Bronchiolitis Obliterans Syndrome Stage Research Articles

Utility of pulmonary function test screening for bronchiolitis obliterans syndrome stage 0-p among recipients of allogeneic hematopoietic stem cell transplantation conditioned with antithymocyte globulin

INTRODUCTION Timely diagnosis of bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic cell transplantation (allo-HCT) is challenging due to the paucity of symptoms early in the disease course. Pulmonary function tests (PFT) are proposed as a screening tool to identify patients at risk of developing BOS in this population. METHODS We performed a retrospective study including patients who underwent allo-HCT with antithymocyte globulin (ATG) conditioning between May 2010 and August 2020, survived without relapse for at least 3 months, and had a pre-transplant PFT and at least 2 post-transplant PFTs. Patients met BOS-0p if their PFTs demonstrated a sustained >10% drop in FEV1 or >25% drop in FEF25-75. A competing risks regression model was used to estimate the cumulative incidence of BOS and BOS-0p. Test performance characteristics for BOS-0p were calculated using 2x2 tables. RESULTS The cumulative incidence of BOS was 2.1% (CI 0.8-4.6) at 12 months and 5.4% (CI 2.8-9.3) at 60 months post-transplant. Meeting BOS-0p during the first 2 years post-transplantation yielded a sensitivity of 64% (CI 31-89), specificity of 71% (CI 64-77), PPV of 10% (CI 4-20), and NPV of 97% (CI 93-99) for subsequent development of BOS. Meeting BOS-0p was associated with increased mortality (HR 2.27, p = 0.006). CONCLUSION Although patients who meet BOS-0p within 2 years of transplant are more likely to develop BOS, prompt repeat testing is needed to confirm entry into the stage if a patient meets spirometric criteria on a single PFT.

1478. Impact of Short versus Long Treatment Durations for Respiratory Tract Infections Caused by Non-fermenting Gram-negative Bacilli in Lung Transplant Recipients

BackgroundIn lung transplant recipients, respiratory tract infections are associated with faster progression through stages of bronchiolitis obliterans syndrome and mortality. Common causative pathogens for respiratory tract infections (RTIs) include non-fermenting gram-negative bacilli (NFGNB). Data to guide optimal treatment durations for NFGNB RTIs in this population are limited.MethodsThis was a single-center, retrospective, cohort study of adult lung transplant recipients who received systemic antibiotic treatment for RTIs caused by NFNGB and had at least 28 days of post-treatment follow-up. Analyses were conducted for each patient’s initial NFGNB RTI as well as all independent NFGNB RTIs episodes. Groups were divided into NFGNB RTIs treated for a short (≤ 10 days) versus long (> 10 days) duration of effective antibiotic therapy. The primary outcome was the incidence of recurrent NFGNB RTIs within 28 days post-treatment. Recurrence was defined as isolation of the same organism in a respiratory culture requiring treatment with systemic antibiotics as determined by the prescribing physician.ResultsWe included 207 lung transplant recipients with 334 NFGNB RTIs (n=129 short; n=205 long) from a period of January 1, 2010 to July 1, 2019. The most common causative pathogen was P. aeruginosa (77% and 82%) and most NFGNB RTIs were treated inpatient (60% and 53%) in both groups. The median duration of therapy was 10 days and 14 days for the short and long treatment durations, respectively. The primary outcome occurred in 14/129 (11%) of the NFGNB RTIs treated for ≤ 10 days and 28/205 (14%) of those treated for > 10 days. No difference in recurrence within 28 days was detected in NFGNB RTIs treated for ≤ 10 days (aOR, 0.69; 95% CI, 0.34-1.4; p=0.149). Use of adjunctive inhaled antibiotics was associated with reduced recurrence (aOR, 0.38; 95% CI, 0.16-0.92; p=0.032).ConclusionIn lung transplant recipients with NFGNB RTIs, no difference in infection recurrence was detected between treatment durations for ≤ 10 days compared to > 10 days. Further investigation analyzing treatment durations for respiratory tract infections as well as the utility of adjunctive inhaled antibiotics are warranted in this patient population.Disclosures All Authors: No reported disclosures

Total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation: a single-center experience and review of literature.

Limited results about treatment with total lymphoid irradiation (TLI) in lung transplant (LTx) recipients suffering from progressive bronchiolitis obliterans syndrome (BOS) have been reported. We performed a retrospective analysis of all LTx recipients undergoing TLI for progressive BOS in our center, focusing on long-term outcomes regarding overall survival and lung allograft function. Treatment with TLI (2004-2017, n=20, 1 BOS stage 1, 6 BOS stage 2, and 13 BOS stage 3) resulted in significant attenuation of the FEV1 -decline in the majority of patients, mainly in those with a rapid decline (P=0.0005). This allowed bridging to redo-transplantation in five patients. However, three patients progressed from BOS to RAS following prior TLI. Overall patient survival was 44% at 2years post-TLI and 38% after 17years. Generally, TLI was well tolerated, with limited side effects and no serious adverse events. TLI may attenuate the decline in FEV1 of LTx recipients with rapid progressive BOS and could thus help to bridge selected patients to redo-transplantation.

Effect of Cyclosporine Inhalation Solution (CIS) on Lung Function and Inflammatory Biomarkers in Patients with Hematopoietic Stem Cell Transplant (HSCT) Associated Bronchiolitis Obliterans Syndrome (BOS)

Background: Chronic graft versus host disease of the lungs may result in bronchiolitis obliterans syndrome (BOS), an inflammatory injury to medium size airways leading to fibrosis. BOS is often treated with an increase in immunosuppression which can be associated with systemic complications (e.g. organ dysfunction, increased susceptibility to infection and blunting of graft versus leukemia effect). In order to provide enhanced local delivery of an immunosuppressant, cyclosporine, we studied the effects of cyclosporine inhalation solution (CIS) in allogeneic hematopoietic stem cell transplant (HSCT) patients with BOS with a short-term assessment of lung function and inflammatory markers in blood and bronchoalveolar lavage (BAL). Methods: Patients who underwent an allogeneic HSCT meeting the NIH consensus clinical definition of BOS were eligible for inclusion, and were treated with CIS and monitored for treatment response with serial pulmonary function tests (PFTs). At baseline, patients were classified as having stable or progressive disease (i.e. > 10% decline in forced expiratory volume in one second (FEV1) in the preceding 18 weeks). Response was defined as either improvement or stabilization at week 18. Improvement was defined as an increase in FEV1 (regardless of baseline categorization) > 10%. Stabilization was defined as FEV1 increase or decrease < 10% in patients with progressive disease at baseline, and with a reduction in systemic immunosuppression by 25% in those with stable disease at baseline. Patients with declining FEV1 > 10% were classified as non-responders, and patients with FEV1 decline > 20% or with worsening clinical status were taken off protocol. BALs were performed at study entry and week 18 of treatment. BAL and serum samples were analyzed via a custom Luminex® panel. The 37 analytes studied included the following categories: 1) chemokines (CCL2, 3, 5, 18; CXCL5, 9, 10, 13), 2) cytokines (IL-1β, -1ra, -2, -2rα, -6, -7, -8, -10, -12p70, -15, -17a, -23, -17E/25, TNFα, IFNγ), 3) matrix metalloproteinases (MMP1-3, 7-9, 12-13), 4) growth-factors (VEGF-α, G-CSF), and 5) others (PD-L1, surfactant protein D, osteopontin, myeloperoxidase). Results: In total, 20 HSCT patients with BOS were enrolled (median age 45.5 yrs: range 14-71; 13 men and 7 women), and 11 patients completed the study through week 18. The average time from transplant was 4.6 yrs (range 1-28, median 3 yrs). Baseline FEV1 was 1.18 liters (range 0.5-2.02), and with an average FEV1 of 36% predicted (range 18-56%). At the time of enrollment, 12 patients had stable disease, and 8 had progressive disease. Nine patients discontinued treatment due to either worsening FEV1 by 25% (n=1), relapse of primary disease (n=1), or side effects (n=7; cough and bronchospasm). Sixteen patients were included in the evaluable patient population (patients who received treatment for at least the first two weeks) with 9 responders (4 with improvement, 5 with stabilization) and 7 non-responders. Among those completing the study (n=11), 4 had improvement in FEV1, 5 had stable disease, and 2 were non-responders. Seven patients were continued on CIS through an extended use protocol. The baseline BAL cell differentials demonstrated a neutrophil predominance (66 + 29 %) that persisted at week 18 (56 + 35%). In the BAL, MMP-7 increased from baseline (150 + 215 pg/mL) to week 18 (1956 + 2624 pg/mL; p value 0.049), while soluble PD-L1 levels fell (97 + 55 pg/mL to 55 + 43 pg/mL; p value 0.04). The other categories of biomarkers in BAL were either undetectable (n = 12) or demonstrated no significant difference (n = 23) in patients with or without a clinical response to CIS. Similarly, concomitant serum biomarkers showed no difference in treatment after CIS, even when classified amongst responders and non-responders. Conclusion: In HSCT-BOS, CIS led to an improvement or stabilization of PFTs and/or a decrease in systemic immunosuppression in 9 of the 11 patients that completed the study. Due to cough and bronchospasm, only 11 of 20 patients were able to complete treatment through week 18. Inflammatory markers in the serum and BAL were not elevated at baseline or at the end of study. These data suggest that later stages of BOS may represent progression from a state of inflammatory injury to a fibrotic process. Based on our findings, we believe patients with later stage BOS may benefit from investigational therapeutics targeting lung remodeling. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Not really. This drug is not commercially available or FDA approved. An IND was obtained for the use of an inhaled formulation of cyclosporine. Aerosolized cyclosporine has been used previously in other patients (lung transplant associated BOS)

Combined diffusing capacity for nitric oxide and carbon monoxide as predictor of bronchiolitis obliterans syndrome following lung transplantation

BackgroundThere is a need for non-invasive parameters that are sensitive to the development of the bronchiolitis obliterans syndrome (BOS) in lung transplantation (LTx) patients. We studied whether the pulmonary diffusing capacity for inhaled nitric oxide is capable of detecting BOS stages.MethodsSixty-one LTx patients were included into this cross-sectional study (19/29/7/3/3 in BOS stages 0/0-p/1/2/3). For analysis stages 0/0-p versus 1/2/3 (“BOS binary-early”), and stages 0/0-p/1 versus 2/3 (“BOS binary-late”) were summarized. Measurements of the combined diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were compared with spirometry and bodyplethysmography, and their relative importance was evaluated by discriminant analysis.ResultsRegarding the recognition of “BOS binary-early”, among spirometric parameters forced expiratory volume in 1 s (FEV1) was best, among bodyplethysmographic parameters airway resistance, and among diffusing parameters DLNO. Regarding “BOS binary-late”, DLNO was inferior to bodyplethysmographic parameters.ConclusionAlthough the study comprised only measurements at a single time point and no follow-up, DLNO outperformed FEV1, the time course of which is used in detecting BOS. Together with its pathophysiological plausibility, this result suggests that the measurement of DLNO, possibly over time, could be an easily applicable tool for the monitoring of LTx patients and should be evaluated in larger studies.

Breath volatile organic compounds of lung transplant recipients with and without chronic lung allograft dysfunction

Introduction. Chronic lung allograft dysfunction with its clinical correlative of bronchiolitis obliterans syndrome (BOS) remains the major limiting factor for long-term graft survival. Currently there are no established methods for the early diagnosis or prediction of BOS. To assess the feasibility of breath collection as a non-invasive tool and the potential of breath volatile organic compounds (VOC) for the early detection of BOS, we compared the breath VOC composition between transplant patients without and different stages of BOS. Methods. 75 outpatients (25 BOS stage 0, 25 BOS stage 1 + 2, 25 BOS stage 3) after bilateral lung transplantation were included. Exclusion criteria were active smoking, oxygen therapy and acute infection. Patients inhaled room air through a VOC and sterile filter and exhaled into an aluminum reservoir tube. Breath was loaded directly onto Tenax® TA adsorption tubes and was subsequently analyzed by gas-chromatography/mass-spectrometry. Results. The three groups were age and gender matched, but differed with respect to time since transplantation, the spectrum of underlying disease, and treatment regimes. Relative to patients without BOS, BOS stage 3 patients showed a larger number of different VOCs, and more pronounced differences in the level of VOCs as compared to BOS stage 1 + 2 patients. Logistic regression analysis found no differences between controls and BOS 1 + 2, but four VOCs (heptane, isopropyl-myristate, ethyl-acetate, ionone) with a significant contribution to the discrimination between controls and BOS stage 3. A combination of these four VOCs separated these groups with an area under the curve of 0.87. Conclusion. Breath sample collection using our reservoir sampler in the clinical environment was feasible. Our results suggest that breath VOCs can discriminate severe BOS. However, convincing evidence for VOCs with a potential to detect early onset BOS is lacking.

Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial.

Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1.

Lung transplant recipients on long-term extracorporeal photopheresis.

Extracorporeal photophoresis (ECP) is an increasingly used therapy to address chronic lung allograft dysfunction (CLAD) following lung transplantation. In 2008, we reported the first single-center experience showing that ECP not only reduces lung function decline in patients with bronchiolitis obliterans syndrome (BOS) but results in stabilization of patients with recurrent acute cellular rejection (ACR). In this study, the original cohort was followed up further 5years. In addition, patients with CLAD were retrospectively classified according to recently published phenotypes. The current cohort included 21 of the original 24 patients, of which nine were initially treated for CLAD, 12 were initially treated for recurrent ACR. Our results show that survival of patients treated with ECP for CLAD was inferior to patients treated for recurrent ACR (66% vs. 82% survival rate). Long-term survivors in the CLAD subgroup were mostly classified as BOS 1 at time of ECP initiation. These long-term data show that patients started on ECP at early BOS stages have better long-term outcome. The subgroup of ECP patients with recurrent ACR has an overall superior survival. To assist prediction of therapy response, we agree with other authors that patients with CLAD should be aimed to be phenotyped and evaluated for an early treatment with ECP.

Early bronchiolitis obliterans syndrome shows an abnormality of perfusion not ventilation in lung transplant recipients

Long-term survival of lung transplant patients is limited, principally because of Bronchiolitis Obliterans Syndrome (BOS). BOS is primarily classified based on airflow obstruction however there is recent data to suggest that the rejection process can lead to a restrictive ventilatory defect with involvement of the pulmonary vasculature. This study evaluates perfusion heterogeneity in different BOS stages by measuring the relative dispersion (RD) of an arterial spin labelling MRI blood flow image. Acinar ventilation heterogeneity (Sacin) was determined using the Multiple Breath Nitrogen Washout technique. In 24 post transplant patients with a range of severity in BOS status, Sacin increased as BOS level rose from stage 0 to stage 3. In contrast, RD-perfusion was not elevated at BOS 1 and 2 combined compared to BOS 0 and becoming elevated only at BOS-3. However, RD-perfusion in BOS-0p was elevated compared to BOS-0, without an increase in Sacin. These results suggest that BOS-0p is different in nature from other BOS stages.

Determinants of Quality of Life After Lung Transplantation

Background: The purpose of this study was to examine clinical and non- clinical determinants of quality of life (QoL) in lung transplant recipients (LTR). Methods: QoL was measured cross-sectional in 152 LTR (4.5±3.2 years after lung transplantation (LTx); 95 (63%) double LTx; 80 (53%) female; age 50±11.9 years; 28 (18%) bronchiolitis obliterans syndrome (BOS) stage ≥ 1) using the SF-36, the Quality of Life Profile for Chronic Diseases Questionnaire as well as the St. GeorgesRespiratory Questionnaire. Gender, age, body mass index (BMI), time after LTx, procedure type, underlying disease, marital- and professional status and exercise capacity (6-minute walk test, 6MWT) were tested for their predictive value by non-parametric significance tests and ANOVA and ANCOVA. Results: There was a significant correlation with higher physical QoL scores for age < 48 years (p<0.05), a BMI of 21.0 - 25.2 kg/m 2 (p<0.05), a 6MWT≥ 430m (p<0.001), for cystic fibrosis patients (p<0.05) without BOS (p<0.05) and who go to work (p=0.018). Females boasted a superior social health (p=0.04) and less respiratory symptoms (p=0.023). Double LTx was a significant predictor for both, mental and physical health (p<0.05). Subsequent analysis of covariance revealed only BMI (p=0.024), BOS stage (p<0.001), underlying disease (p=0.01) and exercise capacity according to 6MWT (p<0.001) as significant predictors for QoL independent of age. Conclusion: The study results suggest that returning to normal BMI and improving exercise capacity seem to be important therapeutic approaches to enhance QoL after LTx. Future investigations should focus on prophylaxis and therapy of BOS to further optimize QoL after LTx.

Predictive Value of Bronchiolitis Obliterans Syndrome Stage 0p in Chronic Graft-versus-Host Disease of the Lung

Bronchiolitis obliterans syndrome (BOS) is a significant post-transplant complication with low survival. BOS stage 0p (BOS 0p) is a parameter detected on pulmonary function tests (PFTs) after lung transplantation to identify patients at risk to develop BOS. We performed a retrospective study on 442 patients who underwent allogeneic stem cell transplant from 2007 to 2011 to evaluate whether development of BOS 0p is a risk factor in this population for BOS. Patients who met criteria for BOS 0p were significantly more likely to develop BOS (hazard ratio [HR], 3.22; P < .001). BOS 0p was significantly associated with a history of lung disease pretransplant (HR, 2.48; P = .001) and chronic graft-versus-host disease (GVHD) outside the lung post-transplant (HR, 23; P < .001). Finally, BOS 0p criteria were adequately sensitive in predicting BOS (85%), with a high negative predictive value (98%). Our findings suggest a routine PFT screening strategy with the intent of detecting BOS 0p, especially among patients with prior lung disease and who developed chronic GVHD, could suitably identify an at-risk population for the development of BOS.

Cardiac mass and function decrease in bronchiolitis obliterans syndrome after lung transplantation: relationship to physical activity?

RationaleThere is a need to expand knowledge on cardio-pulmonary pathophysiology of bronchiolitis obliterans syndrome (BOS) following lung transplantation (LTx).ObjectivesThe purpose of this study was to assess MRI-derived biventricular cardiac mass and function parameters as well as flow hemodynamics in patients with and without BOS after LTx.MethodsUsing 1.5T cardiac MRI, measurements of myocardial structure and function as well as measurements of flow in the main pulmonary artery and ascending aorta were performed in 56 lung transplant patients. The patients were dichotomized into two gender matched groups of comparable age range: one with BOS (BOS stages 1–3) and one without BOS (BOS 0/0p).Measurements and Main ResultsSignificantly lower biventricular cardiac mass, right and left ventricular end-diastolic volume, biventricular stroke volume, flow hemodynamics and significant higher heart rate but preserved cardiac output were observed in patients with BOS 1–3 compared to the BOS 0/0p group (p<0.05). In a stepwise logistic regression analysis global cardiac mass (p = 0.046) and days after LTx (p = 0.0001) remained independent parameters to predict BOS. In a second model an indicator for the physical fitness level - walking number of stairs - was added to the logistic regression model. In this second model, time after LTx (p = 0.005) and physical fitness (p = 0.01) remained independent predictors for BOS.ConclusionThe observed changes in biventricular cardiac mass and function as well as changes in hemodynamic flow parameters in the pulmonary trunk and ascending aorta are likely attributed to the physical fitness level of patients after lung transplantation, which in turn is strongly related to lung function.

Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplant

Bronchiolitis obliterans (BO) is the leading cause of mortality beyond the first year after pediatric lung transplant, but the performance of an open lung biopsy is often required for diagnosis. Bronchiolitis obliterans syndrome (BOS) is a clinical diagnosis based on spirometric data that is the accepted standard for staging chronic allograft dysfunction. We determined the sensitivity, specificity, and positive and negative predictive values of BOS for predicting BO in children. A chart review was conducted on 139 open lung biopsies and 43 lung explants performed at our center from 1990 through June 2010 in pediatric recipients of lung transplants. Results were excluded from analysis if insufficient data existed to calculate a stable BOS stage before biopsy/explant. The criteria for inclusion in the study were met by 67 open lung biopsies and 31 lung explants. The sensitivity, specificity, positive predictive value, and negative predictive value of BOS for predicting BO were 91.0%, 25.8%, 72.6%, and 57.1%. We found that early declines in lung function are sensitive, but not specific, for BO. The low specificity of BOS for identifying BO illustrates the challenge facing clinicians in determining the etiology of pulmonary decline after lung transplant.

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation

The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

Bronchiolitis obliterans syndrome (BOS) is the major cause of late graft failure after lung transplantation. The objective was to determine whether de novo donor human leukocyte antigen (HLA)-specific antibodies (DSA) are associated with the development of BOS or patient survival. Data were analyzed from 188 lung transplant recipients with a follow-up period up to 8 years. HLA antibody monitoring was performed at 3-month intervals post-transplant at routine outpatient clinic attendances and during the investigation of any acute deterioration. HLA antibody data were available for 148 patients; 66 (45%) had produced HLA antibodies after transplant, of which 38 (26%) were DSA and 28 (19%) non-donor-specific HLA antibodies. De novo DSA was associated with development of BOS Stage 1 (BOS1; hazard ratio [HR] = 2.302, p = 0.0015), BOS2 (HR = 3.627, p < 0.0001) and BOS3 (HR = 5.736, p < 0.0001). De novo persistent DSA correlated strongly with shorter time to onset of BOS3 (HR = 6.506, p = 0.0001). There was a significant reduction in patient survival associated with de novo DSA (HR = 1.886, p = 0.047). In multivariable analyses, de novo DSA was an independent predictor for development of all stages of BOS as well as an independent predictor of poor patient survival. De novo DSA is a major risk factor for progression to BOS and shorter patient survival. Treatments to remove antibodies or limit antibody-mediated damage could be considered when DSA are first detected. However, a randomized, controlled trial of treatment options would enable a clearer understanding of the benefits, if any, of antibody-removal therapies.

Clinical features and outcomes of influenza infections in lung transplant recipients: a single-season cohort study.

For lung transplant recipients (LTRs) influenza infections pose a considerable risk for complications. These infections have mainly been described in hospitalized patients. The aim of this study was to describe characteristics of predominantly outpatient-treated influenza infections. We conducted a single-season (2010/2011) retrospective observational study using database information of our cohort. Patients with evidence for respiratory tract infection received empirical oseltamivir and an oral antibiotic, pending results from nasopharyngeal swab analysis. In laboratory-confirmed influenza infection, treatment was continued and serial weekly swabs were performed until virologic results were negative. We identified 22 infections in 21 of 173 patients followed up; influenza A virus was diagnosed in 13 and influenza B virus in 9 infections. Leading presenting symptoms were cough and rhinorrhea. Oseltamivir was given within 48 h of symptom onset in 13 infections and within 72 h in 21 infections. Prolonged viral shedding (PVS) for ≥ 7 days was detected in 15 infections; median shedding duration for influenza A was 21 days. In univariable analysis, viral load (VL) at diagnosis was associated with extended duration of shedding (P = 0.006). Multivariable analysis confirmed this association. Bronchiolitis obliterans syndrome stage increased in 3 patients at 6-month follow-up. In this study, PVS of influenza virus was detected in the majority of LTRs and high VL at diagnosis was predictive for prolonged shedding, which occurred despite extended antiviral therapy.

Large-Airway Lymphocytic Bronchitis Predicts Bronchiolitis Obliterans Syndrome

Purpose Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. While acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large airway lymphocytic inflammation conveys the same risk. We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality. Methods and Materials Endobronchial biopsies were collected and graded during surveillance following lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0 to 2 “E-score” and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively. Results We found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Lymphocytic bronchitis was more prevalent in subjects who were in BOS stage 0p (26%, P=0.04) and BOS stages 1-3 (31%, P Conclusions These findings support the inclusion of endoscopic biopsies in lung transplant surveillance, as lung allograft recipients with significant large-airway lymphocytic inflammation are at increased risk for BOS and may be targets for more aggressive interventions to prevent rejection. Large-airway lymphocytic bronchitis may be a critical feature of BOS pathogenesis.

Association of Large-Airway Lymphocytic Bronchitis with Bronchiolitis Obliterans Syndrome

Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. Although acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large-airway lymphocytic inflammation conveys the same risk. We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality. Endobronchial biopsies were collected and graded during surveillance after lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0-2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively. We found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazard ratio, 1.76; 95% confidence interval, 1.11-2.78; P = 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P < 0.01). These results support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.

Impact of Sinus Surgery on Pseudomonal Airway Colonization, Bronchiolitis Obliterans Syndrome and Survival in Cystic Fibrosis Lung Transplant Recipients

Background: Lung transplantation (LTx) is a therapy for patients with cystic fibrosis (CF) end-stage lung disease. Pseudomonal airway colonization (PAC) is common in CF. Objectives: We investigated the influence of post-transplant sinus surgery and daily nasal douching on PAC after LTx and the influence of PAC on survival and bronchiolitis obliterans syndrome (BOS). Methods: CF patients transplanted at our centre were included (November 1992 to December 2009). Clinical data, including microbiological data before and after LTx were collected. Survival and BOS following LTx were compared for CF recipients with and without PAC by Kaplan-Meier statistics and Cox regression analysis. Results: Ninety-four CF patients were transplanted, of whom 82 (87%) underwent sinus surgery after transplantation, and 65% of 66 patients with pre-transplant PAC had persistent PAC after transplantation. Upper and lower PAC is related. Patients without PAC after transplantation had a significantly better survival rate, and BOS was less frequent with a later onset. PAC was the only significant parameter for the development of BOS stage 2 in the multivariate analysis for cytomegalovirus infection, acute rejection and PAC. Conclusions: Sinus surgery and daily nasal douching reduced PAC in LTx recipients. Absence of post-transplant PAC had a positive impact on post-transplant survival and the development of BOS.

Circulating Fibrocytes Correlate With Bronchiolitis Obliterans Syndrome Development After Lung Transplantation: A Novel Clinical Biomarker

Development of bronchiolitis obliterans syndrome (BOS) after lung transplantation confers increased patient morbidity and mortality. Fibrocytes are circulating bone marrow-derived mesenchymal cell progenitors that influence tissue repair and fibrosis. Fibrocytes have been implicated in chronic pulmonary inflammatory processes. We investigated the correlation of circulating fibrocyte number with BOS development in lung transplant patients. We prospectively quantified circulating fibrocyte levels among lung transplant patients. Patients were stratified according to the development of BOS as indicated by predicted forced expiratory volume in 1 second. Fibrocyte activity was analyzed by flow cytometry (cluster of differentiation 45+, collagen 1+) in a blinded manner related to clinical presentation. Thirty-nine patients (61.5% men) underwent double (33.3%), left (25.6%), or right (41.0%) lung transplantation. Average patient age was similar between BOS and non-BOS patients (58.3±3.9 vs 60.3±2.0 years, p=0.67). Chronic obstructive lung disease was the most common indication for lung transplantation (41.0%). Median forced expiratory volume in 1 second was lower among BOS patients compared with non-BOS patients (1.08 vs. 2.18 L/s, p=0.001). Importantly, circulating fibrocyte numbers were increased in BOS patients compared with non-BOS patients (8.91 vs 2.96×10(5) cells/mL, p=0.03) by flow cytometry and were incrementally increased with advancing BOS stage (p=0.02). Increased circulating fibrocyte levels correlate with the development of BOS after lung transplantation and positively correlate with advancing BOS stage. Quantification of circulating fibrocytes could serve as a novel biomarker and possible therapeutic target for BOS development in lung transplant patients.