Ron Olivenstein

The relationship between late asthmatic responses and antigen-specific immunoglobulin

The aim of this study was to examine the relationships between allergen-induced early and late airway responses and antigen-specific IgE, IgG, and lymphocyte subsets in blood and bronchoalveolar lavage (BAL). Brown Norway rats were sensitized at 7 weeks of age with ovalbumin (1 mg s.c.) with use of Bordetella pertussis as an adjuvant. Three weeks after sensitization, animals were anesthetized and challenged with an aerosol of ovalbumin (5% wt/vol in saline) for 5 minutes. Each animal was studied for 8 hours with repeated measurements of lung resistance. Blood was obtained at 0, 1, 2, and 3 weeks before ovalbumin challenge. Ovalbumin-specific IgE and IgG were determined by ELISA. No specific antibody was detectable before sensitization. Ovalbumin-specific IgE and IgG rose between 1 to 2 weeks after sensitization and peaked at 3 weeks. The IgE level did not correlate with the magnitude of either the early or the late responses. In a similar manner no correlation existed between the magnitude of specific IgG and the late response. However, a significant inverse correlation (r = -0.73; p < 0.01) occurred between specific IgG and the early response. No correlation occurred between the ratio of helper (W3/25 +) to suppressor (OX-8 +) lymphocytes in blood and BAL and airway responses to allergen. The size of the early and late responses were correlated, suggesting a common stimulus. Despite the blunting of the early response by repeated sensitization the late response was unaffected, suggesting that the factors that determine the physiologic expression of the early and late responses are different.

Increased expression of the calcium-activated chloride channel hCLCA1 in airways of patients with obstructive chronic bronchitis.

BACKGROUNDnInterleukin (IL)-9 and its effect on enhancing the human calcium-activated chloride channel 1 (hCLCA1) expression have been shown to induce mucin production. Increased expression of hCLCA1 may, in turn, contribute to mucus overproduction in chronic obstructive pulmonary disease (COPD) with a chronic bronchitis (CB) phenotype.nnnOBJECTIVEnTo determine the expression of IL-9, IL-9 receptor (IL-9R), hCLCA1 and mucoglycoconjugates in COPD.nnnMETHODSnBronchial biopsies were obtained from six patients with obstructive CB and six healthy control subjects. IL-9, IL-9R and hCLCA1 expression were detected using immunohistochemistry. Additionally, in situ hybridization was performed to determine the expression of hCLCA1 messenger RNA. Mucin production was assessed using periodic acid-Schiff staining.nnnRESULTSnThere was a significantly higher number of IL-9 immunoreactive cells in the submucosa of patients with COPD than that of healthy control subjects (P<0.05). Also, a significant increase in the expression of IL-9R, hCLCA1 (protein and messenger RNA) and mucin (periodic acid-Schiff-positive cells) was noted in the bronchial epithelium of patients with COPD compared the control subjects (P<0.05).nnnCONCLUSIONnIncreased expression of IL-9, IL-9R and hCLCA1 in the bronchial mucosa of patients with obstructive CB suggests that mucus overproduction in this disease may be, at least in part, due to hCLCA1.

Asthma biomarkers in the age of biologics

The heterogeneous nature of asthma has been understood for decades, but the precise categorization of asthma has taken on new clinical importance in the era of specific biologic therapy. The simple categories of allergic and non-allergic asthma have given way to more precise phenotypes that hint at underlying biologic mechanisms of variable airflow limitation and airways inflammation. Understanding these mechanisms is of particular importance for the approximately 10% of patients with severe asthma. Biomarkers that aid in phenotyping allow physicians to “personalize” treatment with targeted biologic agents. Unfortunately, testing for these biomarkers is not routine in patients whose asthma is refractory to standard therapy. Scientific advances in the recognition of sensitive and specific biomarkers are steadily outpacing the clinical availability of reliable and non-invasive assessment methods designed for the prompt and specific diagnosis, classification, treatment, and monitoring of severe asthma patients. This article provides a practical overview of current biomarkers and testing methods for prompt, effective management of patients with severe asthma that is refractory to standard therapy.

Recognition and management of severe asthma: A Canadian Thoracic Society position statement

ABSTRACT RATIONALE: While severe asthma affects approximately 5% of all individuals with asthma, this small minority of individuals accounts for a large proportion of the asthma-related costs. Greater understanding of the pathophysiology of asthma combined with the emergence of novel biologic therapies for severe asthma supported the need for a thorough review of the diagnosis, investigation, phenotyping, and management of severe asthma. OBJECTIVES: We aimed to propose a practical approach to distinguish uncontrolled asthma due to inadequate asthma management from severe asthma despite optimal asthma management. Moreover, based on emerging scientific evidence, we sought to provide guidance for characterizing individuals with severe asthma and considering a phenotype-specific management. We also aimed to review other novel new potential therapeutic approaches. METHODS: We systematically reviewed the relevant literature focusing on randomized controlled trials and when available, systematic reviews of randomized controlled trials. The proposed key messages, based on scientific evidence and expert opinion, were agreed upon by unanimous consensus. MAIN RESULTS: We defined severe asthma and outlined its significant impact from the societal and patient perspectives. We outlined a practical approach to distinguish severe from uncontrolled but not severe asthma, based on stepwise investigation and management of potential reasons for uncontrolled asthma. After reviewing the current evidence we concluded that: 1) Several biomarkers (e.g. sputum or blood eosinophil count, total IgE, or FeNO) can help identify potential responders to new therapeutic options; 2) Tiotropium may be considered as an add-on therapy for individuals 12 years of age and over with severe asthma uncontrolled despite combination ICS/LABA therapy; 3) The chronic use of macrolides may decrease asthma exacerbations in individuals 18 years of age and over with severe asthma independent of their inflammatory profile; 4) Children aged 6 years and older and adults who are sensitized to at least one relevant perennial allergen and who remain poorly controlled asthmatics despite high dose ICS and a second controller can benefit from the addition of anti-IgE therapy to reduce asthma exacerbations; due to the known risk of side effects associated with high-dose ICS in children, omalizumab should also be considered in children and adolescents who repeatedly exacerbate or have poor control when therapy is stepped down from high-dose to moderate-dose ICS and at least one other controller; 5) Anti-IL5 therapies may be considered for adults 18 years of age and over with severe eosinophilic asthma who experience recurrent asthma exacerbations in spite of high doses of ICS in addition to at least one other controller; and 6) Although bronchial thermoplasty has shown a decrease in asthma exacerbations in one study, its role in the treatment of severe asthma remains uncertain. CONCLUSIONS: After reviewing existing and emerging therapies for severe asthma, we developed key messages for phenotyping individuals with severe asthma and suggested phenotype-specific targeted therapies. We highlighted gaps in knowledge in the pathophysiology of severe asthma, the identification of responders, and the assessment of the efficacy of novel therapies that should be targeted by future research. RÉSUMÉ JUSTIFICATION: Bien que lasthme sévère touche environ 5 % des asthmatiques, une grande proportion des coûts liés à lasthme est imputable à cette petite minorité. Une plus grande compréhension de la pathophysiologie de lasthme, combinée à lémergence de traitements biologiques novateurs pour lasthme sévère, a rendu nécessaire la révision approfondie du diagnostic, de linvestigation, du phénotypage et de la prise en charge de lasthme sévère. OBJECTIFS: Nous avions pour but de proposer une approche pratique pour distinguer lasthme non contrôlé dû à une prise en charge inadéquate, de lasthme sévère dépit dune prise en charge optimale de lasthme. De plus, à partir des données probantes scientifiques émergentes, nous avons cherché à donner des indications pour la caractérisation des personnes souffrant dasthme sévère et envisager une prise en charge spécifique à leur phénotype. Nous avions aussi pour but dexaminer dautres approches thérapeutiques novatrices potentielles. MÉTHODES: Nous avons passé en revue la littérature pertinente de façon systématique, en mettant laccent sur les essais contrôlés randomisés et, lorsquelles étaient disponibles, sur les revues systématiques dessais contrôlés randomisés. PRINCIPAUX RÉSULTATS: Nous avons défini lasthme sévère et décrit ses effets importants du point de vue sociétal et du point de vue du patient. Nous avons présenté une approche pratique afin de distinguer lasthme sévère de lasthme non contrôlé mais non sévère, fondée sur une investigation par étapes et la prise en charge des causes possibles de lasthme non contrôlé. Après avoir examiné les données probantes disponibles, nous avons conclu que : 1) Plusieurs biomarqueurs (ex.: numération des éosinophiles dans les expectorations ou dans le sang, IgE totales ou de FeNO) peuvent aider à répertorier les répondeurs potentiels aux nouvelles options thérapeutiques; 2) Le tiotropium peut être envisagé en tant que traitement additionnel pour les individus âgés de 12 ans et plus souffrant dasthme sévère non contrôlé malgré une thérapie associant les CSI et les ABAP; 3) Lusage chronique des macrolides peut diminuer les exacerbations de lasthme chez les individus âgés de 18 ans et plus souffrant dasthme sévère indépendamment de leur profil inflammatoire; 4) Les enfants âgés de six ans et plus et les adultes sensibilisés à au moins un allergène pérenne pertinent qui demeurent des asthmatiques mal contrôlés malgré une forte dose de CSI et un deuxième contrôleur peuvent bénéficier de lajout dun traitement anti-IgE afin de réduire les exacerbations de lasthme; en raison du risque connu deffets secondaires associés à une dose élevée de CSI chez les enfants, lomalizumab devrait aussi être envisagé chez les enfants et les adolescents qui souffrent dexacerbations à répétition ou dont lasthme est mal contrôlé, lorsque le traitement passe dune forte dose dICS à une dose modérée dICS assortie dau moins un autre contrôleur; 5) Les traitements par anti-IL5 peuvent être envisagés pour les adultes de 18 ans et plus souffrant dasthme éosinophilique sévère qui sont aux prises avec des exacerbations de lasthme récurrentes malgré des doses élevées dICS associées à au moins un autre contrôleur; et 6) Bien que la thermoplastie bronchique ait démontré une diminution des exacerbations de lasthme dans une étude, son rôle dans le traitement de lasthme sévère demeure incertain. CONCLUSION: Après avoir examiné les traitements existants et émergents pour lasthme sévère, nous avons défini des messages-clés pour phénotyper les individus souffrant dasthme sévère et suggérer des thérapies ciblées spécifiques au phénotype.

Interleukin-33 in asthma: insights into pro-inflammatory roles of airway structural cells

Background nInterleukin-33 (IL-33) is a novel cytokine that triggers inflammatory immune responses, but evidence of its role in human asthma, a common allergic airway disease, is lacking. There is also a paucity of information regarding which cells express IL-33, and what conditions promote its expression. We sought to investigate whether IL-33 is expressed in the lung tissue from patients with asthma.