Adherence to inhaled corticosteroids and long-acting ß2-agonists in asthma: A MASK-air study.

INTRODUCTION: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting ß2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA. MATERIALS AND METHODS: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day. RESULTS: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001). CONCLUSIONS: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.

Identification by cluster analysis of patients with asthma and nasal symptoms using the MASK-air® mHealth app.

BACKGROUND: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app. METHODS: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels. FINDINGS: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians. INTERPRETATION: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma.

Sputum cytology during late-phase responses to inhalation challenge with different allergens.

BACKGROUND: In mouse models of allergic asthma, exposure to different allergens can trigger distinct inflammatory subtypes in the airways. We investigated whether this observation extends to humans. METHODS: We compared the frequency of sputum inflammatory subtypes between mild allergic asthma subjects (n = 129) exposed to different allergens in inhalation challenge tests. These tests were performed using a standardized protocol as part of clinical trials of experimental treatments for asthma, prior to drug randomization. Five allergen types were represented: the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae, ragweed, grass, and cat. RESULTS: Of 118 individuals with a sputum sample collected before allergen challenge (baseline), 45 (38%) had paucigranulocytic, 51 (43%) eosinophilic, 11 (9%) neutrophilic, and 11 (9%) mixed granulocytic sputum. Of note, most individuals with baseline paucigranulocytic sputum developed eosinophilic (48%) or mixed granulocytic (43%) sputum 7 hours after allergen challenge, highlighting the dynamic nature of sputum inflammatory subtype in asthma. Overall, there was no difference in the frequency of sputum inflammatory subtypes following challenge with different allergen types. Similar results were observed at 24 hours after allergen challenge. CONCLUSIONS: Unlike reported in mice, in humans the sputum inflammatory subtype observed after an allergen-induced asthma exacerbation is unlikely to be influenced by the type of allergen used.

A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma.

BACKGROUND: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses. METHODS: Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR. RESULTS: Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1 and area under the %FEV1 /time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast. CONCLUSIONS: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.

[Development and validation of patient's knowledge measurement tools: The model of the Questionnaire de Connaissances sur l'Asthme destiné aux Patients Adultes (QCA-PA)]. / Développement et validation d'outils de mesure des connaissances du patient : le modèle du Questionnaire de connaissances sur l'asthme destiné aux patients adultes (QCA-PA).

INTRODUCTION: Poor asthma knowledge among asthmatic patients contributes to poor control of the disease. Education is a priority, but it needs a good assessment of the patient's knowledge. AIM: To give a patient's knowledge questionnaire development method following the example of the Questionnaire de Connaissances sur l'Asthme destiné aux Patients Adultes (QCA-PA). METHODS: The QCA-PA was developed according to Dussault, Valois and Frenette's seven steps and includes 54 "true/false/don't know" items. A total of 101 asthmatic adults completed the questionnaire four times during three visits over a period of about one month. On the second visit, it was answered twice, before and after an individualized education session on asthma. RESULTS: The QCA-PA demonstrates different proofs of validity: content, response process, internal structure, relationship to other variables, and consequences of testing. Confirmatory factorial analysis showed a unidimensional structure. CONCLUSIONS: QCA-PA is a new rigorously validated knowledge measurement tool based on the most recent international recommendations. It could help health professionals to better target their educational interventions towards asthma patients.

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.

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

BACKGROUND: 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. AIM: To determine the relationship between the magnitudes of early asthmatic response (EAR) and LAR in mild asthmatic subjects according to the type of allergen inhaled and its determinants. METHODS: This is a retrospective analysis of a large database of ABPs, all performed with a common standardized methodology. Patients were either challenged with house dust mites (HDMs), animals or pollens allergens. EAR was defined as a ≥ 20% fall in forced expiratory volume in 1 s (FEV1 ) < 3 h following ABP and LAR as a ≥ 15% fall in FEV1 between 3 and 7 h post-ABP. The ratio of EAR % fall in FEV1 /LAR % fall in FEV1 was compared between the groups of subjects according to the allergen used for ABP. RESULTS: Data from 290 subjects were analysed: 87 had an isolated EAR and 203 had a dual response (EAR + LAR). Dual responders had a significantly lower baseline PC20 , a more marked fall in FEV1 at EAR, and a trend towards higher baseline sputum eosinophil percentages. The ratio of EAR over LAR was significantly lower in HDM compared with pollen ABP, indicating a larger LAR for a similar EAR. No correlations were observed between the ratio of EAR over LAR and the various parameters recorded in the different groups analysed. CONCLUSION: Different mechanisms may be involved in modulating the magnitude of the LAR, according to the type of allergen. HDM seems to induce a stronger LAR than pollens, animal allergens being intermediary in this regard.

Obesity and atopy.

The prevalence of obesity has increased worldwide, and weight gain has been shown to influence the development and clinical expression of various conditions including asthma. The relationships between atopy and obesity remain uncertain, both in adults and in children. Although there are physiopathologic mechanisms which could explain how obesity could influence the immune system and promote the process of sensitization, evidences in favour of a possible role of obesity on the development of atopy have been inconsistent. Furthermore, the bulk of evidence suggests that atopy does not mediate the relationship between obesity and asthma, although in some populations, particularly in children and women, such association has been reported. Such lack of relationship has also been found with rhinoconjunctivitis although it has been observed for atopic dermatitis. Several factors may explain these variable results, including populational or environmental characteristics, socioeconomic status, confounding factors, in addition to sample size, and methodology of the performed studies. The possibility that obesity influences atopy through its effects on sex hormones is suggested by a more frequent link between atopy and obesity in women, particularly postpuberal. Further research should be conducted on the influence of weight gain on atopy and atopic diseases.

[Bronchial thermoplasty in the treatment of severe adult asthma]. / La thermoplastie bronchique dans le traitement de l'asthme sévère de l'adulte.

Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma.

[Asthma in the elderly]. / L'asthme de la personne âgée.

Asthma is a common condition in the elderly although often confounded with chronic obstructive pulmonary disease (COPD) in this population. Asthma in the elderly seems to represent a specific phenotype characterized by more severe, but often less perceived, airway obstruction, a neutrophilic or mixed-type of airway inflammation and frequent comorbidities. Patients aged 65 years and over have an increased asthma-related morbidity and mortality compared to younger patients, probably due to difficulties in regard to diagnosis, assessment of the disease severity and treatment. Research is urgently needed to determine the optimal treatment of the aged patient. In this document we will review the state of knowledge on this topic and discuss the challenges of multidisciplinary asthma management in the elderly.

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.

OX40L blockade and allergen-induced airway responses in subjects with mild asthma.

BACKGROUND: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.

Asthma and obesity.

The prevalence and incidence of asthma have increased among obese children and adults, particularly among women. Obesity seems to be a predisposing factor for the development of asthma, but the underlying mechanisms of its influence are still uncertain. Various hypotheses have been proposed to explain the link between obesity and asthma such as a common genetic predisposition, developmental changes, altered lung mechanics, the presence of a systemic inflammatory process, and an increased prevalence of associated comorbid conditions. Over-diagnosis of asthma does not seem to be more frequent in obese compared to non-obese subjects, but the added effects of obesity on respiratory symptoms can affect asthma control assessment. Obesity can make asthma more difficult to control and is associated with a reduced beneficial effect of asthma medications. This could be due to a change in asthma phenotype, particularly evidenced as a less eosinophilic type of airway inflammation combined to the added effects of changes in lung mechanics. Weight loss is associated with a universal improvement of asthma and should be part of asthma management in the obese patient. Additional research should be conducted to better determine how obesity influences the development and clinical expression of asthma, establish the optimal management of asthma in this population and determine how obesity affects long-term asthma outcomes in these patients.

Monitoring sputum eosinophils in mucosal inflammation and remodelling: a pilot study.

Normalisation of eosinophil counts in sputum of asthmatic patients reduces eosinophilic exacerbations. However, the effect of this strategy on airway remodelling remains to be determined. We compared bronchial inflammation and collagen deposition after 2 yrs of treatment guided by either sputum eosinophils (sputum strategy, SS) or by clinical criteria (clinical strategy, CS). As a pilot study, 20 mild asthmatic patients were randomly assigned to CS or SS strategies. Bronchial biopsies were obtained when minimum treatment needed to maintain control was identified and this was continued for 2 yrs. Biopsies were immunostained for inflammatory cells, mucin 5A (MUC5A) and collagen. The mean dose of inhaled corticosteroids at the start and end of the study was similar in both SS and CS groups. Forced expiratory volume in 1 s increased in both groups at the study end. In SS, mucosal lymphocyte and eosinophil counts, but not neutrophils, were reduced at the end of the study. In CS, only activated eosinophil and neutrophil counts decreased. MUC5A staining decreased in SS but not CS. No change in collagen deposition underneath the basement membrane was observed in either strategy. Treatment strategies that normalise sputum eosinophils also reduce mucosal inflammatory cells and MUC5A expression, but do not change subepithelial collagen deposition in mild to moderate asthma.

Influence of comorbid conditions on asthma.

Various conditions such as rhinosinusitis, gastro-oesophageal reflux disease, psychological disturbances, chronic infections and obstructive sleep apnoea are often observed in asthmatic patients and may affect asthma control and outcomes. These comorbidities may change the asthma phenotype, be part of the same pathophysiological process, act as confounding factors in the diagnosis or assessment of control of asthma, and/or result from specific environmental exposures. The influences of these conditions on asthma are variable and for many of them still uncertain; nevertheless, they may alter asthma responses to current therapy. A systematic evaluation and an appropriate treatment of asthma-associated comorbid conditions should be part of asthma management, particularly for severe disease. With regard to clinical research, associated conditions may influence the results of trials and should be taken into account in the subjects' inclusion criteria and analysis of data.

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.

Asthma, airway inflammation and epithelial damage in swimmers and cold-air athletes.

Endurance athletes show an increased prevalence of airway hyperresponsiveness. The aim of the present study was to evaluate the long-term effects of training on airway responsiveness, inflammation and epithelial damage in swimmers and cold-air athletes. In total, 64 elite athletes (32 swimmers and 32 cold-air athletes), 32 mild asthmatic subjects and 32 healthy controls underwent allergy skin prick testing, methacholine challenge and induced sputum analysis. Overall, 69% of swimmers and 28% of cold-air athletes had airway hyperresponsiveness. Sputum neutrophil count correlated with the number of training hours per week in both swimmers and cold-air athletes. Eosinophil counts were higher in swimmers than in healthy subjects, although they were lower than in asthmatic subjects, and correlated with airway hyperresponsiveness in swimmers only. The eosinophil count in cold-air athletes was similar to that in healthy subjects. Bronchial epithelial cell count was not correlated with airway hyperresponsiveness but was significantly increased in swimmers, compared with healthy and asthmatic controls. In conclusion, the present authors observed significant airway inflammation only in competitive athletes with airway hyperresponsiveness. However, the majority of elite athletes showed evidence of bronchial epithelial damage that could possibly contribute to the development of airway hyperresponsiveness.

Improving knowledge transfer on chronic respiratory diseases: a Canadian perspective. How to translate recent advances in respiratory diseases into day-to-day care.

BACKGROUND: Chronic diseases represent an increasing burden for health care systems. Ongoing research efforts provide regularly new scientific evidence on how optimize current medical care. In regard to respiratory diseases, as for other health problems, optimal management of these conditions has been summarized in recent consensus guidelines but implementation of these recommendations is still poor. Not only are the key messages of such guidelines often unknown to the practitioner and the patient but even when it is, they are often insufficiently integrated into current care, often related to behavioral, organizational and communication barriers. METHODS: Literature review on the topic of Clinical Practice Guidelines implementation and reference to recent projects aimed at improving management of asthma in the province of Quebec and elsewhere, as models for such implementation process. RESULTS: The basic principles of an effective translation of current knowledge into day-to-day care are known, but healthcare delivery structures, practice tools and resources, and regional/local leadership should be available to make it happen. Ideally, implementation requires a multidisciplinary effort of care providers, specialists, general practitioners, allied health professionals, patients and their family. The general public, health administrators and policy makers should also be aware of the consequences of poor management of these diseases and be supportive of the proposed initiatives. Finally, these last should be adequately evaluated to ensure their effectiveness and determine if they should be improved. Recently projects performed in Quebec have proposed disease management models to identify asthma care gaps and improve translation of current Guidelines into day-to-day care. CONCLUSIONS: Although the human and socio-economical burden of chronic diseases is still increasing, their current management is still often deficient. In the recent decades, Practice Guidelines have been developed to guide Practitioners towards optimal care, but implementation of these Guides is still poor. Recent Canadian and International initiatives have proposed valid models to help address current care gaps.