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.

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 ß2-agonists.

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS. METHODS: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders. RESULTS: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007). CONCLUSIONS: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study.

BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA. METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models. RESULTS: Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates. CONCLUSION: Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

A decade of living lobar lung transplantation: recipient outcomes.

OBJECTIVE: Living lobar lung transplantation was developed as a procedure for patients considered too ill to await cadaveric transplantation. METHODS: One hundred twenty-eight living lobar lung transplantations were performed in 123 patients between 1993 and 2003. Eighty-four patients were adults (age, 27 +/- 7.7 years), and 39 were pediatric patients (age, 13.9 +/- 2.9 years). RESULTS: The primary indication for transplantation was cystic fibrosis (84%). At the time of transplantation, 67.5% of patients were hospitalized, and 17.9% were intubated. One-, 3-, and 5-year actuarial survival among living lobar recipients was 70%, 54%, and 45%, respectively. There was no difference in actuarial survival between adult and pediatric living lobar recipients (P =.65). There were 63 deaths among living lobar recipients, with infection being the predominant cause (53.4%), followed by obliterative bronchiolitis (12.7%) and primary graft dysfunction (7.9%). The overall incidence of acute rejection was 0.8 episodes per patient. Seventy-eight percent of rejection episodes were unilateral. Age, sex, indication, donor relationship, preoperative hospitalization status, use of preoperative steroids, and HLA-A, HLA-B, and HLA-DR typing did not influence survival. However, patients on ventilators preoperatively had significantly worse outcomes (odds ratio, 3.06, P =.03; Kaplan-Meier P =.002), and those undergoing retransplantation had an increased risk of death (odds ratio, 2.50). CONCLUSION: These results support the continued use of living lobar lung transplantation in patients deemed unable to await a cadaveric transplantation. We consider patients undergoing retransplantations and intubated patients to be at significantly high risk because of the poor outcomes in these populations.

Near fatal asthma: clinical and airway biopsy characteristics.

Background. Inflammation and remodeling are integral parts of asthma pathophysiology. We sought to describe the clinical and pathologic features of near fatal asthma exacerbation (NFE). Methods. Bronchial biopsies were collected prospectively from NFE I subjects. Another NFE II group and a moderate severity exacerbation control group (ME II) were retrospectively identified-no biopsies obtained. Results. All NFE II (n = 9) subjects exhibited remodeling and significant inflammation (eosinophilic, neutrophilic). NFE II group (n = 37) had a significant history of prior intubation and inhaled corticosteroids usage compared to ME II group (n = 41). They also exhibited leukocytosis, eosinophilia, and longer hospitalization days. Conclusions. Remodeling, eosinophilic, and neutrophilic inflammation were observed in NFE. NFE is associated with prior intubation and inhaled corticosteroids usage.

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.

Pericardial constriction after lung transplantation.

Pericardial constriction is extremely rare after lung transplantation. We present a case and review the potential contributing factors for pericardial constriction after lung transplantation. Treatment for this condition, irrespective of the cause, remains pericardiectomy.

Long-term pulmonary function after living-donor lobar lung transplantation in adults.

BACKGROUND: Living-donor lobar lung transplantation was developed as an alternative to cadaveric transplantation. However, whether two pulmonary lobes provide comparable intermediate and long-term pulmonary function to full-sized bilateral cadaveric grafts in adults is unknown. METHODS: An analysis of the pulmonary functions of 59 bilateral lobar and 43 bilateral cadaveric adult lung transplant recipients who survived more than 3 months after transplantation was performed. RESULTS: Mean follow-up was 3.8 +/- 2.8 years. In lobar recipients, mean percent predicted forced vital capacity and forced expiratory volume in 1 second improved between 1 and 6 months after transplantation (42.5% +/- 13.4% and 46.9% +/- 14.0% at 1 month versus 63.6% +/- 14.1% and 64.5% +/- 13.7% at 6 months; p < 0.001 and <0.001, respectively). In cadaveric recipients, mean percent predicted forced vital capacity improved after transplantation (54.3% +/- 14.5% at 1 month versus 74.2% +/- 21.3% at 12 months; p < 0.01). As compared with the cadaveric group, mean percent predicted forced vital capacity and forced expiratory volume in 1 second were lower 1 and 3 months after transplantation in the lobar recipients (p = 0.001 at both times); however, by 6 months after transplantation, these values were comparable and remained so throughout the follow-up period. In a subset of lobar and cadaveric recipients, maximal exercise, heart rate, peak oxygen consumption, anaerobic oxygen consumption threshold, and ability to maintain oxygen saturation were also comparable. CONCLUSIONS: In those adult recipients surviving more than 3 months after transplantation, lobar lung transplantation provides comparable intermediate and long-term pulmonary function and exercise capacity to bilateral cadaveric lung transplantation.

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 (betaAbetaA) and a member of the TGF-beta superfamily, is involved in the inflammatory repair process. Using cDNA microarray analysis, we discovered strong induction of the activin betaA gene in human mast cells (MC) on stimulation with PMA and calcium ionophore (A23187). Activin betaA 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 WBB6F(1)-W/W(v) 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