Understanding the measurement properties of the incremental shuttle walk test in patients with severe asthma.

BACKGROUND AND OBJECTIVE: We investigated the repeatability and validity of the incremental shuttle walk test (ISWT) distance compared to peak oxygen uptake (VO2pk ) during maximal incremental cycle ergometer (ICE) and treadmill (ITM) tests in adults with severe asthma. METHODS: Adults with severe asthma, Medical Research Council (MRC) dyspnoea ≥2, were recruited from specialists caring for patients with severe asthma. All participants performed three ISWT (familiarization and two subsequent tests on the same day), an ICE and an ITM in a randomized order, on separate days, to intolerance with expiratory gas analysis. RESULTS: A total of 50 patients (32 females, mean (SD), age: 54 (13) years, forced expiratory volume in 1 s (FEV1 ): 1.9 (0.8) L and body mass index (BMI): 32 (6) kg/m2 ) completed all five tests. The mean (SD) ISWT distance for each test was 400 (156), 418 (142) and 438 (157) m (P = 0.001), respectively. There was a strong correlation between the ISWT distance with VO2pk derived from ITM (r = 0.74, P < 0.001) and ICE (r = 0.75, P < 0.001). CONCLUSION: There was a small increase in the mean ISWT distance on sequential testing. In clinical practice, the coefficient of repeatability and heteroscedasticity need to be considered when assessing whether a true change has occurred within an individual patient. The ISWT has validity compared to VO2pk on both ICE and ITM, but they are not interchangeable.

Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study).

BACKGROUND: IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. OBJECTIVES: We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. METHODS: Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. RESULTS: Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. CONCLUSION: We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.

Enabling Adults With Severe Asthma to Exercise: A Qualitative Examination of the Challenges for Patients and Health Care Professionals.

BACKGROUND: Adults living with severe asthma have lower physical activity levels, particularly high-intensity physical activity, compared with their healthy peers. Physical inactivity is associated with increased morbidity and mortality. OBJECTIVE: To understand patient and health care professional attitudes toward exercise and physical activity to inform future strategies for the improvement of healthy lifestyle behaviors, including exercise. METHODS: Participants recruited from a specialist difficult asthma service were interviewed individually, and health care professionals (HCPs) from primary care, secondary care, and a tertiary center were invited to attend focus groups. Interviews and focus groups were transcribed verbatim. We performed thematic analysis on interviews and focus groups separately, followed by an adapted framework analysis to analyze datasets together. RESULTS: Twenty-nine people with severe asthma participated in a semi-structured interview. A total of 51 HCPs took part in eight focus groups across the East Midlands, United Kingdom. Final analysis resulted in three major themes: barriers to exercise and exercise counseling - in which patients and HCPs identified disease and non-disease factors affecting those living with severe asthma; attitudes toward HCP support for exercise - highlighting education needs for HCPs and preference for supervised exercise programs; and areas for system improvement in supporting patients and HCPs - challenges exist across health sectors that limit patient support are described. CONCLUSIONS: Patients identified the important role of HCPs in supporting and advising on lifestyle change. Despite a preference for supervised exercise programs, both patient and HCP barriers existed. To meet patients' varied support needs, improved integration of services is required and HCP skills need extending.

Mepolizumab and exacerbations of refractory eosinophilic asthma.

BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)

The relationship between clinical outcomes and medication adherence in difficult-to-control asthma.

Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub-optimal adherence (<80%) in 65% of patients on inhaled corticosteroids (ICS) or combined ICS/long-acting ß2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV(1) and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non-adherence is correlated with poor clinical outcomes.

Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1ß, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83­0.95); serum CXCL10, 0.83 (95% CI, 0.70­0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78­0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1ß, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

Does body mass index influence the outcomes of a Waking-based pulmonary rehabilitation programme in COPD?

Body mass index (BMI) is an important prognostic measure in chronic obstructive pulmonary disease (COPD). However, its effects on pulmonary rehabilitation (PR) are unknown. This study aimed to evaluate the effectiveness of a walking-based PR programme across the BMI range and the impact of BMI on exercise performance and health status. A total of 601 patients with COPD completed a PR programme. The effects of BMI on exercise capacity (incremental and endurance shuttle walk tests (ISWT and ESWT)) and health status (chronic respiratory questionnaire (CRQ)) before and after PR were evaluated. 16% of patients were underweight, with 53% overweight or obese. At baseline, the obese had worse ISWT (-54 m ± 14 m; p = 0.001) despite a higher predicted forced expiratory volume in 1 s (7.4m ± 1.6%; p < 0.001). Patients in all BMI categories made clinically important improvements in ISWT distance: BMI <21, 62 m; 21-25, 59 m; 25-30, 59 m; >30, 65 m (p = < 0.001). All four domains of the CRQ increased above the level of clinical significance for all BMI categories (all p < 0.001). The majority of patients with COPD were overweight associated with a lower walking capacity. A walking-based PR programme was comparably effective across the BMI spectrum. Patients with COPD should be referred for standard PR, independent of BMI.

IgE sensitization to Aspergillus fumigatus is associated with reduced lung function in asthma.

RATIONALE: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear. OBJECTIVES: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma. METHODS: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data. MEASUREMENTS AND MAIN RESULTS: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV1 % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024). CONCLUSIONS: A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.

Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes.

BACKGROUND: Severe asthma is a heterogeneous condition. Airway remodelling is a feature of severe asthma and can be determined by the assessment of high-resolution computed tomography (HRCT) scans. The aim of this study was to assess whether airway remodelling is restricted to specific subphenotypes of severe asthma. METHODS: A retrospective analysis was performed of HRCT scans from subjects who had attended a single-centre severe asthma clinic between 2003 and 2008. The right upper lobe apical segmental bronchus (RB1) dimensions were measured and the clinical and sputum inflammatory characteristics associated with RB1 geometry were assessed by univariate and multivariate regression analyses. Longitudinal sputum data were available and were described as area under the time curve (AUC). Comparisons were made in RB1 geometry across subjects in four subphenotypes determined by cluster analysis, smokers and non-smokers, and subjects with and without persistent airflow obstruction. RESULTS: Ninety-nine subjects with severe asthma and 16 healthy controls were recruited. In the subjects with severe asthma the RB1 percentage wall area (%WA) was increased (p=0.009) and lumen area (LA)/body surface area (BSA) was decreased (p=0.008) compared with controls but was not different across the four subphenotypes. Airway geometry was not different between smokers and non-smokers and RB1 %WA was increased in those with persistent airflow obstruction. RB1 %WA in severe asthma was best associated with airflow limitation and persistent neutrophilic airway inflammation (model R(2)=0.27, p=0.001). CONCLUSIONS: Airway remodelling of proximal airways occurs in severe asthma and is associated with impaired lung function and neutrophilic airway inflammation.

Chemokine receptor expression in tumour islets and stroma in non-small cell lung cancer.

BACKGROUND: We have previously demonstrated that tumour islet infiltration by macrophages is associated with extended survival (ES) in NSCLC. We therefore hypothesised that patients with improved survival would have high tumour islet expression of chemokine receptors known to be associated with favourable prognosis in cancer. This study investigated chemokine receptor expression in the tumour islets and stroma in NSCLC. METHODS: We used immunohistochemistry to identify cells expressing CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CCR1 in the tumour islets and stroma in 20 patients with surgically resected NSCLC. Correlations were made with macrophage and mast cell expression. RESULTS: There was increased expression of CXCR2, CXCR3, and CCR1 in the tumour islets of ES compared with poor survival (PS) patients (p = 0.007, 0.01, and 0.002, respectively). There was an association between 5 year survival and tumour islet CXCR2, CXCR3 and CCR1 density (p = 0.02, 0.003 and <0.001, respectively) as well as stromal CXCR3 density (p = 0.003). There was a positive correlation between macrophage density and CXCR3 expression (rs = 0.520, p = 0.02) and between mast cell density and CXCR3 expression (rs = 0.499, p = 0.03) in the tumour islets. CONCLUSION: Above median expression of CXCR2, CXCR3 and CCR1 in the tumour islets is associated with increased survival in NSCLC, and expression of CXCR3 correlates with increased macrophage and mast cell infiltration in the tumour islets.

Tumour necrosis factor-alpha expression in tumour islets confers a survival advantage in non-small cell lung cancer.

BACKGROUND: The role of TNFalpha in cancer is complex with both pro-tumourigenic and anti-tumourigenic roles proposed. We hypothesised that anatomical microlocalisation is critical for its function. METHODS: This study used immunohistochemistry to investigate the expression of TNFalpha in the tumour islets and stroma with respect to survival in 133 patients with surgically resected NSCLC. RESULTS: TNFalpha expression was increased in the tumour islets of patients with above median survival (AMS) compared to those with below median survival (BMS)(p = 0.006), but similar in the stroma of both groups. Increasing tumour islet TNFalpha density was a favorable independent prognostic indicator (p = 0.048) while stromal TNFalpha density was an independent predictor of reduced survival (p = 0.007). Patients with high TNFalpha expression (upper tertile) had a significantly higher 5-year survival compared to patients in the lower tertile (43% versus 22%, p = 0.01). In patients with AMS, 100% of TNFalpha+ cells were macrophages and mast cells, compared to only 28% in the islets and 50% in the stroma of BMS patients (p < 0.001). CONCLUSIONS: The expression of TNFalpha in the tumour islets of patients with NSCLC is associated with improved survival suggesting a role in the host anti-tumour immunological response. The expression of TNFalpha by macrophages and mast cells is critical for this relationship.

A Feasibility Study of a Randomized Controlled Trial of Asthma-Tailored Pulmonary Rehabilitation Compared with Usual Care in Adults with Severe Asthma.

BACKGROUND: Currently, the acceptability and efficacy of pulmonary rehabilitation for adults with severe asthma is unknown. OBJECTIVE: To investigate the feasibility of performing a randomized controlled trial of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC). METHODS: Adults with severe asthma were recruited and randomized 2:1 to AT-PR and UC. The primary outcomes were recruitment, retention, and serious adverse event rates. Secondary outcome measures included those for a future trial assessing the feasibility of collecting data. Assessments were performed at baseline, 12 weeks, and 9 months including measures of physical performance, health-related quality of life, and asthma control. A recruitment rate of 30% was estimated with 95% CI of ±7%, a retention rate of 75% ± 14% if we recruited 40 patients to AT-PR, and a serious adverse event rate of 2.5%. RESULTS: Sixty-one (26%) of 238 eligible patients were recruited (38 women; mean age, 54 ± 13 years; body mass index, 32 ± 7 kg/m2; FEV1, 1.9 ± 0.7 L; FEV1/forced vital capacity, 69% ± 11%). Fifty-one patients were randomized to AT-PR (n = 34) and UC (n = 17). The retention rate was 62% for the AT-PR group and 53% for the UC group, with a serious adverse event rate of 3.3% related to the study visits. Overall collection of the outcome measures was feasible. The results of the AT-PR group were suggestive of improvements in exercise performance, health-related quality of life, and asthma control, but the UC group results were either unchanged or worsened. CONCLUSIONS: Both recruitment and retention rates were within the a priori estimated 95% CI. Our results indicate that AT-PR may be efficacious for adults with severe asthma but any future intervention and trial design would need further modifications to improve acceptability and retention rate.

Evidence of a role of tumor necrosis factor alpha in refractory asthma.

BACKGROUND: The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma. METHODS: We measured markers of TNF-alpha activity on peripheral-blood monocytes in 10 patients with refractory asthma, 10 patients with mild-to-moderate asthma, and 10 control subjects. We also investigated the effects of treatment with the soluble TNF-alpha receptor etanercept (25 mg twice weekly) in the patients with refractory asthma in a placebo-controlled, double-blind, crossover pilot study. RESULTS: As compared with patients with mild-to-moderate asthma and controls, patients with refractory asthma had increased expression of membrane-bound TNF-alpha, TNF-alpha receptor 1, and TNF-alpha-converting enzyme by peripheral-blood monocytes. In the clinical trial, as compared with placebo, 10 weeks of treatment with etanercept was associated with a significant increase in the concentration of methacholine required to provoke a 20 percent decrease in the forced expiratory volume in one second (FEV1) (mean difference in doubling concentration changes between etanercept and placebo, 3.5; 95 percent confidence interval, 0.07 to 7.0; P=0.05), an improvement in the asthma-related quality-of-life score (by 0.85 point; 95 percent confidence interval, 0.16 to 1.54 on a 7-point scale; P=0.02), and a 0.32-liter increase in post-bronchodilator FEV1 (95 percent confidence interval, 0.08 to 0.55; P=0.01). CONCLUSIONS: Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).

Cluster analysis and clinical asthma phenotypes.

RATIONALE: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model. OBJECTIVES: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups. METHODS: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care. MEASUREMENTS AND MAIN RESULTS: Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 mug beclomethasone equivalent/d [95% confidence interval, 307-3,349 mug]; P = 0.02). CONCLUSIONS: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.

Patient Perceptions of Living with Severe Asthma: Challenges to Effective Management.

BACKGROUND: The management of severe asthma poses many challenges related to treatment, adherence, and psychosocial morbidity. There is little direct data from the patient perspective to understand and negotiate the complexities of managing severe asthma. OBJECTIVE: To explore the patient perceptions of living with severe asthma and the experience of managing severe asthma, in order to better understand the support that might promote more effective self-management for severe asthma. METHODS: Participants were recruited from a specialist Difficult Asthma Service. Semistructured interviews were conducted by researchers independent of the patient's care. Interviews were transcribed verbatim and inductive thematic analysis was performed. RESULTS: Twenty-nine participants (13 male: mean [standard deviation] age, 49.5 [13.6] years: mean Asthma Control Questionnaire 2.2 [1.2]) participated in an interview. Analysis resulted in 4 major themes describing the experience and challenges to managing severe asthma: understanding of severe asthma, emotional impact of living with severe asthma (subtheme: fear of hospitalization), public perceptions of asthma, and concerns about medications. CONCLUSIONS: Health care professionals need to consider and discuss with patients their perceptions of severe asthma and the relevant treatments; particular attention should focus around education of disease control and actively exploring thoughts around hospitalization. Our data highlight the potential for psychological and social support to enhance self-management by directly addressing the wide-ranging individual challenges patients face. There is also a need for greater public awareness and education about severe asthma to minimize patient distress particularly in the work environment.