How to manage a child with Difficult Asthma

Sejal Saglani1,2, Louise Fleming1,2

1 Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London

2 Respiratory Paediatrics, Royal Brompton Hospital, London

Correspondence to:

Dr Sejal Saglani

Reader in Respiratory Paediatrics

Imperial College London

368 Sir Alexander Fleming Building

Exhibition Road

London, SW7 2AZ

Tel: +44 2075943167

Fax: +44 2075943119

Email: s.saglani@imperial.ac.uk

Key words: paediatric, problematic severe asthma, severe asthma, difficult asthma, diagnosis,

management

Funding: SS is an NIHR Career Development Fellow, supported by grant ID: CDF-2014-07-019.

Word count: 3,423

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Abstract (150 words)

Introduction: Children with difficult asthma have significant morbidity and fail to achieve asthma

control despite being prescribed high dose maintenance treatment. If control remains poor after

diagnostic confirmation, detailed assessments of the reasons for asthma being difficult-to-control

are needed. Underlying modifiable factors including non-adherence to medication, persistent

environmental exposures that trigger asthma symptoms and psychosocial factors contribute to poor

control in these patients.

Areas covered: The focus of this review is to provide a practical approach to the diagnosis and

management of difficult asthma including an overview of long term assessments to identify potential

progression to true, severe asthma. A multi-disciplinary team is critical to enable modifiable factors

to be identified and addressed. Significant resources are required to manage paediatric difficult

asthma optimally and only specialist centres should be tasked with the assessment of these patients.

Although this may have an impact on healthcare resources, long term benefits for lung health are

significant.

Expert commentary: The management of paediatric difficult asthma is not simple and involves numerous professionals with varied expertise. However, if it is not undertaken with the appropriate skills, there is a significant risk of children receiving inappropriate invasive investigations and therapies that will have no impact on morbidity.

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1. Introduction

Although the majority of children with asthma achieve symptom control on low or moderate doses

of maintenance inhaled steroids, there is a small proportion that remain uncontrolled despite high

doses of prescribed maintenance therapy 1. These children are prescribed treatments equivalent to

stage 4/5 of the British Thoracic Society (BTS) and the GINA2 guidelines for asthma management,

and either need at least this amount of therapy to achieve control, or have persistent symptoms and

frequent exacerbations despite maximal treatment. Children with poor control despite maximal

prescribed therapy have Problematic Severe Asthma3. However, the reasons for poor control may be

very varied and can broadly be divided into two sub-categories. The first, “Difficult Asthma” is the

term used to describe patients whose asthma is difficult to control because of a failure to address

the basics of asthma management, an incorrect diagnosis has been made, or there has been a failure

to address associated comorbidities. Underlying reversible and modifiable factors that can result in

poor control include poor adherence, unfavourable environmental exposures such as tobacco and

aero-allergens to which the patient is sensitised, poor inhaler technique and psychosocial issues. If

modifiable factors are successfully identified and addressed, then control can be achieved in children

with Difficult Asthma without the need for escalating therapy or additional invasive investigations.

The second sub-category of children that have poor asthma control despite maximal therapy are

those with true severe asthma. These patients remain with persistent symptoms, or can only be

controlled on maximal doses of maintenance therapy, often including oral steroids, AFTER

underlying reversible or modifiable factors have been identified and addressed4. Importantly, more

than half of all children with problematic severe asthma have difficult asthma because of underlying

modifiable or reversible factors preventing asthma control5. Therefore, the overall approach to

managing a child with Problematic Severe Asthma includes an initial step to identify and treat

Difficult Asthma, and if symptoms persist after this step, true severe asthma can be confirmed, which

requires additional investigation and management (Figure 1).

Very clear criteria and definitions that allow distinctions between difficult and severe asthma have

been specified for both adults and children aged 6 years and above by the European Respiratory

Society and American Thoracic Society4. An important point to consider when faced with a child that

has poor asthma control despite maximal doses of prescribed maintenance therapy is that once

above a threshold of treatment (>800mcg/day or equivalent of budesonide) the child should be

referred to a specialist for further management. The National Review of Asthma Deaths in the UK

identified 20% of asthma deaths occurred in patients who should have been referred to a specialist

for management of problematic asthma6. The focus of this review will be on the approach that

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should be taken when faced with a school-aged child (>6 years) with Problematic Severe Asthma,

with particular emphasis on how to identify those with Difficult Asthma, identification of the

modifiable factors that can contribute to poor control and how they can be addressed to help

achieve good control. Gaps in the literature will be highlighted as will the impact of such an

approach on healthcare resources. Importantly, the potential long term benefits in terms of lung

health and quality of life for patients and families and benefits to healthcare costs, if the optimal

approach is adopted, will be discussed.

2. Diagnosis of Difficult asthma: the need for a multi-disciplinary team (MDT) approach

(figure 2)

2.1 Step 1: Confirm diagnosis:

When faced with a child on escalating doses of asthma medication with an apparent refractory

phenotype, it is important to start by ensuring the diagnosis of asthma is correct. The factors upon

which a diagnosis has been made need to be confirmed and recorded. The presence of reversible

airflow obstruction, airway hyperresponsiveness, evidence of physician confirmed wheeze, and/or

evidence of peak flow variability need to be established. Several factors should lead to extra caution

before confirming the diagnosis in children. Absence of allergic sensitisation to aero-allergens is very

unusual in children with true, severe asthma. >85% of patients are sensitised to at least one aero-

allergen7,8, and most children are strongly sensitised to multiple allergens5. In contrast to adult

patients, spirometry at baseline in children may be normal8, although this does not refute the

diagnosis, evidence of airway hyperresponsiveness or reversibility and improvement after

bronchodilator are essential to make the diagnosis. Although some children with asthma develop a

productive cough, especially during exacerbations, the majority do not have a productive cough. The

presence of a wet cough should alert the need for additional investigation to exclude other

diagnoses including causes of bronchiectasis and chronic suppurative lung diseases. Symptoms that

are unusual and some of the differential diagnoses that should be considered in patients presenting

with Difficult Asthma have been summarised in Table 1.

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Table 1. Unusual clinical features and differential diagnoses to consider in children with difficult

asthma

Unusual clinical features Differential diagnosis

Stridor Tracheo-bronchomalacia

Vascular ring

Wet/ productive cough

Nasal polyps

Cystic fibrosis

Bronchiectasis

Aspiration

Chest pain / heartburn Gastroesophageal reflux

Poor growth / Failure to thrive

Symptoms from birth Congenital lung disease

Failure to respond to bronchodilators Vocal cord dysfunction

2.2 Step 2: Address the obvious basics:

When faced in the clinic with a child on large amounts of treatment that are ineffective, after

confirming the diagnosis of asthma, the next essential step is to ensure the child’s maintenance

treatment is being taken. This includes ascertaining that the child is taking the medication that the

physician thinks has been prescribed – is the formulation, dose and frequency correct? If those are

correct, then is the child taking the treatment with an appropriate device and with good technique?

An objective assessment of inhaler technique is one of the most simple, but fundamental checks that

should be undertaken at every appointment, as frequently as the performance of spirometry9,10. It

has been shown that no matter how confident the child is that they are using their device correctly,

most make a mistake when assessed9. It is essential that metred dose inhalers are not used without

a spacer, and that all school-aged children should use a spacer via mouthpiece, not with a mask.

Only children with sufficient ability to breath hold and take a forceful inhalation should be

prescribed dry powdered devices. Serious inhaler errors with these devices are found in more than

half of patients11. Medication errors are found in 20-25% of children with difficult asthma 12, making it

apparent that an early assessment and correction of these simple basics may be all that is needed to

improve control. In order to maintain clarity about the prescribed medication, a written, personal

asthma management plan should be issued to all patients so that there is no confusion about device,

dose or frequency and also to provide clarity about self-management of acute symptoms13.

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Identify and address co-morbidities: The majority of children with Difficult Asthma are atopic and

have multiple allergies [Sharples ERJ]. Allergic rhinitis, food allergies and atopic dermatitis are often

more severe and difficult to control and their management needs to be optimised to aid asthma

control. In addition, other co-morbidities that may contribute to poor asthma control must be

considered and treated, including the presence of gastroesophageal reflux (especially if the child has

clinical symptoms) and obesity.

2.3 Step 3: Identify and address more complex modifiable factors contributing to poor control

The basic factors that were highlighted in Step 2 above can be addressed in a routine clinic setting by

either a nurse specialist or physician. However, identification of the other modifiable factors that

contribute to poor asthma control require significantly more time, effort and expertise. The need for

a multi-disciplinary team approach is essential in order to ensure a complete and thorough

evaluation of all remaining factors is made, and thus children must be referred to a specialist difficult

asthma service to have a comprehensive assessment12,14.

3. Adherence to maintenance medication:

Poor adherence to maintenance therapy is one of the most common causes of asthma deaths. In the

UK, 80% of deaths attributable to asthma were in patients who had failed to collect the expected

number of prescriptions for maintenance therapy6. This is likely the commonest reason for poor

asthma control and Difficult Asthma in both adults15 and children12,16. Use of maintenance inhaled

steroids for at least 80% of the prescribed dose is considered acceptable. However, this level of

adherence is rarely seen and usual rates range from only 30-70% in adults and children 17. An

objective assessment of adherence is therefore mandatory for all children with Difficult Asthma. This

can be achieved in several ways. A check of prescription refills requested in the last 12 months can

be used to calculate adherence, but this approach only provides an answer to the question of

whether a prescription was collected, not whether the medicine was dispensed or whether it was

actually taken. If, however, the prescription uptake is poor (<80% of expected) then no further

assessments are needed and adherence requires addressing. If the prescription uptake is

satisfactory, then a multi-faceted approach to eliciting adherence is required whereby a home visit

should be undertaken to assess the availability of medication, evidence of stockpiling and the

availability of medication that has not expired16. However, each of these assessments provide only a

snapshot of adherence and families may argue that until recently they were administering

medication, and despite this their child’s asthma was not controlled. Another means of obtaining a

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snapshot of adherence is to use a questionnaire to ascertain the patient or family’s assessment of

adherence. However, this cannot be recommended since it is recognised as being unreliable, and

families will undoubtedly over report adherence rates18.

A useful objective assessment of adherence over a longer period of time that is currently available is

the use of electronic monitoring. Monitoring devices are attached to the maintenance inhaler and

record the time and date of an actuation. After a 2-3 month period the data can be downloaded and

adherence calculated19. A disadvantage of currently available electronic monitoring devices is the

inability to confirm an inhalation has been taken as they only record actuation. An advantage of long

term monitoring is that objective measures of asthma control including spirometry with

bronchodilator reversibility, symptoms scores and exhaled nitric oxide levels can be recorded before

and after the monitoring period. If there is an improvement in objective measures that tallies with a

good level of adherence, patients and families are more easily persuaded that asthma control can be

achieved if the medication is taken. Adult studies in patients with difficult asthma have shown the

most sensitive parameter that improves after a period of monitored or directly observed inhaled

steroid therapy is exhaled nitric oxide20. The exhaled nitric oxide suppression test can be used to

demonstrate non-adherence to patients and their families, but if being undertaken whilst an in-

patient, this can be extremely expensive and place a huge demand on healthcare resources. This

approach should only be undertaken if families are not convinced even after a period of electronic

monitoring that adherence is an issue for their child. Of note, to date, there are no publications

showing the efficacy of the exhaled nitric oxide suppression test in children. However, directly

observed therapy with the help of school can be undertaken for children as a way of addressing non-

adherence. Training provided to an identified member of staff in supervising the inhaled steroid

being taken can be used and the child is instructed to attend for their treatment at the start and end

of the school day, with teachers keeping a record of the medication having been taken. There are

drawbacks since week-ends and school holidays cannot be accommodated with this regimen and

using the help of schools may not be feasible in all countries, but as long as school attendance is not

an issue, this provides a potential means of ensuring maintenance treatment is taken on most days

of the week.

Several reports have addressed reasons for non-adherence in children with asthma. A recent report

that investigated this has shown that most patients have unintentional non-adherence 21, and for

these use of reminders such as apps or a personalised mobile health intervention 22 may succeed.

However, it is more likely that a more complex, individualised and multi-step approach is needed to

tackle non-adherence. The steps including identification of non-adherence using objective measures,

followed by a discussion to highlight the issue and subsequently an individualised intervention plan

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that allows for the reasons for non-adherence in a particular patient / family 23. The benefit of

identifying, targeting and addressing non-adherence in patients with difficult asthma on healthcare

outcomes has been demonstrated24, but the process requires significant healthcare resources to be

undertaken well. Input from specialist nursing staff, physician and a clinical psychologist are the

minimal levels of input required, but are frequently unavailable in routine clinics, thus highlighting

the need for a specialist service to address this relatively basic, but complex problem that is the most

important modifiable factor that needs to be corrected to optimise asthma control.

4. Environmental exposures

4.1 Tobacco smoke

An assessment of passive and/or active smoke exposure is mandatory for all children with difficult

asthma. Reliance on parental reports and history taking is inadequate. Levels of salivary or urinary

cotinine are needed to determine actual exposure. Carbon monoxide monitors can be used to detect

active smoking in the young person. This can be used in the routine clinical setting and smoking

cessation advice offered immediately. Detection of both active and passive smoking are of particular

importance in children with difficult asthma because of the recognised association between tobacco

smoke exposure and increased resistance to steroids in children25. Objective evidence of smoke

exposure is required to convince families that even their efforts to minimise exposure by “only

smoking outside” are not enough and still result in unacceptable levels of smoke exposure 26,27. The

impact of passive smoke exposure has been confirmed by studies that have assessed improvements

in lung function and asthma control before and after the introduction of banning smoking in public

places28. Once evidence of tobacco smoke exposure has been identified, the need to minimise this

must be addressed and parents should be clearly told how best to seek help to allow them to stop

smoking29 since simple advice and guidance from the physician alone on the importance of reducing

smoke exposure is unlikely to work30. Importantly, this issue must be re-addressed to ensure a

reduction in smoke exposure has been achieved before any decisions about escalation of therapy

are made.

4.2 Allergen exposure (food / aero)

Although the majority of children with problematic asthma are atopic7, a key factor that

distinguishes children with difficult asthma from those with true, severe asthma is the degree of

aero and food allergen sensitisation5. Multiple allergies and severe asthma has also recently been

identified as a phenotype of paediatric asthma from an unbiased cluster analysis31. Children with

difficult asthma have less severe sensitisation (sensitised to fewer allergens and not to the same

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degree of severity) and they are less likely to be sensitised to food allergens. However, regardless of

the degree of sensitisation, it is known that persistent allergen exposure to an allergen that a child is

already sensitised will certainly increase symptoms and exacerbations32 particularly when they have

a viral infection33. It is therefore essential that allergen exposure is minimised in all patients with

difficult asthma, and objective evidence of allergen exposure and methods of reduction can often

only be achieved by a nurse led home visit. Important perennial allergens that can be avoided

include house dust mite, moulds and pet dander. All of these are associated with increased

symptoms in children with asthma that is poorly controlled34 and basic strategies to minimise

exposures must be undertaken before any escalation of therapy35.

4.2 Exposure to air pollution

Air pollution is increasingly recognised to contribute to lung health, and importantly has been shown

to have an impact on acute symptoms and severity of asthma in childhood especially those living in

urban areas36. Although a reduction in exposure to ambient air pollution can only be addressed at a

public health level, consideration for the individual child is important because of known interactions

between aeroallergen and pollution exposure37. Hospitalisation for asthma is increased with

aeroallergen exposure, but this effect is enhanced on days of high pollution levels38. It is therefore

important to minimise all allergen exposures in order to achieve better daily symptom control and

minimise exacerbations in children with difficult asthma.

5. Psychosocial factors

Although it is known that psychological factors contribute to asthma severity, published evidence

that summarises the size of the problem in children with difficult asthma is scarce. A review of the

literature on the prevalence of psychopathology in difficult asthma has shown that almost half of all

patients with difficult asthma has psychopathology at the syndrome and symptom level 39.

Disappointingly, none of the studies included children. Thus, the actual prevalence of

psychopathology, its contribution to asthma symptoms or the effects of any interventions in children

with difficult asthma remain largely unknown. A single centre, retrospective review of a staged

investigation protocol of problematic severe asthma showed psychosocial factors contributed to

difficult asthma in 48% of children12, bearing an uncanny resemblance to the prevalence rates

reported in adults. The paediatric literature remain sparse in data relating to types of interventions

or efficacy of interventions. However, it is apparent from adult studies that spending time identifying

the role of psychological factors in contributing to persistent symptoms, especially in the presence of

good adherence, is critical, since a mislabel of severe asthma may simply lead to significant adverse

effects of inappropriate medications with no impact on symptoms40. Several contrasting reasons

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may underlie psychological presentations and the importance of identifying these and undertaking

an intervention such as cognitive behavioural therapy has been reported41. An important role for the

psychologist is also to address factors contributing to non-adherence42. Interventions may not bear

fruit quickly and the impact on healthcare resources is not small as many clinics do not have access

to psychology input. However, it has to be understood that a specialist service for the management

of paediatric difficult asthma can only be accredited as such if there is a psychologist that forms an

integral part of the MDT. Without such expertise, misdiagnosis and mismanagement will continue.

6. Dysfunctional breathing

Dysfunctional breathing, including breathing pattern disorder, vocal cord dysfunction and

hyperventilation, is an important consideration in children with Problematic Severe Asthma and is

associated with worse asthma control43. The prevalence of dysfunctional breathing in children is

almost certainly under-estimated. Dysfunctional breathing may co-exist with asthma or be the main

driver of symptoms in those with little objective evidence of asthma. A breathing pattern assessment

by an appropriately trained paediatric physiotherapist is an important part of the workup of children

with Problematic Severe Asthma. Breathing re-training is recommended for adults with severe

asthma (BTS/SIGN) and is supported by good quality evidence; unfortunately there is a paucity of

data in children44. However, the importance of physiotherapy cannot be overlooked and a

respiratory physiotherapist is an essential member of the MDT. An approach including education,

self-management, exercise and advice regarding diet, posture and airway hygiene in addition to

breathing re-training can be extremely beneficial. Close collaboration between physiotherapy and

psychology is particularly important for those with anxiety disorders causing hyper ventilation and

panic attacks.

7. Regular follow-up and longitudinal assessment of outcomes

The modifiable factors that result in a child having difficult asthma may be identified extremely

efficiently if the MDT approach described is adopted (Figure 2). However, what remains equally

important is the continuing assessment and follow-up of patients with difficult asthma in order to

ensure:

1. Maintenance therapy is reduced to the minimal amount needed to achieve control

2. Symptoms do improve after all modifiable factors have been addressed, and there is no

progression to true severe asthma – either after short term follow-up or in the longer term

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3. The basics of inhaler technique / device / adherence / allergen exposure are all being

maintained

An asthma education programme delivered by members of the MDT may be an approach that can

be used to reinforce all of the basics of management. However, this requires significant resources,

and at present cannot be recommended as there are no data showing the benefit of an education

programme for difficult asthma in children.

A retrospective analysis of follow-up of children with difficult asthma for up to six years revealed

that those in whom underlying modifiable factors were identified and addressed had an

improvement in lung function and reduction in exacerbations over time, while being able to reduce

maintenance dose of inhaled steroids such that the majority fell below the threshold for problematic

severe asthma5. However, there was a large drop out in the number of patients that could be traced

for the full 6 years, highlighting the need for better prospective longitudinal data of outcomes for

children with difficult asthma. These missing data are essential in light of recent cohort studies that

have followed children with severe asthma to adulthood and shown the irreversible reduction in

lung function and prevalence of COPD45.

8. Expert Commentary

The overall approach to the management of a child with problematic severe asthma is to confirm the

diagnosis, exclude underlying modifiable factors that contribute to difficult asthma, and only after

those have been addressed to confirm a diagnosis of true severe therapy resistant asthma14.

Identifying and managing difficult asthma is essential before progressing to invasive investigations

and introducing additional therapies such as monoclonal antibody therapies. The approach to the

diagnosis and management of difficult asthma is not a simple one and involves numerous

professionals with varied expertise, it involves a large amount of time and investment of significant

healthcare resources. However, if this initial step is not taken with due diligence and if factors

contributing to a child’s asthma being difficult are missed, the potential resulting impact on

resources is even greater since the child will continue to have admissions, exacerbations, costs of

inappropriate expensive medications and significant adverse effects from inappropriate medications.

A specialist service for paediatric difficult asthma now needs to be recognised as being mandatory

and integral to the care of patients with problematic severe asthma, in a similar manner to the

accepted requirement for specialist services for managing cystic fibrosis.

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9. Five-year view

A universal acceptance and clear understanding of the distinctions between the terms problematic

severe asthma, difficult asthma and true, severe asthma needs to be achieved. Specialist, multi-

disciplinary clinical services that manage children with problematic severe asthma need to be

accepted as a mandatory requirement, and funding to allow the resources needed to deliver these

services need to be made available. A key factor for the next five years is to establish an annual

assessment of all patients, whether they have difficult or true, severe asthma, in order to ensure the

basics of asthma management continue to be addressed and to monitor potential progression from

difficult asthma to true, severe asthma and the need for additional therapies. Poor lung function and

recurrent exacerbations will contribute to poor long term outcome, making an annual assessment

essential to avoid missing factors that may indicate disease progression. Studies that investigate the

efficacy of paediatric interventions, especially to improve adherence are needed. Finally, data

indicating the long term, outcome in adulthood for children that have difficult or true, severe asthma

is urgently needed. Only this information will allow the efficacy of investment in specialist services in

childhood to be justified.

10. Key issues in the management of childhood difficult asthma

Confirm the diagnosis

Treat associated diagnoses, especially allergic rhinitis

Identify and address the obvious basics of asthma management: inhaler dose, technique,

device, asthma plan, asthma education, adherence check by performing prescription uptake

check, objective evidence of smoke exposure

Identify and address more complex modifiable factors: confirm adherence using electronic

monitoring; home visit for allergen exposure, availability of medication, smoke exposure,

psychosocial factors; school visit

Physiotherapy assessment for dysfunctional breathing

Address adherence in an individualised manner – tailoring the intervention to the reasons

for non-adherence

Regular follow-up of progress with annual review of all basics

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