dramatically near CLAD onset to 17.7±23.9 ng/ mL (p=0.003), and remained elevated after developing CLAD at 15.2±13.9 ng/ mL (p Conclusion BAL complement levels are increased upon developing both BOS and rCLAD and remain elevated after developing CLAD. These findings indicate ongoing activation of the complement regardless of CLAD phenotype.

Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome

Purpose The outcome after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS tends to an earlier, more severe and more rapid course as compared to BOS. Underlying differences of the immunologic phenotype, potentially unveiling therapeutic targets, have not yet been well-defined. Methods From June 2013 to August 2015, we collected whole blood samples from 142 consecutively transplanted patients 3 weeks after lung transplantation, excluding only those patients with missing blood samples or who did not consent to have the samples drawn. The samples were analyzed by flow cytometry. CD3+ CD8+ T cells were defined as cytotoxic T cells. Follow up ended as of 09/2018 and full data was available from 138 patients. CLAD diagnosis was made according to ISHLT consensus criteria based on a persistent >20% decline of FEV1 in spirometry. RAS was diagnosed in the presence of a >20% decline of FEV1 concomitant with a >10% decline of the total lung capacity and confirmed by CT scans. Results In this cohort, 115 patients did not develop CLAD at the end of follow up (control group). BOS was observed in 18 patients, whereas RAS was observed in 5 patients. In the BOS group, 7 patients were graded 1, 1 patient was graded 2, and 10 patients were graded 3. There was no significant difference in the percentage of CD8 T cells amongst lymphocytes between the control and the CLAD group (5.2±8.2% vs. 5.7±7.1%, respectively: p=0.40), three weeks after transplantation. In addition, there was also no significant difference between the control and the BOS subgroup (5.2±8.2% vs. 3.9±5.8%, respectively: p=0.27). However, a significant difference was detected between the BOS and RAS groups (3.9±5.8 vs. 12.0±8.6%, respectively: p Conclusion The development of the most severe and frequently early subtype of chronic lung rejection, the restrictive allograft syndrome, is preceeded by a high frequency of cytotoxic effector CD8+ T cells in peripheral blood as early as three weeks post transplantation. Cytotoxic T cells are also known to contribute to acute rejections and might be targeted by multiple immunosuppressive treatments.

Decreased Serum Levels of Irisin are Associated with the Development of Chronic Lung Allograft Dysfunction after Bilateral Living-Donor Lobar Lung Transplantation

Purpose Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Recently, decreased serum irisin levels have been shown to cause alveolar epithelial apoptosis resulting in lung emphysema in patients with chronic obstructive pulmonary disease. Similar to the patients with emphysema, the patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT) could show emphysematous changes, because in LDLLT, small lobar grafts expand to fit into the recipient's chest cavity due to the size mismatch. However, the relationship between serum irisin levels and CLAD after LDLLT remains unknown. Methods Blood samples were collected from a total of 33 patients who underwent bilateral LDLLT, including patients with CLAD (the CLAD group, n=11) and those without CLAD (the non-CLAD group, n=22). Serum samples were assayed for irisin using ELISA kit and compared between the two groups. Appropriate cut-off values of irisin level were set for the diagnosis of CLAD. Results The median follow-up period was 4366 (1055-7180) days. Serum irisin levels of the CLAD group were significantly lower than those of the non-CLAD group (9.5 ± 3.4 vs. 13.2 ± 4.2 ng/mL, P = 0.018) (Fig. 1). An ROC analysis of the performance of the serum irisin level as a marker of CLAD yielded an AUC of 0.76 (sensitivity=0.91 and specificity=0.64 at a threshold level of 12.6 ng/mL). Moreover, patients with irisin level ≥12.6 ng/mL (n=16) showed significantly better CLAD-free survival than those with irisin level Conclusion Decreased serum irisin levels are associated with the development of CLAD after bilateral LDLLT. Irisin might be a novel biomarker for the diagnosis of CLAD after LDLLT.

CT at onset of chronic lung allograft dysfunction in lung transplant patients predicts development of the restrictive phenotype and survival

PurposeTo describe early signs for restrictive subtype of chronic lung allograft dysfunction (CLAD) after lung transplantation in computed tomography (CT) and to evaluate the predictive value for disease progression and survival. Material and methods52 CT examinations in lung transplant patients at CLAD onset were scored for CT features referring to airways disease, parenchymal or pleural abnormality. Patients with and without later development of restrictive CLAD (TLC≤80%) were compared. A radiological score for inflammation including pleural effusion, central and peripheral ground glass opacities and consolidations was calculated and used for survival analysis. ResultsCT of patients with later development of restrictive CLAD showed significantly more often abnormalities at CLAD onset, in particular consolidations (57% vs. 4%; p<0.001) and ground glass attenuations (71% vs. 7%; p<0.001) than those of patients without the restrictive phenotype. CT score for inflammation was significantly higher in patients with than without later restrictive CLAD (3.4 vs. 0.6; p<0.001). Survival of patients with a high score (>2) for inflammation in CT at CLAD onset was significantly lower than of those with a low score (443 vs. 2415 days; p=0.019). ConclusionsCT at CLAD onset differs in patients with/without later development of the restrictive phenotype. It is therefore an indicator for future development of restrictive CLAD and predictor for survival. It should be implemented in the diagnostic work-up at diagnosis of CLAD.

Lung clearance index is sensitive to small airway disease in pediatric lung transplant recipients

The principal obstacle to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD), which primarily affects the small airways. After transplant, patients are monitored with spirometry, which is a generally insensitive detector of small airways obstruction. The lung clearance index (LCI) is a measure obtained during multiple breath washout (MBW) maneuvers. We hypothesized that among lung allograft recipients, LCI would detect small airways disease not detected with spirometry. This study enrolled 15 patients, 5 of whom already had a diagnosis of CLAD. We added MBW as an additional index of peripheral airway function to the established post-transplant routine care protocol. Of trials, 87.9% yielded valid measurements, and single maneuvers were 2-8 minutes. LCI did not yield any false-negative findings-no patients were considered obstructed by forced expiratory volume in 1 second (FEV1) but normal by LCI. At enrollment, 6 patients without CLAD had an elevated LCI, and 4 progressed to CLAD. Only 2 of these 4 patients would have been identified by a decrease in FEV1. LCI identified lung allograft dysfunction in more patients than the use of standardized spirometric measures, including patients with abnormal FEV1. These data suggest that LCI from MBW may be a more sensitive means to detect allograft peripheral airway disease than standard methods for measurement of small airways function.

Histopathological Findings Associated With Gastroesophageal Reflux Disease and Aspiration After Lung Transplantation: Initial Brazilian Single-Center Experience

BackgroundGastro-esophageal reflux disease (GERD) and broncho-aspiration (BA) are known to increase the risk for chronic lung allograft dysfunction (CLAD). However, specific lung injury mechanisms are not clearly known. The objective of the study was to describe histopathological findings in surveillance lung transbronchial biopsies that can be correlated with episodes of BA in the lung allograft. MethodsThis retrospective analysis of surveillance transbronchial biopsies was performed in lung transplant recipients, with available data of broncho-alveolar fluid (cultures and cytology), lung function parameters, and esophageal functional tests. ResultsWere analyzed 11 patients, divided into 3 groups: (1) GERD group: 4 patients with GERD and CLAD diagnosis; (2) control group: 2 patients without GERD or CLAD; and (3) BA group: 5 patients with foreign material in lung biopsies. A histopathological pattern of neutrophilic bronchitis (NB) was present in 4 of 4 cases in the GERD group and in 1 of 5 cases in the BA group in 2 or more biopsy samples; culture samples were all negative; the 5 NB-positive patients developed CLAD and died (3/5) or needed re-transplantation (2/5). The other 3 patients in the BA group had GERD without NB or CLAD. Both patients in the control group had transient NB in biopsies with positive cultures but remained free of CLAD. ConclusionsSurveillance transbronchial biopsies may provide useful information other than the evaluation of acute cellular rejection and can help to identify high-risk patients for allograft dysfunction related to gastro-esophageal reflux.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Epithelial and Erythrocyte Microvesicles From Bronchoalveolar Lavage Fluid Are Elevated and Associated With Outcome in Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) is the major outcome limitation for lung transplant recipients (LTR) after the first year, and therapies targeting immunological pathways show only limited success. Because microvesicles (MV) are biomarkers of endothelial dysfunction and coagulation but are also involved in immunological responses, we hypothesized that MV, found in bronchoalveolar lavage (BAL) fluids (BALF) of LTR at CLAD diagnosis, are elevated and potential prognostic biomarkers. The BALF was collected from 37 LTR at time point of CLAD diagnosis and 37 LTR without any complication at routinely performed BAL. The MV concentration and origin were determined by flow cytometry by detection of different antigens. Patient- and transplant-related risk factors were included in a retrospective statistical analysis. The BALF-MV levels of epithelial and red blood cell (RBC) origin were significantly higher in CLAD patients (mean: 1533/μL and 158/μL) compared to controls (436/μL, 57/μL). The LTR with high levels of epithelial MV >580/μL showed a significantly shorter overall survival at 4 years after BAL (39.5%) compared to patients with low MV (66.4%) and this proofed to be an independent prognostic factor in multivariate Cox analysis (hazards ratio = 3.05). Furthermore, LTR with high levels of RBC MV ≥225/μL were also associated with worse disease-specific survival, with probabilities at 4 years after BAL of 85.8% vs. 36.0%. Epithelial and RBC BALF-MV are elevated at CLAD diagnosis, have a potential as biomarkers, and support the hypothesis of a pathway, including activation of coagulation and complement, endothelial barrier dysfunction, and microangiopathy.

Impact of Forced Vital Capacity Loss on Survival after the Onset of Chronic Lung Allograft Dysfunction

Emerging evidence suggests a restrictive phenotype of chronic lung allograft dysfunction (CLAD) exists; however, the optimal approach to its diagnosis and clinical significance is uncertain. To evaluate the hypothesis that spirometric indices more suggestive of a restrictive ventilatory defect, such as loss of FVC, identify patients with distinct clinical, radiographic, and pathologic features, including worse survival. Retrospective, single-center analysis of 566 consecutive first bilateral lung recipients transplanted over a 12-year period. A total of 216 patients developed CLAD during follow-up. CLAD was categorized at its onset into discrete physiologic groups based on spirometric criteria. Imaging and histologic studies were reviewed when available. Survival after CLAD diagnosis was assessed using Kaplan-Meier and Cox proportional hazards models. Among patients with CLAD, 30% demonstrated an FVC decrement at its onset. These patients were more likely to be female, have radiographic alveolar or interstitial changes, and histologic findings of interstitial fibrosis. Patients with FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC (P < 0.0001; 3-yr survival estimates 9% vs. 48%, respectively). The deleterious impact of CLAD accompanied by FVC loss on post-CLAD survival persisted in a multivariable model including baseline demographic and clinical factors (P < 0.0001; adjusted hazard ratio, 2.73; 95% confidence interval, 1.86-4.04). At CLAD onset, a subset of patients demonstrating physiology more suggestive of restriction experience worse clinical outcomes. Further study of the biologic mechanisms underlying CLAD phenotypes is critical to improving long-term survival after lung transplantation.

Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation

Restrictive allograft syndrome (RAS) has recently been defined as a novel phenotype of chronic lung allograft dysfunction (CLAD) after lung transplantation. The goal was to describe computed tomographic (CT) changes of RAS patients and to correlate this with spirometry and survival. All 24 established RAS patients at our center were retrospectively included. CT scans from pre-CLAD, CLAD, post-CLAD and late-CLAD subjects were systematically evaluated by a blinded observer using a semi-quantitative scoring system. Changes in CT patterns were correlated with spirometry and survival. The most prominent CT features at diagnosis of CLAD as compared with pre-CLAD were appearance of central (p = 0.020) and peripheral ground glass opacities (p = 0.052), as well as septal and non-septal lines (p = 0.020). Survival after diagnosis of CLAD was only associated with the absolute value of forced vital capacity (FVC) at diagnosis (R = 0.46 and p = 0.021), and not with any CT alterations. Evolution of CT abnormalities after diagnosis of CLAD included significant increases in (traction) bronchiectasis (p < 0.0001), central (p = 0.051) and peripheral (p = 0.0002) consolidation, architectural deformation (p = 0.0002), volume loss (p = 0.0004) and hilus retraction (p = 0.0036). The absolute FVC decrease post-CLAD diagnosis correlated with CT alterations. In the early stages of RAS, central and peripheral ground glass opacities are the most prominent feature on CT, whereas, in later stages, bronchiectasis, traction, central and peripheral consolidation, architectural deformation, volume loss and hilus retraction are more pronounced. CT changes, however, could not predict survival, whereas FVC at diagnosis of CLAD seems to be the best predictor of survival.

Pilot Study Exploring Lung Allograft Surfactant Protein A (SP-A) Expression in Association With Lung Transplant Outcome

Primary graft failure and chronic lung allograft dysfunction (CLAD) limit lung transplant long–term outcomes. Various lung diseases have been correlated with surfactant protein (SP) expression and polymorphisms. We sought to investigate the role of SP expression in lung allografts prior to implantation, in relation to posttransplant outcomes. The expression of SP-(A, B, C, D) mRNA was assayed in 42 allografts. Posttransplant assessments include pulmonary function tests, bronchoscopy, broncho-alveolar lavage fluid (BALF) and biopsies to determine allograft rejection. BALF was assayed for SP-A, SP-D in addition to cytokines IL-8, IL-12 and IL-2. The diagnosis of CLAD was evaluated 6 months after transplantation. Lung allografts with low SP-A mRNA expression prior to implantation reduced survival (Log-rank p < 0.0001). No association was noted for the other SPs. Allografts with low SP-A mRNA had greater IL-2 (p = 0.03) and IL-12 (p < 0.0001) in the BALF and a greater incidence of rejection episodes (p = 0.003). Levels of SP-A mRNA expression were associated with the SP-A2 polymorphisms (p = 0.015). Specifically, genotype 1A1A0 was associated with lower SP-A mRNA expression (p < 0.05). Lung allografts with low levels of SP-A mRNA expression are associated with reduced survival. Lung allograft SP-A mRNA expression appears to be associated with SP-A gene polymorphisms.

Survival Determinants in Lung Transplant Patients With Chronic Allograft Dysfunction

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality after lung transplantation. In this retrospective single-center study, we aimed to identify different phenotypes of and risk factors for mortality after CLAD diagnosis using univariate and multivariate Cox proportional hazard survival regression analysis. CLAD was diagnosed in 71 of 294 patients (24.2%) at 30.9±22.8 months after transplantation. Pulmonary function was obstructive in 51 (71.8%) of the CLAD patients, restrictive in 20 (28.2%) patients, of whom 17 had persistent parenchymal infiltrates on pulmonary computer tomography (CAT) scan. In univariate analysis, previous development of neutrophilic reversible allograft dysfunction (NRAD, P=0.012) and a restrictive pulmonary function (P=0.0024) were associated with a worse survival, whereas there was a strong trend for early development of CLAD and persistent parenchymal infiltrates on CAT scan (P=0.067 and 0.056, respectively). In multivariate analysis, early development of CLAD (P=0.0067), previous development of NRAD (P=0.0016), and a restrictive pulmonary function pattern (P=0.0005) or persistent parenchymal infiltrates on CAT scan (P=0.0043) remained significant. Although most CLAD patients develop an obstructive pulmonary function, 28% develop a restrictive pulmonary function, compatible with the recently defined restrictive allograft syndrome phenotype. Early-onset CLAD, previous development of NRAD, and the development of restrictive allograft syndrome are associated with worse survival after CLAD has been diagnosed.

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Survival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD.A retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV1) within 6 weeks of commencing therapy.Mean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP.Rescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.