European Respiratory Society

Paediatric Asthma

Edited by Kai-Håkon Carlsen and Jorrit Gerritsen
Paediatric Asthma

Asthma is a disease of many faces and is frequently seen in children. This Monograph covers all aspects of paediatric asthma, across all ages, from birth through to the start of adulthood. It considers diagnostic problems in relation to the many phenotypes of asthma, covers the treatment of both mild-to-moderate and severe asthma, and discusses asthma exacerbations as well as exercise-induced asthma. The issue also provides an update on the pathophysiology of asthma, the role of bacterial and viral infections, and the impact of environmental factors, allergy, genetics and epigenetics. Finally, this Monograph considers the economic burden of the disease, as well as new and future developments in asthma therapy.

  • European Respiratory Society Monographs
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  4. Page 1
    Abstract
    Correspondence: Karin C. Lødrup Carlsen, Dept of Paediatrics, Oslo University Hospital, PO Box 4956 Nydalen, NO-0424 Oslo, Norway. Email: k.c.l.carlsen@medisin.uio.no

    The childhood asthma prevalence increase, during recent decades, may represent a shift in distribution of asthma phenotypes. The lung meets the external environment directly through the airways, as well as indirectly, by way of circulatory, neural and immunological responses. However, it is not clear how, and to what extent, environmental factors together with constitutional and genetic factors co-act to result in asthma and define asthma severity. Despite decades of research there has not been a significant breakthrough in understanding the mechanisms, genetics, therapeutic interventions and possible preventive strategies of asthma. Thus, we still lack significant knowledge that could help target asthmatic children with optimal management or ultimately prevent asthma developing. These gaps in knowledge are likely to stem from our inability to identify relevant sub-groups of childhood asthma, or even to define asthma in a reasonably objective manner. The present chapter will briefly describe the importance of characterising childhood asthma phenotypes and approaches that have been and are currently undertaken to identify them.

  5. Page 10
    Abstract
    Correspondence: J.A. Castro-Rodriguez, Lira 44, 1er. Piso, casilla 114-D, Santiago, Chile. Email: jacastro17@hotmail.com

    In infants and preschool children the symptoms suggestive of asthma (e.g. wheeze) may be a clinical expression of a number of diseases with different aetiologies. If this is true, then it is unlikely that these different diseases would respond to the same treatment. Consequently, implementation of a management strategy which is effective for each individual patient is challenging, and controversies remain with respect to which patients should be given anti-asthma treatment, and when the treatment should be started and for how long. Whilst acknowledging these uncertainties, practicing physicians may use the Asthma Predictive Index (API) as a guide in clinical practice to identify young children with recurrent wheezing who are at risk of the subsequent development of persistent asthma, and who may benefit from preventative anti-asthma medication. We acknowledge that a number of questions on the most appropriate management strategy remain unanswered, including which type of medication is the best for individual patients (e.g. short-acting β-agonist versus inhaled corticosteroid (ICS) versus leukotriene receptor antagonist (LTRA)), dose (high versus low) and schedule (regular versus as needed).

  6. Page 22
    Abstract
    Correspondence: A. Bush, Dept of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Email: a.bush@rbh.nthames.nhs.uk

    Problematic severe asthma is the description of children referred to specialist care with asthma not responding to standard therapy. The initial step is to ensure that the diagnosis is right, and to evaluate co-morbidities. The next step is a detailed multidisciplinary assessment, including, if possible, a home visit. More than half have “difficult asthma”, which improves if the basic management is correct; this may not be possible, but if the basics are not right, they are not candidates for potentially toxic new therapies. The remainder are termed “severe therapy resistant” asthmatics, and an individualised treatment plan is developed after a detailed and invasive protocol of investigations, including bronchoscopy and assessment of the response to intramuscular triamcinolone. Most treatments are unlicensed, with the exception of omalizumab (Xolair®; Genentech, San Francisco, CA, USA), and the evidence base is poor. International collaborations will be essential if the mechanisms of severe therapy resistant asthma are to be understood, and evidence-based treatment delivered.

  7. Page 40
    Abstract
    Correspondence: S. Lau, Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. Email: susanne.lau@charite.de

    At school age a more stable phenotype of asthma has developed. Most of the subjects are atopic. Different risk factors have been identified for the different phenotypes. Children with persistent wheeze in infancy and at school age are more likely to be atopic and have an increased risk of wheeze at age 13 years. Early sensitisation, especially to house dust mite, is a risk factor for asthma at school age that is associated with impaired lung function. Remission rates in adolescence are approximately 30%. During early puberty, approximately 3% of individuals develop new asthma. Asthmatics appear to be more susceptible for respiratory viral infections, often accompanied by exacerbations and hospital admission. Although, anti-inflammatory therapy cannot influence the development of lung function, sufficient symptom control can achieve a better quality of life. Allergen avoidance may reduce bronchial inflammation as a secondary measure in sensitised individuals. As primary prevention, early exposure to microbial antigens in farming communities and sufficient vitamin D levels could be identified.

  8. Page 49
    Abstract
    Correspondence: K-H. Carlsen, PO Box 4950 Nydalen, 0424 Oslo, Norway. Email: k.h.carlsen@medisin.uio.no

    Exercise-induced asthma (EIA) is common in asthmatic children and adolescents. Treatment of childhood EIA is among the main aims of all international guidelines. Physical activity and fitness is found to improve with optimal control in children with EIA. Physical training does not improve asthma, but improves fitness and quality of life (QoL) in asthmatic children. Mechanisms of EIA include water loss and heat loss caused by increased ventilation during physical exercise, whereas the mechanisms of asthma development in adolescent athletes include respiratory epithelial damage, increased parasympathetic tone and airways inflammation leading to remodelling over time. In this chapter the basis for diagnosis of EIA and asthma in adolescent athletes and recommended treatment is discussed.

  9. Page 59
    Abstract
    Correspondence: S. Taylor-Black, Dept of Pediatrics, Box 1198, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA. Email: Sarah.Taylor-Black@mssm.edu

    Asthma and food allergy coexist in many children, although it remains unclear whether or not food allergy and asthma are simply associated with each other due to underlying predisposition to allergy or whether they are actually causally related. Several studies have shown that food allergic individuals who develop asthma are at higher risk for severe asthma. In addition, asthma in individuals with food allergy places those patients at higher risk for severe allergic reactions to food, such as anaphylaxis, particularly if the asthma is poorly controlled. Food allergy should be considered in children with acute, life-threatening asthma exacerbations with no identifiable triggers and in highly atopic children with severe persistent asthma resistant to medical management. Management of food allergy and asthma according to well-defined national guidelines is essential to establish good control of these conditions, particularly when they are concomitant. In patients with concurrent food allergy and asthma, education about heightened risks is an important step in treatment, and intramuscular epinephrine is the drug of choice in treatment of anaphylaxis.

  10. Page 71
    Abstract
    Correspondence: W. Lenney, Academic Dept of Child Health, University Hospital of North Staffordshire, Newcastle Road, Stoke-on-Trent, ST4 6QG, UK. Email: w.lenney46@hotmail.co.uk

    Asthma is the commonest chronic illness of childhood and has a huge, yet variable, burden that impacts on the child, their family, the healthcare system and society as a whole. The economic burden can be broken down to assess the direct and the indirect costs of the disease. Many studies have been undertaken in numerous countries and the burden clearly differs depending on the healthcare system in which the child is cared for, the severity of the child's disease, the social status of the child's family and a number of other factors included in some of the studies. For the affected child there are physical, social and psychological effects, which have a detrimental effect on their quality of life. The lives of their parents and siblings are also affected. Despite increasing medication costs and an increase in the worldwide prevalence of paediatric asthma, there is evidence that carefully planned asthma management programmes can reduce the burden on individual patients and the wider society. Improved understanding of the various aspects of the burden of paediatric asthma, along with help to develop these management programmes and target them to the needs of particular communities, could maximise these positive results. The single most important factor in reducing the burden of paediatric asthma is to improve asthma control; therefore, we need to be vigilant in optimising the care of children with asthma at all times.

  11. Page 82
    Abstract
    Correspondence: K.C. Lødrup Carlsen, Dept of Paediatrics, Oslo University Hospital, Oslo, NO-0407, Norway. Email: k.c.l.carlsen@medisin.uio.no

    Lung function, asthma and allergy are complexly involved in children and adults; however, the role of lung function development in relation to asthma and allergy is not clear. Does reduced lung function in early post-uterine life infer a (causal) risk for later asthma, or is it simply a marker for ongoing disease development? If so, what is the association between reduced lung function, allergic sensitisation, allergen exposure and viral infections? These interactions are poorly understood, as is the underlying pathophysiology and characteristics of different types of asthma throughout childhood into adulthood. The ‘‘atopic march’’ indicates that one clinical allergic disease presentation should be succeeded by the next; however, the denominator setting for this developmental cascade is not clear. Recent hypotheses focus on epithelial barrier dysfunction, which may increase the likelihood of immunological responses to environmental compounds passing through a leaky membrane. Whilst high allergen exposure amongst sensitised individuals is associated with more severe disease, the relationship between allergen exposure and development of sensitisation, asthma and lung function is much more complex.

  12. Page 97
    Abstract
    Correspondence: G.H. Koppelman, Dept of Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: g.h.koppelman@umcg.nl

    Asthma is a complex disorder caused by interaction of genetic and environmental factors.

    In the last decade a lot of genes related to asthma and atopy were discovered. Candidate gene studies showed the involvement of genes related to innate and specific immunity, and replicated examples of interaction of genes and the environment. New genes identified through positional cloning studies, such as ADAM33, revived the interest in the airway epithelium and mesenchyme as important structural cells in asthma. Most genome-wide association studies discovered genes related to asthma that functions at the interface of airway structural cells and inflammation, such as IL33, IL1RL1 and TSLP.

    Epigenetics refers to heritable changes in gene expression without changes in DNA sequence, and includes DNA methylation, histone modifications and microRNAs. Several environmental factors known to be relevant in asthma may influence epigenetic modifications, however, the specific role of epigenetics in asthma is not clear. The ultimate goal of research in (epi)genetics of asthma is to identify susceptible subjects, and to contribute to (preventative) interventions.

  13. Page 115
    Abstract
    Correspondence: N.G. Papadopoulos, Allergy Dept, 2nd Pediatric Clinic, University of Athens, 41 Fidippidou str., 11527 Goudi, Athens, Greece. Email: ngp@allergy.gr

    A considerable proportion of asthma morbidity, mortality and health costs are attributed to asthma exacerbations. Epidemiological studies have convincingly shown that viral respiratory infections are the major causes of asthma exacerbations in both adults and children. Viruses, rhinoviruses in particular, infect the airway epithelium resulting in local and systemic immune responses as well as neural responses, inducing inflammation and airway hyperresponsiveness (AHR). The effects of an infection may vary according to genetic background, the current immune status of the host and parallel environmental stimuli, in addition to the particular infectious agent itself. Moreover, several studies have emphasised the importance of atopy and allergic inflammation in the induction and prolongation of virus-induced respiratory diseases. Identification of the mechanisms involved in the pathogenesis of asthma exacerbations and asthma persistence should facilitate development of future treatments tailored to the underlying cause.

  14. Page 128
    Abstract
    Correspondence: S. Lau, Charité Campus Virchow, Klinik f. Pädiatrie mit Schwerpunkt Pneumologie und Immunologie, Augustenburger Platz 1, 13353 Berlin, Germany. Email: susanne.lau@charite.de

    Asthma is one of the most frequent chronic diseases and various phenotypes in infancy and childhood have been described. Approximately two-thirds of schoolchildren are allergic to inhalant allergens. In particular, mite allergy and pet allergy are associated with chronic allergic airway disease, and continuous exposure may cause a decline in lung function in early life. However, in terms of a dose–response relationship between exposure and sensitisation and exposure and asthma the literature is controversial. Therefore, the structure of preventive measures may vary for different phenotypes in different areas of the world.

  15. Page 134
    Abstract
    Correspondence: J. Grigg, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, 4 Newark Street, London E1 2AT, UK. Email: j.grigg@qmul.ac.uk

    Over the last decade there have been significant advances in our understanding of the health effects of air pollution in children. Linking data from large prospective cohort studies to locally generated air pollution clearly demonstrates that exposure to both traffic emissions and indoor second-hand smoke are important risk factors for the development of preschool wheeze and school-age asthma. Uncertainties still remain, especially about the size of this association, and the individual components responsible for driving increased vulnerability to asthma. Improvements in modelling and new ways of thinking about exposure, for example combining second-hand smoke with traffic emissions into a single exposure variable, may help policy makers take the decisions necessary to reduce the long-term health burden of indoor and outdoor pollution in children.

  16. Page 143
    Abstract
    Correspondence: J. Paton, University of Glasgow, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK. Email: james.paton@glasgow.ac.uk

    There are a number of psychological factors that are recognised to be important in childhood asthma. Anxiety and depression are more common in children with asthma and are associated with worse asthma outcomes. Acute and chronic stresses, usually arising from a child's family environment, are associated with asthma exacerbations and worse asthma outcomes. While both depression and stress may affect asthma indirectly by impacting on asthma management, there is growing evidence of more direct effects mediated through changes in the immune system or via the autonomic nervous system.

    Anxiety and depression are easy to miss clinically and are often overlooked. Clinicians looking after children with poorly controlled or difficult-to-control asthma need to be particularly alert because asthma control may not improve until psychological factors are addressed. Surprisingly, the evidence base for the effect of psychological interventions is very limited.

  17. Page 158
    Abstract
    Correspondence: P.J.F.M. Merkus, Dept of Pediatrics, Division of Respiratory Medicine, Route 804 Post, 804, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: p.merkus@cukz.umcn.nl

    Airway hyperresponsiveness (AHR) is a hallmark of asthma, but may also exist in children and adults with other lung disorders. It reflects an abnormal response with airway narrowing following exposure to a wide variety of non-sensitising stimuli of chemical or physical origin. The response may be abnormally sensitive: the degree of airway narrowing may increase markedly with increasing stimuli, and may result in complete airway closure. This abnormal response may be due to the presence of airway inflammation, abnormal airway mechanics or a combination of both. The airway challenge tests are subdivided into direct and indirect challenges. The direct challenges mainly have an effect on airway smooth muscle and, as such, predominantly reflect airway mechanics, whereas AHR assessed from indirect tests correlate better with the degree of airways inflammation. Therefore, direct and indirect tests are not interchangeable. AHR assessment is helpful for the diagnosis of asthma, but the role of routine AHR assessment in the management of children with asthma is unclear. In specific groups of children with asthma, knowledge of the degree of AHR may help to optimise individual treatment.

  18. Page 172
    Abstract
    Correspondence: J.H. Wildhaber, Dept of Paediatrics, Hospital Fribourgeois, Chemin des Pensionnats 2, CH-1708 Fribourg, Switzerland. Email: wildhaberj@h-fr.ch

    Shortness of breath, cough, wheezing and/or chest tightness are the classical symptoms of acute asthma with its underlying pathophysiological mechanisms of bronchoconstriction, airway inflammation and airway hypersecretion. Therefore, the logical treatment for acute asthma is to act against the pathophysiological mechanisms of asthma using a supportive treatment to reduce respiratory distress caused by these pathophysiological mechanisms.

    The classical medical treatment for acute asthma consists of inhaled bronchodilators and inhaled or systemic steroids. Supportive therapy is performed by supplying additional oxygen and/or, if necessary, adding ventilator support, either noninvasive or invasive.

    According to the severity of acute asthma, acute episodes can be either treated by one single measure, such as an increased use of short-acting bronchodilators or a combination of additional measures, such as the additional use of inhaled steroids. In severe cases, repetitive measures and the use of systemic treatment as well as ventilatory support and consequently hospital admission may be necessary.

  19. Page 188
    Abstract
    Correspondence: G. Wennergren, Dept of Paediatrics, University of Gothenburg, Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Email: goran.wennergren@pediat.gu.se

    Many infants and preschool children have asthmatic symptoms with wheezing, triggered predominantly by colds. However, the pathogenesis of wheezing in this age group is heterogeneous.

    The heterogeneity of asthma in infants and preschool children is reflected by the varied effectiveness of the medication.

    Children with signs of atopy and who also wheeze between colds respond positively to inhaled corticosteroids (ICS), while the effects of ICS are often unsatisfactory in viral wheeze. Periodic treatment with ICS or montelukast has been shown to reduce symptoms, to some degree, in preschool wheezers with intermittent wheezing in conjunction with viral infections. However, the available data indicate that the treatment effect in episodic viral wheeze is, at best, modest.

    Randomised controlled trials in preschool children have not shown that early steroid treatment has a disease-modifying effect and early steroid treatment does not appear to reduce the prevalence of asthma at school age.

  20. Page 199
    Abstract
    Correspondence: J. Gerritsen, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Email: jorrit@gmail.com

    Treatment of chronic asthma throughout childhood ranges from primary preventive therapy from birth to drug treatment, either intermittently or on a daily basis. Treatment of childhood asthma is focused on reducing symptoms and the assessment of as normal as possible daily life. Inhaled corticosteroids (ICS) are effective in modifying the disease but do not cure asthma. The knowledge about the deposition of inhalant medication, especially in young children, is very limited and many problems have to be elucidated in future research.

  21. Page 210
    Abstract
    Correspondence: P.L.P. Brand, Isala Klinieken, dr van Heesweg 2, 8025 AB, Zwolle, The Netherlands. Email: p.l.p.brand@isala.nl

    Although (near) total asthma control is possible using currently available medication, asthma remains poorly or partly controlled in many children. Poor adherence to treatment (including poor inhalation technique) is the main reason for this paradox, followed by ongoing exposure to environmental triggers and relevant comorbidity. During follow-up of children with asthma, the medical team should therefore focus on factors potentially hampering asthma control. Forging and maintaining a partnership with patients and parents is of paramount importance. Such a partnership should aim at shared decision making, taking the patient’s and parents’ illness and medication perceptions, and their treatment goals and preferences into account. Asthma education should be aimed at developing self-management, not transferring knowledge. By discussing and assessing adherence and control at every follow-up visit, aligning with the goals and preferences of the patients and their parents, identifying and treating relevant comorbidity, and by involving asthma nurses and allied health professionals as needed, asthma can be successfully and consistently controlled in the large majority of children.

  22. Page 224
    Abstract
    Correspondence: P.D. Sly, Queensland Children's Medical Research Institute, Level 4, Foundation Building, Royal Children's Hospital, Herston Rd, Herston, Queensland, Australia. Email: p.sly@uq.edu.au

    Treatment of childhood asthma has not changed substantially in recent decades, with no truly new drugs having been introduced since the turn of the last century. Mainstream therapy consists largely of inhaled corticosteroids in combination with β-agonists. Montelukast has a role in treating viral-induced wheeze in younger children and in preventing exercise-induced asthma. Review of the currently registered clinical trials for childhood asthma does not reveal any exciting new drug prospects. In recognition of the generally poor adherence with asthma therapy, a substantial research effort is underway to test strategies designed to improve asthma management with existing medications. Novel drugs with potential activity in asthma are currently being trialled in adults with asthma and some of these may eventually find their way into paediatric use. However, the most exciting advances in childhood asthma are likely to come from trials designed to prevent asthma. While several potential strategies can be identified from epidemiological studies, well conducted randomised clinical trials will be required to determine whether they are effective.