Bronchial Thermoplasty Global Registry (BTGR): 2-year results.

OBJECTIVES: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. DESIGN: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. SETTING: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. RESULTS: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). CONCLUSIONS: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. TRIAL REGISTRATION NUMBER: NCT02104856.

Complete splenic infarction in association with COVID-19.

COVID-19 predominantly affects the respiratory system. As a novel disease, understanding of its management and complications continues to grow. Herein, we present a case of almost complete splenic infarction in a patient with COVID-19 pneumonia. This case highlights the need to maintain diagnostic vigilance whilst investigating secondary complications of COVID-19. It is also important to stress the high incidence of thromboembolic complications in patients with COVID-19, which may occur anywhere in the vasculature.

5-Year Survival after Endobronchial Coil Implantation: Secondary Analysis of the First Randomised Controlled Trial, RESET.

BACKGROUND: Lung volume reduction surgery is a proven treatment for emphysematous patients with hyperinflation, but the precarious health of candidates has prompted development of less invasive approaches. Bronchoscopic implanted endobronchial coils, shape-memory nitinol filaments, shrink emphysematous lung tissue to restore elastic recoil and to tether airways to maintain patency. Studies have demonstrated an acceptable safety profile and improvements in lung function, exercise capacity, and quality of life out to 3 years. Volume reduction is key. However, data for longer-term survival are limited. OBJECTIVE: The aim of this study was to establish the 5-year overall and transplant-free survivals of subjects whose procedure in the first randomized controlled trial, RESET, achieved clinically meaningful reduction in residual volume (RV). METHODS: Patients and their primary care doctors were contacted to confirm vital status and history of additional interventions. Death certificates were acquired via the General Registry Office. Survival time was calculated for responders achieving a reduction of ≥10% in RV compared to non-responders. RESULTS: 39 patients completed the planned bilateral sequential treatments. Six patients received unilateral implants. At 5 years, 22 patients had died. The overall survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 50.6%, respectively. Two patients underwent lung transplantation at 52 and 59 months and were alive at 5 years. The transplant-free (TF) survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 46.7%, respectively. Volume reduction responders (n = 18) at 3 months had a 5-year TF survival of 66.7% compared to 36.4% for non-responders (n = 22; p = 0.07). Higher baseline inspiratory capacity (HR 0.13, 95% CI 0.02-0.73; p = 0.02) and partial pressure of oxygen (pO2) (HR 0.57, 95% CI 0.38-0.86; p < 0.01) values were predictive of survival for the entire cohort and were not influenced by age. CONCLUSIONS: Endobronchial coil implantation appears to confer a 5-year survival advantage for those who achieved a 10% reduction in RV at 3 months. Ongoing trials are designed to clarify the mechanisms of action of coils and to refine patient selection.

Endobronchial Coils Versus Lung Volume Reduction Surgery or Medical Therapy for Treatment of Advanced Homogenous Emphysema.

Rationale: Bronchoscopic lung volume reduction utilizing shape-memory nitinol endobronchial coils (EBC) may be safer and more effective in severely hyperinflated homogeneous emphysema compared to medical therapy or lung volume reduction surgery (LVRS). Methods: The effect of bilateral EBC in patients with homogeneous emphysema on spirometry, lung volumes and survival was compared to patients with homogeneous emphysema randomized in the National Emphysema Treatment Trial (NETT) to LVRS or medical therapy. NETT participants were selected to match EBC participants in age, baseline spirometry, and gender. Outcomes were compared from baseline, at 6 and 12 months. Results: There were no significant baseline differences in gender in the EBC, NETT-LVRS or medical treatment patients. At baseline no differences existed between EBC and NETT-LVRS patients in forced expiratory volume in 1 second ( FEV1) or total lung capacity (TLC) %-predicted; residual volume (RV) and diffusing capacity of the lung for carbon monoxide (DLco) %-predicted were higher in the EBC group compared to NETT-LVRS (p < 0.001). Compared to the medical treatment group, EBC produced greater improvements in FEV1 and RV but not TLC at 6 months. FEV1 and RV in the EBC group remained significantly improved at 12-months compared to the medical treatment group. While all 3 therapies improved quality of life, survival at 12 months with EBC or medical therapy was greater than NETT-LVRS. Conclusion: EBC may be a potential therapeutic option in patients with severe homogeneous emphysema and hyperinflation who are already receiving optimal medical treatment.

In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70°C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1-1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0-10; p=0.03) and epithelial integrity increased (14%, IQR 6-29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.

Effectiveness of bronchial thermoplasty in severe asthma in 'real life' patients compared with those recruited to clinical trials in the same centre.

Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in 'real life' patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients.

Endobronchial coils for severe emphysema are effective up to 12 months following treatment: medium term and cross-over results from a randomised controlled trial.

BACKGROUND: There is a clinical need for therapeutic options to reduce hyperinflation associated with severe emphysema. Endobronchial Coils (coils) are nitinol devices implanted bronchoscopically under fluoroscopic guidance to re-tension the lung. We report the medium term effectiveness and safety of coils in a study of patients with emphysema. METHODS: Forty five subjects with severe airflow obstruction and hyperinflation received bilateral sequential treatment with coils (30 day interval between treatments) as part of a randomised controlled trial with a primary endpoint 90 days after the final treatment (Clinicaltrials.gov NCT01334307). Further assessments were made at 180 and 360 days and in this study the primary outcome was the effect of coil treatment on the St. George's Respiratory Questionnaire (SGRQ) 360 days following treatment. RESULTS: At 360 days following treatment, there was an improvement in the SGRQ score of -6.1±14.0 points (p = 0.01) compared to baseline. Improvements in secondary outcomes were seen with increases in forced expiratory volume in the first second of 8.9 ±22.2% (p = 0.002) and 6-minute walking distance of 34.1±52.4m (p = 0.003). The safety profile was acceptable out to 360 days post-treatment. CONCLUSIONS: Statistically and clinically meaningful benefits in quality of life, exercise capacity and pulmonary function in patients treated with coils are sustained twelve months after treatment. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov NCT01334307.

T helper cell subsets specific for Pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis.

BACKGROUND: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. METHODS: Peripheral blood human memory CD4(+) T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. RESULTS: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4(+) T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6(+). Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. CONCLUSIONS: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions.

Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease.

BACKGROUND: The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown. METHODS: Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype. RESULTS: Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects. CONCLUSIONS: Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial.

BACKGROUND: Few treatment options exist for patients with severe emphysema. We assessed the clinical benefits and safety of lung volume reduction coils (LVRCs) for the treatment of patients with severe emphysema with hyperinflation. METHODS: In a randomised study, we recruited patients with severe emphysema (aged ≥35 years) from three centres in the UK. Using a computer-generated randomisation sequence, we randomly allocated patients in a one-to-one ratio (block sizes of four and stratified by centre) to either LVRC treatment (treatment group) or best medical care (usual care group). The primary endpoint was the difference in response in the St George's Respiratory Questionnaire (SGRQ) between treatment and usual care groups at 90 days after final treatment (by intention-to-treat analysis). The trial is registered with ClinicalTrials.gov, number NCT01334307. FINDINGS: Between Jan 27, 2010, to Oct 25, 2011, we recruited and randomly allocated 47 patients: 23 to treatment and 24 to usual care (23 patients in each group were included in the intention-to-treat analysis). SGRQ response at 90 days after final treatment was greater in the treatment group than it was in the usual care group (between-group difference in change from baseline -8·36 points [95% CI -16·24 to -0·47]; p=0·04). We detected no between-group difference in serious adverse events. INTERPRETATION: Our findings suggest that treatment with endobronchial coils can improve quality of life for patients with severe emphysema and hyperinflation. FUNDING: PneumRx.

Bronchial thermoplasty for severe asthma.

PURPOSE OF REVIEW: Bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass, has been recently introduced for the treatment of severe asthma. This review summarizes the preclinical development, efficacy and adverse effects of bronchial thermoplasty. In addition, the potential mechanisms of action and place in management of severe asthma are discussed. RECENT FINDINGS: The efficacy and adverse profile of bronchial thermoplasty has been assessed in three randomized controlled trials, the first two of which showed clinical benefits of bronchial thermoplasty compared with usual care in patients with moderate or severe asthma. The third trial reports the results of a comparison with sham bronchial thermoplasty in 288 adults with severe asthma. Bronchial thermoplasty improved asthma quality of life questionnaire scores compared with sham bronchial thermoplasty; in the posttreatment period, there were fewer severe exacerbations and emergency department visits. Bronchial thermoplasty causes short-term increases in asthma-related morbidity. Follow-up data to date support the long-term safety of the procedure. SUMMARY: Bronchial thermoplasty has a role in the management of patients with severe asthma who have uncontrolled symptoms despite current therapies. Future studies need to identify factors that predict a beneficial clinical response.