MAY 2019 I 1

Leader in digital CPD for Southern African

healthcare professionals

AsthmaEarn up to 3 free CEUs

Professor Soren PedersenDepartment of Paediatrics, Kolding HospitalDenmark

Professor Adnan CustovicProfessor of Paediatric Allergy,Imperial College London,United Kingdom

This report was made possible by an unrestricted educational grant from Cipla. The content of the report is independent of the sponsor. The experts participated voluntarily.

Preschool wheeze and asthma – novel approaches to management and understanding of subtypesIntroduction The Divisions of Pulmonology and Neonatology of Tygerberg Children’s Hospital hosted the eighth annual Here be Lungs Congress, 6-8 March 2019. ‘Here be lungs’, as in ‘Here be dragons’, is a reference to the situation sailors of old found themselves in when they sailed off into unknown, uncharted waters. In Chinese, ‘lung’ means ‘dragon’ and the lung in Chinese medicine is the boundary between the inner and outer world - the lung is the whole respiratory system and has to do with boundary, breath and renewal; across this boundary vital materials are taken in and waste materials excreted.

One of the aims of this conference was to navigate newly described and insufficiently explored neonatal, infant and childhood lung conditions. This best practice report highlights the advice of Professor Soren Pedersen (Denmark) on the management of asthma and wheeze in preschool children, and why it is so important. Professor Adnan Custovic (UK) explains how careful synergy of data-driven methods and clinical interpretation may help us to better understand the heterogeneity of asthma and enable the discovery of true asthma endotypes.

EARN FREECPD POINTS

Join our CPD community at

www.denovomedica.com

and start to earn today!

2 I MAY 2019

Preschool wheeze and asthma – novel approaches to management and understanding of subtypes

“Most parents will not report wheeze until lung function has been reduced by as much as 50%.”

Professor Soren Pedersen

KEY MESSAGES

• When preschool children are classified into a wheeze phenotype, this classification is likely to change significantly within a one-year period

• Often, a two-month trial of inhaled corticosteroids (ICSs) is required to assist with the asthma diagnosis

• ICSs remain first-line treatment for multiple-trigger wheeze but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or if there is suspicion that interval symptoms are being under-reported

• Response to ICSs is inconsistent, perhaps due to differences in symptom presentation and/or persistence, or other underlying inflammatory features

• Children with moderate-to-severe asthma are present in each of several different asthma endotypes

• Clinical evidence of the heterogeneity of severe asthma is indicated by the differential response to each asthma step-up therapy

• Allergic sensitisation, high allergen exposure and respiratory virus infection act synergistically to increase the risk of exacerbations

• Add-on omalizumab therapy nearly eliminates seasonal peaks in exacerbations and reduces the need for use of other medications to control asthma

• Different patterns of immune responses to viruses are associated with fundamentally different longitudinal patterns of asthma

• Up to 75% of adult chronic obstructive pulmonary disease (COPD) begins with poor lung function trajectories in childhood

• Social functioning, cognitive functioning and physical wellbeing are compromised in children with uncontrolled asthma, compared to healthy children

• Poor asthma control is associated with more severe exacerbations and a more rapid loss of lung function.

Management of asthma and wheeze in preschool childrenA clinical presentation may have many symptoms that are not specific for asthma - wheeze/cough/breathlessness, tiredness and reduced physical activity, nocturnal wake-ups, recurrent bronchitis or pneu-monia (with several courses of antibi-otics being ineffective), and cold air or activity-induced symptoms. This makes it

very complicated to decide what is asthma and what is not asthma; and who should be treated and who should not. Among children under five years of age, 45% will show symptoms of wheeze and asthma, with 35% continuing to be symptomatic after the age of five years. Viral triggers are common to both groups.

Classification and management of preschool wheezing disordersProfessor Pedersen is of the opinion that phenotyping may be very important in the future, but it has been shown that when children with preschool wheeze are classified into episodic (viral) wheeze or multiple-trigger wheeze, the classification is likely to change significantly within a one-year period, with no mutually exclu-sive subgroups that remain consistent over time. Furthermore, wheeze patterns

in young children vary over time and with treatment, rendering the distinc-tion between episodic viral wheeze and multiple-trigger wheeze unclear in many patients; so it is not easy to make treat-ment recommendations. ICSs remain first-line treatment for multiple-trigger wheeze but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or if there is suspicion

MAY 2019 I 3

Preschool wheeze and asthma – novel approaches to management and understanding of subtypes

that interval symptoms are being under-reported. Often, a two-month trial of ICSs is required to assist with the asthma diagnosis. Close follow-up to monitor treatment effect is recommended, with treatment being discontinued if there is

no benefit. Professor Pedersen recom-mends TRACK as a valid, easy-to-admin-ister, caregiver-completed questionnaire of respiratory control in preschool aged children with symptoms consistent with asthma (Table 1).1-3

Table 1. TRACK questionnaire for respiratory control in preschool aged children3

1. During the past four weeks, how often was your child bothered by breathing problems such as wheezing, coughing or shortness of breath?

2. During the past four weeks, how often did your child’s breathing problems wake him or her up at night?

3. During the past four weeks, to what extent did your child’s breathing problems interfere with his or her ability to play, go to school, or engage in the usual activities appropriate for a child of his or her age?

4. During the past three months, how often did you need to treat your child’s breathing problems with quick-relief medications?

5. During the past 12 months, how often did your child need to take oral corticosteroids for breathing problems not controlled by other medications?

Each response is scored from 0 to 20 points on the basis of a five-point Likert-type scale for a total score of 0 to 100. A cut-off point score of 80 is thought to accurately identify children whose symptoms are controlled relative to those whose symptoms are not.

Which treatment should be considered? Response to ICS therapy is inconsist-ent, perhaps due to differences in symp-tom presentation and/or persistence, or other underlying inflammatory features. The Individualized Therapy for Asthma in Toddlers (INFANT) study found that phenotyping with aeroallergen sensitisa-tion and blood eosinophils is useful for guiding treatment selection and identifies children with a high exacerbation prob-ability, for whom treatment with a daily ICS is beneficial. Infants and preschool-ers with recurrent wheezing or asthma have fewer exacerbations and improve their symptoms and lung function during treatment with an ICS.4,5

With regard to variability of symptoms in asthma, there has long been debate about whether it is preferable to treat intermittently with an ICS when symp-toms worsen or if continuous treatment is more beneficial. The reality is that for those preschoolers on chronic, regular treatment, there is only 40-50% adher-ence. With intermittent treatment, par-ents will act on multiple antecedent signs and symptoms (respiratory symptoms, allergy/cold, behavioural triggers); how-ever only 55% administer treatment for symptoms such as shortness of breath and gasping.6

Regular treatment with an ICS is best documented and numerous studies show better outcomes than intermittent use of

an ICS in several indicators of lung func-tion, airway inflammation, asthma con-trol, reliever use and symptom-free days, with lower use of oral steroids. Meta-analysis shows regular ICS treatment is the most effective treatment for frequent wheezing in preschool children. The safety of both regular and intermittent use has been established, but a modest growth suppression was associated with daily, compared to intermittent, inhaled budesonide and beclomethasone, with a reduction in growth rate of approximately 0.4cm. Other studies show temporary reduction in growth velocity in prepu-bertal children (1.0cm) with intermittent use of an ICS for persistent asthma. Inhibition of growth is most likely to be seen in the 5-9-year age group, but not after 9-10 years of age. The decrease in attained height 1-4 years after the ini-tiation of ICS therapy is thought not to decrease attained adult height. Females are more at risk of growth inhibition.7-9

Professor Pedersen cautioned that with intermittent ICS treatment in preschool, there is a risk of undertreating as par-ents underestimate symptoms. With con-tinuous ICS treatment there is the risk of overtreatment when patients are not closely followed up - treatment should not continue indefinitely and should be stopped if there are no symptoms.

EARN FREECPD POINTS

Join our CPD community at

www.denovomedica.com

and start to earn today!

4 I MAY 2019

Preschool wheeze and asthma – novel approaches to management and understanding of subtypes

“…the same intervention used across all children with severe asthma will not result in a consistently positive outcome.”

Professor Adnan Custovic

Severe and uncontrolled paediatric asthma – additional treatment challenges Increasing evidence indicates that asthma is an umbrella diagnosis for a collection of distinct diseases (endotypes), with varying phenotypic expression of characteristic symptoms and accompanying variable air-flow obstruction. There is little consensus in the medical community on how best to

define these endotypes. Careful synergy of data-driven methods and clinical interpre-tation may help us to better understand the heterogeneity of asthma and enable the discovery of true asthma endotypes. This is essential to achieving better mech-anism-based treatment targeting.10

Is severe asthma a separate endotype?Unbiased, data-driven methodologies have been used to identify asthma subtypes, with inconsistent results. Four features have been identified (age of onset, allergic sensitisa-tion, severity and recent exacerbations) that have given rise to a potentially meaningful five-cluster model of asthma – ‘early-onset mild atopic’ (35.5%), ‘early-onset mild non-atopic’ (25%), ‘late-onset’ (17%), ‘difficult’ (21.5%) and ‘exacerbation-prone’ (2%). Children with moderate-to-severe asthma were present in each cluster, suggesting that severe asthma is not a single entity, but an extreme end of the spectrum of several dif-ferent asthma endotypes. Lung function was significantly diminished among children with ‘difficult’ asthma and blood eosino-philia was a significant feature of ‘difficult’, ‘early-onset mild atopic’ and ‘late-onset’ asthma. This implies that the same inter-vention used across all children with severe asthma will not result in a consistently

positive outcome.10

Other studies indicate that severe asthma in children is heterogeneous, although in most patients it is characterised by eosinophilic airway inflammation.11 Clinical evidence of heterogeneity in treatment responses comes from the Best Add-on Therapy Giving Effective Responses (BADGER) trial, showing a differential response to each step-up therapy. Long-acting β-agonist (LABA) step-up was significantly more likely to pro-vide the best response at group level, com-pared to either doubling the dose of ICS or adding leukotriene receptor antagonists (LTRAs). However, many children had a best response to ICS step-up (25%) or LTRA step-up (25%), highlighting the need to regu-larly monitor and appropriately adjust each child’s asthma therapy and to find biomark-ers to help the physician to make an informed decision as to which treatment to prescribe.12

Why do exacerbations occur?Viewing viral infections as the sole cause of exacerbations is an oversimplification. Large studies examining potential factors associated with exacerbations in adults and children have indicated that allergic sensitisation, high allergen exposure and virus infection (mostly rhinovirus) may act synergistically to exacerbate asthma.

The combination of these three factors increased the risk of hospital admission 20-fold among children and eight-fold among adults. There is an association between increased serum IgE levels with concurrent respiratory virus infection and an increased probability of acute, severe asthma exacerbations.13,14

Strategies to reduce risk of exacerbationsOmalizumab – a recombinant human-ised monoclonal antibody against human IgE - used as add-on therapy in a cohort of inner-city youths reduced the rate of autumn exacerbations (70%), with a marked reduction in hospitalisation for exacerbation compared to the period before anti-IgE treatment was introduced. Further to improved asthma control, add-on omalizumab nearly eliminated seasonal

peaks in exacerbations and reduced the need for other medications to control asthma. A persistent positive effect on the severe exacerbation rate was seen, with a modest effect on asthma control.15,16

It is necessary to consider the expense of biologics such as omalizumab and the question of whether they need to be admin-istered throughout the year. A study of pre-seasonal (four-month) treatment with

MAY 2019 I 5

Preschool wheeze and asthma – novel approaches to management and understanding of subtypes

“In asthma … intermittent unpredictable symptoms and perceived loss of control could significantly impact quality of life.”

Professor Soren Pedersen

an anti-IgE shows that this strategy can be used to great effect. The biggest effect of anti-IgE was in the most severe group (STEP 5,) which had an exacerbation dur-ing the run-in period; but there was little difference compared to placebo in chil-dren in STEP 2-4. Also of interest was the observation that those on anti-IgE treat-ment had significantly increased IFN-α in response to respiratory virus infection, correlating with those afforded the greatest protection from exacerbations.17

Severe, therapy-resistant asthmatic chil-dren show very high levels of atopy (markedly stronger IgE responses and higher skin-test wheals) when compared to difficult and mild-to-moderate asthmatic children. How is allergic asthma defined? Sensitisation is an umbrella term. Machine-learning method-ologies have identified four different sensi-tisation clusters, reflecting multiple different atopic vulnerabilities where timing and type of allergic sensitisation may be predictive of asthma. Only one of these groups, ‘multiple early sensitisation’ representing 25% of sen-

sitised children, is relevant to asthma, with a 30-fold increase in the likelihood of asthma. This ‘multiple early’ subtype is associated with all severe outcomes.18-20

A recent study of innate antiviral immune responses mapped cytokine responses induced by rhinovirus. Machine-learning models suggest that there are six different patterns of immune responses to viruses. These are associated with funda-mentally different longitudinal patterns of disease. Children with strong interferon, proinflammatory and regulatory responses do not have asthma. Two patterns are asso-ciated with asthma, but with very different types of the disease. Very low interferon responses, high proinflammatory responses and moderate regulatory responses are associated with a high risk of exacerbation, lower respiratory tract infection, trouble-some early childhood wheezing and early sensitisation. A high interferon response with moderate proinflammatory and regu-latory responses is associated with late-onset mild allergic asthma.21

Impact of severe wheezing on lung function trajectoriesChildren with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have persistently diminished lung function throughout childhood and are at risk of a progressive loss of lung func-tion from age three to 11 years. Up to 75% of adult COPD begins with poor lung function trajectories in childhood,

with maternal smoking, multiple early-life sensitisation and wheezing exacerba-tions having a major impact. Reducing childhood smoke exposure and minimis-ing the risk of early-life sensitisation and wheezing exacerbations may reduce the risk of diminished lung function in early adulthood.22,23

Why achieve control in paediatric asthma? What is the impact of asthma control on quality of life?In asthma, physiological abnormali-ties may be mild or absent on a chronic basis, but intermittent unpredictable symptoms and perceived loss of control could significantly impact quality of life. Uncontrolled asthma impacts the sleep of children to a significantly greater degree than well-controlled asthma. Social func-tioning, cognitive functioning and physi-cal well-being are compromised in those with uncontrolled asthma, when com-pared to healthy children and patients with controlled asthma. Children with uncontrolled asthma are also at higher risk for anxiety and depression.24,25

Those with uncontrolled asthma are at higher risk for limitations in outdoor activity, physical activity and daily activity,

which can lead to social isolation. Children with asthma have lower physical function-ing, general well-being and emotional functioning domain scores and those with untreated asthma have a higher percentage of body fat and a greater frequency of obe-sity than their healthy peers. Uncontrolled asthma is associated with reduced fit-ness levels and less time spent in intensive activity during the day. Improvement in asthma control is associated with a con-tinuous, clinically relevant increase in daily physical activity and cardiovascular fitness from four weeks onwards. To help patients achieve optimal health, asthma manage-ment should include routine assessment of activity limitations.25-28

EARN FREECPD POINTS

Are you a member of Southern Africa’s leading

digital Continuing Professional Development website earning FREE CPD

points with access to best practice content?

Only a few clicks and you can register to start earning today

Visit

www.denovomedica.com

For all Southern African healthcare professionals

DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

Published by

70 Arlington Street, Everglen, Cape Town, 7550Tel: (021) 976 0485 I info@denovomedica.com

deNovo MedicaReg: 2012/216456/07

6 I MAY 2019

Preschool wheeze and asthma – novel approaches to management and understanding of subtypes

DeNovo Medica

@deNovoMedica

Find us at

What is the impact of asthma control on lung function outcomes?

Decline in lung function does not occur in all asthma patients. Identified risk factors for lung function decline include young age, male gender, longer duration of dis-ease, black ethnicity, more prominent eosinophilic airway inflammation, asthma

exacerbations and smoking. Poor asthma control is associated with more severe exacerbations and a more rapid loss in lung function, compared to patients tak-ing the ICS, budesonide.29

References Click on reference to access the scientific article.1. Schultz A, Devadason SG, Savenije OE, et al. The transient

value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr 2010; 99(1): 56-60. DOI: 10.1111/j.1651-2227.2009.01508.x.

2. Brand PL, Caudri D, Eber E, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J 2014; 43(4): 1172-1177. DOI: 10.1183/09031936.00199913.

3. Murphy KR, Zeiger RS, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): A caregiver-completed questionnaire for preschool-aged children. J Allergy Clin Immunol 2009; 123(4): 833-839.

4. Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016; 138(6): 1608-1618. DOI: 10.1016/j.jaci.2016.09.028.

5. Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics 2009; 123(3): e519-525. DOI: 10.1542/peds.2008-2867.

6. Garbutt JM, Freiner D, Highstein GR, et al. Home use of albuterol for asthma exacerbations. Ann Allergy Asthma Immunol 2009; 102(6): 504-509. DOI: 10.1016/S1081-1206(10)60125-1.

7. Chauhan BF, Chartrand C, Ducharme FM. Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. Cochrane Database Syst Rev 2013; 2: CD009611. DOI: 10.1002/14651858.CD009611.pub3.

8. Papi A, Nicolini G, Baraldi E, et al. Regular vs prn nebulized treatment in wheeze preschool children. Allergy 2009; 64(10): 1463-1471. DOI: 10.1111/j.1398-9995.2009.02134.x.

9. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012; 367: 904-912.

10. Deliu M, Yavuz TS, Sperrin M, et al. Features of asthma which provide meaningful insights for understanding the disease heterogeneity. Clin Exp Allergy 2018; 48(1): 39-47. DOI: 10.1111/cea.13014.

11. Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol 2012; 129(4): 974-982. DOI: 10.1016/j.jaci.2012.01.059.

12. Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362(11): 975-985. DOI: 10.1056/NEJMoa1001278.

13. Green RM, Custovic A, Sanderson G, et al. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ 2002; 324(7340): 763-765.

14. Murray CS, Poletti G, Kebadze T, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006; 61(5): 376-382.

15. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011; 364(11): 1005-1015. DOI: 10.1056/NEJMoa1009705.

16. Deschildre A, Marguet C, Langlois C, et al. Real-life

long-term omalizumab therapy in children with severe allergic asthma. Eur Respir J 2015; 46(3): 856-859. DOI: 10.1183/09031936.00008115.

17. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol 2015; 136(6): 1476-1485. DOI: 10.1016/j.jaci.2015.09.008.

18. Belgrave DCM, Simpson A, Semic-Jusufagic A, et al. Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J Allergy Clin Immunol 2013; 132(3): 575-583. DOI: 10.1016/j.jaci.2013.05.041.

19. Simpson A, Tan VYF, Winn J, et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am J Respir Crit Care Med 2010; 181(11): 1200-1206. DOI: 10.1164/rccm.200907-1101OC.

20. Lazic N, Roberts G, Custovic A, et al. Multiple atopy phenotypes and their associations with asthma: similar findings from two birth cohorts. Allergy 2013; 68(6): 764-770. DOI: 10.1111/all.12134.

21. Custovic A, Belgrave D, Lin L, et al. Cytokine responses to rhinovirus and development of asthma, allergic sensitization, and respiratory infections during childhood. Am J Respir Crit Care Med 2018; 197(10): 1265-1274. DOI: 10.1164/rccm.201708-1762OC.

22. Belgrave DC, Buchan I, Bishop C, et al. Trajectories of lung function during childhood. Am J Respir Crit Care Med 2014; 189(9): 1101-1109. DOI: 10.1164/rccm.201309-1700OC.

23. Belgrave DCM, Granell R, Turner SW, et al. Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies. Lancet Respir Med 2018; 6(7): 526-534. DOI: 10.1016/S2213-2600(18)30099-7.

24. Hallstrand TS, Curtis R, Sullivan SD, et al. Quality of life in adolescents with mild asthma. Pediatr Pulmonol 2003; 36(6): 536-543.

25. Dean BB, Calimlim BC, Sacco P, et al. Uncontrolled asthma among children: impairment in social functioning and sleep. J Asthma 2010; 47(5): 539-544. DOI: 10.3109/02770900903580868.

26. Haselkorn T, Chen H, Miller DP, et al. Asthma control and activity limitations: insights from the Real-world Evaluation of Asthma Control and Treatment (REACT) study. Ann Allergy Asthma Immunol 2010; 104(6): 471-477. DOI: 10.1016/j.anai.2010.04.006.

27. Vahlkvist S, Pedersen S. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma. Allergy 2009; 64(11): 1649-1655. DOI: 10.1111/j.1398-9995.2009.02081.x.

28. Vahlkvist S, Inman MD, Pedersen S. Effect of asthma treatment on fitness, daily activity and body composition in children with asthma. Allergy 2010; 65(11): 1464-1471. DOI: 10.1111/j.1398-9995.2010.02406.x.

29. O’Byrne PM, Pedersen S, Lamm CJ, et al. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009; 179(1): 19-24. DOI: 10.1164/rccm.200807-1126OC.