Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils.

BACKGROUND: Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. OBJECTIVE: The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. METHODS: Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. RESULTS: During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. CONCLUSIONS: The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes.

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

BACKGROUND: In severe asthmatics with persistent airway eosinophilia, blockade of interleukin-5 has significant steroid-sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics. OBJECTIVES: In a cross-sectional study, the number and growth potential of eosinophil-lineage-committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, eight COPD patients and eight normal subjects. The effect of anti-IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (substudy of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n = 9) or placebo (n = 8), as six monthly subcutaneous injections. RESULTS: Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony-forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP numbers consistent with blockade of systemic eosinophilopoiesis. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose. CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg subcutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5-driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma.

Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial.

BACKGROUND: Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor. OBJECTIVE: In this study, we investigated the role of CCR3 agonists in asthma by observing the effect of a small molecule antagonist of the CCR3 receptor (GW766994) on sputum eosinophil counts in patients with eosinophilic asthma. METHODS: Clinical and physiological outcomes, the chemotactic activity of sputum supernatant for eosinophils and the presence of eosinophil progenitors in sputum and blood samples were also studied. RESULTS: In a double-blind parallel group study, 60 patients with asthma were randomized to 300 mg of GW766994 twice daily or matching placebo for 10 days followed by prednisone 30 mg for 5 days. Of these patients, 53 had a sputum eosinophil count > 4.9% at baseline. Despite plasma concentrations of drug consistent with > 90% receptor occupancy during the dosing period, the CCR3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells (CD34(+) 45(+) IL-5Rα(+)) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV1 ; however, there was a modest but statistically significant improvement in PC20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC20 is statistically significant, it is not of clinical significance. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.

Noninvasive methods for assessment of airway inflammation in occupational settings.

The present document is a consensus statement reached by a panel of experts on noninvasive methods for assessment of airway inflammation in the investigation of occupational respiratory diseases, such as occupational rhinitis, occupational asthma, and nonasthmatic eosinophilic bronchitis. Both the upper and the lower airway inflammation have been reviewed and appraised reinforcing the concept of 'united airway disease' in the occupational settings. The most widely used noninvasive methods to assess bronchial inflammation are covered: induced sputum, fractional exhaled nitric oxide (FeNO) concentration, and exhaled breath condensate. Nasal inflammation may be assessed by noninvasive approaches such as nasal cytology and nasal lavage, which provide information on different aspects of inflammatory processes (cellular vs mediators). Key messages and suggestions on the use of noninvasive methods for assessment of airway inflammation in the investigation and diagnosis of occupational airway diseases are issued.

Occupational asthma.

Work-related asthma is highly prevalent and represents a significant societal and financial burden worldwide. This State of the Art series article explores the epidemiology, clinical features, diagnosis and management of occupational asthma (OA), which comprises sensitiser-induced asthma and irritant-induced asthma (IIA). Sensitiser-induced OA is the development of asthma through sensitisation to a substance in the workplace. OA is largely underdiagnosed, and its clinical manifestations are non-specific, which makes its diagnosis challenging. Early and accurate diagnosis of OA through comprehensive testing is primordial to avoid unwarranted removal from exposure and to allow early management of confirmed cases. Despite optimal management, up to 70% of patients with OA will have persistent asthma several years after diagnosis. IIA classically refers to the development of de novo asthma acutely following an intense exposure to an irritant agent. However, some cases of IIA following multiple high-level exposures or a chronic low-dose exposure have been reported.

Risk of perinatal mortality associated with asthma during pregnancy.

BACKGROUND: Thirteen studies investigating the association between asthma during pregnancy and perinatal mortality reported generally no increased risk. Most of these studies should be interpreted with caution because they were limited in terms of statistical power. A study was therefore undertaken to evaluate whether maternal asthma during pregnancy increases the risk of perinatal mortality. METHODS: Through three administrative databases from Québec (Canada), a cohort of women with and without asthma who had at least one pregnancy between 1990 and 2002 was formed. Perinatal mortality was identified by diagnostic codes. The adjusted odds ratio (OR) of perinatal mortality in women with and without asthma was compared using Generalised Estimation Equation (GEE) models. The first model included all potential confounders (except small for gestational age, SGA), the second model excluded birth weight, gestational age at birth and SGA and the third model excluded birth weight, gestational age at birth but included only SGA. This analysis was also stratified for birth weight and gestational age at birth. RESULTS: The cohort was formed of 13 100 and 28 042 single pregnancies in women with and without asthma. The crude OR of perinatal mortality was 1.35 (95% CI 1.08 to 1.67), which decreased to 0.93 (95% CI 0.75 to 1.17) after adjustment for birth weight and gestational age at birth. Women with asthma had a higher rate of low birthweight babies and preterm delivery than those without asthma. CONCLUSION: The increased risk of low birthweight babies and premature delivery in women with asthma may partly explain the association between maternal asthma and the increased risk of perinatal mortality.

Comparative airway response to high- versus low-molecular weight agents in occupational asthma.

Airway responses to occupational agents in sensitised workers may vary clinically and physiologically. The patterns of change in airway responsiveness, type of response and fall in expiratory flows following laboratory exposure to high- or low-molecular weight agents (HMW and LMW agents, respectively) were compared in sensitised workers. Data on workers who underwent specific inhalation challenges with occupational sensitisers (117 exposed to HMW agents and 130 to LMW agents) were collected from their medical charts. Maximum falls in forced expiratory volume in one second (FEV(1)) were of similar magnitude for both types of agents. Compared with HMW agents, LMW agents induced more frequently late or dual responses and higher increases in airway responsiveness. After exposure to HMW agents, there was a mean+/-sd reduction in doubling concentrations of methacholine of 0.5+/-1.7 for early responses, compared with 2.8+/-1.2 and 1.4+/-2.0 for late and dual responses, respectively. Isolated early responses were more frequently found in females, smokers, workers with a higher % predicted FEV(1) and higher provocation concentration causing a 20% fall in FEV(1), and in those with longer asthma duration. Workers' characteristics, as well as the type of agent they are sensitised to, may help to predict the type of response after specific inhalation challenge.

Isolated late asthmatic reaction after exposure to a high-molecular-weight occupational agent, subtilisin.

High-molecular-weight agents generally induce immediate asthmatic reactions. We report the case of a subject who experienced a reaction that started after the first hour following exposure to subtilisin, a high-molecular-weight occupational agent. Any occurrence of immediate reaction was ruled out by measuring both FEV1 and lung volumes every 10 min in the first hour. This reaction was IgE-mediated as shown by immediate skin reactivity and increased specific IgE levels.

Closed-circuit apparatus for specific inhalation challenges with an occupational agent, formaldehyde, in vapor form.

Specific inhalation challenges are an important tool for confirming occupational asthma. In recent years, we have described two closed-circuit apparatuses that allow exposure to stable and controlled concentrations of particles and isocyanate gases. More recently, we developed a similar apparatus that generates chemicals in vapor form. The aim of this work is to describe its performance in the specific case of formaldehyde. This instrument is made of four parts: a generator as such, an exposure chamber, a monitor, and an automated regulatory system. This apparatus was assessed in four subjects suspected of having formaldehyde-induced asthma or alveolitis. The concentrations of formaldehyde were increased from 0.5 to 1 mg/m3 to 3 mg/m3 keeping the concentration at a value of 3 mg/m3 or less (threshold limit value). The dispersion of obtained values by comparison with the median data (6 values) was as follows: maximum value, 12 to 84%; minimum value, 20 to 58%; interquartile range, 0.13 to 0.9 mg/m3. We observed that target concentrations took a few minutes to be reached, but, once they were obtained, delivered concentrations were stable. The new vapor-delivery apparatus allows us to obtain concentrations of formaldehyde that are close to target concentrations with an acceptable dispersion of values around target concentration. Its use should be extended to other chemicals besides formaldehyde.

Differential cell counts in sputum in respiratory epidemiology: a pilot study.

BACKGROUND: The aim of this pilot study was to determine whether measuring sputum differential cell counts, particularly eosinophils, could be a useful method of validating self-reported symptoms suggesting asthma in epidemiologic studies. MATERIALS AND METHODS: In this cross-sectional study, we selected four groups of adult subjects by reported symptoms and diagnoses from among those previously randomly identified in a population study. Subjects were selected with no respiratory symptoms ever (normal group), or reporting a diagnosis of asthma (asthma group), or reporting recurrent wheezing not diagnosed as asthma (wheeze group), or reporting exposure to industrial irritants, but not asthma or wheezing (exposed group). Current respiratory symptoms, airway responsiveness to methacholine challenge, and sputum cell counts were determined. The study was completed by 107 subjects aged 20 to 44 years. RESULTS: There were no significant differences in FEV(1) percent predicted, total cell count, and sputum eosinophil count among the four groups. Subjects with reported asthma had greater airway responsiveness as reflected in a lower bronchial reactivity (BR) index. There was a weak correlation between BR index and sputum eosinophils. CONCLUSION: In a community setting, induced sputum eosinophil cell counts in subjects reporting asthma or wheezing were most often within the normal range and not sufficiently often abnormal to be useful in validating a diagnosis of asthma in epidemiologic studies.

Nonsensitizing causes of occupational asthma.

Irritant-induced asthma and RADS are related conditions that need further study focusing on the following questions: (1) Are there differences between the pathologic and functional features that follow single or multiple exposures to an irritant material? (2) What is the time course of the changes? (3) What are the physiologic correlates in terms of onset of airway hyperresponsiveness? (4) What are the risk markers (besides exposure)? (5) Are there means of modulating the reaction by using anti-inflammatory preparations? Developing an animal model of irritant-induced asthma and conducting prospective epidemiologic surveys in high-risk workers may be most effective routes to provide satisfactory answers to these questions. Further examination of the physiopathology of such conditions as byssinosis, grain-dust-induced respiratory disease, and aluminum potroom asthma as well as of the differences from and similarities to OA is also warranted.

[Is atopy a risk factor of occupational asthma?]. / L'atopie est-elle un facteur de risque de l'asthme professionnel?

General reviews about occupational asthma divide the susceptible allergens capable of initiating asthma into two distinct groups: those of high and of low molecular weight. Atopy would be a risk factor for developing occupational asthma to high molecular weight allergens but not to those of low molecular weight. In this work we have examined several studies and have analysed in a critical manner the relationship which exists between atopy and occupational asthma. The high molecular weight allergens studied were: snow crabs, laboratory animals, flour, proteolytic enzymes and psyllium. Those of low molecular weight were: red cedar, isocyanates, phthalic anhydride. Amongst allergens of high molecular weight there is a undeniable relationship between atopy and sensitisation to the allergen incriminated. However, the relation between atopy and asthma is more debatable except for baker's asthma. For more allergens of low molecular weight, atopy does not seem to favour the appearance of asthma, however, it may play a role in the occurrence of asthma to red cedar. The difference between the two groups of allergens is not as clear-cut as in the work that has appeared up until now and the exclusion of atopics from being hired would appear excessive.

[Bronchial irritation syndrome following inhalation or urea. Histologic and immunohistochemical evaluation]. / Syndrome d'irritation bronchique consécutif à l'inhalation d'urée. Evaluation histologique et immuno-histochimique.

We herein report the case of a subject exposed to urea fumes. After exposure, the subject immediately experienced throat and chest burning. A few hours later, she had cough, dyspnea and wheezing during exercise. The functional pulmonary testing performed two months later showed non-specific airway responsiveness. Bronchoscopy with broncho-alveolar lavage and bronchial biopsies was performed. Biopsies showed injury of the epithelial layer that was atrophic and devoid of ciliated cells. There was fibrosis of connective tissue as well as an inflammatory infiltrate. Immunohistochemistry stains showed that most of the inflammatory cells were T-lymphocytes. There were no degranulated eosinophils. The subject was given inhaled steroids. Four months later, bronchial responsiveness was normal.

[Current trends in asthma management]. / Actualités de la prise en charge de la maladie asthmatique.

INHALED CORTICOSTEROIDS: There has been substantial improvement in asthma management over the last few years. Inhaled glucocorticoids (ICS) are the most effective therapy in the treatment of asthma. COMPLEMENTARY TREATMENTS: Additional treatments such as theophyllines, long-acting beta 2 agonists or more recently leukotriene antagonists allow in most cases the maintenance of ICS at safe dosages without substantial adverse effects. COMPLIANCE: Compliance is a major issue that can only be improved using global management strategies in which asthma education plays a prominent role.

Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations.

INTRODUCTION: Oral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids. METHODS AND ANALYSIS: The design is a prospective cohort study of 1008 children aged 1-17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host-environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations. RESULTS: Results will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists. TRIAL REGISTRATION NUMBER: This study is registered at Clinicaltrials.gov (NCT02013076).

Canadian Thoracic Society Asthma Management Continuum--2010 Consensus Summary for children six years of age and over, and adults.

BACKGROUND/OBJECTIVE: To integrate new evidence into the Canadian Asthma Management Continuum diagram, encompassing both pediatric and adult asthma. METHODS: The Canadian Thoracic Society Asthma Committee members, comprised of experts in pediatric and adult respirology, allergy and immunology, emergency medicine, general pediatrics, family medicine, pharmacoepidemiology and evidence-based medicine, updated the continuum diagram, based primarily on the 2008 Global Initiative for Asthma guidelines, and performed a focused review of literature pertaining to key aspects of asthma diagnosis and management in children six years of age and over, and adults. RESULTS: In patients six years of age and over, management of asthma begins with establishing an accurate diagnosis, typically by supplementing medical history with objective measures of lung function. All patients and caregivers should receive self-management education, including a written action plan. Inhaled corticosteroids (ICS) remain the first-line controller therapy for all ages. When asthma is not controlled with a low dose of ICS, the literature supports the addition of long-acting beta2-agonists in adults, while the preferred approach in children is to increase the dose of ICS. Leukotriene receptor antagonists are acceptable as second-line monotherapy and as an alternative add-on therapy in both age groups. Antiimmunoglobulin E therapy may be of benefit in adults, and in children 12 years of age and over with difficult to control allergic asthma, despite high-dose ICS and at least one other controller. CONCLUSIONS: The foundation of asthma management is establishing an accurate diagnosis based on objective measures (eg, spirometry) in individuals six years of age and over. Emphasis is placed on the similarities and differences between pediatric and adult asthma management approaches to achieve asthma control.