Risk Of Bronchiolitis Obliterans Syndrome Research Articles

A potential mechanism by which aspiration of duodenogastric fluid augments the risk for bronchiolitis obliterans syndrome after lung transplantation

ObjectiveAspiration of duodenogastric refluxate may damage the respiratory epithelium of lung allografts in transplant recipients. We sought to define a mechanism by which aspiration of duodenogastric fluid augments the risk of bronchiolitis obliterans syndrome after lung transplant in a murine model. MethodsWe analyzed the immunological effects of acute aspiration of duodenogastric fluid (0.5 mL/kg) on transplant naive (strain DBA/2J) and transplanted mice (strain B6D2F1/J to strain DBA/2J). Serum antibodies to the lung self-antigens (SAgs) K-alpha1 tubulin and collagen-V were determined by enzyme-linked immunosorbent assay. Exosomes were isolated from serum, and immunoblot membranes were probed for antibodies to lung SAgs. Lung sections were assessed for fibrotic burden and obliterative bronchiolitis lesions by histologic and immunohistochemical analyses, including trichrome staining. ResultsTransplanted mice that received duodenogastric fluid developed higher levels of antibodies to the lung SAgs K-alpha1 tubulin and collagen-V and exosomes with lung SAgs on posttransplant days 14 and 28 than transplanted mice with sham aspiration or transplant naive mice (with and without aspiration). All lung allografts demonstrated severe grade A4 rejection on posttransplant day 14, with the highest mean fibrotic burden and mean number of obliterative bronchiolitis-like lesions per microscopic field on day 28 in recipients with aspiration. ConclusionsThis study links aspiration of duodenogastric fluid after lung transplant to higher autoimmune responses to lung SAgs and the release of circulating exosomes with lung SAgs, which together promote sustained immune responses leading to extensive lung parenchymal damage and, ultimately, severe obliterative bronchiolitis—the histologic hallmark of bronchiolitis obliterans syndrome.

Human leukocyte antigen mismatch on lung transplantation outcomes.

Human leucocyte antigen (HLA) mismatch is a known risk factor for renal transplantation; however, there are conflicting and limited data on its ramifications within lung transplantation (LTx). Therefore, our study evaluated the effects of total HLA, HLA-A, -B and -DR mismatches on LTx outcomes. We retrospectively examined the United Network for Organ Sharing database for adult patients who had undergone LTx for the first time between January 2005 and July 2021. Total HLA mismatch (0-3, 4, 5 and 6) and HLA locus mismatch (0-1 and 2) were analysed, with the end points of interest being mortality and bronchiolitis obliterans syndrome (BOS) development. Kaplan-Meier curve analysis found a significant difference in both overall survival (n = 27 651; 11 830 events) and BOS development (n = 25 444; 8901 events) for the total number of HLA (P < 0.001, P < 0.001), HLA-A (P < 0.001, P = 0.006) and HLA-DR (P < 0.001, P < 0.001) mismatches. With reference to 0-3 total HLA mismatches, multivariable Cox regression model found that 6 mismatches had an increased risk of mortality (P = 0.002) while 4 (P = 0.010), 5 (P = 0.007) and 6 (P < 0.001) mismatches had an increased risk of BOS. HLA-B mismatch was not associated with an increased mortality (P = 0.975) or BOS risk (P = 0.512). This study demonstrates a significant relationship between increased HLA mismatches and BOS development, with decreased overall survival only apparent with 6 mismatches. HLA-A and -DR mismatches were associated with an increased risk of mortality and BOS development compared to groups with at least 1 locus match.

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease?

With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the "lung microbiome" has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.

The impact of HLA-DR mismatch status on retransplant-free survival and bronchiolitis obliterans syndrome‒free survival among sensitized lung transplant recipients

Donor‒recipient HLA-DR locus matching may be protective against bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. It is unknown whether this benefit is more significant among sensitized (calculated panel reactive antibodies (CPRAs) of >0%) and highly sensitized (CPRAs of ≥80%) recipients who may be at a higher risk for BOS. This was a retrospective cohort study of adults in the Scientific Registry of Transplant Recipients who underwent lung transplantation between May 5, 2005 and May 31, 2019. Retransplant-free survival and BOS-free survival were compared among recipients with 0 vs ≥1 DR mismatches, grouped according to sensitization. Among all 20,355 included recipients, 0 DR mismatch status was associated with improved retransplant-free survival (hazard ratio [HR] = 0.83, 95% CI = 0.74-0.93, p = 0.002) and BOS-free survival (HR = 0.86, 95% CI = 0.77-0.96, p = 0.007). Among sensitized recipients, 0 DR mismatch status was also associated with improved retransplant-free survival (HR = 0.79, 95% CI = 0.65-0.97, p = 0.02) and BOS-free survival (HR = 0.82, 95% CI = 0.67-1.00, p = 0.04). There was however no difference in retransplant-free or BOS-free survival between sensitized and non-sensitized recipients with 0 DR mismatches. Among highly sensitized recipients, 0 DR mismatch status was not associated with retransplant-free or BOS-free survival. Among sensitized and highly sensitized recipients, 0 DR mismatch status was not associated with reduced use of plasmapheresis or reduced biopsy-proven, treated acute cellular rejection compared with non-sensitized recipients. HLA-DR matching is associated with a similar improvement in retransplant-free and BOS-free survival among non-sensitized and sensitized lung transplant recipients. DR matching does not confer a more substantial retransplant-free or BOS-free survival benefit to highly sensitized recipients than to non-sensitized recipients.

Decline in Club Cell Secretory Proteins, Exosomes Induction and Immune Responses to Lung Self-antigens, Kα1 Tubulin and Collagen V, Leading to Chronic Rejection After Human Lung Transplantation.

Chronic lung allograft dysfunction (CLAD), is a major hurdle for long-term lung allograft survival after lung transplant and roughly 50% of lung transplant recipients (LTxRs) develop CLAD within 5 years. The mechanisms of CLAD development remain unknown. Donor-specific immune responses to HLA and lung self-antigens (SAgs) are vital to the pathogenesis of CLAD. Reduction in Club cell secretory protein (CCSP) has been reported in bronchoalveolar lavage (BAL) fluid samples from LTxRs with bronchiolitis obliterans syndrome (BOS). CCSP levels in BAL fluid and development of antibodies to lung SAgs in plasma were determined by ELISA. Cytokines in BAL fluid were analyzed by 30-plex Luminex panel. Exosomes from BAL fluid or plasma were analyzed for SAgs, natural killer (NK) cells markers, and cytotoxic molecules. We demonstrate that LTxRs with BOS have lower CCSP levels up to 9 months before BOS diagnosis. LTxRs with antibodies to SAgs 1-year posttransplant also developed DSA (43%) and had lower CCSP. BOS with lower CCSP also induced Interleukin-8 and reduced vascular endothelial growth factor. Exosomes from BOS contained increased SAgs, NK cells markers, and cytotoxic molecules. We conclude lower CCSP leads to inflammation, pro-inflammatory cytokine production, immune responses to HLA and SAgs, and induction of exosomes. For the first time, we demonstrate that CCSP loss results in exosome release from NK cells capable of stimulating innate and adaptive immunity posttransplant. This increases the risk of BOS, suggesting a role of NK cell exosomes in CLAD development.

Circulating exosomes with lung self-antigens as a biomarker for chronic lung allograft dysfunction: A retrospective analysis

Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS. Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software. Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs-containing exosomes at 6 and 12 months before BOS. Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.

Impact of Ambient Particulate Matter (PM) Exposure of Lung Donors and Recipients on Bronchiolitis Obliterans Syndrome (BOS) and Mortality after Lung Transplant (LT)

A Belgian study found proximity to a motorway increased risk of BOS after LT. Using zip codes as a surrogate for habitat location we investigated the impact of PM2.5 concentration (conc) (PM≥ 2.5 μm/m3) exposure of donors and recipients on BOS and mortality after LT in the US. UNOS Standard Transplant Analysis and Research (STAR) database (June 30, 2017) identified adult LT recipients and their donors between 2005 and 2015, and their zip code of residence at LT. Average ambient PM2.5 conc (PM≥ 2.5 μm/m3) associated with donor and recipient residencies 1 year prior to LT were estimated by mapping each zip code to a census tract, using a crosswalk from HUD, downscaled from a 12 × 12-km sq grid resolution detailed chemistry - transport model application using a Bayesian space-time downscaler, and then fused with surface observations. PM2.5 conc was classified into low (<8 μg/m3), medium (8-12 μg/m3) and high (>12 μg/m3) exposure categories. Cox proportional hazards regression and Kaplan-Meier curves assessed the impact of PM2.5 on 1 year and long term incidence of BOS and all cause mortality. 17,760 LT were analyzed. Median followup was 1101 days (IQR 511-2073, range 1-4448). 25% of LT had high donor exposure and 24% had high recipient exposure. Recipient exposure to PM2.5 had no impact on 1-year survival. However, higher PM2.5 donor exposure appeared to increase risk of early death, although estimates were imprecise (Table). Higher concentration of recipient or donor PM2.5 did not increase long-term mortality risk, and curiously higher recipient PM reduced BOS incidence (Table). PM2.5 is only one aspect of air quality and does not appear to increase long term risk of BOS or death after LT. Donor PM. exposure may have a small impact on 1 year survival after LT. Additional research on other air quality measures including isolating primary and secondary components of PM2.5 and focusing on traffic-related air pollutants is needed.

Association of Discharge Immunosuppression Regimen and Post-Transplant Outcomes in Lung Transplantation: An Analysis of OPTN Data

The optimal immunosuppressive (IS) regimen after lung (LU) transplant is unknown, therefore we sought to examine OPTN data to compare the impact of 4 different IS combinations on outcomes of treated acute rejection (AR), bronchiolitis obliterans syndrome (BOS), and graft survival. We used OPTN data for adult recipients of primary, DD, LU alone transplants during 2005-2015, who were alive at discharge and on one of the following discharge IS regimens: cyclosporine + azathioprine (CYA+AZA), cyclosporine + MMF (CYA+MMF), tacrolimus + azathioprine (TAC+AZA), or TAC+MMF. One-year treated AR was compared by IS regimen using a chi-square test. Freedom from BOS and graft survival within 5 years were estimated using Kaplan-Meier methods and compared by IS regimen using a log-rank test. Cox regression analysis was performed to assess the association of IS regimen and BOS, adjusted for other covariates. Of 14,798 recipients in the study cohort, 10,842 (73%) were on TAC+MMF, 2,968 (20%) on TAC+AZA, 587 (4%) on CYA+AZA, and 401 (3%) were on CYA+MMF. One-year rates of treated AR were significantly different across IS regimens (56% for CYA+AZA, 36% for CYA+MMF, 32% for TAC+AZA, and 27% for TAC+MMF) (p<0.0001). Unadjusted freedom from BOS and graft survival were significantly different across IS regimens (Figures 1 and 2). The results of the adjusted Cox regression model showed that the TAC+MMF regimen was associated with a significantly decreased risk of BOS within 5 years compared to the other 3 regimens. In this non-randomized OPTN registry analysis, TAC+MMF was associated with a lower rate of unadjusted one-year treated AR and reduced, adjusted risk of BOS within 5 years compared to the other regimens. Unadjusted graft survival was higher for TAC-based regimens compared to CYA-based regimens. Limitations of this analysis included the small numbers of patients in some of the IS groups, and not accounting for changes in the IS regimen post-discharge.

Early Post-Transplantation Spirometry Is Associated with the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (allo-HCT) is often diagnosed at a late stage when lung dysfunction is severe and irreversible. Identifying patients early after transplantation may offer improved strategies for early detection that could avert the morbidity and mortality of BOS. This study aimed to determine whether a decline in lung function before and early after (days +80 to +100) allo-HCT are associated with a risk of BOS beyond 6 months post-transplantation. In a single-center cohort of 2941 allo-HCT recipients, 186 (6%) met National Institutes of Health criteria for BOS. Pretransplantation and post-transplantation day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors, including donor source, graft source, conditioning regimen, use of total body irradiation, and immunoglobulin levels. Pre-transplantation forced expiratory flow between 25% and 75% of maximum (FEF25-75), day +80 forced expiratory volume in 1 second (FEV1), and day +80 FEF25-75 had the strongest associations with increased risk of BOS. Assessment of the multivariable model showed that a decline in day +80 FEF25-75 added additional risk to the day +80 FEV1 model (P = .03), whereas FEV1 decline at day +80 added no additional risk to the day +80 FEF25-75 model (P = .645). Moreover, day +80 FEF25-75 conferred additional risk when considered with pretransplantation FEF25-75. These results suggest that day +80 FEF25-75 may be more important than FEV1 in predicting the development of BOS. This study highlights the importance of obtaining early post-transplantation pulmonary function tests for the potential risk stratification of patients at risk for BOS.

Impact of combined heart and lung transplantation on bronchiolitis obliterans syndrome, cardiac allograft vasculopathy, and long-term survival.

Evidence from animal studies and small case series suggests that primary graft dysfunction occurs less often following combined organ transplantation than following isolated organ transplantation. In this large-scale national registry study, we aimed to investigate whether survival and the rates of bronchiolitis obliterans syndrome (BOS) and coronary allograft vasculopathy (CAV) are affected by simultaneous heart and/or lung transplantation (HLTx). Clinical data from the United Network of Organ Sharing database were retrospectively reviewed to identify transplant-naive patients who had undergone heart and/or lung transplantation between 1987 and 2016. The comparisons were conducted for isolated vs combined organ transplant. The outcomes included all-cause mortality, as well as the incidence of BOS and CAV RESULTS: Of the 98,310 patients reviewed, 63,976, 1,189, and 33,145 had received isolated heart transplantation (iHTx) (65%), HLTx (1%), and isolated lung transplantation (iLTx) (34%), respectively. In the early post-operative period, the mortality rates were higher after HLTx than after iHTx or iLTx (on crude and propensity score-matched analyses). However, the adjusted hazard risk for mortality associated with HLTx was significantly lower relative to the iLTx-associated risk beyond 3 years postoperatively, and similar relative to the iHTx-associated risk beyond 7 years postoperatively. On both crude and adjusted analyses, the incidence of BOS and CAV was significantly lower after HLTx than after iHTx or iLTx (p < 0.001 for all comparisons). Combined (rather than single) organ transplantation may provide immunoprotective benefits enhancing long-term survival and attenuating the risk of BOS and CAV.

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS. Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders. A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007). We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

MiR-155 Plays an Essential Role in Anti-MHC-Induced Obliterative Airway Disease

Purpose Previous studies in our lab demonstrated that development of Abs to HLA often precedes development of Abs to self-Antigens (SAgs), Collagen V (Col-V) and K-alpha1 Tubulin (Kα1T), increasing the risk of bronchiolitis obliterans syndrome as a significant risk factor for acute and chronic rejection (CR). Circulating exosomes expressing donor HLA, SAgs have been proposed to stimulate immune responses leading to lung allograft rejection. miR-155 was among the first miRNAs linked to inflammation, potent upregulation of Toll like receptors in multiple cell lineages leading to production of inflammatory cytokines including IL17 which has been proposed to play an important role in the development of CR following lung transplantation. In our present study, we elucidated the role of miR-155 in anti-MHC-induced obliterative airway disease (OAD) model and their role in inducing circulating exosomes with lung SAgs and contribution to OAD. Methods Wild-type C57BL/6 miR-155 knock-out (KO) B6.Cg-Mir155tm1Rsky/J mice (8-12 wks) were procured. Anti-H-2Kb (AF6-88.5.5.3, BioXcell,) Abs was administered intrabronchially. Mouse Abs to lung-SAgs, Col-V or Kα1T, was detected by ELISA. Circulating exosomes were isolated using total exosome isolation kit and analyzed for lung SAgs, CIITA and 20S proteosome by western blots. Results Anti-MHC class I Ab administration into the wild type mice developed Abs against lung SAgs, Col-V days 8, 16, 30, and K-α1T day 8. Anti-MHC class I Abs administrated to wild-type mice released exosomes with increased levels of SAgs, Col-V or K-α1T, CIITA and 20S proteasome on day 2; which increased by day 16. In contrast, miR-155KO mice demonstrated neither Abs to SAgs nor exosomes containing SAgs. Histopathological studies revealed that lungs from wild-type animals administered with anti-MHC class I Ab demonstrated significant inflammatory cells around the vessels and bronchiole with increase in fibrosis. miR-155KO mice did not show any significant lesions. Conclusion Our results demonstrate that Abs to lung SAgs and induction of circulating exosomes with lung SAgs occurs prior to development of OAD following anti-MHC administration into native lungs. Further, miR-155 plays an obligatory role in the pathogenesis of anti-MHC induced OAD since miR-55KO mice did not develop Abs to lung SAgs, induce circulating exosomes with lung SAgs, nor result in OAD.

Long-Term Impact of Cytomegalovirus Serologic Status on Lung Transplantation in the United States

Cytomegalovirus (CMV) infection has been associated with poor outcomes after solid organ transplantation. The long-term impact of donor and recipient CMV serological status on lung transplant outcomes remains unclear. Accordingly, we evaluated the impact of donor and recipient CMV status on long-term patients as well as allograft survival after single (SLT) and double lung transplantation (BLT). The Scientific Registry of Transplant Recipients was used to track all adult lung transplants in United States from May 2005 to June 2016. Patient mortality and bronchiolitis obliterans syndrome were determined up to 5 years using Cox proportional hazards modeling. Additionally, landmark analysis was performed conditional on survival at 1 year. Compared with donor negative-recipient CMV-IgG negative (D-R-), donor positive-recipient negative (D+R-) and donor positive-recipient positive (D+R+) groups had increased mortality at 1 and 5 years after BLT, with the former demonstrating highest risk. Although mortality was not increased with CMV seropositive donors after SLT at 1 year, both D+R- and D+R+ groups demonstrated greater mortality at 5 years. Risk of bronchiolitis obliterans syndrome was not affected by CMV serological status. Conditional landmark analysis confirmed that lungs from CMV seropositive donors conferred highest risk for long-term mortality. CMV seronegative recipients undergoing either BLT or SLT from CMV seropositive donors have the highest risk of long-term mortality that extends beyond the first year. Further studies are needed to determine the causes of higher mortality observed in the CMV seronegative recipients and risks and benefits of extension of CMV prophylaxis, particularly in the high-risk group.

CD8 T Effector Memory T Cells as Predictive Biomarker of Severe Acute Rejection in Lung Transplantation

Severe acute rejection (AR) after lung transplantation (LT) increases the risk of bronchiolitis obliterans syndrome with subsequent impairment in patient and graft survival. The identification of biomarkers to minimize AR rate and improve long term graft survival should be a priority in transplant field. Previously, the CD8 effector memory T (TEM) cells have been identified as a potential biomarker of acute rejection in patient awaiting for a lung transplantation(1). The aim of the study was to correlate CD8 TEM with severity of acute rejection after LT. Material and Methods 76 patients with end-stage lung disease were recruited from 2010 in our institution and prospectively followed after LT. Flow cytometry and monoclonal antibodies to identify CD8 T cell subsets in peripheral blood were used. Protocol biopsy at 21 day post transplantation was performed to identify acute rejection. Results and Discussion A total of 41 (54%) of LT recipients had acute rejection and 9 of them were severe (grade A3 or A4). Before transplant, the patients with severe acute rejection had significantly higher CD8 TEM/mm3 than no AR group (median 328.5; IQR: 187.2-507.6) vs (median 70.2; IQR: 49.3-123.8); p=0.027, whereas the levels of CD8 TEM in mild AR group are reduced compared with severe AR (median 95.4; IQR: 45.8 – 189.8); p=0.0748. The CD8 TEM levels pre-LT are increased in those with subsequent severe AR. Conclusion Monitoring the levels of CD8 TEM prior lung transplantation could identify patients at risk of suffering severe acute rejection. This biomarker should be validated in larger multicentre studies before be used in clinic. Reference San Segundo, D et al. PLoS One. 2013 Nov 13;8(11):e80601

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

Clinical implications of donor age: A single-institution analysis spanning 3 decades

BackgroundWe sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. MethodsFrom 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score ≥1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. ResultsIn the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori–defined donor age groups: age <40, 40 to 54, and age ≥55 years (64%, 61%, and 69%, P = .8). Unadjusted 5-year freedom from BOS ≥1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. ConclusionsLong-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed.

HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation.

Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells maypromote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes forHLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12845 non-KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36-0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91-0.99). Survival improved with the higher-affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.

Low Levels of Exhaled Surfactant Protein A Associated With BOS After Lung Transplantation.

BackgroundThere is no clinically available marker for early detection or monitoring of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS), the main long-term complication after lung transplantation. Sampling and analysis of particles in exhaled air is a valid, noninvasive method for monitoring surfactant protein A (SP-A) and albumin in the distal airways.MethodsWe asked whether differences in composition of exhaled particles can be detected when comparing stable lung transplant recipients (LTRs) (n = 26) with LTRs who develop BOS (n = 7). A comparison between LTRs and a matching group of healthy controls (n = 33) was also conducted. Using a system developed in-house, particles were collected from exhaled air by the principal of inertial impaction before chemical analysis by immunoassays.ResultsSurfactant protein A in exhaled particles and the SP-A/albumin ratio were lower (P = 0.002 and P = 0.0001 respectively) in the BOS group compared to the BOS-free group. LTRs exhaled higher amount of particles (P < 0.0001) and had lower albumin content (P < 0.0001) than healthy controls.ConclusionsWe conclude that low levels of SP-A in exhaled particles are associated with increased risk of BOS in LTRs. The possibility that this noninvasive method can be used to predict BOS onset deserves further study with prospective and longitudinal approaches.

Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation.

CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung diseases, however overall survival is hampered by chronic lung allograft dysfunction development, which presents itself obstructively as the bronchiolitis obliterans syndrome (BOS). We hypothesized that, due to cellular damage and activation during chronic inflammation, sCD59 serum levels can be used as biomarker preceding BOS development. We analyzed sCD59 serum concentrations in 90 LTx patients, of whom 20 developed BOS. We observed that BOS patients exhibited higher sCD59 serum concentrations at the time of diagnosis compared to clinically matched non-BOS patients (p = 0.018). Furthermore, sCD59 titers were elevated at 6 months post-LTx (p = 0.0020), when patients had no BOS-related symptoms. Survival-analysis showed that LTx patients with sCD59 titers ≥400 pg/ml 6 months post-LTx have a significant (p < 0.0001) lower chance of BOS-free survival than patients with titers ≤400 pg/ml, 32% vs. 80% respectively, which was confirmed by multivariate analysis (hazard ratio 6.2, p < 0.0001). We propose that circulating sCD59 levels constitute a novel biomarker to identify patients at risk for BOS following LTx.

Cytomegalovirus Hyper Immunoglobulin for CMV Prophylaxis in Thoracic Transplantation.

Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)− transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R− heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease.