Richard G. Barbers

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.

RATIONALE Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma

BACKGROUND Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV₁ values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β₂-agonists.

Regulation of activin A expression in mast cells and asthma: its effect on the proliferation of human airway smooth muscle cells.

Activin A, a homodimeric protein (βAβA) and a member of the TGF-β superfamily, is involved in the inflammatory repair process. Using cDNA microarray analysis, we discovered strong induction of the activin βA gene in human mast cells (MC) on stimulation with PMA and calcium ionophore (A23187). Activin βA mRNA was also highly induced in primary cultured murine bone marrow MC (BMMC) after stimulation by IgE receptor cross-linking. Secretion of activin A was evident in human mast cell-1 line cells 3 h after stimulation and progressively increased over time. Activin A was present in the cytoplasm of activated but not unstimulated murine bone marrow MC as demonstrated by immunofluorescence studies, suggesting that secretion of activin A by MC was due to de novo synthesis rather than secretion of preformed protein. Activin A also colocalized with human lung MC from patients with asthma by double-immunofluorescence staining. Furthermore, secretion of activin A was significantly increased in the airway of wild-type mice after OVA sensitization followed by intranasal challenge. Secretion of activin A, however, was greatly reduced in MC-deficient WBB6F1-W/Wv mice as compared with wild-type mice, indicating that MC are an important contributor of activin A in the airways of a murine asthma model. Additionally, activin A promoted the proliferation of human airway smooth muscle cells. Taken together, these data suggest that MC-derived activin A may play an important role in the process of airway remodeling by promoting the proliferation of airway smooth muscle.

A Decade of Living Lobar Lung Transplantation: Perioperative Complications after 253 Donor Lobectomies†

Living lobar lung transplantation places two donors at risk for each recipient. We examined the perioperative outcomes associated with the 253 donor lobectomies performed at our institution during our first decade of living lobar lung transplantation. There have been no perioperative or long‐term deaths. 80.2% of donors (n = 203) had no perioperative complications, while fifty (19.8%) had one or more complication. The incidence of intraoperative complications was 3.6%. Complications requiring reoperation occurred in 3.2% of donors. 15.0% of donors had other perioperative complications; the most serious were two donors who developed pulmonary artery thrombosis, while the most common was the need for an additional thoracostomy tube or a thoracostomy tube for ≥14 d for persistent air leaks and/or drainage. Right‐sided donors were more likely to have a perioperative complication than left‐sided donors (odd ratio 2.02, p = 0.04), probably secondary to right lower and middle lobe anatomy. This experience has shown donor lobectomy to be associated with a relatively low morbidity and no mortality, and is important if this procedure is to be considered an option at more pulmonary transplant centers, given continued organ shortages and differences in philosophical and ethical acceptance of live

ROLE OF TRANSPLANTATION (LUNG, LIVER, AND HEART) IN SARCOIDOSIS

Organ transplantation is an option for sarcoidosis patients with end-stage lung, liver or heart disease. Survival statistics vary for the organ transplanted but are not too different from survival rates for other systemic disorders. Although infection and rejection are troublesome for all organ recipients including those with sarcoidosis, there is the added problem of recurrence of sarcoidosis in the allograft. Sarcoidosis is not an absolute contraindication for organ transplantation for the majority of transplantation centers.

Outcomes after lung transplantation and practices of lung transplant programs in the United States regarding hepatitis C seropositive recipients.

Background. The estimated prevalence of hepatitis C virus (HCV) infection among lung transplant (LT) recipients is 1.9%. Many thoracic transplant programs are reluctant to transplant HCV-seropositive patients due to concerns of hepatic dysfunction caused by immunosuppression. The aims of this study are to survey current practices of US LT programs regarding HCV-seropositive patients and using the Organ Procurement and Transplantation Network/United Network for Organ Sharing database and to assess the clinical outcomes of HCV-positive compared with HCV-negative LT recipients. Methods. A survey of US transplant centers that have performed more than 100 LTs was conducted. In addition, 170 HCV-seropositive and 9259 HCV-seronegative recipients who received HCV-seronegative donor organs between January 1, 2000, to December 31, 2007, were identified from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Outcome variables including patient survival were compared between the two groups. Results. A total of 64.4% centers responded to the survey. Ten of 29 (34.5%) programs would not consider HCV-seropositive patients for LT. Among the 19 programs that will consider HCV-seropositive patients, only five centers would transplant actively viremic patients. Overall patient survival rates of HCV-seropositive patients were similar to HCV-seronegative patients (84.7% at 1 year, 63.9% at 3 years, 49.4% at 5 years for HCV-seropositive group vs. 82.0% at 1 year, 65.0% at 3 years, 51.4% at 5 years for HCV-seronegative group, P=0.712). Relative risk of recipients for death remained statistically insignificant after adjusting for recipient age, donor age, obesity, sensitization, serum creatinine, and medical condition at time of transplant (relative risk [RR]=1.07 [0.84–1.38], P=0.581). Conclusions. Since 2000, patient survival rates of HCV-positive patients are identical to those who are HCV-negative. However, most of these HCV-seropositive patients were probably nonviremic.

Lung transplantation for cystic fibrosis: an update and practical considerations for referring candidates.

In this article, the authors provide an update to Maurer and Chaparros 1995 review in this journal of lung transplantation for cystic fibrosis. Bilateral (sequential) cadaver donor transplantation is the usual procedure of choice. The four-year survival rate for adult, all-disease, double-bilateral lung transplantation has improved to 53%. Because of lower [corrected] survival rate among adults, living-donor lobar transplantation should be performed only when cadaver lungs are unlikely to become available. The International Society for Heart and Lung Transplantation and the Cystic Fibrosis Foundation have promulgated uniform guidelines for transplantation candidate selection. Issues of diabetes mellitus, mechanical ventilation, osteoporosis, malnutrition, fungi and drug-resistant bacteria, pleural fibrosis, and sinusitis in relation to transplantation candidacy are discussed. Some practical points regarding transplantation center referral are presented, and a list of cystic fibrosis transplantation centers in the United States is supplied.

Lack of autophagy induces steroid-resistant airway inflammation

BACKGROUND Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. METHODS We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients

We examined the relationship between voriconazole utilization and non‐melanoma skin cancer (NMSC) development among adult lung and heart/lung transplant patients who were continuously enrolled in a large U.S. commercial health plan.

Cystic Fibrosis: Bilateral Living Lobar Versus Cadaveric Lung Transplantation

Living donor transplantation is now an acceptable option that should be considered for selected cystic fibrosis patients with end-stage lung disease. Two lungs obtained from live donors can adequately support an adult cystic fibrosis patient. The morbidity from lobectomy to the healthy donor is minimal.