Troublesome Asthma Research Articles

Role of IL-5 in asthma and airway remodelling.

Asthma is a common and burdensome chronic inflammatory airway disease that affects both children and adults. One of the main concerns with asthma is the manifestation of irreversible tissue remodelling of the airways due to the chronic inflammatory environment that eventually disrupts the whole structure of the airways. Most people with troublesome asthma are treated with inhaled corticosteroids. However, the development of steroid resistance is a commonly encountered issue, necessitating other treatment options for these patients. Biological therapies are a promising therapeutic approach for people with steroid-resistant asthma. Interleukin 5 is recently gaining a lot of attention as a biological target relevant to the tissue remodelling process. Since IL-5-neutralizing monoclonal antibodies (mepolizumab, reslizumab and benralizumab) are currently available for clinical use, this review aims to revisit the role of IL-5 in asthma pathogenesis at large and airway remodelling in particular, in addition to exploring its role as a target for biological treatments.

Non-randomised feasibility study testing a primary care intervention to promote engagement in an online health community for adults with troublesome asthma: protocol

IntroductionIn the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can...

Allergic sensitization to lipocalins reflects asthma morbidity in dog dander sensitized children.

BackgroundSensitization to dog is an important risk factor for asthma in children, but the clinical relevance of IgE to available dog‐ and furry animal allergen molecules is uncertain.MethodsSpirometry, methacholine challenge, fraction of exhaled nitric oxide, nasal challenge with dog extract and questionnaires were performed in 59 dog‐sensitized children (age 10–18 years). Serum IgE to dog‐, cat‐, horse extracts and the allergen molecules Can f 1–6, Fel d 1, Fel d 2, Fel d 4 and Equ c 1 were evaluated.ResultsMedian numbers of positive IgE results to furry animal allergen molecules among children without asthma was 3, with asthma 5.5 and with troublesome asthma 9 (asthma vs. no asthma; p = 0.039; troublesome asthma vs. no asthma; p = 0.009). The odds ratio for asthma if sensitized to any lipocalin was 7.2 (95% confidence Interval: 1.44–35.9). Children with troublesome asthma had higher IgE levels to the lipocalins Can f 2, Can f 4 and Can f 6 compared to the rest of the study population (44 vs. 4.1 kUA/L, p = 0.015; 5.8 vs. 0.9 kUA/L, p = 0.018 and 1.3 vs. 0.7 kUA/L, p = 0.03 respectively). Furthermore, a positive nasal challenge was more common among children with troublesome asthma (83% vs. 36%, p = 0.036).ConclusionsPolysensitization to furry animal allergens and lipocalins is associated with asthma in dog‐sensitized children. Children with troublesome asthma have higher IgE levels to several dog lipocalins than other dog sensitized children.Key messagePolysensitization to furry animal allergens and high IgE levels to the dog lipocalins Can f 2, Can f 4 and Can f 6 is associated with asthma severity in dog dander sensitized children. Molecular allergy diagnostics may thus help the clinicians to evaluate the impact of allergic sensitization on asthma morbidity.

Tiotropium bromide as adjunct therapy in children with asthma: a clinical experience

BackgroundThe Global Initiative for Asthma has only recently added tiotropium bromide as adjunct controller therapy in severe asthma (Step 4 or 5) in adults (2015) and children (2019). Although not yet approved for pediatric use by Health Canada, it has been occasionally offered by asthma specialists as a therapeutic trial in children with troublesome asthma or treatment for adverse effects. The objective of this study was to describe the indications and real-life clinical experience in initiating tiotropium in children with asthma.MethodsWe designed a retrospective mixed-method case series study of children aged 1–17 years who initiated tiotropium in our tertiary-care centre between 2013 and 2020. Clinical information was extracted from electronic medical records and tiotropium dispensing, from drug claims. Parents/children and physicians independently completed a questionnaire about treatment goals, perceived efficacy, safety, satisfaction, and lessons learned.ResultsThe 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4–17.8) years. Children were primarily on Step 4 (85%) or 5 (6%) prior to tiotropium initiation, yet most (84%) did not increase their treatment step after tiotropium initiation. The physicians’ treatment goals were to improve asthma control, alleviate adverse effects of current therapy, and/or improve lung function. The most improved symptoms were coughing/moist cough, difficulty breathing, whistling breath, and bronchial secretions/mucus. Although most parents and physicians reported a significant benefit with tiotropium bromide, physicians particularly remarked, as their “lesson learned’, on the improvement in chronic symptoms in asthmatic children, particularly those with prominent moist cough and in lung function, in those with seemingly none (or incompletely) reversible obstruction as well as the ability to decrease the ICS and/or LABA dose to lessen adverse effects. A few physicians raised caution on the risk of lower adherence with an additional inhaler.ConclusionIn children with severe asthma on Step 4 or 5, tiotropium bromide was primarily used as substitute, rather than additional, adjunct therapy to improve asthma control, alleviate adverse effects, and/or to improve lung function. The latter two indications, combined with its perceived effectiveness in children with prominent moist cough, also suggest additional indications of tiotropium to be formally explored.

Cytokine Responses to Rhinovirus and Development of Asthma, Allergic Sensitization, and Respiratory Infections during Childhood.

Immunophenotypes of antiviral responses, and their relationship with asthma, allergy, and lower respiratory tract infections, are poorly understood. We characterized multiple cytokine responses of peripheral blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. In a population-based birth cohort, we measured 28 cytokines after stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes, using longitudinal models. We also ascertained phytohemagglutinin-induced T-helper cell type 2 (Th2)-cytokine responses (PHA-Th2). We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related (IFN), proinflammatory (Inflam), Th2-chemokine (Th2-chem), and regulatory (Reg). Clusters differed in their clinical characteristics. Children with an IFNmodInflamhighestTh2-chemhighestReghighest rhinovirus-16-induced pattern had a PHA-Th2low response, and a very low asthma risk (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01-0.81; P = 0.03). Two clusters had a high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTh2-chemlowRegmod cluster exhibited a PHA-Th2lowest response and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (OR, 1.37; 95% CI, 1.07-1.76; P = 0.014) and lower respiratory tract infection hospitalizations (OR, 2.40; 95% CI, 1.26-4.58; P = 0.008) throughout childhood. In contrast, the IFNhighestInflammodTh2-chemmodReghigh cluster with a rhinovirus-16-cytokine pattern was characterized by a PHA-Th2highest response, and a low prevalence of asthma/sensitization in infancy that increased sharply to become the highest among all clusters by adolescence (but with a low risk of asthma exacerbations). Early-onset troublesome asthma with early-life sensitization, later-onset milder allergic asthma, and disease protection are each associated with different patterns of rhinovirus-induced immune responses.

Persistent asthma phenotype related with late-onset, high atopy, and low socioeconomic status in school-aged Korean children

BackgroundTreatment guidelines for asthma have been established based on asthma severity; there are limitations in the identification of underlying pathophysiology and prediction of prognosis in heterogeneous phenotypes of asthma. Although the complex interactions between environmental and genetic factors affect the development and progression of asthma, studies on asthma phenotypes considering environmental factors are limited. This study aimed to identify asthma phenotypes using latent class analysis including environmental factors in school-age children.MethodsWe included 235 children (6–8 years) with parent-reported, physician-diagnosed asthma from the Children’s HEalth and Environmental Research (CHEER) study, which is a 4-year prospective follow-up study with 2-year intervals. At every survey, pulmonary function tests, methacholine challenge tests and blood tests with questionnaire were conducted.ResultsFour asthma phenotypes were identified. Cluster 1 (22% of children) was characterized by high prevalence of atopy and mild symptoms; subjects in cluster 2 (17%) consisted of less atopy and normal lung function, but intermittent troublesome; cluster 3 (29%) experienced late-onset atopic troublesome asthma with decreased lung function in combination with low socioeconomic status; and cluster 4 was associated with early-onset and less-atopic infrequent asthma.ConclusionsLate-onset, high atopy, and low socioeconomic status are associated with troublesome persistent asthma phenotype in school-age children. Environmental factors might be implicated in the clinical heterogeneity of asthma. Asthma phenotypes considering diverse factors might be more helpful in the identification of asthma pathogenesis and its prevention.

The potential to predict the course of childhood asthma

Many children experience pre-school or early childhood wheezing. In a significant proportion symptoms disappear as the child grows, but others have persistent and troublesome asthma which can be life-long. Tools to predict course of disease in young children are a priority for families and clinicians. This review summarizes evidence from several longitudinal population-based birth-cohort studies that have identified risk factors for persistence and remission of childhood asthma. These factors include clinical characteristics, environmental and other exposures, familial factors, biomarkers of allergic inflammation, measurements of lung function and airway responsiveness, and genetic variants. This review also introduces the concept of polygenic risk and genetic risk scores, and describes results from a recent study that suggests promise for the use of genetic information in predicting the course of childhood asthma. We conclude with a discussion of implications and future directions.

The clinical expression of asthma in schoolchildren has changed between 1996 and 2006

Several studies have reported diverging trends in the prevalence of asthma and wheeze. The aim of this study was to investigate the clinical expression of childhood asthma in 1996 and 2006 by studying asthma morbidity, treatment, and environmental exposures in school children with physician-diagnosed asthma and wheeze, respectively. All children enrolled in first or second grade (7-8 yr-old) in three municipalities in northern Sweden were invited to a questionnaire study in 1996 and 2006, respectively. In 1996, 3430 (97%) participated; and in 2006, 2585 (96%) participated. The same parental completed questionnaire, including the ISAAC questions, was used in both surveys. Physician-diagnosed asthma was reported at 5.7% in 1996 and 7.4% in 2006. A significantly greater proportion of children with asthma were using inhaled corticosteroids (ICS) in 2006, 67% vs. 55% in 1996. This increase was parallel to a major decrease in severe asthma symptoms such as disturbed sleep because of wheeze (49% vs. 38%) and troublesome asthma (21% vs. 11%). The prevalence of current wheeze among the asthmatics decreased significantly; however, this was seen only among children not using ICS. Parental smoking decreased significantly as did the proportion living in damp buildings. In conclusion, although asthma remains a major public health issue in school age children, children with asthma had less respiratory symptoms and a better asthma control in 2006 compared to 1996. This parallels with an increase in treatment with ICS, more beneficial environmental conditions, and an increased diagnostic intensity resulting in a larger proportion of children with mild symptoms being diagnosed as having asthma.

OMALIZUMAB SYMPOSIUM

Nowadays, in many regions of the world, many patients with asthma are well managed because of the availability of effective therapies, such as inhaled corticosteroids, long-acting β adrenoceptor agonists and short-acting bronchodilators. National and international asthma management guidelines, which were initially developed in the early 1990s, have been revised to take account of research findings and new medications. Despite effective therapies and the wide dissemination of useful guidelines, there is still a small proportion of patients with troublesome asthma. It is probable that this asthma, which is poorly responsive to conventional therapy with corticosteroids and β adrenoceptor agonists, has a different pathophysiological basis to the more typical asthma, which is well controlled with available therapies, such as inhaled corticosteroids. Observational studies have established the relationship between allergy, asthma and raised serum concentrations of IgE. With the development of omalizumab, which is an mAb that binds to IgE, it has been possible to investigate the putative causative role of IgE in asthma and to determine the clinical efficacy of this antibody. The papers in this symposium describe the unmet need in asthma therapy, summarize the findings of the clinical trials, which were the basis of registering omalizumab for the treatment of asthma, and propose clinical criteria for its use in severe asthma.

New insights into occupational asthma

To examine recent publications on the types of agents involved in occupational asthma, the mechanisms by which they induce asthma, and how best to evaluate and treat workers suspected of this respiratory condition. High rates of occupational asthma and inhalation accidents were found in workers in crafts and related occupations in the manufacturing industries, and in plant and machine operatives; cleaners and construction workers may also be at risk. Further data support a role for CD4 T cells in low-molecular-weight agent-induced asthma, such as with isocyanates, and neurogenic mechanisms may also be involved. The use of noninvasive measures of airway inflammation in the diagnosis and management of occupational asthma such as sputum eosinophils monitoring is promising, although this is less obvious for exhaled nitric oxide. Finally, the persistence of troublesome asthma even after withdrawal from relevant exposure has been re-emphasized and surveillance programs have been proposed. Further data have been gathered on the prevalence of occupational asthma in various working populations, its mechanisms of development, the contribution of noninvasive measures of airway inflammation in the diagnosis and management of this condition, and its management and prevention.

Parental education and guided self-management of asthma and wheezing in the pre-school child: a randomised controlled trial

Background: The effects on morbidity were examined of providing an educational intervention and a written guided self-management plan to the parents of pre-school children following a recent attendance at hospital...

Consequences of occupational asthma

Seventy-nine patients attending hospital for follow-up of occupational asthma were interviewed, on average 6 years after asthma developed. Although 90% thought their symptoms had improved, 10% had required a hospital admission (apart from for investigation), 72% still took medication and most reported symptoms in the last 3 months. One-third were currently unemployed and 40-73% reported limitation in everyday activities, such as housework or shopping. Symptoms on waking were used as an index of troublesome asthma. Those 31 in whom this occurred at least once a week reported limitation in everyday activities significantly more commonly than others. This relation was more marked in men than women. Limitation in everyday activities was, however, more frequently reported by women than men, who were also more likely than men to be unemployed, suggesting that factors other than impairment of function also contribute to handicap in occupational asthma.

Home recording of peak expiratory flow rates and perception of asthma.

Fourteen asthmatic children, aged 7.9 to 18.0 years (mean, 11.3 years), recorded peak expiratory flow rates three times a day at home for four weeks in an attempt to improve perception of their airway obstruction. Pulmonary function tests were performed and a subjective severity score was recorded before and after this period. The accuracy of the parents' perceptions of their child's airway obstruction was also assessed. These children were unable to accurately predict their degree of airway obstruction, and no improvement in prediction was seen following the learning period. Parents' perceptions of the child's airway obstruction were also inaccurate. Recording of peak expiratory flow rate at home did not improve the child's perception of his asthma. Rational management of troublesome asthma requires the use of an inexpensive peak flowmeter to provide continual objective measurements of lung function.

Unilateral lung disease detected by radioisotopic scanning in children thought to have asthma

The clinical courses of three children are described. They were initially thought to have troublesome asthma alone or in association with other diseases. The children had radioactive gas lung scans using 13N for studies of ventilation and perfusion which in each case revealed one entirely healthy lung and one disordered lung. The technique of 13N gamma scanning is described and its clinical value in such patients is discussed.

Unilateral lung disease detected by radioisotopic scanning in children thought to have asthma

The clinical courses of three children are described. They were initially thought to have troublesome asthma alone or in association with other diseases. The children had radioactive gas lung scans using 13N for studies of ventilation and perfusion which in each case revealed one entirely healthy lung and one disordered lung. The technique of 13N gamma scanning is described and its clinical value in such patients is discussed.