Elsevier

Paediatric Respiratory Reviews

Volume 28, September 2018, Pages 47-54
Paediatric Respiratory Reviews

Review
Preschool wheeze, genes and treatment

https://doi.org/10.1016/j.prrv.2017.11.003Get rights and content

Abstract

Preschool wheeze is a common but poorly understood cause of respiratory morbidity that is both distinct from and overlaps with infantile bronchiolitis and school age asthma. Attempts at classification by epidemiology, pathophysiology, therapeutic response and clinical phenotype are imperfect and yet fundamental to both treatment choice and research design. The four main therapeutic classes for preschool wheeze, namely beta2 agonists, anticholinergics, corticosteroids and leukotriene modifiers are employed with variable and often scanty evidence base, with evidence for a genetic influence on response variations. The article will discuss the pharmacogenetics of the various options, summarise current treatment recommendations, and explore future research directions.

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:

  • Describe preschool wheeze classification.

  • Discuss preschool wheeze treatment options and pharmacogenetics.

  • Propose a treatment strategy.

  • Explore future research directions.

References (107)

  • M.O. Aksoy et al.

    Glucocorticoid effects on the beta-adrenergic receptor-adenylyl cyclase system of human airway epithelium

    J Allergy Clin Immunol

    (2002)
  • W.D. Carroll et al.

    Parental concerns about inhaled corticosteroid use and the impact on asthma control: comparison of canadian families’ attitudes with global reports in the room to breathe survey

    Chest

    (2010)
  • K.G. Tantisira et al.

    FCER2: A pharmacogenetic basis for severe exacerbations in children with asthma

    J Allergy Clin Immunol

    (2007)
  • E. Valovirta et al.

    Intermittent or daily montelukast versus placebo for episodic asthma in children

    Ann Allergy, Asthma Immunol

    (2011)
  • E. Bucchioni et al.

    Adenosine 5′-monophosphate increases levels of leukotrienes in breath condensate in asthma

    Respir Med

    (2004)
  • M. Fernandez-Nieto et al.

    Changes in sputum eicosanoids and inflammatory markers after inhalation challenges with occupational agents

    Chest

    (2009)
  • W.-L. Song et al.

    Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans

    J Biol Chem

    (2008)
  • S.L. Ralston et al.

    Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis

    Pediatrics

    (2014)
  • Grigg J, Silverman M. Wheezing disorders in young children: one disease or several phenotypes? In: Frey U, Gerritsen J,...
  • G. Davies et al.

    Children admitted with acute wheeze/asthma during November 1998–2005: a national UK audit

    Arch Dis Child

    (2008)
  • C.A. Stevens et al.

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

    Thorax

    (2002)
  • F.D. Martinez et al.

    Asthma and wheezing in the first six years of life

    N Engl J Med

    (1995)
  • S.A. Collins et al.

    Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitization data in the first 6 years of life: evidence from the Southampton Women’s survey

    Pediatr Pulmonol

    (2013)
  • P.L.P. Brand et al.

    Classification and pharmacological treatment of preschool wheezing: changes since 2008

    Eur Respir J

    (2014)
  • A. Simpson et al.

    Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study

    Am J Respir Crit Care Med

    (2010)
  • S. Saglani et al.

    The safety and quality of endobronchial biopsy in children under five years old

    Thorax

    (2003)
  • C.J. Bossley et al.

    Pediatric severe asthma is characterized by eosinophilia and remodeling without T H2 cytokines

    J Allergy Clin Immunol

    (2012)
  • R. O’Reilly et al.

    Increased airway smooth muscle in preschool wheezers who have asthma at school age

    J Allergy Clin Immunol

    (2013)
  • K. Malmström et al.

    Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

    Thorax

    (2011)
  • K. Malmström et al.

    Lung function, airway remodeling, and inflammation in infants: outcome at 8 years

    Ann Allergy, Asthma Immunol

    (2015)
  • A. Jochmann et al.

    Infection and inflammation in induced sputum from preschool children with chronic airways diseases

    Pediatr Pulmonol

    (2016)
  • M.E. Krawiec et al.

    Persistent wheezing in very young children is associated with lower respiratory inflammation

    Am J Respir Crit Care Med

    (2001)
  • I.D. Pavord et al.

    Induced sputum eicosanoid concentrations in asthma

    Am J Respir Crit Care Med

    (1999)
  • K.J. Baines et al.

    Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples

    J Allergy Clin Immunol

    (2011)
  • E.A. Gaillard et al.

    Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial?

    Clin Exp Allergy

    (2015)
  • L. Fleming et al.

    Use of sputum eosinophil counts to guide management in children with severe asthma

    Thorax

    (2012)
  • L. Fleming et al.

    Sputum inflammatory phenotypes are not stable in children with asthma

    Thorax

    (2012)
  • M. Lu et al.

    FeNO and asthma treatment in children: a systematic review and meta-analysis

    Medicine (Baltimore)

    (2015)
  • T. Gomersal et al.

    A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma

    Pediatr Pulmonol

    (2016)
  • S. Sonnappa et al.

    Relationship between past airway pathology and current lung function in preschool wheezers

    Eur Respir J

    (2011)
  • NICE

    Measuring Fractional Exhaled Nitric Oxide Concentration in Asthma : NIOX MINO, NIOX VERO and NObreath

    (2014)
  • A. Oommen et al.

    Urinary leukotriene E4 in preschool children with acute clinical viral wheeze

    Eur Respir J

    (2003)
  • C.F. Robertson et al.

    Short-course montelukast for intermittent asthma in children: a randomized controlled trial

    Am J Respir Crit Care Med

    (2007)
  • C.D. Funk

    Prostaglandins and leukotrienes: advances in eicosanoid biology

    Science

    (2001)
  • A. Marmarinos et al.

    Urinary leukotriene E4 levels in atopic and non-atopic preschool children with recurrent episodic (viral) wheezing: a potential marker

    J Asthma

    (2014)
  • M. Sanak et al.

    Elevated urinary leukotriene E4 excretion in asthma: a comparison of HPLC-mass spectrometry and ELISA

    Allergy

    (2010)
  • E. Glowacka et al.

    Exhaled eicosanoid profiles in children with atopic asthma and healthy controls

    Pediatr Pulmonol

    (2013)
  • N. Rabinovitch et al.

    Urinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthma

    J Allergy Clin Immunol

    (2010)
  • P.L.P. Brand et al.

    Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

    Eur Respir J

    (2008)
  • T.W. Guilbert et al.

    Long-term inhaled corticosteroids in preschool children at high risk for asthma

    N Engl J Med

    (2006)
  • Cited by (0)

    View full text