Gregory I. Snell

A review of lung transplant donor acceptability criteria

Abstract (A consensus report from The Pulmonary Council of the International Society for Heart and Lung Transplantation)

Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema

The need for a less invasive procedure than surgical lung volume reduction that can produce consistent improvements with reduced morbidity remains a medical goal in patients with emphysema. We sought to determine the effect of bronchoscopic thermal vapour ablation (BTVA) on lung volumes and outcomes in patients with emphysema. 44 patients with upper lobe-predominant emphysema were treated unilaterally with BTVA. Entry criteria included: age 40–75 yrs, forced expiratory volume in 1 s (FEV1) 15–45% predicted, previous pulmonary rehabilitation and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from high-resolution computed tomography (HRCT) ≥1.2. Changes in FEV1, St Georges Respiratory Questionnaire (SGRQ), 6-min walk distance (6MWD), modified Medical Research Council (mMRC) dyspnoea score, and hyperinflation were measured at baseline, and 3 and 6 months post-BTVA. At 6 months, mean±se FEV1 improved by 141±26 mL (p<0.001) and residual volume was reduced by 406±113 mL (p<0.0001). SGRQ total score improved by 14.0±2.4 points (p<0.001), with 73% improving by ≥4 points. Improvements were observed in 6MWD (46.5±10.6 m) and mMRC dyspnoea score (0.9±0.2) (p<0.001 for both). Lower respiratory events (n=11) were the most common adverse event and occurred most often during the initial 30 days. BTVA therapy results in clinically relevant improvements in lung function, quality of life and exercise tolerance in upper lobe predominant emphysema.

A Feasibility and Safety Study of Bronchoscopic Thermal Vapor Ablation: A Novel Emphysema Therapy

PURPOSE This study reports the feasibility and safety of novel second-generation bronchoscopic lung volume reduction (LVR) technology, independent of collateral ventilation. DESCRIPTION Eleven patients with severe heterogeneous emphysema underwent unilateral bronchoscopic application of vapor thermal energy (mean 4.9 cal/g alveolar tissue; range, 3 to 7.5) with bronchial thermal vapor ablation (BTVA) aiming to induce a controlled inflammatory airway and parenchymal response with resultant LVR. EVALUATION Nine women and 2 men, with a mean age of 61 years, forced expiratory volume in 1 second (FEV(1)) of 0.77 +/- 0.17 L (32% predicted), residual volume (RV) of 4.1 +/- 0.9 L (219% predicted), and gas transfer of 7.8 +/- 2.2 (34% predicted), underwent unilateral upper lobe treatments. Serious adverse events in 5 included probable bacterial pneumonia and exacerbations of airways disease in 2. Although no important FEV(1) or RV changes occurred during 6 months of follow-up, gas transfer improved, 16% to 9.0% +/- 2.1% (38% predicted), the Medical Research Council Dyspnoea Score improved from 2.6 to 2.1, and the St. George Respiratory Questionnaire Total Score improved from 64.4 at baseline to 49.1. CONCLUSIONS These preliminary data on unilateral BTVA therapy confirm feasibility, an acceptable safety profile, and the potential for efficacy.

Relation of interlobar collaterals to radiological heterogeneity in severe emphysema.

Background: A study was undertaken to assess the prevalence of interlobar collateral ventilation in patients with severe emphysema to identify factors that may help to predict patients with significant collateral ventilation. Methods: Between April 2002 and August 2003, ex vivo assessment of the lungs 17 consecutive patients with smoking related severe emphysema was performed. To assess collateral flow, all lobes of explanted specimens were selectively intubated using a wedged cuffed microlaryngeal intubation tube and then manually ventilated using a bagging circuit. Interlobar collateral ventilation was defined as the ability to easily inflate a non-intubated lobe at physiological pressures. Pre-transplant demographic characteristics, physiological data, radiological results, and explant histology were assessed for retrospective relationships with the degree of interlobar collateral ventilation in the explanted lung. Results: A total of 23 lungs were evaluated, 15 of which (66%) had significant collateral interlobar airflow. There were no significant differences in any demographic, physiological, or pathological variables between patients with collateral ventilation and those with no collateral ventilation. However, there was a significant relationship between the presence of interlobar collateral ventilation and radiological scores (p<0.05). Conclusions: Interlobar collateral ventilation occurs to a much greater extent in patients with radiologically homogeneous emphysema than in those with heterogeneous emphysema. Heterogeneity of emphysema may predict patients with a significantly reduced risk of interlobar collateral ventilation.

Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1–2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time‐dependent variable (HR 2.1 [1.3–3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long‐term outcome in lung transplantation.

A donor history of smoking affects early but not late outcome in lung transplantation.

Backgrounds. Liberalization of tobacco exposure history as an exclusion to lung donation has recently occurred to increase donor organ availability. This study investigated the effect of donor smoking status and current and cumulative cigarette dose on early and late outcomes in lung transplantation. Methods. From 1995 to 2002, 173 heart-lung and bilateral single-lung transplant recipients were retrospectively reviewed. Seventy-seven (45%) of 173 donors were ever-smokers and 64 of those 77 were current smokers. These were divided into subgroups by current number of cigarettes smoked to investigate acute dose effects and by pack-year to investigate cumulative dose effects. Risks of smoking were assessed by univariate and multivariate hazard regression models. Results. Univariate analysis revealed that there were significant differences between current and cumulative dose subgroups in early postoperative variables, including Pao2/Fio2 ratio, ventilation time, and intensive care unit stay. Additionally, these variables were dose dependent. There was no significant difference in 3-year survival between never-smokers and ever-smokers (73% versus 64%, P=0.27), and a rate of decline of survival was similar. There was a trend for the percentage of patients dying of bronchiolitis obliterans syndrome to be lower in the ever-smokers group compared with the never-smokers group (6% versus 11%, respectively). Multivariate analysis revealed current and cumulative smoking as a risk factor for early but not late outcomes. Conclusions. Donor smoking history had a significant effect on early outcomes in lung transplantation in a current and cumulative dose-dependent fashion. However, no significant effect on late outcomes, including bronchiolitis obliterans syndrome, was seen.

Efficacy of Bronchoscopic Thermal Vapor Ablation and Lobar Fissure Completeness in Patients with Heterogeneous Emphysema

Background: Bronchoscopic thermal vapor ablation (BTVA) ablates emphysematous tissue through a localized inflammatory response followed by contractive fibrosis and tissue shrinkage leading to lung volume reduction that should not be influenced by collateral ventilation. Objectives: To determine the correlation of clinical data from a trial of BTVA with fissure integrity visually assessed by computed tomography (CT). Methods: We conducted a single-arm study of patients with upper lobe-predominant emphysema (n = 44). Patients received BTVA either to the right upper lobe or left upper lobe, excluding the lingula. Primary efficacy outcomes were forced expiratory volume in 1 s (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) at 6 months. Lobar volume reduction from CT was another efficacy outcome measurement. The fissure of the treated lobe was analyzed visually on preinterventional CT. Incompleteness of the small fissure, the upper half of the right large fissure and the whole left large fissure were estimated visually in 5% increments, and the relative amount of fissure incompleteness was calculated. Pearson correlation coefficients were calculated for the association between fissure incompleteness and change in efficacy outcomes (baseline to 6 months) of BTVA. Results: A total of 38 out of 44 patients (86%) had incompleteness in the relevant fissure. Calculated relevant fissure incompleteness was a mean of 13% of fissure integrity (range 0–63). Correlation coefficients for the association of incompleteness with outcomes were as follows: FEV1 = 0.17; lung volume reduction = –0.27; SGRQ score = –0.10; 6-min walk distance = 0.0; residual volume (RV) = –0.18, and RV/total lung capacity = –0.14. Conclusions: Lobar fissure integrity has no or minimal influence on BTVA-induced lung volume reduction and improvements in clinical outcomes.

Pulmonary Rehabilitation Following Lung Transplantation

Pulmonary rehabilitation (PR) following lung transplantation (LT) is regarded as part of best practice management; however, the optimal duration and composition of PR programs for LT patients is unknown. This study aimed to describe changes in functional outcomes of LT patients who participated in our standard outpatient post-LT PR program. A prospective, repeated measures design was used. Functional exercise capacity (6-minute walk distance [6MWD]), lung function (forced expiratory volume in 1 second [FEV(1)], forced vital capacity [FVC]) and quality of life (Short Form 34 [SF-36]) were assessed at 1, 2, and 3 months following LT. All subjects attended a 1-hour outpatient group exercise training class 3 days per week until 12 weeks post-LT and education sessions facilitated by the multidisciplinary team. Patients with postoperative complications (mechanical ventilation, major myopathy) were excluded. Data were analyzed using descriptive statistics and analysis of variance with repeated measures. Thirty-six subjects (50% men), 81% bilateral LT, mean age 46 +/- 14 years were included. Significant improvements were demonstrated in 6MWD (451 +/- 126 m to 543 +/- 107 m, P < .001), FEV(1) (71% +/- 18% to 81% +/- 4%, P < .0001), FVC (69% +/- 14% to 81% +/- 18%, P < .0001), and all SF36 domains (P < .05). Large improvements were seen in the first month of rehabilitation, with smaller but clinically significant improvements continuing in the second month. Further prospective, longitudinal studies are required to determine whether a longer period of pulmonary rehabilitation would result in additional improvements.

An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis

Background and objective:  We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti‐fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy.

Acute Fibrinoid Organizing Pneumonia after Lung Transplantation

RATIONALE The barrier to long-term success after lung transplantation is the development of chronic lung allograft dysfunction. As the experience with lung transplantation accrues, it has become increasingly apparent that not all chronic allograft dysfunction is consistent with the traditionally recognized small-airway histological process of obliterative bronchiolitis (OB). OBJECTIVES To identify and describe chronic allograft dysfunction that is not consistent with the well-described bronchiolitis obliterans syndrome and to further characterize a novel histopathological process, acute fibrinoid organizing pneumonia (AFOP), that has led invariably to respiratory decline and death after lung transplantation. METHODS We evaluated 194 bilateral lung transplant recipients, identifying 87 individuals who developed chronic allograft dysfunction. They were then classified according to features on spirometry, chest imaging, and histopathological specimens. MEASUREMENTS AND MAIN RESULTS Two main phenotypes of chronic allograft dysfunction were identified; 39 (45%) recipients were categorized as having developed OB and 22 (25%) as having AFOP. Survival in those who developed AFOP was significantly worse than in those who developed OB (median time to death 101 vs. 294 d; P = 0.02), with all exhibiting a rapid decline in respiratory function leading to death. CONCLUSIONS AFOP is a novel form of chronic allograft dysfunction exhibiting spirometric, radiological, and histopathological characteristics that differentiate it from OB. The further characterization of chronic allograft dysfunction and its heterogeneous manifestations will allow the targeting of clinical and experimental efforts to prevent and treat chronic allograft dysfunction.