non-BOS Patients Research Articles

Risk Factors for Bronchiolitis Obliterans Syndrome in Pediatric Lung Transplant Recipients

<h3>Purpose</h3> The purpose of this study is to describe the survival of pediatric patients who develop bronchiolitis obliterans syndrome (BOS) after lung transplant (LTx) and to identify the risk factors leading to the diagnosis. <h3>Methods</h3> The UNOS Registry was queried to identify pediatric LTx recipients (age <18yo) from 1999 to 2019. Kaplan-Meier analysis was used to identify median time to BOS diagnosis. Cox-regression analysis was used to identify potential risk factors leading to diagnosis. <h3>Results</h3> 900 lung transplant recipients were identified. 48% (n=431) of these patients were diagnosed with BOS in the post-transplant period. These patients developed BOS after a median of 4.6 years (95% CI: 4.3-5.0). Compared to non-BOS patients, those who developed BOS were less often infants (9% vs. 15%, p=0.008), more frequently aged 2-11yrs (28% vs. 22%, p=0.049), less frequently ventilator dependent at time of LTx (14% vs. 22%, p=0.001), and more frequently experienced graft rejection within 1-yr post-LTx (38% vs. 23%, p<0.001). Multivariate analysis revealed ages 12-17yrs (HR 1.3, CI 1.0-1.6), donor-recipient weight ratio <0.8 (HR 1.6, CI 1.2-2.2), OB (non-retransplant) diagnosis (HR 1.9, CI 1.3-2.9), and graft rejection within 1-yr post-LTx (HR 1.9, CI 1.6-2.4) to be significant predictors of developing BOS. Within those who developed BOS, ages 12-17yrs (HR 2.0, CI 1.1-3.6) and graft rejection within 1-yr post-LTx (HR 1.5, CI 1.2-2.0) were found to be significant predictors of mortality. On Kaplan-Meier analysis, early BOS (within 3-yrs post-LTx) had significantly lower graft survival from the diagnosis of BOS compared to those who developed BOS later (after 3yrs). (<b>Figure</b>, p<0.001). <h3>Conclusion</h3> BOS remains a significant cause of mortality in children after LTx. Adolescent age, OB (non-retransplant) diagnosis, and graft rejection within 1-yr post-LTx are significant predictors of developing BOS. Early development of BOS (within 3yrs post-LTx) resulted in significantly worse graft survival than later development.

Economic Burden of Bronchiolitis Obliterans Syndrome (BOS) Following Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) in Patients with Commercial Insurance in the United States

Background Bronchiolitis obliterans syndrome (BOS), also known as respiratory chronic Graft versus Host Disease (cGvHD), is an obstructive airway disease of the lungs following alloHSCT that has significant morbidity and mortality. BOS is characterized by T-cell mediated inflammation and fibrosis of bronchiolar walls that reduces the diameter of the bronchioles resulting in progressive and irreversible airflow obstruction. BOS is a well described complication following lung transplant and can also be a complication following alloHSCT, with similar histopathology and clinical symptoms. There is currently no approved therapy for the treatment of BOS. While data on alloHSCT costs are available (Milliman 2017; Broder et al., 2017), little is known about the impact of BOS on healthcare resource use (HRU) and costs in alloHSCT. The aim of this study is to quantify the economic burden of BOS in alloHSCT patients. Methods We performed a retrospective analysis of commercial claims data from the IQVIA PharMetrics Plus™ database for patients aged 0-64 who were treated with alloHSCT from 1/1/2007 to 9/30/2017. Patients were observable 12 months before and after index alloHSCT. Those who developed BOS were identified using International Classification of Disease (ICD) diagnosis codes (ICD-9: 491.8, 491.9, 515, 516.34, 561.8; ICD-10: J41.8, J42, J84.09, J84.89, J84.115) and propensity score matched to identify patients who did not develop BOS after alloHSCT. We calculated mean annual per patient rates of hospitalizations, tests and treatments for BOS, as well as costs in the follow-up year for inpatient admissions, Emergency Department (ED) and non-ED outpatient visits, and prescription medications. Costs for the index HSCT were included in the first follow-up year costs. All analyses were repeated for the subset of patients observable in the second post-alloHSCT year. The effect of BOS was estimated as the difference in HRU and costs between the matched BOS and non-BOS alloHSCT patients. Results We identified 161 alloHSCT patients with commercial insurance coverage who developed BOS. A majority were male (60%). Mean age was 51.0 yrs (+/- SD: 12.13); a small proportion (2%) were under age 18. We also identified 161 matched alloHSCT patients who did not develop BOS. More BOS patients were diagnosed with leukemias or lymphomas compared with non-BOS patients (94% vs. 84%) in the pre-alloHSCT year, and more had pulmonary disease (asthma or COPD; 24% vs. 16%). No other differences were statistically significant at p&amp;gt;0.05. In the year following alloHSCT, BOS patients had higher mean per patient annual numbers of inpatient admissions (3.9 [+/- SD: 3.3] vs. 2.6 [+/- SD: 2.5]). More BOS patients received lung function testing, including spirometry (60% vs. 42%), and more were treated with ventilation, oxygen therapy or pulmonary rehabilitation (61% vs. 39%). Costs were higher for BOS patients ($560,048 vs. $408,764), with inpatient costs responsible for most of this difference ($446,622 vs. $300,146). Lung function test costs were over 3 times as high for BOS patients ($35,744 vs. $10,192) and lung function treatment costs 2.5 times as high ($31,761 vs. $7,994). Costs for patients observable in the second post-alloHSCT year were considerably lower, as the costs for the initial alloHSCT costs were reflected in the first year expenditures. Nonetheless, costs remained higher for BOS patients ($72,829 vs. $43,665), with higher inpatient, outpatient and prescription drug costs and HRU (Table, Figure). Conclusion AlloHSCT patients who develop BOS in the U.S. have higher rates of hospitalization and have more lung function tests and treatments, compared with alloHSCT patients with no diagnosis of BOS in the first 1-2 years post-alloHSCT. These higher rates of healthcare service use are accompanied by mean annual per patient costs that are $151,000 higher in the first post-alloHSCT year. Disclosures Sacks: Breath Therapeutics Inc.: Other: Employee of Precision Health Economics (PHE). PHE received funding from Breath Therapeutics for this research. . Healey:Breath Therapeutics Inc.: Other: Employee of Precision Health Economics (PHE). PHE received funding from Breath Therapeutics for this research. . Cyr:Breath Therapeutics Inc.: Other: Employee of Precision Health Economics (PHE). PHE received funding from Breath Therapeutics for this research. . Batt:Breath Therapeutics Inc.: Other: Scientific Adviser to Precision Health Economics (PHE). PHE receieved funding from Breath Therapeutics for this research.. Henig:Breath Therapeutics Inc.: Employment.

Precision medicine: integration of genetics and functional genomics in prediction of bronchiolitis obliterans after lung transplantation.

Lung transplantation (LTx) can be a life saving treatment in end-stage pulmonary diseases, but survival after transplantation is still limited. Posttransplant development of chronic lung allograft dysfunction with bronchiolits obliterans syndrome (BOS) as the major subphenotype, is the main cause of morbidity and mortality. Early identification of high-risk patients for BOS is a large unmet clinical need. In this review, we discuss gene polymorphisms and gene expression related to the development of BOS. Candidate gene studies showed that donor and recipient gene polymorphisms affect transplant outcome and BOS-free survival after LTx. Both selective and nonselective gene expression studies revealed differentially expressed fibrosis and apoptosis-related genes in BOS compared with non-BOS patients. Significantly, recent microarray expression analysis of blood and broncho-alveolar lavage suggest a role for B-cell and T-cell responses prior to the development of BOS. Furthermore, 6 months prior to the development of BOS differentially expressed genes were identified in peripheral blood cells. Genetic polymorphisms and gene expression changes are associated with the development of BOS. Future genome wide studies are needed to identify easily accessible biomarkers for prediction of BOS toward precision medicine.

Validation of a post-transplant chronic lung allograft dysfunction classification system.

Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction (CLAD). Our study evaluated the prevalence and prognostic importance of obstructive and restrictive CLAD phenotypes, with or without an identifiable underlying cause, to validate the recently proposed classification system for CLAD. Data for patients who underwent LTx between 2004 and 2015 with a minimal survival of 180 days post-LTx were retrospectively collected. Double LTx patients with CLAD (defined as a persistent forced expiratory volume in 1 second decline of ≥ 20% compared with baseline) were subsequently classified according to obstructive (forced expiratory volume in 1 second /forced vital capacity [FVC] < 70%, total lung capacity > 90%, and FVC > 80%) or restrictive (total lung capacity ≤ 90% or FVC ≤ 80%) pulmonary function and to the presence of an unknown (bronchiolitis obliterans syndrome [BOS]/restrictive allograft syndrome [RAS]) or known (non-BOS/non-RAS) underlying cause. After a median of 3.2 years, CLAD developed in 39% of double LTx patients (n = 219), of which 20% (n = 43) had an identifiable cause. Survival was worse in patients with restrictive CLAD (26%) compared with obstructive CLAD (64%; p < 0.0001). Non-BOS patients suffered from inferior survival compared with BOS patients (p = 0.0016), whereas there was no significant difference in survival between RAS and non-RAS (p = 0.17). Patients who evolved from an obstructive (BOS) to a restrictive (RAS) phenotype (10%) experienced better survival than RAS patients and a worse outcome compared with BOS patients (p < 0.0001). Given the differences in outcome, accurate diagnosis of CLAD phenotypes is important, because this helps to inform patients about their prognosis, to reveal underlying pathogenesis, to identify homogenous patient populations for clinical trials, and to guide future therapeutic approaches.

Machine Learning Algorithms Utilizing Quantitative CT Features May Predict Eventual Onset of Bronchiolitis Obliterans Syndrome After Lung Transplantation

Long-term survival after lung transplantation (LTx) is limited by bronchiolitis obliterans syndrome (BOS), defined as a sustained decline in forced expiratory volume in the first second (FEV1) not explained by other causes. We assessed whether machine learning (ML) utilizing quantitative computed tomography (qCT) metrics can predict eventual development of BOS. Paired inspiratory-expiratory CT scans of 71 patients who underwent LTx were analyzed retrospectively (BOS [n = 41] versus non-BOS [n = 30]), using at least two different time points. The BOS cohort experienced a reduction in FEV1 of >10% compared to baseline FEV1 post LTx. Multifactor analysis correlated declining FEV1 with qCT features linked to acute inflammation or BOS onset. Student t test and ML were applied on baseline qCT features to identify lung transplant patients at baseline that eventually developed BOS. The FEV1 decline in the BOS cohort correlated with an increase in the lung volume (P = .027) and in the central airway volume at functional residual capacity (P = .018), not observed in non-BOS patients, whereas the non-BOS cohort experienced a decrease in the central airway volume at total lung capacity with declining FEV1 (P = .039). Twenty-three baseline qCT parameters could significantly distinguish between non-BOS patients and eventual BOS developers (P < .05), whereas no pulmonary function testing parameters could. Using ML methods (support vector machine), we could identify BOS developers at baseline with an accuracy of 85%, using only three qCT parameters. ML utilizing qCT could discern distinct mechanisms driving FEV1 decline in BOS and non-BOS LTx patients and predict eventual onset of BOS. This approach may become useful to optimize management of LTx patients.

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.

Infections and neutrophils in the pathogenesis of bronchiolitis obliterans syndrome in children after allogeneic stem cell transplantation.

It is plausible that infections post-hematopoietic SCT play a role in the pathogenesis of BOS. A prospective study for children with history, questionnaire, examination, PFTs, and blood counts at one, three, six, nine, 12, 18, and 24 months post-SCT was conducted. Between September 2009 and September 2011 (n = 39), six developed BOS at 200 days (range 94-282), three patients had probable clinical respiratory infection, and all six had higher neutrophil count compared to non-BOS patients (4.7 vs. 2.4 at three months and 6.3 vs. 2.9 at six months ×10(9) /L, p = 0.03). Contribution of clinical and subclinical infection needs to be considered in the pathogenesis of BOS.

Exhaled nitric oxide and carbon monoxide in lung transplanted patients

BackgroundExhaled nitric oxide (eNO) and carbon monoxide (eCO) are markers of pulmonary inflammation associated with acute graft rejection and lung infections in lung transplant (LTX) recipients. Regarding eNO and eCO levels in LTX patients affected by bronchiolitis obliterans syndrome (BOS), published data are discordant. ObjectivesWe aim to evaluate eNO at multiple flows, alveolar concentration of nitric oxide (CalvNO), maximum conducting airway wall flux (J'awNO) and eCO levels in LTX patients to assess the potential role of these parameters in BOS evaluation. MethodsFractional exhaled nitric oxide (FeNO), CalvNO and J'awNO were analysed in 30 healthy subjects and 27 stable LTX patients (12 BOS patients). Pulmonary function tests were performed after eNO and eCO assessment. Receiver operating characteristic (ROC) curves were conducted to evaluate diagnostic accuracy for BOS of eNO parameters. ResultsLTX patients reported higher values of FeNO at flow rates of 50 (p < 0.01), 150 (p < 0.05), 350 ml/s (p < 0.001), and CalvNO (p < 0.0001) than healthy controls. BOS patients showed higher FeNO at flow rates of 150 (p < 0.05) and 350 ml/s (p < 0.01) and CalvNO (p < 0.001) than non-BOS patients. CalvNO reported a remarkable diagnostic accuracy for BOS (AUC: 0.82). There were no significant differences of eCO levels between LTX patients and healthy controls. ConclusionLTX patients affected by BOS showed higher levels of FeNO 150 and 350, and CalvNO than non-BOS LTX patients, probably due to chronic airway inflammation and fibrotic remodelling. CalvNO may be a potential biomarker of BOS in LTX patients.

Profiling of peripheral blood mononuclear cells does not accurately predict the bronchiolitis obliterans syndrome after lung transplantation

After lung transplantation (LTx), circulating mononuclear cell composition and their subsets may be predictive for the bronchiolitis obliterans syndrome (BOS). We investigated the cellular composition in patients developing BOS, or not, by analyzing peripheral blood taken at multiple time points after transplantation. PBMCs of 11 BOS and 39 non-BOS patients were analyzed by FACS for monocytes, dendritic cells, NK-, NKT-, B- and T cells as well as B- and T cell subsets. Analysis of blood samples taken monthly during the first year post-LTx showed that circulating NK, NKT and dendritic cell percentages were not indicative of BOS development, whereas increases in T cells, monocytes and lowered fractions of B cells were related to BOS development. B- and T cell subset analysis at month 5 post-LTx indicated that IgM+IgD− memory B cells and central memory CD8+ T cells were decreased, whereas NKT cells were increased in BOS patients compared to non-BOS patients. Prior to BOS diagnosis, the composition of specific mononuclear cells on a group level differs from patients remaining BOS free. However, given the overlap in percentages of cellular frequencies between the patient groups investigated, this analysis does not allow prediction or risk stratification for development of BOS in individual patients.

Longitudinal Study of Pulmonary Microbial Dynamics in Lung Transplant Recipients with and without Bronchiolitis Obliterans Syndrome

Purpose The development of Bronchiolitis Obliterans Syndrome (BOS) has been previously linked to microbial pathogens within the transplanted lung. With advanced molecular technology, we are now able to further define microbial communities within the transplanted lung. We hypothesized that these microbial communities will be distinct in lung transplant recipients who develop BOS compared to those who remain stable. Methods and Materials Eighteen lung transplant recipients were included in this analysis. Nine patients developed BOS within 2 years. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at 1, 3, 6, and 12 months post transplant. Bacterial 16S rDNA extracted from the BAL fluid was amplified using barcoded primers and PCR products were pooled and sequenced using 454 pyrosequencing. All the sequence reads were denoised and clustered into similar operational taxonomic units. Taxonomy annotation was assigned according to Ribosomal Database Project. Results The bacterial community of transplanted lungs was taxonomically diversified and consisted of micro-organisms belonging to 14 phyla. Inter-individual variation of the microbial community was greater than intra-individual variation for all patients. There was a distinct difference in the microbial community at the phylum and class taxonomic level between BOS and non-BOS patients (p Conclusions The pulmonary microbiota in lung transplant recipients is taxonomically diverse and dynamic over time and is distinct in patients who develop early BOS compared to those who remain stable. Our findings provide novel approaches to address the relationship between microbial communities and BOS development after lung transplantation.

S53 Alarmins in bronchiolitis obliterans syndrome after lung transplantation

IntroductionSurvival after lung transplantation is limited to a median of 5-year due to development of bronchiolitis obliterans syndrome (BOS). BOS is the clinical manifestation of chronic allograft dysfunction, characterised by...

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.

Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation

Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS. Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L). Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001). Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

Bronchiolitis Obliterans Syndrome and Additional Costs of Lung Transplantation

The influence of bronchiolitis obliterans syndrome (BOS) on costs after lung transplantation was investigated by comparing the costs of patients with and without this condition. Follow-up costs were prospectively investigated in a medical technology assessment of the Dutch Lung Transplant Program, in relation to the development of the BOS. First, average follow-up costs per week per patient were compared between patients who did or did not develop BOS. Second, in the BOS group, these costs were compared before and after the onset of BOS. Dutch Lung Transplant Program, University Hospital of Groningen. Data on 53 patients (37 patients without BOS and 16 with BOS) who underwent transplantation between November 1990 and April 1995 were available. The average follow-up time of these 53 patients was 1.5 years. The follow-up costs amounted to an average (in Dutch guilders [Dfl]) of 1,774/wk for non-BOS patients, compared to 3,072/wk for BOS patients (+ 73%; p = 0.002; one Dfl = 50 cents US currency). This difference in costs was largely accounted for by an increase in used health-care resources, in particular hospitalization and medication. For the BOS patients, the average costs per week before and after the onset of BOS were 1,941 Dfl and 2,422 Dfl, respectively. BOS is associated with substantial extra costs. These findings reemphasize the need to focus efforts on prevention of BOS to enhance the cost-effectiveness of lung transplantation.

Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation. The Munich Lung Transplant Group.

Bronchiolitis obliterans syndrome (BOS) is the most serious long-term sequel of lung or heart-lung transplantation (H/LTX). Neutrophilia in the lower respiratory tract is a prominent feature of BOS. Because polymorphonuclear leukocytes (PMN) are capable of releasing large quantities of reactive oxygen species, we measured indicators of oxidative stress and glutathione levels representing antioxidant defense in H/LTX patients (HLTX, n=6; double-LTX, n=7; single-LTX, n=9). We analyzed 19 bronchoalveolar lavage (BAL) samples from 13 non-BOS patients (nine female, four male: age 39+/-4 years) and 17 BAL samples from nine BOS patients (five female, four male: age 33+/-2 years). PMN were the predominant BAL cell population in BOS (61.7+/-7.8% vs. 12.3+/-3.4%, P<0.001). Myeloperoxidase activity in the epithelial lining fluid and oxidized methionine residues in BAL-derived proteins were elevated in BOS (8.6+/-1.6 U/ml vs. 2.2+/-0.6 U/ml, P<0.01; and 12.6+/-1.1% vs. 7.7+/-0.8%, P<0.001, respectively). In addition, the concentration of reduced glutathione in epithelial lining fluid was decreased in BOS (162.6+/-20.1 microM vs. 345.8+/-57.1 microM, P<0.01), whereas the proportion of oxidized glutathione was increased (13.9+/-2.0O% vs. 6.7+/-1.2%, P<0.001). PMN, myeloperoxidase, and oxidized methionine residues were inversely correlated, whereas reduced glutathione was positively correlated with forced expiratory volume in 1 sec (P<0.05 to P<0.001). We conclude that excessive oxidative stress and a lack of glutathione are associated with BOS after H/LTX and may play relevant roles in the development of this disorder.

Detection of Small Airway Dysfunction Using Specific Airway Conductance

To assess the potential utility of specific airway conductance (sGaw) in detecting small airways dysfunction, the postlung-transplant bronchiolitis obliterans syndrome (BOS) was used as a model of small airways dysfunction. BOS is defined as an otherwise unexplained 20% reduction in FEV1. We hypothesized that if sGaw is sensitive to small airways dysfunction, it should decrease before the decline in FEV1. The pulmonary function test and sGaw measurements of patients who underwent heart-lung or bilateral lung transplantation between May 1981 and January 1993 were reviewed. Patients with and without BOS were identified. A significant decrease in sGaw was defined as a 20% fall from baseline. Twenty-six BOS and 15 non-BOS patients had at least three sGaw measurements such that trends could be examined. Eleven of the 26 BOS patients (42%) had a significant decrease in sGaw before a 20% decrease in FEV1, as compared to 2 of the 15 non-BOS patients (13%) (p=0.08). In comparison, 12 of the 26 BOS patients (46%) and 4 of the 15 non-BOS patients (27%) had a significant decrease in forced expiratory flow at 25 to 75% of the forced lung volume (FEF(25-75)) (p=0.32), an accepted test of small airways dysfunction. sGaw tended to decrease before FEV1 in BOS. The trend in sGaw was similar to the trend in FEF(25-75). We conclude that (1) small airways may contribute more to airway conductance than previously thought, and (2) further prospective studies are warranted to better define the relative contribution of small and large airways to sGaw.