Asthma with Irreversible Airway Obstruction in Smokers and Nonsmokers: Links between Airway Inflammation and Structural Changes.

BACKGROUND: The development of irreversible airway obstruction (IRAO) in asthma is related to lung/airway inflammatory and structural changes whose characteristics are likely influenced by exposure to tobacco smoke. OBJECTIVE: To investigate the interplay between airway and lung structural changes, airway inflammation, and smoking exposure in asthmatics with IRAO. METHODS: We studied asthmatics with IRAO who were further classified according to their smoking history, those with ≥20 pack-years of tobacco exposure (asthmatics with smoking-related IRAO [AwS-IRAO]) and those with <5 pack-years of tobacco exposure (asthmatics with nonsmoking-related IRAO [AwNS-IRAO]). In addition to recording baseline clinical and lung function features, all patients had a chest computed tomography (CT) from which airway wall thickness was measured and quantitative and qualitative assessment of emphysema was performed. The airway inflammatory profile was documented from differential inflammatory cell counts on induced sputum. RESULTS: Ninety patients were recruited (57 AwS-IRAO and 33 AwNS-IRAO). There were no statistically significant differences in the extent of emphysema and gas trapping between groups on quantitative chest CT analysis, although Pi10, a marker of airway wall thickness, was significantly higher in AwS-IRAO (p = 0.0242). Visual analysis showed a higher prevalence of emphysema (p = 0.0001) and higher emphysema score (p < 0.0001) in AwS-IRAO compared to AwNS-IRAO and distribution of emphysema was different between groups. Correlations between radiological features and lung function were stronger in AwS-IRAO. In a subgroup analysis, we found a correlation between airway neutrophilia and emphysematous features in AwS-IRAO and between eosinophilia and both airway wall thickness and emphysematous changes in AwNS-IRAO. CONCLUSIONS: Although bronchial structural changes were relatively similar in smoking and nonsmoking patients with asthma and IRAO, emphysematous changes were more predominant in smokers. However, neutrophils in AwS-IRAO and eosinophils in AwNS-IRAO were associated with lung and airway structural changes.

Longitudinal comparison of outcomes in patients with smoking-related asthma-COPD overlap and in non-smoking asthmatics with incomplete reversibility of airway obstruction.

BACKGROUND: There is a need to characterize the impact of the smoking status on the clinical course of asthmatics with incomplete reversibility of airway obstruction (IRAO). OBJECTIVE: To compare longitudinal health care use, symptom control, and medication needs between smoking and non-smoking asthmatics with IRAO. MATERIALS AND METHODS: This was a 12-month follow-up of a cross-sectional study comparing asthmatics with IRAO according to their tobacco exposure. One group had a tobacco exposure ≥20 pack-years and was considered to have asthma-COPD overlap (ACO) and the second with a past tobacco exposure <5 pack-years was considered as non-smokers with IRAO (NS-IRAO). Study participants were contacted by telephone every 3 months to document exacerbation events and symptom control. RESULTS: A total of 111 patients completed all follow-up telephone calls: 71 ACO and 40 NS-IRAO. The number of exacerbations per patient over the 12-month follow-up was similar in both groups. However, ACO reported worse symptom control throughout the follow-up as compared to NS-IRAO, although no significant variations within a group were observed over the study period. CONCLUSION: Although asthma control scores were poorer in ACO patients over 1 year compared to NS-IRAO, exacerbation rate was similar and low in both groups of asthmatics. These observations suggest that poorer asthma control in ACO was not driven by the number of exacerbations but may reflect the influence of chronic airway changes related to the COPD component.

Asthma-COPD Overlap Phenotypes and Smoking :Comparative features of asthma in smoking or non-smoking patients with an incomplete reversibility of airway obstruction.

The development of COPD features, such as an incomplete reversibility of airway obstruction (IRAO), in smoking or non-smoking asthmatic patients, a condition often named Asthma-COPD Overlap (ACO), has been recognized for decades. However, there is a need to know more about the sub-phenotypes of this condition according to smoking. This study aimed at comparing the clinical, physiological and inflammatory features of smoking and non-smoking asthmatic patients exhibiting IRAO. In this cross-sectional study, patients with an IRAO with (ACO, ≥20 pack-years) or without (NS-IRAO, <5 pack-years) significant smoking history completed questionnaires about asthma control (ACQ, score 0-6, 6 = better score) and quality of life (AQLQ, score 1-7, 1 = better score) and performed expiratory flows, lung volume and carbon monoxide diffusion capacity measurements. Blood sampling and induced sputum were obtained for systemic and lower airway inflammation assessment. A total of 115 asthmatic patients were included (75 ACO: age 61 ± 10 years, 60% women and 40 NS-IRAO: age 64 ± 9 years, 38% women). ACO patients had worse asthma control scores (1.8 ± 0.9 vs 1.4 ± 0.9, P = 0.02) and poorer asthma quality of life (5.3 ± 1.0 vs 5.9 ± 1.0, P = 0.003). In addition, ACO had higher residual volume (145 ± 45 vs 121 ± 29% predicted, P = 0.008) and a lower carbon monoxide diffusing capacity corrected for alveolar volume (90 ± 22 vs 108 ± 20% predicted, P = 0.0008). No significant differences were observed in systemic or lower airway inflammation. In conclusion, in smokers and non-smokers, the presence of IRAO in asthmatics is associated with different phenotypes that reflect the addition of smoking-induced changes to asthma physiopathology.

Comparative prevalence of co-morbidities in smoking and non-smoking asthma patients with incomplete reversibility of airway obstruction, non-smoking asthma patients with complete reversibility of airway obstruction and COPD patients.

BACKGROUND: Asthma with incomplete reversibility of airway obstruction (IRAO) may often be associated to smoking-induced changes. Nevertheless, a high proportion of patients showing IRAO have never smoked. These patients with IRAO often share features of patients with chronic obstructive pulmonary disease (COPD). Although IRAO is still a poorly defined condition, it has been associated with a higher morbidity and mortality than asthma with complete reversibility of airway obstruction (CRAO) or even COPD alone. A high prevalence of comorbidities could contribute to the reported poorer clinical outcome in IRAO, in comparison to CRAO or COPD alone. AIM: To determine the prevalence of past and current comorbidities in IRAO patients compared to patients with CRAO or COPD. METHODS: This was a retrospective, cross-sectional study. Demographic data, clinical characteristics and 36 predetermined comorbidities documented from self-report and chart review, were recorded from smoking-associated IRAO (S-IRAO), non-smoking IRAO (NS-IRAO), CRAO and COPD patients. RESULTS: A total of 199 patients were included in the final analysis (111F/88M, mean (±SD) age of 63 ± 10 years). The CRAO group had more comorbidities than the three other groups, but this difference was significant only with the NS-IRAO group (P = 0.04). For most comorbidities, the prevalence of comorbidities in both IRAO sub-groups was intermediate between CRAO and COPD, with significant differences between S-IRAO and NS-IRAO only for hypertension (P = 0.03), nasal polyps (P = 0.002) and pneumonia (P = 0.04). Typical asthma-associated comorbidities tended to be more prevalent in NS-IRAO patients and COPD-associated comorbidities in S-IRAO patients. CONCLUSION: In this study, the prevalence of comorbidities was not superior in patients with IRAO, compared to those with CRAO or COPD alone. The prevalence of comorbidities in the two main types of IRAO patients reflects exposure to cigarette smoke and asthma-related mechanisms.

The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects.

BACKGROUND: Neutrophils are effector cells recruited to airways in patients with asthma. Migration of neutrophils occurs predominantly through activation of the CXCR1 and CXCR2 receptors by CXC chemokines, including IL-8 and Gro-α. The dual CXCR1/CXCR2 antagonist SCH 527123 has been developed to target neutrophil migration to alleviate airway neutrophilia. This study investigated the effects of SCH 527123 on neutrophil levels within the bone marrow, peripheral blood and airways, and on isolated bone marrow and peripheral blood neutrophil migration from mild allergic asthmatics. METHODS: Thirteen subjects with mild allergic asthma completed a double blind, placebo-controlled, multi-center crossover study and were randomized to daily dosing of 30 mg SCH 527123 and placebo for 8 days. Subjects provided bone marrow, peripheral blood and sputum samples pre-dosing and on the last day of dosing. Neutrophil numbers were quantified in all samples and chemotaxis assays were performed on neutrophils purified from bone marrow and peripheral blood. RESULTS: Neutrophil numbers fell significantly in the peripheral blood and sputum following treatment with SCH 527123 compared to placebo treatment. No change in neutrophil numbers was observed in bone marrow. SCH 527123 reduced IL-8-induced migration of purified peripheral blood neutrophils (p < 0.05), but had limited effects on migration of neutrophils purified from bone marrow. CONCLUSIONS: The results from this study demonstrate that oral administration of the dual CXCR1/CXCR2 antagonist SCH 527123 reduces neutrophil levels in the circulation and airways through inhibition of migration. There were no toxic effects of SCH 527123 on granulocytic progenitor cells in the bone marrow.

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses.

BACKGROUND: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. OBJECTIVE: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. METHODS: Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. RESULTS: QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. CONCLUSION: QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge. METHODS: 25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15. RESULTS: Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen. CONCLUSIONS: This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01365533.

Prolonged bronchoprotection against inhaled methacholine by inhaled BI 1744, a long-acting beta(2)-agonist, in patients with mild asthma.

BACKGROUND: Long-acting ss(2)-agonists are an established controller medication in asthma. BI 1744 is a novel L\long-acting ss(2)-agonist with a preclinical profile that suggests 24-hour bronchodilation and bronchoprotection may be achieved. OBJECTIVE: To examine the bronchoprotective effects of single doses of BI 1744 against methacholine provocation in subjects with mild asthma. METHODS: Thirty-one subjects with mild asthma were randomized to receive single doses of BI 1744 (2, 5, 10, 20 microg) or placebo on separate days according to a double-blind, 5-way crossover design. Methacholine challenges were performed at 30 minutes and at 4, 8, 24, and 32 hours after each single dose of medication, and the results were expressed as PC(20) FEV(1). RESULTS: All doses of BI 1744 produced statistically significant increases in the methacholine PC(20) compared with placebo as long as 32 hours. The mean (geometric SEM) methacholine PC(20) 24 hours after dosing with placebo was 1.73 (1.13) mg/mL, which increased after 2 microg to 3.86 (1.14) mg/mL, after 5 microg to 5.67 (1.14) mg/mL, after 10 microg to 9.42 (1.13) mg/mL, and after 20 microg to 13.71 (1.14) mg/mL (all P < .0001). After 32 hours, the methacholine PC(20) value remained significantly increased for all doses. No safety or tolerability concerns were identified. CONCLUSION: BI 1744 provides significant bronchoprotection against inhaled methacholine for up to 32 hours after single-dose administration.

How should we quantify asthma control? A proposal.

BACKGROUND: Current asthma guidelines suggest a series of criteria to assess if asthma is controlled. However, there is a need to develop a simple and practical method to quantify the degree of such control, both in clinical practice and research. STUDY OBJECTIVES: This report describes a new method to quantify asthma control based on a percentage score. It also aims at comparing the percentage scores obtained with patient's self-evaluation of asthma control and a current validated Mini Asthma Quality of Life (MAQOL) questionnaire. SETTING AND SUBJECTS: Forty-two subjects (25 female and 17 male patients) with asthma of different severity recruited from a tertiary center asthma clinic. METHODS: The asthma scoring method provided a percentage control for symptoms, baseline expiratory flows and, an optional parameter, for airway inflammation assessed from induced-sputum eosinophil count. These control parameters were compared to an overall assessment of asthma control by the patient (also on a 100% scale) and the score obtained from a validated MAQOL questionnaire. RESULTS: Mean +/- SEM scores for symptoms, expiratory flows, and airway eosinophilia (last 2 weeks) were 87.8 +/- 1.4%, 88.6 +/- 1.8%, and 66.2 +/- 3.9%, respectively. No significant correlation was found between these three parameters (p > 0.05). The mean global asthma control score and the score estimated by the patient were 80.9 +/- 1.5% and 91.7 +/- 1.5%, respectively (not significantly different). There was a significant correlation between asthma control score (percentage) and percentage symptom score (p < 0.001), while it almost achieved significance for FEV(1) (p = 0.05). Only symptom scores correlated with the MAQOL questionnaire. CONCLUSIONS: We developed a simple easy-to-use asthma control scoring system based on a percentage of optimal control. The percentage symptom score but not the global control score of this new method correlated with patient's global assessment of asthma control. This could be a simple tool that is potentially useful both for the clinician and for research purposes, to quantify global or specific aspects of asthma control.

Diisocyanate antigen-stimulated monocyte chemoattractant protein-1 synthesis has greater test efficiency than specific antibodies for identification of diisocyanate asthma.

We previously reported that diisocyanate-human serum albumin (DIISO-HSA) stimulated production of monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells is significantly associated with a clinical diagnosis of diisocyanate asthma (DA). Others have reported that antibodies for DIISO-HSA are specific but insensitive markers of DA. This study was performed to evaluate test characteristics of the in vitro MCP-1 assay compared with DIISO-HSA-specific immunoglobulin (Ig) G and IgE in identifying workers with DA. MCP-1 was quantitated in peripheral blood mononuclear cell supernatants 48 hours after incubation with DIISO-HSA antigens. Assay results were compared with outcomes of specific inhalation challenge (SIC) testing. Nineteen of 54 (35%) workers assayed for antibodies and MCP-1 stimulation had SIC-confirmed DA. Mean MCP-1 produced by SIC-positive workers was greater than SIC-negative workers (p < or = 0.001). Diagnostic sensitivity, specificity, and test efficiency for specific IgG were 47%, 74%, and 65%, respectively, and for specific IgE were 21%, 89%, and 65%, respectively. Sensitivity, specificity, and test efficiency of the MCP-1 test were 79%, 91%, and 87%, respectively. This study indicates that the MCP-1 stimulation assay has greater sensitivity and specificity than the specific antibody assays in correctly identifying DA.