Inhaled aztreonam improves symptoms of cough and sputum production in patients with bronchiectasis: a post hoc analysis of the AIR-BX studies.

INTRODUCTION: Inhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment. METHODS: Post hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial. RESULTS: Aztreonam improved cough (difference 0.22, 95% CI 0.08-0.37; p=0.002), sputum production (0.30, 95% CI 0.15-0.44; p<0.0001) and sputum colour (0.29, 95% CI 0.15-0.43; p<0.0001) versus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all p<0.05). Patients with higher sputum production and sputum colour scores had a greater response on the overall QOL-B (difference 4.82, 95% CI 1.12-8.53; p=0.011 for sputum production and 5.02, 95% CI 1.19-8.86; p=0.01 for sputum colour). In contrast, treating patients who had lower levels of bronchitic symptoms resulted in shorter time to next exacerbation (hazard ratio 1.83, 95% CI 1.02-3.28; p=0.042). CONCLUSION: Baseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment.

Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

INTRODUCTION: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV1; 51-70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3 mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2 mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3 mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.

A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies.

RATIONALE: The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable. OBJECTIVES: To determine whether a modified Delphi process early during guideline development discriminates recommendations that should be informed by a systematic review from those that can be based upon expert consensus. METHODS: The same questions addressed by IOM-compliant pulmonary or critical care guidelines were addressed by expert panels using a modified Delphi process, termed the Convergence of Opinion on Recommendations and Evidence (CORE) process. The resulting recommendations were compared. Concordance of the course of action, strength of recommendation, and quality of evidence, as well as the duration of recommendation development, were measured. MEASUREMENTS AND MAIN RESULTS: When 50% agreement was required to make a recommendation, all questions yielded recommendations, and the recommended courses of action were 89.6% concordant. When 70% agreement was required, 17.9% of questions did not yield recommendations, but for those that did, the recommended courses of action were 98.2% concordant. The time to completion was shorter for the CORE process (median, 19.3 vs. 1,309.0 d; P = 0.0002). CONCLUSIONS: We propose the CORE process as an early step in guideline creation. Questions for which 70% agreement on a recommendation cannot be achieved should go through an IOM-compliant process; however, questions for which 70% agreement on a recommendation can be achieved can be accepted, avoiding a lengthy systematic review.

Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency.

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha1-proteinase inhibitor, Liquid Alpha1-PI, compared with the Lyophilized Alpha1-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha1-antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha1-PI or Lyophilized Alpha1-PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC0-7 days) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha1-PI concentration versus time curves for both formulations were superimposable. Mean AUC0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha1-PI and Lyophilized Alpha1-PI, respectively. The LS mean ratio of AUC0-7 days (90% CI) for Liquid Alpha1-PI versus Lyophilized Alpha1-PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha1-PI was well tolerated and adverse events were consistent with Lyophilized Alpha1-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha1-PI is bioequivalent to Lyophilized Alpha1-PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores.

BACKGROUND: The Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome measure assessing symptoms, functioning and health-related quality of life for patients with non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8 scales (Respiratory Symptoms, Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions and Treatment Burden). METHODS: Psychometric analyses of QOL-B V.3.0 used data from two double-blind, multicentre, randomised, placebo-controlled, phase III trials of aztreonam for inhalation solution (AZLI) in 542 patients with non-CF bronchiectasis and Gram-negative endobronchial infection. RESULTS: Excellent internal consistency (Cronbach's α ≥0.70) and 2-week test-retest reliability (intraclass correlation coefficients ≥0.72) were demonstrated for each scale. Convergent validity with 6 min walk test was observed for Physical and Role Functioning scores. No floor or ceiling effects (baseline scores of 0 or 100) were found for the Respiratory Symptoms scale (primary endpoint of trials). Baseline Respiratory Symptoms scores discriminated between patients based on baseline FEV1% predicted in only one trial. The minimal important difference score for the Respiratory Symptoms scale was 8.0 points. AZLI did not show efficacy in the two phase III trials. QOL-B responsivity to treatment was assessed by examining changes from baseline QOL-B scores at study visits at which protocol-defined pulmonary exacerbations were reported. Mean Respiratory Symptoms scores decreased 14.0 and 14.2 points from baseline for placebo-treated and AZLI-treated patients with exacerbations, indicating that worsening respiratory symptoms were reflected in clinically meaningful changes in QOL-B scores. CONCLUSIONS: Previously established content validity, reliability and responsivity of the QOL-B are confirmed by this final validation study. The QOL-B is available for use in clinical trials and routine clinical practice.

Efficacy and safety of sirolimus in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS: We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS: During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS: In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.

RATIONALE: Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. OBJECTIVES: To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). METHODS: Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. MAIN RESULTS: 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse events were similar between groups. CONCLUSIONS: Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION NUMBER: NCT00669331.

Prevalence of pulmonary artery dilation in non-cystic fibrosis bronchiectasis: a computed tomography analysis from a cohort of the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry.

Although pulmonary artery (PA) dilation is independently associated with significant morbidity and mortality in patients with pulmonary diseases irrespective of diagnosed pulmonary hypertension, its relationship with nontuberculous mycobacteria (NTM) is unknown. The Bronchiectasis and NTM Research Registry is a multicenter registry created to foster research in non-cystic fibrosis (CF) bronchiectasis and NTM lung disease. The majority of patients with non-CF bronchiectasis at Oregon Health & Science University have NTM infections. To determine the prevalence of PA dilation in these patients and its association with supplemental oxygen use, severity of bronchiectasis, tobacco use, and NTM in the sputum culture, we evaluated the chest computed tomography (CT) scans from 321 patients in a cross-sectional analysis. We measured the severity of bronchiectasis by applying modified Reiff criteria and measured the diameters of the PA and aorta (Ao), with PA dilation defined as a PA:Ao ratio >0.9. In our cohort, the mean age was 67.3 years and 83.2% were female. The mean modified Reiff score was 7.1, indicating moderate disease severity. Forty-two patients (13.1%) were found to have PA dilation. PA dilation was positively associated with the use of supplemental oxygen (P<0.001), but there was no association between PA dilation and NTM infection.

Chronic obstructive pulmonary disease and bronchiectasis.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) and bronchiectasis are two different but related diseases that occur separately, but can coexist. In this review, we will examine the recent research regarding patients with COPD who have coexisting bronchiectasis. RECENT FINDINGS: Recent research has focused on defining distinct COPD phenotypes with the ultimate goal of changing the outcomes using tailored therapies. A frequent exacerbator phenotype has been identified. COPD patients with Pseudomonas aeruginosa are a phenotype with worse outcomes. Patients with coexisting COPD and bronchiectasis may represent a unique phenotype. SUMMARY: Patients with coexisting COPD and bronchiectasis could represent a unique phenotype with more severe disease, worse outcomes, more isolation of potentially pathogenic microorganisms, and more frequent exacerbations, with the potential for targeted therapies.

Pilot Evaluation of a Management Toolkit for Airway Clearance Therapy in Bronchiectasis (IMPACT BE).

Background: Airway clearance therapies (ACTs) are recommended as an integral part of the management of non-cystic fibrosis bronchiectasis (BE) to prevent inflammation, mucus accumulation, and infection that occur because of ineffective secretion clearance. Adherence to ACTs is low, in part because of perceived burden and a lack of standardization of education and training programs for patients. Poor adherence is associated with more frequent exacerbations, worse health outcomes, and worse quality of life. Structured educational programs increase adherence to ACT among people with cystic fibrosis and may show similar results for people with BE. Objective: This pilot study evaluated the feasibility, clinical utility, sustainability, and expert opinions of this educational program addressing gaps in ACT knowledge and skills in people with BE. Methods: The Individual Management of Patient Airway Clearance Therapy- Bronchiectasis (IMPACT BE) was implemented in nine BE centers with 100 patients. Qualitative and quantitative data were collected from patients and providers. Results: The IMPACT BE program demonstrated good uptake in a clinic setting by multidisciplinary team members, with improvements in medical teams' evaluation of their ability to provide education to patients. All healthcare teams indicated that this program could become a sustainable part of their clinic. Qualitative responses from patients indicated the program was comprehensive and easy to use. Conclusion: In this pilot study, IMPACT BE was found to be useful in teaching airway clearance to people with BE. The open-access toolkit was well received by both patients and a diverse array of providers in a clinic setting.

Prevalence of pulmonary artery dilation in non-cystic fibrosis bronchiectasis: A CT analysis from a cohort of the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry.

Although pulmonary artery (PA) dilation is independently associated with significant morbidity and mortality in patients with pulmonary diseases irrespective of diagnosed pulmonary hypertension, its relationship to nontuberculous mycobacteria (NTM) is unknown. To determine the prevalence of PA dilation in patients with NTM-predominant non-CF bronchiectasis, we evaluated the chest computed tomography (CT) scans from 321 patient in the United States based Bronchiectasis and NTM Research Registry. The majority of our cohort had NTM infection. We measured the severity of bronchiectasis using modified Reiff criteria and measured the diameters of the PA and aorta (Ao), with PA dilation defined as a PA:Ao ratio > 0.9. Forty-two patients (13%) were found to have PA dilation. PA dilation was positively associated with the use of supplemental oxygen (p < 0.001), but there was no association between PA dilation and NTM infection.

Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.

BACKGROUND: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. METHODS: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. RESULTS: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. CONCLUSIONS: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

Thoracic endometriosis unmasked by ovarian hyperstimulation for in vitro fertilization.

Thoracic endometriosis syndrome is a well-described, rare manifestation of endometriosis. We present a case of a 35-year old woman undergoing controlled ovarian stimulation prior to in vitro fertilization (IVF) who developed bilateral hemorrhagic pleural effusions. She was initially diagnosed with ovarian hyperstimulation syndrome, a complication of infertility therapy; however, she was later found to have occult thoracic endometriosis. We describe ovarian hyperstimulation syndrome and review the manifestations of thoracic endometriosis syndrome. Although endometriosis is a hormone-dependent disease, the rate of IVF complications related to endometriosis is low.

The Pathogenesis of Bronchiectasis.

Bronchiectasis is a condition defined by permanently dilated airways and characterized by chronic cough and sputum and in many patients, recurrent exacerbations. Bronchiectasis is a heterogeneous condition, with numerous underlying risk factors and initiating conditions. These factors share in common the ability to impair the mechanisms by which the airways are protected from inflammatory or infectious insults. These underlying factors result in chronic bacterial infection of the airways, inciting a host inflammatory response in which the airways are the collateral damage. The damaged airways are unable to clear the infection, leading to ongoing inflammation and progressive damage.

Criteria and definitions for the radiological and clinical diagnosis of bronchiectasis in adults for use in clinical trials: international consensus recommendations.

Bronchiectasis refers to both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions. Disease heterogeneity and the absence of standardised definitions have hampered clinical trials of treatments for bronchiectasis and are important challenges in clinical practice. In view of the need for new therapies for non-cystic fibrosis bronchiectasis to reduce the disease burden, we established an international taskforce of experts to develop recommendations and definitions for clinically significant bronchiectasis in adults to facilitate the standardisation of terminology for clinical trials. Systematic reviews were used to inform discussions, and Delphi processes were used to achieve expert consensus. We prioritised criteria for the radiological diagnosis of bronchiectasis and suggest recommendations on the use and central reading of chest CT scans to confirm the presence of bronchiectasis for clinical trials. Furthermore, we developed a set of consensus statements concerning the definitions of clinical bronchiectasis and its specific signs and symptoms, as well as definitions for chronic bacterial infection and sustained culture conversion. The diagnosis of clinically significant bronchiectasis requires both clinical and radiological criteria, and these expert recommendations and proposals should help to optimise patient recruitment into clinical trials and allow reliable comparisons of treatment effects among different interventions for bronchiectasis. Our consensus proposals should also provide a framework for future research to further refine definitions and establish definitive guidance on the diagnosis of bronchiectasis.

An official American thoracic society statement: position statement on ATS activities for the promotion of respiratory and sleep/wake health and the care of the critically ill in the United States.

BACKGROUND: The 1997 American Thoracic Society (ATS) statement "A Framework for Health Care Policy in the United States" outlined core principles for the Society's activities in the public health arena. In the succeeding 10 years, profound changes have taken place in the United States health care environment. In addition, the 2005 publication of the Society's Vision highlighted some differences between the original Statement and our current priorities. Therefore, the Health Policy Committee embarked on a re-analysis and re-statement of the Society's attitudes and strategies with respect to health and public policy. This Statement reflects the findings of the Committee. PURPOSE: To outline the key aspects of an internal ATS strategy for the promotion of respiratory and sleep/wake health and the care of the critically ill in the United States. METHODS: Committee discussion and consensus-building occurred both before and after individual members performed literature searches and drafted sections of the document. Comments were solicited on the draft document from ATS committee and assembly chairs and the Executive Committee, resulting in substantive revisions of the final document. RESULTS: Specific strategies are suggested for the ATS in the arenas of research, training and education, patient care, and advocacy so as to enhance the delivery of health care in the fields of respiratory medicine, sleep medicine, and critical care. CONCLUSIONS: The American Thoracic Society's Mission, Core Principles, and Vision provide clear guidance for the formulation of specific strategies that will serve to promote improved respiratory health and care of the critically ill in the United States.

IL10 polymorphisms are associated with airflow obstruction in severe alpha1-antitrypsin deficiency.

Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1)