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Concept: Pulmonary hypertension

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BACKGROUND: Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. METHOD: A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. RESULTS: The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787). CONCLUSIONS: Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.

Concepts: Pulmonology, Cystic fibrosis, Organ transplant, Pulmonary hypertension, Lung transplantation, Extracorporeal, Extracorporeal membrane oxygenation, Lung allocation score

170

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.

Concepts: Pulmonology, Myocardial infarction, Pulmonary artery, Nitric oxide, Pulmonary hypertension, Guanylate cyclase, Sildenafil, Riociguat

166

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) experience impaired health-related quality of life (HRQL). The objective of this study was to evaluate HRQL in a nation-wide sample. PATIENTS AND METHODS: This is a prospective, multicenter, non-interventional study of HRQL including 139 (89%) PAH and 17 (11%) CTEPH patients (women 70.5%; mean age, 52.2) recruited from 21 Spanish hospitals. 55% had idiopathic PAH, 34% other PAH and 11% CTEPH. HRQL was measured using the Short Form 36 Health Survey (SF-36) and EuroQoL-5D (baseline and after 6 months). RESULTS: HRQL in the patients with PAH or CTEPH was impaired. The physical component of SF-36 and the EuroQol-5D correlated with the functional class (FC). Mean EuroQol-5D visual analogical scale (EQ-5D VAS) scores were 73.5±18.4, 62.9±20.7 and 51.3±16.0 (P<.0001) in patients with FC I, II and III, respectively. Every increase of one FC represented a loss of 4.0 on the PCS SF-36 and a loss of 9.5 on the EQ-5D VAS. Eight patients who died or received a transplant during the study period presented poorer initial HRQL compared with the rest of the population. No significant changes in HRQL were observed in survivors after 6 months of follow-up. CONCLUSIONS: HRQL is impaired in this population, especially in PAH/CTEPH patients near death. HRQL measurements could help predict the prognosis in PAH and CTPH and provide additional information in these patients.

Concepts: Pulmonology, Cardiology, Blood pressure, Pulmonary artery, Pulmonary hypertension, Iloprost

162

The objective of this prospective study was to assess the prevalence of anxiety and depression disorders and their association with quality of life (QoL), clinical parameters and survival in patients with pulmonary hypertension (PH).

Concepts: Pulmonology, Myocardial infarction, Coronary artery disease, Cardiology, Blood pressure, Chronic obstructive pulmonary disease, Pulmonary artery, Pulmonary hypertension

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Background Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5. Methods We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. Results In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. Conclusions Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).

Concepts: Clinical trial, Asthma, Medical terms, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Placebo, Pulmonary hypertension

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Background Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. Methods In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. Results During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. Conclusions Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437 .).

Concepts: Clinical trial, Death, Asthma, Heart, Chronic obstructive pulmonary disease, Pulmonary hypertension, Tiotropium, Boehringer Ingelheim

33

Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented. However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited.

Concepts: Medicine, Asthma, Lung, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Pulmonary hypertension, Human lung

29

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease and is treated with inhaled medication to optimize the patient’s lung health through decreasing their symptoms, especially breathlessness. Halotherapy is the inhalation of micronized dry salt within a chamber that mimics a salt cave environment. Recent media reports suggest that this therapy may help with the symptoms of COPD.

Concepts: Medicine, Pulmonology, Asthma, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Pulmonary hypertension, Air pollution

28

Expressing forced expiratory volume in 1 s (FEV1) as % predicted relies on the assumption of proportional variability and generalisability of prediction equations that may be unrealistic, especially for elderly people. We evaluated the prognostic implications of alternative ways of expressing FEV1. We enrolled 318 patients with chronic obstructive pulmonary disease (COPD) and 475 controls in the Salute Respiratoria nell'Anziano (SARA) study. The risk for 5-, 10- and 15-year mortality associated with FEV1 was studied by expressing FEV1 % pred, standardised by height cubed (FEV1·Ht(-3)) and as a multiple of the sex-specific first percentile (FEV1 quotient (FEV1Q)). In the group with COPD, the incidence rate ratio for the worst versus the best quintile of FEV1Q was 4.65 (95% CI 2.33-10.37), compared to 2.98 (1.53-6.27) for FEV1 % pred and 3.95 (2.01-8.45) for FEV1·Ht(-3). The corresponding incidence rate ratios at 15 years were 4.52 (2.84-7.43), 3.16 (2.02-5.07) and 3.52 (2.25-5.63), respectively. In the control group, even moderate reduction of FEV1Q was associated with long-term mortality, while FEV1 % pred was not associated with the outcome. FEV1Q may be more informative about prognosis in an elderly population compared to FEV1 % pred.

Concepts: Epidemiology, Asthma, Lung cancer, Medical statistics, Chronic obstructive pulmonary disease, Ratio, Pulmonary hypertension, Spirometry

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This report describes a case involving the rare combination of persistent truncus arteriosus type A2, double aortic arch, and mitral stenosis. At the age of 26 days, the patient underwent division of the right-sided aortic arch with tracheal compression and bilateral pulmonary banding. Fontan completion was successfully achieved after separation of the pulmonary artery from the arterial trunk, atrial septostomy, and modified Blalock-Taussig shunt at the age of 7 months and bilateral bidirectional Glenn anastomosis at the age of 1 year and 3 months. At this writing, the patient is doing well 2 years and 6 months after Fontan completion.

Concepts: Blood, Cardiology, Heart, Artery, Pulmonary artery, Cardiovascular system, Pulmonary hypertension, Persistent truncus arteriosus