Mini-Symposium: Asthma PhenotypesInflammatory Phenotypes in Stable and Acute Childhood Asthma
Introduction
Asthma is a heterogeneous syndrome comprising different phenotypes that manifest with cough, wheeze, shortness of breath, and chest tightness. It is the most common chronic disease in childhood and the prevalence has been increasing in industrialised countries over decades. Although both childhood and adulthood asthma share similar features, there are epidemiological and clinical characteristics suggesting a difference in the nature, disease history and magnitude of airway inflammation1, 2. In children with asthma, the patterns of inflammation and remodelling vary among individuals. We cannot yet differentiate with certainty whether the future course of a child with wheezing will be persistent asthma or transient wheeze3, 4. The reasons for the variability in the clinical course of asthma that leads to persistence and even progression in some children but is intermittent in others remain unknown. The temporal course and causes of chronic airway inflammation and remodelling, as well as the interplay between these key histopathologic changes in asthma, are also poorly clarified5.
Childhood asthma frequently persists to adulthood and the available evidence suggests that the severity of childhood asthma predicts the severity of asthma in adulthood1, 2. Children with severe asthma experience persistent symptoms despite maximal conventional treatment. Fraction of exhaled nitric oxide (FEno) and sputum eosinophils can be used as markers of airway inflammation to guide treatment with corticosteroids, but very few data are available on their utility in children6. Currently there is no standard definition for what constitutes disease persistence as opposed to disease progression in asthma or criteria on how and when progression should be measured or evaluated. Despite the availability of evidence based guidelines for the management of paediatric asthma, a significant gap remains between accepted best practices for paediatric asthma care and actual care delivered to asthmatic patients. Current therapies are targeting both airway inflammation and airway hyperreactivity, which often effectively relieve and prevent symptoms in the majority of patients. However, some patients experience persistent symptoms and a progressive decline in lung function, described as irreversible or refractory asthma. There are many unanswered questions about different inflammatory phenotypes in relation with airway remodelling; the contribution of distinct airway resident cells to development of irreversible asthma; the role of biomarkers in predicting persistent asthma; and effectiveness of current therapies on childhood asthma and disease progression.
Section snippets
Features of childhood asthma
Normally the lower airway is sterile. Nonetheless, defects in the local immune system can lead to infection in the lower airways7, 8. Both clinical and experimental evidence suggest an important role for respiratory infections as triggers of asthma attacks in adults and in children. Viral respiratory infections are considered the most common precipitating factors of acute asthma and have been shown to be associated with more than 80% of asthma exacerbations in children9, 10. Atypical bacteria,
Inflammatory phenotypes in stable childhood asthma
The airway inflammatory patterns in asthma are heterogeneous and current guidelines describe asthma as a disorder where many cells and cellular elements play a role in disease pathogenesis20. Asthma can be defined as eosinophilic or non-eosinophilic based on the presence of eosinophils in sputum. Further studies demonstrated that inflammatory process in asthma is more heterogeneous in terms of response to treatment5. Atopy and eosinophilic bronchitis are important in asthma, and about 50% of
Inflammatory phenotypes in acute childhood asthma
Acute asthma is one of the most common problems confronting the emergency department. The least understood phenotype in human asthma is the severe form of the disease exemplified by acute severe exacerbations requiring hospitalisation. One of the underlying trigger mechanisms is the consistent observation at the time of hospitalisation that most affected children also have respiratory viral infections. This suggests that inflammation arising from host antiviral defence may interact with
Comparison of inflammatory phenotypes between adults and children
A cross-sectional study investigated each of the four different inflammatory phenotypes in adults and children with stable and acute asthma. The different patterns of inflammatory phenotypes are summarised in Figure 1 26.
The distribution of phenotypes was similar between adult stable asthma and children with stable asthma. However, there were differences in the relative frequency of the phenotypes between acute adult asthma and children with acute asthma (Figure 1), as well as between acute
Potential biomarkers on monitoring distal airway inflammation
Endobrochial biopsy and bronchoalveolar lavage (BAL) have been traditionally been used for assessment of airway inflammation. A number of research groups have demonstrated an association between FeNO and airway eosinophils, measured either using BAL or endobronchial biopsy in children with asthma6, 39. However, bronchoscopy is not particularly practical for most children or most centres. Even in specialised centres, bronchoscopic assessment of airway inflammation cannot be performed on multiple
Conclusions and future directions
This review has given an outline of airway inflammatory phenotypes in various forms of asthma in children with a developmental perspective on similarities and differences to adults with asthma. Asthma still remains a challenge because the number of emergency visits and hospitalizations for asthmatic children. There are many factors underlying the exacerbation-prone phenotypes and these have recently been reviewed43. Most of these factors are probably common to children and adults, but there are
References (43)
Follow up students of asthma from childhood to adulthood
Peadiatr Respir Rev
(2002)- et al.
A comparison of the clinical characteristics of children and adults with severe asthma
Chest
(2003) How early do airway inflammation and remodeling occur?
Allergology International
(2008)- et al.
Effect of montelukast on peripheral airway obstruction in children with asthma
Ann Allergy Asthma Immunol
(2006) - et al.
Asthma in remission: can relapse in early adulthood be predicted at 18 years of age?
Chest
(2005) Follow-up studies of asthma from childhood to adulthood
Paediatr Respir Rev
(2002)- et al.
Comparison of induced sputum inflammatory profile between childhood and adult-onset asthma
Respiratory Medicine
(2006) - et al.
Asthma exacerbation and sputum eosinophil counts: a randomised controlled trial
Lancet
(2002) - et al.
Clinical assessment of asthma progression in children and adults
J Allergy Clin Immunol
(2008) - et al.
Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation
J Allergy Clin Immunol
(2004)
Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study
Lancet
A clinical index to define risk of asthma in young children with recurrent wheezing
Am J Respir Crit Care Med
Development of wheezing disorders and asthma in pre-school children
Peadiatrics
Airway eosinophilia in children with severe asthma
Am J Respir Crit Care Med
Infection in the pathogenesis and course of chronic obstructive pulmonary disease
N Engl J Med
Virulence factors in the colonization and persistence of bacteria in the airways
Am J Respir Crit Care Med
Viruses and bacteria in acute asthma exacerbations-a GA2LEN-DARE systematic review
Allergy
Pathogenic bacteria and viruses in induced sputum of pharyngeal secretions of adults with stable asthma
Thorax
The importance and features of the distal airways in children and adults
J Allergy Clin Immunol
Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function
Am J Respir Crit Care Med
Is forced expiratory volume in one second the best measure of severity in childhood asthma?
Am J Respir Crit Care Med
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Chronic obstructive pulmonary diseases in children
2015, Jornal de PediatriaCitation Excerpt :In the management of patients with asthma, the following are essential: (i) management supported by evidence-based medicine; (ii) to perform the diagnosis and, if possible, the phenotype (e.g., allergic and non-allergic); (iii) to exclude and treat comorbidities; (iv) to assess and recommend the adequate use of prescribed drugs; (v) to assess, advise, and encourage treatment adherence; (vi) to assess and advise about environmental prophylaxis; (vii) to assess and advise on the triggering factors; (viii) to educate patient's caregivers about asthma and the factors influencing it; (ix) to give instructions on the adequate use of devices for administration of metered-dose and dry powder inhalers; (x) instructions for patients to be able to recognize when asthma control is deteriorating and what medications to use, when it occurs; (xi) to identify non-controlled patients and causes of lack of control; (xii) to advise that inhaled medications should be used with spacers; (xiii) to advise on the hygiene of spacers, which must be washed and left to soak in water with detergent; (xiv) LABA must not be used in children younger than 4 years; (xv) SABA are the agents of choice in PE; (xvi) IC alone or associated with bronchodilators are the basis of asthma treatment; (xvii) children younger than 6 years can use inhaled medication with spacer and those older than 6 years can use dry powder inhalers; (xviii) to assess pulmonary function regularly; (xix) to advise on the need for long-term medical care; (xx) omalizumab should be prescribed in reference centers for the management of patients with difficult-to-control asthma. There are several phenotypes and risk factors (RF) for RWI, creating difficulties for asthma diagnosis and resulting in an excessive assessment for comorbidities.32–37 The main RF include: presence of familial and/or personal allergy, early sensitization, severe RSV infection, maternal smoking during pregnancy, and unfavorable airway geometry.
New and future strategies to improve asthma control in children
2015, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Four of the 5 CAMP clusters were moderately to highly atopic.85 Most pediatric patients with atopic asthma, especially those with severe asthma, are characterized by a younger presentation, less-controlled disease with increased symptoms and exacerbations, increased atopy, and increased airway hyperresponsiveness and reversibility compared with other phenotypes.20,86-90 Immunologically, most pediatric patients with atopic asthma, including those with severe asthma, have an eosinophilic or TH2 profile.
Diagnosis of Asthma in Infants and Children
2014, Middleton's Allergy: Principles and Practice: Eighth EditionSevere Asthma in Children
2014, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :Although this research is incomplete, particularly in children with severe asthma, 3 phenotypes of airway inflammation have been described: (1) eosinophilic inflammation,48,49 (2) paucigranulocytic inflammation,48,49 and (3) neutrophilic inflammation.44,48,49 Children with an eosinophilic phenotype are typically identified in the preschool or early school-age years50 and are characterized by increased symptoms, less-controlled disease, more atopy, impaired lung function, increased airway hyperresponsiveness, and increased frequency of exacerbations compared with the other phenotypes.49,51 While the eosinophilic phenotype is thought to be more corticosteroid responsive,52 the contribution of eosinophilia in children is unclear.
Difficult Childhood Asthma. Management and Future
2012, Clinics in Chest MedicineCitation Excerpt :However, these features may be associated with altered lung growth or specific airway remodeling, and possibly future asthma severity. Inflammatory phenotypes also exist and are discussed in the pathophysiology section.12,31,33,78,113,114,128 Cytology may be not sufficient, but the analysis of the nature of inflammation may improve the classification of severe asthma and the development of targeted treatments.
Residential hazards, high asthma prevalence and multimorbidity among children in Saginaw, Michigan
2012, Science of the Total EnvironmentCitation Excerpt :In practice, the housing environment is populated by risk factors in several dimensions that can result in a continuum of adverse human health effects (Dixon et al., 2009; Gibson, 2011; Nriagu et al., 2011). Asthma itself is a heterogeneous syndrome comprising of different disease phenotypes characterized by variable and recurring airflow obstruction, bronchial hyper-responsiveness, and underlying inflammation that manifest with cough, wheeze, shortness of breath, and chest tightness (Castro-Rodriguez et al., 2000; He et al., 2011). Because of their multi-factorial nature, the intersection of housing and asthma should be marked by disease comorbidity (refers to one or more other diseases among people with an index-disease) or disease clustering (meaning co-occurrence of diseases at a significantly higher rate than is expected) conditions.