Pretransplant Pulmonary Function Tests Research Articles

Pulmonary function as a continuum of risk: critical care utilization and survival after allogeneic hematopoietic stem cell transplantation - a multicenter cohort study.

Abnormal pre-transplant pulmonary function tests (PFTs) are associated with reduced survival after allogeneic HCT. Existing scoring systems consider risk dichotomously, attributing risk only to those with abnormal lung function. In a multicenter cohort of 1717 allo-HCT recipients, we examined the association between pre-transplant PFT measures and need for ICU admission (120d), frequency of mechanical ventilation (120d) and overall survival (5 y). Predictive models were developed and validated using Cox proportional hazards, incorporating age, FEV1 (forced expiratory volume in 1-second) and diffusing capacity (DLCO). In univariate analysis, hazard ratios for each outcome (95% CI) were: mechanical ventilation (FEV1: 0.60 [0.52-0.69], DLCO: 0.69 [0.61-0.77], p < 0.001), ICU admission (FEV1: 0.74 [0.67-0.82], DLCO: 0.79 [0.72-0.86], p < 0.001) and overall survival (FEV1: HR 0.87 [0.81-0.94], DLCO: 0.83 [0.77-0.89], p < 0.001). A multivariable Cox model was developed and compared to the HCT-CI Pulmonary score in a validation cohort. This model was better at predicting need for ICU admission and mechanical ventilation, while both models predicted overall survival (p < 0.001). In conclusion, the risk conferred by pre-transplant pulmonary function should be considered in a continuous rather than dichotomous manner. A more granular prognostication system can better inform risk of critical care utilization in the early post-HCT period.

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.

Prognostic implication of pre-transplant FEV1 on long-term outcomes following allogeneic hematopoietic stem cell transplantation.

Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and ≤65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning.

Impact of preheart transplant spirometry and DLCO measurement on post-transplant pulmonary outcomes

Pulmonary function tests (PFT) are a frequent component of heart transplant evaluation. In cardiac surgery abnormal PFTs, especially reduced DLCO, have been associated with poor outcomes. We sought to evaluate the impact of pretransplant PFTs on post-transplant pulmonary outcomes and patient survival. Among the 652 adult heart transplant recipients between January 1, 2010 and July 31, 2021, 462 had PFTs and constituted the patient cohort. Obstructive ventilatory defects (OVD), restrictive ventilatory defects (RVD), and reduced DLCO were defined according to established criteria. The primary outcome was the combined endpoint of a post-transplant pulmonary complication defined as reintubation, postoperative pneumonia, prolonged intubation, or tracheostomy. Secondary outcomes included 90-day all-cause mortality, length of stay, and the odds of individual pulmonary complications. Kaplan-Meier survival analysis, multivariable Cox proportional-hazards regression, and multivariable logistic regression were performed to compare outcomes between the groups. Patients with severe OVD (OR 1.48, 95% CI 1.18-5.23, p=0.02) or severely reduced DLCO (OR 1.95, 95% CI 1.19-3.20, p=0.008) had increased odds of post-transplant pulmonary complications. Following multivariable adjustment, severe OVD (aOR 2.67, 95% CI 1.15-6.19, p=0.02) and severely reduced DLCO (aOR 1.79, 95% CI 1.05-3.04) remained strongly associated with post-transplant pulmonary complications. Patients with any degree of extrinsic RVD, moderate or less OVD, or moderately reduced DLCO or less did not have increased odds of post-transplant pulmonary complications. Ninety-day post-transplant survival was significantly reduced for both severe OVD (97.2% vs 86.5%, p=0.04) and severely reduced DLCO (97.3% vs 90.4%, p=0.004). Post-transplant ICU and hospital length of stay were nominally longer for both groups as well. Severe OVD or severely reduced DLCO on preheart transplant PFTs were associated with increased odds of post-transplant pulmonary complications and early mortality.

Pre-Transplant Pulmonary Function Test Parameters of FEF50% (Forced expiratory flow at 50% of forced vital capacity) and RV (residual volume) in Combination Can Predict the Risk for Development of Lung Gvhd after Allogeneic Transplantation

BackgroundChronic graft vs host disease (GVHD) of the lung is a significant post-transplant complication that impacts patients' quality of life and overall survival. It manifests as bronchiolitis obliterans syndrome (BOS), an irreversible progressive airflow obstruction. Risk factors identified include busulfan, peripheral blood stem cell source, post-transplant viral infections, history of lung disease, and acute GVHD. Diagnosis involves changes in pulmonary function tests (PFTs), ruling out infection and presence of chronic GVHD in other organ systems. Without routine monitoring patients can present with moderate to severe symptoms. The predictive value of pre-transplant PFTs has not been clearly elucidated. In this retrospective study, we examined the role of pre-transplant PFT parameters with respect to the development of lung GVHD.MethodsPatients receiving allogeneic HCT at Princess Margaret Cancer Centre between 2004 to 2013 were included in the analysis. Pre-HCT PFT results were routinely obtained within 30 days prior to transplant. PFT parameters included % predicted FEV1, DLCO, TLC, RV, RV/TLC, FRC, FVC, FEV1/FVC, FEF50% and FEF75%. After transplant, PFT was repeated around day 120, then annually, or when clinically indicated.Our definition of lung GVHD required at least the first two of the 2005 NIH consensus criteria for the diagnosis of chronic lung GVHD: 1) FEV1/forced vital capacity ratio <0.7 and FEV1<75% predicted, 2) evidence of airway obstruction on high-resolution computed tomography or a residual volume on PFTs >120%, 3) absence of infection in the respiratory tract, and 4) histologic diagnosis of BOS or at least 1 other manifestation of chronic GVHD in an additional organ system.The primary endpoint was cumulative incidence (CI) of lung GVHD at 3 years. The cut-off values in each PFT parameter with respect to development of lung GVHD were calculated using binary recursive partitioning (rpart) method provided by rpart package using R. Pearson's correlation test was used to look for relationship among the PFT parameters. The parameters with cut-offs identified by rpart were analyzed by factor analysis with Varimax rotation method.For multivariable analysis, Fine-Gray proportional hazard regression with competing risks was applied. The clinical variables included in the model were busulfan, acute GVHD, and stem cell source (peripheral vs bone marrow). All statistical tests were performed using EZR and SPSS.ResultsA total of 605 patients with available PFTs were reviewed. The CI of lung GVHD at 3 years was 10.6% (7.9 - 13.7) with a median onset at 12.6 months (range of 1.7 - 55.8).Univariate analysis of each PFT parameter as a continuous variable did not show an impact on development of GVHD. With recursive partitioning, cut-offs were identified for DLCO (68%), FEF50% (39%), FRC (130%) and RV (93%).In Pearson's correlation analysis, DLCO and FEF50% did not have a significant association with the other PFT parameters selected from rpart, while RV was significantly associated with TGV (r= 0.65). In the factor analysis, based on the factor loading, FEF50% and RV were selected for multivariate analysis.Multivariate analysis showed that FEF50% < 39% and RV ≥ 93% were independent risk factors of lung GVHD development. The patients with pre-transplant FEF50 ≥ 39% had significantly less risk compared to those with < 39% (p=0.025; HR 0.389), and RV ≥ 93% showed a 2 fold higher risk than those < 93% (p=0.036, HR 2.63).A risk score model was created using the cut-offs from FEF50% and RV. For FEF50%, score 0 was assigned to ≥ 39% while score 1 was < 39%. For RV, score 0 was assigned to < 93%, while score 1 was ≥ 93%. A risk score was summed from the two parameters. Risk scores of 2 were classified as high risk, scores of 1 intermediate risk and score of 0 low risk. The 3 year CIs of lung GVHD were then compared according to the new risk score. The high risk group had an incidence of 33.5% (11.8 - 57.0%; n=28, 4.6%), intermediate risk 11.4% (8.3 - 15.2%; n=445, 73.6%) and low risk 3.0% (0.8 - 8.2%; n=132, 21.8%; p = 0.003; Figure).Conclusions1) Pre-transplant PFT parameters can predict the risk of lung GVHD development.2) FEF50% and RV were predictive of lung GVHD development independent from the other clinical risk factors acute GVHD, busulfan and stem cell source which were not confirmed in our cohort.3) A risk score model using pre-transplant FEF50% and RV may help in prediction of lung GVHD. [Display omitted] DisclosuresKim:Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy.

Lung Transplantation Outcomes in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare slowly progressive disease that leads to respiratory failure. The aim of this study was to analyse the results of lung transplantation (LT) in LAM patients and the sirolimus effect in LT. LAM patients from a referral centre were retrospectively reviewed. Those who underwent LT were considered for the analysis. Demographics, postoperative complications, survival, recurrence of LAM and pulmonary function test (PFT) were analysed. All patients followed a standard triple immunosuppressive therapy based on tacrolimus, mycophenolate mofetil and corticosteroids. Sirolimus was introduced in our centre in November 2007 as a treatment for LAM patients and was indicated in cases of abnormal FEV1 or presence of angiomyolipomas. From 1980 to 2018, 76 LAM patients have been followed-up. Of these, 28 (37%) patients underwent LT. Twenty (71%) were bilateral LT (BLT) and 8 (29%) single LT (SLT). Pre-transplant PFT were: FVC 53±18%, FEV1 35±18% and FEV1% 48±19%. The best post-transplant pulmonary function was achieved at a median of 8 (7-13) months and 18 (8-35) months for SLT and BLT, respectively. Following BLT, the best PFT results were FVC 85±14%, FEV1 88±14% and FEV1% 104±20. In case of SLT, the best FVC was 63 ±12%, FEV1 53±7% and FEV1% 85±10%. Two (7%) patients developed LAM recurrence, in both cases, immunosuppressive treatment was adjusted and the purine synthesis inhibitor was changed to sirolimus. Survival after LT was 67% at 5 years and 58% at 10 years with a mean follow-up after LT of 11.7 years. Since the introduction of sirolimus in 2007, no newly diagnosed LAM cases were submitted to LT. While on sirolimus only 9 patients underwent LT. Survival in LAM patients submitted to LT exceeds 10 years. LT in LAM patients allows an improvement in spirometric values. A significant decrease in the number of LT indications in LAM has been observed since the introduction of sirolimus treatment.

Pre-Heart Transplant Spirometry Predicts Post-Transplant Survival

Lung disease is common in the advanced heart failure population. While pulmonary function testing (PFT) is typically performed as part of a heart transplant evaluation, little is known regarding the prognostic utility of PFTs for outcomes after transplantation. We evaluated whether PFT parameters correlated with survival, length of stay, or time on ventilator following heart transplantation. International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant (TTX) registry data was combined with single-center data from the University of Nebraska Medical Center. Cox proportional hazard modeling was used to evaluate univariate and multivariate predictors of survival. A total of 1083 patients (802 from a total of 62,327 from the TTX registry, 281 from the UNMC database) had pre-transplant PFT data available for evaluation. At the time of transplant, the mean age was 50.6 (± 14.5) years, 24.2% were female, 51% had a history of tobacco use, and 8% had a history of chronic obstructive pulmonary disease. Forced expiratory volume in 1 second (FEV1) < 50% of predicted and forced vital capacity (FVC) < 50% of predicted each had significantly higher mortality within the first 5 years post-transplant (p < 0.0001 and p=0.0001, respectively) compared to patients with FEV1 or FVC 50-70% or > 70% (Figure 1). FEV1/FVC < 0.7 and DLCO < 60% predicted were not associated with increased mortality. FEV1 and FVC below 50% of predicted both had longer lengths of stay (p=0.0005 for FEV1 and <0.0001 for FVC), but were not associated with more time on the ventilator. After adjusting for male gender, age, body mass index, smoking history, COPD, creatinine, albumin, and total bilirubin, either FEV1 or FVC < 50% remained independent predictors of mortality with a hazard ratio of 2.65 (p < 0.0001, 95% CI 1.6, 4.3). Abnormal pulmonary function (FEV1 or FVC < 50% prior to transplantation is associated with increased mortality and longer length of stay following transplant.

Absence of Pre-Transplant Pulmonary Features of Sarcoidosis is of Low Negative Predictive Value in End-Stage Cardiac Sarcoidosis

Purpose Cardiac sarcoidosis is a potentially reversible etiology of heart failure if identified and managed in a timely fashion. Given the multisystem nature of the disease and need for a high index of suspicion, diagnosis of cardiac sarcoidosis is difficult, and the underlying cause remains speculative. Methods In a single-center retrospective case-control study of 15 patients with pathologic evidence of cardiac sarcoidosis that required cardiac transplantation or left ventricular assist device placement, diagnosed by diagnostic granulomas on native heart cardiectomy or apical core, and 33 matched controls, we collected pre-transplant pulmonary function testing (PFT) and right heart catheterization (RHC) data. We performed a blinded review of pre-transplant chest CT to categorize each scan as likely, possible, or unlikely for sarcoidosis. Results Mean age in the cardiac sarcoidosis group was 59 years and 67% were male. The FVC, FEV1, TLC, and DLCO were similar in both groups. RHC showed comparable hemodynamics with a non-significant trend towards lower cardiac index and lower mixed venous O2 saturation in the sarcoidosis group. Figure 1 shows the distribution of chest CT interpretation. Sensitivity and specificity of the chest CT classification in predicting cardiac sarcoidosis were 0.79 and 0.38, respectively, with positive predictive value of 0.41 (95%CI, 0.22-0.61) and negative predictive value of 0.77 (0.46-0.95). Conclusion PFT and RHC data did not independently differentiate the likelihood of cardiac sarcoidosis in our sample. Chest CT scans may identify patients with nonischemic heart failure who need to be considered for workup of cardiac sarcoidosis. However, absence of clear pulmonary radiographic or PFT finding at the time of tertiary referral did not exclude the diagnosis. It remains unclear whether sarcoidosis with end-stage physiology limited to the heart represents a distinct pathological entity from pulmonary-predominant sarcoidosis.

Effect of Azithromycin on Airflow Decline–Free Survival After Allogeneic Hematopoietic Stem Cell Transplant

Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post-lung transplant bronchiolitis obliterans syndrome. To evaluate if the early administration of azithromycin can improve airflow decline-free survival after allogeneic HSCT. The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017. Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen. The primary efficacy end point was airflow decline-free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years. Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline-free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70; P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0; P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4; P = .002). Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline-free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation. clinicaltrials.gov Identifier: NCT01959100.

Comprehensive Analysis of Pre-Transplant Pulmonary Function Test Parameters Including FEV1, FVC, DLco, FEF50%/75%, Frc, RV and TLC As Prognostic Factors for Long-Term Outcomes after Allogeneic Transplantation

BackgroundThe pulmonary function test (PFT) is an integral part of the assessment of patients prior to hematopoietic cell transplantation (HCT). The HCT comorbidity index (HCT-CI) is a routinely used scoring system using PFTs to determine patient outcomes post HCT. FEV1 and DLCO are used as determinants distinguishing between moderate (DLCO or FEV1 66-80%) and severe dysfunction (DLCO or FEV1 ≤ 65%). While there is a supportive evidence of its use in HCT, there is a debate on stratification of the current threshold of PFTs. Our study attempted to analyze the prognostic impact of each parameter of PFT on outcomes including overall survival (OS), relapse and non-relapse mortality (NRM) including FEV1, FVC, DLCO, FEF50%/75%, FRC, RV as well as TLC.MethodsA retrospective review was conducted to analyze pre-transplant PFT values with respect to transplant outcomes in 605 patients receiving allogeneic HCT at Princess Margaret Cancer Centre from 2004 to 2013. PFT results were collected within 30 days prior to HCT. PFT parameters include % predicted FEV1, DLCO, TLC, RV, RV/TLC, FRC, FVC, FEV1/FVC, FEF50% and FEF75%. The main outcomes include OS, cumulative incidence of relapse (CIR) and NRM. The cut-off values in each PFT parameters with respect to OS were calculated using binary recursive partitioning (rpart) method provided by rpart package using R. Each PFT parameter was analyzed for correlation with other PFT parameters using Pearson’s correlation test. All the statistical tests were done using EZR and SPSS. OS analysis was done using Kaplan-Meier method, and OS was compared according to the new cutoff derived from rpart and according to the cutoff used in the HCT-CI score. Then prognostic stratification power was compared between these two cutoffs. For the multivariable analysis, all variables were included in the model with the exception of those already included in the HCT-CI score. For the outcome of OS, Cox prop ortional hazard regression model was adopted. Six clinical variables were included in the multivariate analysis including: pre-transplant FEV1 <81%, conditioning regimen (reduced intensity vs myeloablative), age ≥60 yrs (vs < 60 yrs), disease risk index (DRI) (high/very high risk vs intermediate vs low risk), GVHD prophylaxis (without or with T-Cell Depletion (TCD)), and HLA mismatch vs matched.ResultsOut of 605 patients, OS rate was 46% at 3 years. NRM was 35.6% and relapse rate was 21.0% at 3 years. For correlation among PFT parameters, FEV1 was significantly associated with TLC (r=0.51), FVC (r=0.79), FEF75 (r=0.58) and FEF50 (r=0.68), and was chosen as a surrogate of OS for further analysis. Univariate analysis for the PFT parameters expressed as continuous variables revealed that OS was associated with FEV1, FVC and TLC, while not with other parameters (i.e. DLCO, FEF50%, FEF70%, FRC or RV). Using recursive partitioning, the optimal value for the best stratification of OS was found: FEV1 at 81%, FEV1/FVC at 92%, and TLC as 88%. The OS rate at 3 years in the group with FEV1 ≥81% was 49.9%, versus FEV1 <81%, 36.6% (p=0.001, HR 0.674). Meanwhile, the group with FEV1 ≥80% showed an OS of 49.2% at 3 years, while with FEV1 between 66-80% and ≤65% showed an OS of 38.1% and 33.5% at 3 years, respectively. (p=0.003, HR 0.774). We then compared the risk stratification power of the new FEV1 cutoff derived from rpart with the cutoff used in the HCT-CI score (65% and 80%). Using C-statistic, it was found that the new cutoff from rpart showed better risk stratification compared to that form HCT-CI score (P<0.01, C-statistic 2.4279). Multivariate analysis confirmed that pre-transplant FEV1 <81% is an independent prognostic factor for OS. The patients with pre-transplant FEV1 <81% showed 48% higher risk of death compared to those with higher FEV1 (p=0.001; HR 1.478). The other prognostic factors included HLA mismatch (p=0.001; HR 1.817]), and DRI (overall p=0.03; p=0.007 between low vs intermediate/high/very high risk).Conclusions1. FEV1 at 81% is a significant and reliable parameter amongst all the PFT parameters affecting HCT outcomes.2. DLCO does not predict long-term HCT outcomes in our cohort.3. Compared to FEV1 cutoff per HCT-CI scoring system, the new cutoff of 81% FEV1 provides better risk stratification power for long-term outcomes after allogeneic HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lung function score including a parameter of small airway disease as a highly predictive indicator of survival after allogeneic hematopoietic cell transplantation.

Some studies on the predictive value of determining pulmonary function prior to allogeneic hematopoietic cell transplantation (allo-HCT) have shown a significant association between pulmonary function test (PFT) parameters and pulmonary complications, and mortality. However, the percentage of patients showing abnormalities in pretransplant PFT parameters is low. We comprehensively evaluated the effect of pretransplant PFT parameters, including a marker of small airway disease (ratio of the airflow rate of 50% vital capacity to the airflow rate of 25% vital capacity (V˙50/V˙25), on outcomes in 206 evaluable patients who underwent allo-HCT at our institute. Notable among the significant parameters in a univariable analysis, V˙50/V˙25 was the most powerful indicator of survival following allo-HCT (delta-Akaike information criterion [∆AIC]=12.47, ∆χ(2) =14.47; P= 0.0001). Additionally, a pretransplant lung function score (pLFS) established by applying three parameters with superior predictive values including V˙50/V˙25 represented a better discriminating variable for the prediction of survival. Our data demonstrate that a pLFS incorporating a parameter of small airway disease, rather than the parameters of central airway obstruction, may be useful for predicting patient survival following allo-HCT.

Impact of Pre-Transplant Diffusion Lung Capacity for Nitric Oxide (DLNO) and of Dlno/Pre-Transplant Diffusion Lung Capacity for Carbon Monoxide (DLNO/DLCO) Ratio on Pulmonary Outcomes in Adults Receiving Allogeneic Stem Cell Transplantation for Haematological Diseases

Background: Pre-transplant pulmonary function testing (PFT) is required in all patients eligible for allogeneic stem cell transplantation (allo-SCT). Diffusion lung capacity for carbon monoxide (DLCO) is the main parameter taken into account but the overall impact of this factor is debated. Diffusion lung capacity for nitric oxide (DLNO) may be of higher interest to predict pulmonary complications, because radiotherapy and chemotherapy used to treat patients with haematological diseases affect mostly the alveolar-capillary membrane, which destruction is more appreciate by DLNO than DLCO measure. Also, DLNO/DLCO ratio represents a new index of gas exchange and an alternative way of investigating the alveolar membrane and the blood reacting with the gas.Methods: We considered all patients who received an allo-SCT for hematological malignancies between March 2012 and January 2014 in our department and for whom a pre-transplant PFT, including DLCO and DLNO measures, was validated. Factors influencing pre-transplant DLCO, DLNO and DLNO/DLCO ratio were analyzed as well as impact of those 3 diffusion lung parameters on general outcomes and pulmonary complications (severe pulmonary complications (SPC) defined as any pulmonary complication responsible for hospitalization, pulmonary related mortality (PRM), acute respiratory distress syndrome (ARDS).Results: We included 103 patients (male: n=68, median age at transplant: 58 years) in this study. Majority of them had a myeloid disease (n=67), and were in complete (n=56) or partial (n=23) remission at transplant. Type of donor was: matched related donor (N=35), haploidentical related donor (n=5), matched unrelated donor (n=43), mismatched unrelated donor (n=9) and umbilical cord blood (n=10). First stem cell source used was peripheral blood stem cell (n=83). Eight five percent of patient received a reduced intensity regimen. With a median follow up of 21.5 months (range: 3.8-34.7), 2 year cumulative incidence of overall survival, Disease free survival, relapse incidence, non-relapse mortality, SPC, ARDS and PRM were respectively 65.4% ( 55.2-73.6), 52.5% (42.7-62.2), 31.8% (22.3-41.7), 15.8% (9.4-23.5), 25.4% (17-34), 7.8% (4-14), and 4.9% (1.8-10.4). Normal DLCO and DLNO percentages of predicted normal value (>80%) were documented in 48 and 44 patients, respectively but median percentages for the all cohort were under the normal at transplant: DLCO: 78.9%, DLNO: 78.1%. Median DLNO/DLCO ratio was 5.3 (range: 2.7-8.6). Regarding factors influencing pre-transplant PFT results, DLCO was significantly decreased in patients with respiratory history (72.3% versus 81.5%, p=0.001), in patients having received therapeutic with cardiac or pulmonary toxicities (74.2% versus 80.6%, p=0.02) and in patients over 58 years (81.0% versus 75.4%, p=0.05). Similarly, DLNO was significantly decreased in patients with respiratory history (74.3% versus 80.9%, p=0.03) and in patients' smokers or with history of smoking (75.3% versus 81.8%, p=0.03). Finally, patients' age was the only parameter with a significant impact on DLNO/DLCO (5.5 in patients >58 years versus 5.2 in patients ≤58years, p=0.04). In univariate analysis, a DLNO value <60% of predicted normal value was associated with higher incidences of SPC (p=0.02) and acute respiratory distress syndrome (ARDS) (p<0.005). When considering DLCO and DLNO as continuous variables, lower percentage were associated with higher risk of SPC for both parameters (p=0.048 and p=0.026, respectively). Also, lower DLNO/DLCO ratio (considered as a continuous variable) was associated with higher PRM (p=0.04). In multivariate analysis, there was a trend for an association between lower value of pre-transplant DLNO (<60%) and higher risk of ARDS (HR: 3.34, 95%CI: 0.99-11.2, p=0.05) and of SPC (HR: 2.5, 95%CI: 0.93-7.12, p=0.06).Conclusion: DLNO and DLNO/DLCO ratio may be more appropriate to predict pulmonary complications than DLCO alone after allo-SCT. These results have to be confirmed prospectively. DisclosuresMohty:Janssen: Honoraria; Celgene: Honoraria. Moreau:Takeda: Other: Adboard; Amgen: Other: Adboard; Novartis: Other: Adboard; Celgene: Honoraria, Other: Adboard; Janssen: Other: Adboard.

Forced Deflation PFT: A Novel Method to Evaluate Lung Function in Infants and Young Children

Pretransplant pulmonary function test (PFT) abnormalities are correlated with risk of early respiratory failure and mortality in adults and older children. While there is an increasing use of allogeneic BMT in infants and young children with metabolic and immune deficiency disorders, lung function has not been systematically studied in this age group. We describe use of forced deflation PFT (dPFT), a novel technique for assessment of lung function in a series of infants and young children and those unable to perform cooperative testing. Forced dPFT studies were coordinated with other procedures requiring general anesthesia and performed according to previously published techniques1. Briefly, a specially constructed forced deflation device was inserted between the endotracheal tube and anesthesia breathing circuit via a 3-way slide valve (Figure). The lungs were inflated three times to 40 cm H2O (total lung capacity) and then rapidly deflated to -40 cmH2O via a pneumotachograph (to residual volume). Raw flow or volume measurements were normalized and converted to %predicted and standard deviation scores using data obtained in healthy children. Between October 2008 and April 2014, 52 dPFT studies were performed in 26 transplant recipients. Indications for BMT were inherited metabolic disease (42%), malignancy (31%), primary immune deficiency (15%) and bone marrow failure (12%). Median age of 21 patients who had pretransplant studies was 0.9±1.3 y (0.1 – 4.9 y); nine of them (43%) had one or more prior lung diseases (respiratory failure [n=7]; pneumonia [n=7]; ARDS [n=3]; bronchopulmonary dysplasia [n=1]; and bronchitis [n=1]). Forced vital capacity (FVC) and forced expiratory flow (FEF75) were normal in all but respiratory system compliance (Crs) was reduced in 5/21 cases. Six out of nine (66.7%) patients with clinical resp. issues pre-BMT also had respiratory complications post-BMT compared with 3/12 (25%) that had no pre-transplant respiratory issues. There were no significant differences in pre-transplant FVC, FEF75 and Crs between those patients who did and who did not have post-transplant pulmonary complications with median follow-up of 1.7±1.5 y (p=0.435, p=0.305, and p=0.301 respectively). There were no complications during the procedures and dPFT studies could be safely done in coordination with other procedures requiring anesthesia. In this pilot study, pre-transplant PFTs were not predictive of post-transplant pulmonary complications, and most patients had normal volume and flows. A larger study would be required to determine prevalence and significance of lung function abnormalities in infants and toddlers undergoing transplantation. 1. Motoyama, E. K., et al. (1987). “Early onset of airway reactivity in premature infants with bronchopulmonary dysplasia.” Am Rev Respir Dis 136(1): 50-57.

Pre-hematopoietic stem cell transplant lung function and pulmonary complications in children.

Pulmonary complications are a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. The relationship between pretransplant pulmonary function tests (PFTs) and development of post-transplant pulmonary complications in children was studied. This is a retrospective single institution cohort study of 410 patients who underwent pretransplant PFT and were monitored to 10 years posttransplant. Pulmonary complications were observed in 174 (42%) patients. Children with pulmonary complications had significantly lower forced expiratory flow at 25-75% of vital capacity (P = 0.02) derived using conventional predicted equations for age, and the Global Lung Initiative-2012 predicted equations (P = 0.01). T-cell depletion (P = 0.001), acute grade 3-4 graft-versus-host disease (P = 0.008), and chronic graft-versus-host disease (P = 0.01) increased risk for pulmonary complications. Patients who had pulmonary complications had a 2.8-fold increased risk of mortality (P < 0.0001). The cumulative incidence of death due to pulmonary complications was significantly higher in children who had low lung volumes, FRC less than 50% (P = 0.005), TLC less than 50% (P = 0.0002), residual volume less than 50% (P = 0.007), and T-cell depletion (P = 0.01). Lower FEV1 (P = 0.0005), FVC (P = 0.0005), TLC (P < 0.0001), residual volume less than 50% (P = 0.01), and restrictive lung disease (P = 0.01) predicted worse overall survival. Abnormal pretransplant PFT significantly increased risk after transplant. These patients may benefit from modified transplant strategies to reduce morbidity and mortality.

Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is used to counsel patients regarding the risk of transplantation and selection of conditioning regimens. Pulmonary disease, most frequently demonstrated by a decreased diffusion capacity of carbon monoxide (DLCO), is the most prevalent comorbidity captured by the HCT-CI. The HCT-CI was validated using the Dinakara method for adjusting DLCO for Hb, but our institution and others utilize the Cotes method. The purpose of this study was to determine the impact of using the Cotes method rather than the Dinakara method on the HCT-CI score. We reviewed pre-transplant pulmonary function tests in 73 patients who underwent allogeneic hematopoietic SCT. Patients were stratified into low, intermediate or high-risk groups based on HCT-CI scores of 0, 1-2 or 3, respectively. We found that compared with the Dinakara method, the Cotes method increased the HCT-CI score in 45% of patients and resulted in total HCT-CI scores predictive of higher non-relapse mortality in 33% of patients. These results indicate that if an institution uses the Cotes method to adjust DLCO for Hb, their patients may be counseled to expect a higher risk of mortality than is actually predicted by the HCT-CI, and may be excluded from transplantation. Therefore, unless the HCT-CI is validated using other methods for correcting DLCO for Hb, the Dinakara method should be used.

Lethal Pulmonary Complications After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) in children is accompanied by a transplant-related mortality of 10% to 30%, which is the result of lethal pulmonary complications (LPCs) in many cases. We retrospectively assessed prevalence and risk factors of LPC following 234 allogeneic HSCTs in 228 patients for malignant or nonmalignant diseases at a single institution. Pulmonary complications (PCs) were observed following 81 of 234 transplants (35%). LPCs were observed in 4% of HSCT within 100 days and in 14% within 5 years after HSCT. Late PCs after day 100 were lethal in 56% (22/39) of the patients with PCs, who are 11% (22/202) of all evaluable patients still alive after day +100. Causes of LPC after day 100 were viral (10 cases), bacterial (1 case), fungal (5 cases) pulmonary infection, or noninfectious (6 cases) PCs. Abnormal pretransplant pulmonary function test was not associated with an increased risk of LPC. Children older than 10 years and those undergoing a second HSCT had an increased incidence of overall LPC. T-cell depletion and mismatched donor HSCT (P = 0.001), but not age, were associated with an increased risk of lethal viral pneumonia. Transplant-related mortality up to 5 years after HSCT in children was associated with LPC in 14%. There were more late (>100 days) than early LPCs, predominantly due to infectious etiologies and affecting children >10 years of age.

Pulmonary function testing prior to reduced intensity conditioning allogeneic stem cell transplantation in an unselected patient cohort predicts posttransplantation pulmonary complications and outcome

Pretransplant pulmonary function tests (PFTs) have been checked mostly in myeloablative allogeneic stem cell transplantation (Allo-SCT). Their value in the setting of reduced intensity conditioning Allo-SCT (Allo-RIC) has been less explored. We retrospectively evaluated the predictive value of PFTs on posttransplant pulmonary complications (PPC) and outcomes in 195 consecutive Allo-RIC patients, based on fludarabine plus busulphan or melphalan. PFT parameters included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, total lung capacity (TLC), residual volume, and diffusion capacity for carbon monoxide (DLCo) corrected for the hemoglobin levels. Pretransplant PFTs abnormalities were observed in 130 patients (66%). The most frequent abnormalities were abnormal DLCO (n = 83, 44%), followed by FEV1/FVC (n = 75, 38%) and FVC (n = 47, 24%). The abnormalities were severe in 25 (13%) patients, moderate in 65 (33%) and mild in 40 patients (21%). Multivariate analysis showed that TLC was significantly associated with PPC, nonrelapse mortality and overall survival (OS), (HR 4.2, 95% CI. 2-8.5; HR 3.8, 95% CI. 1.7-8.5; HR 2.3, 95% CI. 1.3-4.1, respectively, P = 0.01), while abnormal FVC had a negative impact on PPC and OS (HR 1.8, 95% CI. 0.98-3.6, P = 0.06 and HR 1.7, 95% CI. 1.1-2.6, P = 0.008). This study emphasizes the valuable role of PFTs in identifying patients at risk for PPC, NRM, and lower OS in the Allo-RIC setting.

Risk Factors Associated with the Development of Pneumonitis After High-Dose Chemotherapy with Cyclophosphamide, BCNU, and Etoposide (CBV) Followed by Autologous Stem Cell Transplant

AbstractAbstract 903 Background:High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) is a standard component of therapy for some patients with hematologic malignancies, particularly those with relapsed or refractory lymphoma. No high-dose chemotherapy regimen has been shown to be superior to another, and thus regimens are chosen based on institutional standards and toxicity profiles. Pneumonitis is a recognized complication of HDC regimens containing BCNU. There has not been a large study of uniformly-treated lymphoma patients to define the incidence and risk factors for developing pneumonitis in the modern era. Methods:We retrospectively examined the medical records of patients who were treated with HDC-ASCT at the Dana-Farber Cancer Institute and Massachusetts General Hospital Cancer Center from 2007–2009 using a regimen containing cyclophosphamide 750 mg/m2 Q12h x4d, BCNU 112.5 mg/m2 daily x4d, and VP-16 (etoposide) 200 mg/m2 Q12h x4d (CBV). Overall (OS) and progression-free survival (PFS), and the incidence of pneumonitis were determined. Univariable and multivariable analyses were performed for characteristics likely to be associated with an increased risk of pneumonitis, which was defined based on a combination of clinical, laboratory, and radiographic factors, with or without bronchoscopy. Results:222 patients were analyzed. The age range was 21–77 (median 54). 61% were male. 71% had non-Hodgkin lymphoma and 29% had Hodgkin lymphoma. The median number of prior chemotherapy regimens was 2; 65% of patients had received prior rituximab, 31% prior bleomycin, and 12% prior gemcitabine. 71% had disease involvement of the mediastinum, and 11% had received prior mediastinal radiation therapy. 43% were past or present smokers. The median follow-up among all living patients was 12 months. The total cumulative incidence of pneumonitis was 22% (49 patients), with 41 patients (19%) receiving corticosteroid treatment, and 18 patients (8%) requiring inpatient hospitalization for pneumonitis. The time range to development of pneumonitis was 26–199 days post-transplant, with a median of 50 days. There were four treatment-related deaths (1.8%): three related to pneumonitis and one related to veno-occlusive disease. On univariable analysis, age, diagnosis of Hodgkin lymphoma, prior mediastinal radiation, prior bleomycin, total BCNU dose delivered, and lack of complete remission status at the time of ASCT were associated with the development of pneumonitis. Gender, body mass index, history of smoking, mediastinal disease involvement, prior rituximab, prior gemcitabine, and pretransplant pulmonary function testing were not found to be statistically significantly different between patients with and without pneumonitis. Stepwise multivariable logistic regression analysis, excluding 31 patients without pneumonitis who had death, relapse, or censoring in the first four months post-transplant, revealed the following variables as independently associated with development of pneumonitis: prior mediastinal radiation (odds ratio 6.5, 95% CI 2.2–18.9, P=0.0005), total BCNU dose above 1000 mg (OR 3.4, 95% CI 1.3–8.7, P=0.012), and age less than 54 (OR 3.0, 95% CI 1.4–6.5, P=0.0037). One year overall survival was 92%, and progression-free survival was 71%. There were no variables, including pneumonitis, associated with PFS on multivariable analysis. Only lack of complete or partial disease response prior to ASCT was associated with inferior OS on multivariable Cox regression modeling (hazard ratio 0.2, 95% CI 0.05–0.72, P=0.01). Conclusions:Pneumonitis is relatively common after HDC-ASCT using CBV conditioning. Increased vigilance for symptoms of pneumonitis is warranted for patients with prior mediastinal radiation and for younger patients. Our data suggests an increased risk with total BCNU dose above 1000 mg, suggesting a possible threshold toxicity effect. Empiric dose reduction may be considered for patients who would receive greater than 1000 mg of BCNU, particularly if they are also younger and/or have had prior mediastinal radiation. Disclosures:No relevant conflicts of interest to declare.

Antithymocyte Globuline Given as Part of the Conditioning Regimen Has No Impact On Lung Function at 1 Year After Transplantation.

Abstract 3306Poster Board III-194 BackgroundPulmonary dysfunction is common following allogeneic hematopoietic stem cell transplantation (HSCT) and is associated with significant morbidity and mortality. The use of Antithymocyte globuline (ATG) has reduced the incidence of graft versus host disease (GVHD), particularly in its chronic form, but the impact of this approach on the prevention of lung dysfunction is not well characterized. MethodsWe performed a retrospective analysis of pulmonary function in all patients transplanted from January 2001 through December 2005 following conditioning with oral busulfan (BU) followed by either cyclophosphamide (CY) or fludarabine (FLU) with or without the addition of ATG. Pulmonary function tests (PFTs) were performed per transplant protocol before and around day 80 and 1 year after transplantation. ResultsOf 406 patients, 13 (3%) were excluded due to lack of pre-transplant PFTs. Seventy five patients received ATG (thymoglobulin, given on days -3 to -1 for total doses of 4.5 – 6 mg/kg), and 318 did not. The median patient age was 49 years for both the ATG (range 9-65) and non-ATG (range 7-66) groups; the median follow-up was 956 (range 19-2071) days and 903 (range 8-2697) days, respectively. The ATG group had proportionally more patients with high risk diseases (62.7% vs 45.7%, p= .03), whereas the use of bone marrow as stem cell source was higher in the non-ATG group (14.6% vs 5.3%, p=.03). The proportion of patients with PFTs at 1 year was similar for both groups (49.3% vs 54.6%, p=.55). No significant statistical differences between the 2 groups were seen in the mean percentage of the predicted values for FEV1, FVC, TLC and DLco at 80 days or 1 year after transplantation. The mean value of FEV1/FVC ratio at 1 year was higher for ATG patients (0.81±0.05 vs 0.77±0.09, p=.003). The mean change in PFT parameters from baseline to 1 year after HSCT also did not show a statistically significant difference between the 2 groups for any PFT parameters except for the FEV1/FVC ratio, which decline was lower in the ATG group (0.4±3.9 vs -2.8±7.3 p=.0002). This difference remained significant in multivariate analysis. The lung function score at 1 year after transplantation was similar in the 2 groups; they also had similar rates of lung function decline (expressed as the annualized rate of FEV1 decline) from baseline to 1 year after HSCT. The risk of developing severe airflow obstruction (AFO) or a restrictive pattern (RP), as well as the cumulative incidence of AFO and RP were not statistically significantly different between the 2 treatment groups at 1 year after HSCT. ConclusionsIn this retrospective analysis, incorporation of ATG into the HSCT conditioning regimen did not appear to be associated with superior outcome in terms of post transplant pulmonary function. However, further evaluations are needed to better clarify the role that ATG might have in the development of late-term pulmonary complications. DisclosuresNo relevant conflicts of interest to declare.

Lung Function, Pulmonary Complications, and Mortality after Allogeneic Blood and Marrow Transplantation in Children

Pulmonary complications (PC) remain a significant barrier to the success of allogeneic blood and marrow transplantation (BMT). Pretransplant pulmonary function tests (PFTs) have been correlated with risk of early respiratory failure and mortality in adult BMT recipients. There is limited data on their relationship to posttransplant outcomes in pediatric patients. We sought, in pediatric allo-BMT recipients (1) to analyze the spectrum of infectious and noninfectious PCs, (2) to evaluate the prevalence and course of PFT abnormalities before and after transplant, and (3) to correlate pretransplant PFT findings with patient outcomes, specifically risk of PC, respiratory failure, and death. We conducted a retrospective review of PC in all patients who underwent allo-BMT at Children's Hospital of Pittsburgh during 1996 to 2006. PFTs were performed in children 6 years and older pretransplant, 3, 6, 12, and 24 months after transplant. PCs occurring within 100 days of BMT were considered early. One hundred ten consecutive children who underwent allo-BMT were included (median age = 9.7 years; 67 males, 43 females). Seventy-five of 110 patients had 370 PFT studies performed; 62 of 73 patients >6 years of age (85%) underwent PFT studies pre-BMT. There was a significantly higher risk of early respiratory failure in patients with reduced pretransplant forced expiratory volume in 1 second (FEV(1)) (P = .0001, odds ratio [OR] 5.1) or forced vital capacity (FVC) (P = .0001, OR 8.5). Forty-three of 110 (39%) patients required mechanical ventilation, and in 30 episodes (70%), patients remained ventilator-dependent until time of death. Posttransplant, we observed statistically significant reductions in FEV(1), FVC, total lung capacity (TLC), and diffusing capacity of the lungs (DLco) at 3 months post-BMT and similar reductions at 6 months post-BMT except for DLco (not significant). Between 12 and 24 months, FEV(1), FVC, TLC, and DLco improved significantly from earlier declines post-BMT; however FEV(1) and FVC remained significantly below pretransplant values. At a median follow-up of 5.5 (1.6-11.6) years, 58 of 110 (53%) patients were surviving. The majority of the patients who died from transplant-related complications suffered from 1 or more PCs (31/32, 97%). Early PC was associated with over 4-fold reduction in probability of survival at 10 years (8/44, 18% with early PC versus 50/66, 76% without early PC). On multivariate analysis, risk of death was significantly associated with high-risk disease status (P = .015; hazard ratio [HR] = 2.5), unrelated donor (P = .03; HR = 2.1), early PC (P = .0001; HR = 7.7) and pathogen identification (P = .02; HR = 2.7). These results suggest that, in children undergoing allo-BMT (1) compromised pretransplant lung function is significantly correlated with risk of early respiratory failure but not of overall survival (OS), (2) reductions in lung volumes and diffusion capacity are common 3- to 6-month posttransplant with partial recovery by 12 to 24 months, (3) there is high mortality following mechanical ventilation, and (4) early PCs are associated with significantly worse OS.