Marie-Eve Boulay

Asthma-related comorbidities

Asthma is often associated with various comorbidities. The most frequently reported asthma comorbid conditions include rhinitis, sinusitis, gastroesophageal reflux disease, obstructive sleep apnea, hormonal disorders and psychopathologies. These conditions may, first: share a common pathophysiological mechanism with asthma; second: influence asthma control, its phenotype and response to treatment; and third: be more prevalent in asthmatic patients but without obvious influence on this disease. For many of these, how they interact with asthma remains to be further documented, particularly for severe asthma. If considered relevant, they should, however, be treated appropriately. Further research is needed on the relationships between these conditions and asthma.

The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti-inflammatory therapies

Allergen bronchoprovocation tests have been used for more than two decades in the investigation of respiratory allergic diseases such as asthma and rhinitis. These bronchial challenges are now well standardized and can offer key information on the therapeutic potential of new agents and on their anti‐inflammatory effects on the airways. Both standard and low‐dose allergen provocations are safe when performed by experienced investigators and do not lead to persistent worsening of asthma or change in airway function. The evaluation of new therapeutic agents by these methods can also provide important information on the mechanisms of development and persistence of airway diseases.

Metalloproteinase-9 in Induced Sputum Correlates with the Severity of the Late Allergen-Induced Asthmatic Response

Background: Asthma is characterized by airway inflammation and remodeling in which matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) play an important role. Allergen exposure activates the inflammatory/repair process in sensitized subjects. Induced-sputum analysis is a non-invasive method that allows the assessment of changes in inflammatory and remodeling mediators implicated in asthma. Objectives: To evaluate the changes in MMP-9 and its principal inhibitor (TIMP-1) in sputum and plasma of mild allergic asthmatic subjects after whole-lung allergen challenge. Methods: Induced sputum and blood samples were obtained at baseline, and 6 and 24 h after challenge. MMP-9 and TIMP-1 levels in sputum and plasma were measured by ELISA. Results: Allergen challenge increased the percentage of sputum eosinophils and MMP-9 levels 6 and 24 h after the challenge compared to baseline levels, but TIMP-1 levels did not vary significantly. A significant correlation was observed between MMP-9 levels at 6 h and the maximum percent fall in FEV1 during the late response. Throughout the study, MMP-9 levels correlated significantly with the number of neutrophils in sputum. Conclusions: This study shows that analysis of induced sputum is a useful tool to study the variations in MMP-9 and TIMP-1 levels following allergen challenge, therefore allowing to evaluate their role in allergen-induced airway damage and repair.

Lower airway inflammatory responses to repeated very‐low‐dose allergen challenge in allergic rhinitis and asthma

Background Low‐dose allergen challenge (LDAC) may be a useful tool for studying the capacity of allergens to induce airway inflammation in atopic subjects.

Asthma and rhinitis: what is the relationship?

Purpose of reviewAsthma and rhinitis are commonly associated and they influence their respective control. New observations have contributed to better understand how to assess those conditions and how they influence each other. Recent findingsRecent studies found that not only the intensity, but also the duration of rhinitis could be correlated with the development of asthma and possibly its remission. The measure of exhaled nitric oxide (FeNO) has been used to show the presence of lower airway inflammation in rhinitic patients, with or without asthma. Furthermore, it has been shown that allergic rhinitis could affect asthma control in children as in adults, and consequently suggested that allergic rhinitis and asthma should be concomitantly approached in regard to their diagnosis and treatment. Additional observations showed improvements in various asthma outcomes with the treatment of rhinitis. SummaryThese new data confirm the strong link between asthma and rhinitis, the importance of their interactions, and the need to identify and treat rhinitis adequately in asthmatic patients.

Discordance between asthma control clinical, physiological and inflammatory parameters in mild asthma☆

BACKGROUND Discrepancies have been observed between clinical, physiological, and inflammatory asthma control criteria, mostly in asthmatic subjects using regular inhaled corticosteroids (ICS) treatment. This study compared the prevalence of discrepancies between these 3 control parameters in mild asthmatic subjects not taking ICS. METHODS A retrospective analysis of demographic data and results from the Asthma Control Scoring System tool was performed in mild patients with asthma not taking ICS. The % score obtained for the clinical (symptoms), physiological (FEV1), and inflammatory (sputum eosinophil percentage) criteria were compared. Discrepancy was defined as a >20% difference between any 2 scores. FINDINGS Data from 213 subjects with mild asthma were analysed. Discrepancies between clinical and inflammatory scores were observed in 32% of subjects, whereas 31% showed discrepancies between physiological and inflammatory scores, and 20% between clinical and physiological scores. Sub-analysis of the discrepancy groups showed that respectively 88% and 89% of subjects had a higher clinical or physiological score than inflammatory score. Twenty-seven percent of subjects had residual airway inflammation despite adequate clinical control and optimal pulmonary function. INTERPRETATION There are significant discrepancies between scores of subjective and objective asthma control criteria. Airway inflammation often persists in subjects with good clinical or physiological asthma control scores. The consequences of this persisting airway inflammation in mild patients remain to be further studied.

The Allergic Rhinitis - Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies

BackgroundThe Nasal Allergen Challenge (NAC) model allows the study of Allergic Rhinitis (AR) pathophysiology and the proof of concept of novel therapies. The Allergic Rhinitis – Clinical Investigator Collaborative (AR-CIC) aims to optimize the protocol, ensuring reliability and repeatability of symptoms to better evaluate the therapies under investigation.Methods20 AR participants were challenged, with 4-fold increments of their respective allergens every 15 minutes, to determine the qualifying allergen concentration (QAC) at which the Total Nasal Symptom Score (TNSS) of ≥10/12 OR a Peak Nasal Inspiratory Flow (PNIF) reduction of ≥50% from baseline was achieved. At the NAC visit, the QAC was used in a single challenge and TNSS and PNIF were recorded at baseline, 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours. 10 additional ragweed allergic participants were qualified at TNSS of ≥8/12 AND ≥50% PNIF reduction; the Cumulative Allergen Challenge (CAC) of all incremental doses was used during the NAC visit. 4 non-allergic participants were challenged with the highest allergen concentration.ResultsIn the QAC study, a group qualified by only meeting PNIF criteria achieved lower TNSS than those achieving either TNSS criteria or PNIIF+TNSS (p<0.01). During the NAC visit, participants in both studies reached their peak symptoms at 15minutes followed by a gradual decline, significantly different from non-allergic participants. The “PNIF only” group experienced significantly lower TNSS than the other groups during NAC visit. QAC and CAC participants did not reach the same peak TNSS during NAC that was achieved at screening. QAC participants qualifying based on TNSS or TNSS+PNIF managed to maintain PNIF scores.ConclusionsParticipants experienced reliable symptoms of AR in both studies, using both TNSS and PNIF reduction as part of the qualifying criteria proved better for qualifying participants at screening. Phenotyping based on pattern of symptoms experienced is possible and allows the study of AR pathophysiology and can be applied in evaluation of efficacy of a novel medication. The AR-CIC aims to continue to improve the model and employ it in phase 2 and 3 clinical trials.

Influence of Natural Exposure to Pollens and Domestic Animals on Airway Responsiveness and Inflammation in Sensitized Non-Asthmatic Subjects

Background: Atopy may be a risk factor in the development of asthma. Indoor allergens are considered to be more potent asthma inducers than outdoor ones such as pollens. Lower airway inflammation may be present in non-asthmatic subjects during natural exposure to relevant allergens and may eventually lead to the development of asthma. Aims: To document seasonal variation in lower airway responsiveness and inflammation in sensitized non-asthmatic subjects, during natural exposure to allergens, and to determine whether it is more marked in those exposed to animals to which they are sensitized. Methods: Twenty-two atopic subjects were seen during and out of the pollen season. All (but the controls) were sensitized to domestic animals, and to trees, grasses or ragweed. Eleven were not exposed to animals at home and 8 were exposed. They were compared with 3 normal controls. A respiratory questionnaire was administered, allergy skin prick tests, spirometry, methacholine challenge, blood and induced sputum with differential cell counts were obtained during the pollen season for all subjects. These tests were repeated out of the pollen season. Results: Throughout the study, none of the subjects had asthma symptoms. Mean PC20 was significantly lower in subjects exposed to animals compared with unexposed subjects or controls, both during and out of the pollen season. In season, subjects exposed to animals had significantly higher sputum eosinophil numbers than unexposed or normal control subjects. Conclusions: Non-asthmatic atopic subjects show variable degrees of airway responsiveness and inflammation. However, subjects exposed to animals show higher airway eosinophilia, which may suggest they are at increased risk of developing airway hyperresponsiveness and asthma.

Allergen‐induced early and late asthmatic responses to inhaled seasonal and perennial allergens

The allergen bronchoprovocation (ABP) test is a validated model to study asthma pathophysiology and response to treatments. The inhibitory effect of agents on the allergen‐induced late asthmatic response (LAR) is a predictor of their efficacy in asthma treatment. However, it is difficult to predict the magnitude of a LAR, which may vary according to immune responsiveness and the type of allergen used for ABP.

Comparative clinical and airway inflammatory features of asthmatics with or without polyps.

BACKGROUND Nasal polyposis (NP) is associated with a more severe and steroid-resistant asthma. OBJECTIVE To compare clinical and airway inflammatory features of asthmatics with or without NP. METHODS Two groups of asthmatic patients were studied: group 1; n=39, with NP; group 2; n=40, without NP. Asthma control was assessed according to the Asthma Control Scoring System (ACSS). Expiratory flows, induced sputum, and blood eosinophils were also measured. RESULTS ACSS score was lower (poorer control) in group 1 (meanA+-SEM = 73A+-3%) compared with group 2 (82A+-2%, p=0.01). FEV1 (mean of predicted value A+- SEM) was 81A+-3 for group 1 and 96A+-3 for group 2 (p=0.001), and the FEV1/FVC ratio was lower in group 1 (70A+-2%) compared with group 2 (76A+-1%, p=0.01). Blood and induced sputum eosinophils, as well as fibronectin and eosinophil cationic protein levels, were higher in group 1. CONCLUSION Asthmatic subjects with NP have increased airway obstruction, increased inflammatory cells and reduced asthma control compared to those without NP. This may suggest a contribution of nasal polyps to the severity of asthma or a common susceptibility to develop upper and lower airways mucosal inflammation.