ReviewPreschool wheeze, genes and treatment
Section snippets
Preschool wheeze
Wheeze may be described as an expiratory sound produced by airway narrowing of intraluminal, intrinsic or extrinsic aetiology. For example, wheeze may occur due to the infective secretions of pneumonia or bronchiectasis, the interstitial oedema of congestive cardiac failure, or from the external pressure of a vascular malformation or thoracic lymphadenopathy, as well as from intrinsic bronchoconstriction. The term preschool wheeze (PSW) is specific to bronchoconstrictive wheeze occurring in
Epidemiological classification
Longitudinal study of birth cohorts identifies wheeze patterns based on symptom evolution. The Tucson Children’s Respiratory Study (TCRS) described four distinct preschool wheezing classes termed ‘never wheezers’, ‘transient early wheezers’, ‘late onset (Non-atopic) wheezers’ and ‘persistent wheezers’ (asthmatic/atopic type) [6], [7] defined according to wheeze onset and persistence. These groups were re-evaluated in the subsequent ALSPAC [8] and Southampton [9] cohorts with consequent
Atopic status
Wheezing diseases are associated with atopy, with features such as eczema, hay fever and serum eosinophilia forming part of the asthma predictive index (API) which predicts asthma persistence into later childhood [6]. Hypothesising that atopic sensitisation represents a group of latent endotypes with differing clinical significance, Lazic et al. used a machine learning approach to generate a five class model of atopic sensitisation based on serial skin prick tests and specific IgE assays to
Beta2 agonists
Inhalation of short-acting beta2 agonist (SABA) is key to acute treatment of childhood wheezing disorders. Effect onset is within 15 min and duration of action can be up to 6 h. Beta2 adrenoceptor (ADRB2) stimulation causes smooth muscle relaxation, with potential adverse effects including hypokalaemia, tachycardia, tremor, myocardial dysfunction, arrhythmia and lactic acidosis. Despite widespread use a 2009 Cochrane review found no clear evidence of benefit in the under 2s [44].
Anticholinergics
Inhaled anticholinergics are widely used in acute preschool wheeze, acting to block muscarinic acetylcholine receptors and reduce smooth muscle contraction and mucus hypersecretion. Onset and duration of action are comparable to SABA, and mechanistic synergy lends itself to combination preparations although these are not commonly used in the UK; in the emergency room so-called ‘burst therapy’ includes frequent co-nebulization of salbutamol, ipratropium bromide and occasionally magnesium [66].
Corticosteroids
Corticosteroids are controversial in the treatment of acute preschool wheeze. They suppress airway inflammation by altering the balance of expression of anti- and pro-inflammatory genes, inhibiting inflammatory cells and upregulating ADRB2 expression and function. Oral or inhaled corticosteroids passively enter the cell and bind cytoplasmic glucocorticoid receptors to form an activated complex which translocates into the nucleus, dimerizes and then binds to glucocorticoid response elements
Leukotriene modifiers
Leukotriene (Cysteinyl leukotriene, cys-LT) modifiers are divided into those that act as competitive antagonists at the cys-LTR1 receptor binding site (montelukast, pranlukast, zafirlukast) and those that disrupt leukotriene synthesis by inhibiting function of 5-lipoxygenase (zileuton). Montelukast is the only one licensed in the preschool age group and acts on bronchial epithelium and airway smooth muscle to reduce the bronchoconstrictive effect of endogenous LTC4, LTD4 and to a lesser extent
Preschool wheeze treatment recommendations
Kaiser et al. conducted a wide-ranging review [72] of preschool wheeze treatment options, but did not include studies comparing montelukast with placebo, focusing instead on intermittent/ continuous ICS as active comparator. In addition, the review was limited to studies in which the need for rescue oral corticosteroids was an outcome. They found that the existing evidence favours intermittent and regular ICS over montelukast or placebo in this age group, however the findings are limited by the
Leukotriene modifiers
Given its tolerability and safety future work should aim to identify the determinants of montelukast response heterogeneity. The promoter polymorphism effect suggested but not proven by Nwokoro et al. warrants exploration in a study constrained by genotype entry criteria, while trials stratified by exacerbation-related uLTE4 increment may bypass the limitations of the candidate gene approach. A similar approach employing exhaled breath condensate [95] or sputum measurements [96] may give a more
Directions for future research
Stratified clinical trials, prostaglandin D2 blockade and genome wide association studies (GWAS) represent areas for consideration in attempts to better phenotype this common condition.
Educational aims
The reader will be able to:
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Describe preschool wheeze classification.
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Discuss preschool wheeze treatment options and pharmacogenetics.
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Propose a treatment strategy.
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Explore future research directions.
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