|Year : 2017 | Volume
| Issue : 1 | Page : 2-10
Asthma: What's new, and what should be old but is not!
Department of Paediatrics, Imperial College; Department of Paediatric Respirology, National Heart and Lung Institute; Royal Brompton and Harefield NHS Foundation Trust, London, UK
|Date of Web Publication||14-Mar-2017|
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP
Source of Support: None, Conflict of Interest: None
Asthma is a common condition, which is commonly, badly diagnosed and badly treated, leading to unnecessary morbidity and even death in childhood, despite which complacency about management at all levels of care persists. Asthma is an umbrella term like anaemia and arthritis and should not be used as an unqualified diagnosis. It is suggested that airway disease should be deconstructed into treatable and untreatable components, such as fixed and variable airflow obstruction and airway inflammation and infection. Every effort should be made to make an objective diagnosis, and treatment should be individualised accordingly. Objective testing for airway inflammation may include determination of atopic status, blood eosinophil count and exhaled nitric oxide; physiological testing includes peak flow measurement, comprising response to exercise and short-acting μ-2 agonists. Most school-age atopic children with recurrent wheeze respond well to low-dose inhaled corticosteroids if these are regularly and correctly administered. The provision of an asthma plan is mandatory. If response is poor, rather than uncritically escalating therapies, a review of adherence and any adverse environmental factor should be considered. Asthma attacks are a red flag sign of a bad prognosis, and should prompt a full review, and changes in the asthma plan as necessary. Also, regular reviews of progress and treatment need are mandatory, even in the well child with asthma. In all contexts, the importance of getting the basic rights cannot be overemphasised; still, asthma deaths are attributed to neglect of this principle. Other issues discussed in this review include the approach to the child who is breathless on exercise and the diagnosis of exercise-induced laryngeal obstruction; the so-called habit/honk cough; the problem of breathlessness and airway disease in the obese child, including the airway as the target of systemic inflammation; and the problem of 'asthma' complicating other airways diseases such as cystic fibrosis and extrapulmonary diseases such as sickle-cell anaemia. Overall, the main message of this review is that it should never be forgotten that asthma is a disease which kills children and should always be taken seriously.
Keywords: Atopy, cough, eosinophil, exercise-induced laryngeal obstruction, exhaled nitric oxide, obesity, peak flow
|How to cite this article:|
Bush A. Asthma: What's new, and what should be old but is not!. Pediatr Respirol Crit Care Med 2017;1:2-10
| Introduction|| |
Asthma is one of the most common conditions in children, and in many parts of the world, it is probably managed with more complacency and less care and attention to detail than almost any other illness. All paediatricians and primary care physicians think that they can diagnose and manage asthma, many without thinking they actually need to do any objective testing, and the result is often the prescribing of unnecessary, potentially hazardous and expensive treatments to normal children, and sometimes tragically, preventable death as a result of mismanagement. The trivialising of the diagnosis of asthma, as a result of overdiagnosis both in primary  and secondary care, has led to attention being diverted away from children at high risk. The purpose of this review is to describe some of the pitfalls to be avoided in school-age children; although many of the same principles apply to preschool wheeze, this will not be discussed in this article. The underpinning message is that asthma is a potentially fatal disease, which needs to be treated with respect by families and paediatricians. Unfortunately, many general principles of basic care which were delineated years ago, and should be yesterday's news, are still not being applied, hence the present study was conducted.
| What Is This Thing Called 'asthma'?|| |
Asthma is no more than an umbrella term, covering a multiplicity of airway diseases, not unlike 'anaemia' and 'arthritis' in terms of lack of specificity. It is better as far as possible to consider the components of the airway disease in the individual child. These are as follows:
- Fixed airflow obstruction: This may be developmental  or secondary to airway remodelling. This is not treatable but is overtreatable. There is no point escalating treatment to try to reverse the irreversible
- Variable airflow obstruction: This is usually secondary to airway smooth muscle constriction in asthma, but bronchoconstriction is not specific to asthma, and variable obstruction may be due to other causes such as airway mucus
- Airway inflammation: In children with asthma, this is usually eosinophilic but may be absent. In our hands, neutrophilic inflammation suggests an alternative diagnosis such as cystic fibrosis 
- Airway infection: This is usually in the context of an acute attack of asthma and traditionally was thought to be viral. However, bacterial infection is at least as common as viral in this context. However, whether bacterial infection is causative of attacks or secondary to a transient airway immunosuppression by viruses is not clear
- Other components of airway disease, which are uncommon in childhood asthma and will not be discussed further, are altered airway sensitivity leading to enhanced or blunted cough, and altered airway liquid. This may manifest as a dehydrated airway, for example, cystic fibrosis, or rarely an overhydrated one as in pseudohypoaldosteronism, and also increased airway mucus disproportionate to any irritant stimulus.
It is better to consider the components of airway diseases, and especially what is treatable, rather than use antiquated umbrella terms. Clearly, the extent of documentation of these different components will vary with the severity of the presenting illness, the context in which the child is seen and the response to simple treatment. However, it is a useful discipline at least mentally to consider the nature of the airway disease being treated
| Diagnosis of Asthma|| |
The first issue is to determine whether the child has a disease at all, and if so, whether it is an airways disease. The diagnosis of 'normal child' is the hardest of all and requires the most experience. All children have intermittent respiratory symptoms; a normal child may have more than ten colds and three attacks of otitis media in a year, and troublesome respiratory symptoms often last for more than 2 weeks after the start of a cold, which may be a surprise to first-time parents. Clearly, a selective approach to diagnostic testing is required. Asthma should be suspected if there is significant breathlessness, wheeze and sometimes cough. If there is no breathlessness, the child does not have asthma; of course, there are many more causes of breathlessness than asthma. Wheeze is a term that is frequently used imprecisely by families and children,,,, and it is important to determine exactly what noise is being described; a video questionnaire may help,, or even asking the parents to video in attack of wheeze (discussed in more detail below). Isolated dry cough is rare if ever due to asthma and is normally non-specific in a community setting. Although cough variant asthma exists, it has undoubtedly been overdiagnosed in the past. There may be a history of other atopic disorders, including eczema, allergic rhinitis and food allergy, and a positive family history of asthma and atopy in first-degree relatives.
There is a wide differential diagnosis of asthma, and clinical history and examination must be used to determine what focused testing is indicated. Important alerts that another diagnosis needs to be considered are given in [Table 1], and a scheme of differential diagnosis is shown in [Table 2]. In particular, chronic productive cough (daily cough for 8 weeks) is rarely due to asthma, and alternative diagnoses must be sought. It should be stressed that a 'do every test in every child' approach is incorrect.
|Table 1: Diagnostic clues on history or examination suggesting that there is a diagnosis to be made|
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If the paediatrician feels a diagnosis of asthma is likely, then further testing to establish the diagnosis is mandatory in school-age children. In what other chronic disease in which objective testing can be performed is long-term treatment instituted without performing those tests? Blind treatment of a putative diagnosis of asthma in school-age children is inexcusable. It is accepted that not all tests are available in every setting, but some tests are available in all but the most deprived settings. These can be divided into tests characterising the presence and nature of any inflammation and tests documenting the presence and temporal variability of airway obstruction. None is diagnostic of asthma, but the general principle should be that the more tests are negative, the more carefully the possibility of an alternative diagnosis should be considered.
These are largely indirect except in the most severe cases and in specialist settings, where sputum induction and bronchoscopy may be performed.
- Skin prick tests for atopic sensitisation (or more expensively, specific IgE): If a school-age child is not atopic, then eosinophilic airway inflammation is unlikely although not absolutely impossible. Of course, not every atopic child has airway disease
- Blood eosinophil count: There is increasing evidence that peripheral blood eosinophilia reflects airway eosinophilia., This test can be performed on a finger-prick sample. Of course, a raised blood eosinophil count may be a manifestation of other atopic disease, but the absence of peripheral blood eosinophilia is a strong pointer that there is no airway eosinophilia
- Exhaled nitric oxide (FeNO): This is elevated in children who are not prescribed inhaled corticosteroids (ICS), but also in atopy without airway disease.
Underpinning the approach of documenting infection is the principle that there is no point in prescribing anti-inflammatory medications such as corticosteroids if there is no airway inflammation present, any more than anti-hypertensives should be prescribed to patients with a normal blood pressure.
These tests may also be negative if the child is well, but failure to demonstrate any evidence of variable airflow obstruction should call into question the diagnosis of asthma.
Peak flow or preferably spirometry in the consulting room: Both may be normal if the child is well at the time, but if reduced, the acute response to a short-acting β-2 agonist (SABA) should be determinedHome peak flow monitoring: 'Monitoring fatigue' is common so the duration should be kept short, probably no more than 2–4 weeks. Measurements should be made morning and evening. If the child is breathless after exercise at home, a measurement of peak flow should be made. It is legitimate for the child to have SABA during this time, and if administered, peak flow response should be measuredChallenge testing: A field exercise test with peak flow monitoring is available to everyone, albeit it may be non-specific. Histamine and methacholine challenge are the province of special centres; their role is to rule out asthma if the test is normal. A degree of bronchial hyper-reactivity may be seen in normal childrenOral corticosteroid trial, with spirometry or peak flow monitoring, may be legitimate in a child who is thought to have fixed airflow obstruction at baseline or documented very variable airflow obstruction. Neither the dose nor duration of therapy has been standardised in paediatrics. A 5–10-day course of prednisolone 1 mg/kg to a maximum of 40 mg/day is reasonable.
It is perfectly possible to deploy at least some objective testing in any setting to try to confirm or refute a diagnosis of asthma. In any event, the possibility of a wrong diagnosis, no matter how eminent the diagnostician, should always be considered during follow-up, in particular, if there is a poor response to standard therapy.
| Treatment of Paediatric Asthma Characterised by Variable Airflow Obstruction and Presumed Eosinophilic Airway Inflammation|| |
Numerous evidence-based guidelines have been published,, and will not be recapitulated here, beyond noting that, as guidelines have become more evidence based, asthma outcomes (below) remain largely unchanged. The aims of treatment include control of current symptoms, prevention of acute attacks (risk reduction), optimising lung growth (which is still an unmet need; a number of asthmatic children have abnormalities in airway growth) and minimising side-effects of medications. It must be emphasised to the families that asthma is potentially a killing disease which must be taken seriously.
Initial treatment is with intermittent SABA. The decision to escalate to ICS is based on frequency of SABA use, but with no evidence base to guide the actual numbers of doses. If the decision is made to escalate treatment, first-line preventive therapy is ICS. There is a worrying tendency for the combination of ICS and long-acting β-2 agonists (LABA) to be used as first-line prevention. Not merely is there no evidence to support this practice, but it may also actually be deleterious.
If ICS are prescribed, the absolutely key principle is that most children will respond to a dose of fluticasone equivalent of 100 mcg twice daily. The BADGER study  showed that very few children got any benefit from escalating the dose above this level, and furthermore, the benefits of add-on therapy were not striking. Hence, before escalating therapy above this ICS dose, it should be back to basics in a detailed review [Table 3]. The cardinal sin in asthma treatment is escalating treatment uncritically without considering that the whole approach is wrong, or being misapplied, or being held back by environmental or psychosocial factors.
|Table 3: Suggested areas for review before escalating treatment in a child who has not responded to low dose inhaled corticosteroids|
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Of great importance is that an appropriate medication delivery device is selected, and the child and family shown how to use it. Techniques should be checked at every health-care encounter because repeated teaching sessions are usually necessary.
If escalation of treatment beyond low-dose ICS is considered appropriate, the choices include high-dose ICS, ICS plus LABA in a combination inhaler or ICS plus leukotriene receptor antagonist (LTRA). ICS-LABA is more likely to be beneficial, but a trial of ICS-LTRA may be quicker (needs be no longer than 2 weeks) and cheaper in at least some contexts. Previous fears about LABA safety  have largely been laid to rest by a recent big study., If the treatment does not work, it should be discontinued. All too often children remain in primary care, prescribed ICS in moderate to high dose, and LABA and LTRA. Such children by definition have problematic severe asthma  and should have been referred for specialist evaluation much sooner. Treatments such as omalizumab and other monoclonals should only be administered in tertiary care settings, after a detailed evaluation of the child.
Beyond pharmacotherapy – more to life than medicines
It is essential that children with all but the most trivial symptoms have an asthma management plan, with detailed instructions about what to do in the event of deterioration or an asthma attack, which should be based on peak flow measurements. The family need to understand the asthma triggers and what can be done to avoid them; asthma education is essential. The role of peak flow monitoring in the well asthmatic is controversial. It is highly unlikely that children will slavishly measure their peak flow twice a day, every day, but measurements should be made at times of high risk, such as viral colds or unavoidable increase in exposure to allergens to which the child is sensitive, and perhaps a few times a month when the child is well, to ensure that lung function is not drifting imperceptibly. Attention should be paid to the child's environment – passive exposure to tobacco is all too common, and in the UK, to pets to which the child is sensitised. Both can cause relative steroid insensitivity,, and both should be addressed before escalating medications.
Management – iterative not instantaneous
Whatever treatment plan is settled upon, regular review of all aspects of care is essential. It may be possible to reduce treatment if the child is well. Spirometry or peak flow, inhaler technique and height and weight should be measured and plotted on an appropriate centile chart. Asthma knowledge should be checked.
| Asthma Attacks – should Be a 'nearly Never' Event|| |
The word 'exacerbation' does patients a disservice and should not be used, implying as it does that the event is a trivial, and readily recoverable event., In asthma , as with other airway diseases such as cystic fibrosis ,, and primary ciliary dyskinesia, attacks are associated with a less favourable long-term course in terms of evolution of lung function and prognosis, but more importantly, in asthma, they should be a significant immediate red flag as signalling a high risk of future attacks and asthma deaths. In the UK, there has been another National Review of Asthma Deaths  which makes depressing reading. In summary, the lessons of the past have not been heeded and the basics have not been done right, and children have died. Importantly, 57% were not under specialist care, so primary care has to identify those at risk. Using current definitions, 60% of those who died did not have 'severe' asthma (although it is difficult to think of a worse outcome than death!). In primary care, alerts should include those who had been prescribed more than six SABA canisters/year; recent discharge from hospital, especially if they have had a really severe asthma attack; those who have attended emergency departments especially in the previous year; and those who repeatedly do not attend follow-up consultations. All these patients can be readily detected in primary care.
The response to an asthma attack should be an immediate and focussed review. This should include whether recovery is complete – the fixed course of 3 or 5 days of prednisolone may not have been sufficient. The seriousness of the situation must be stressed to the family. The events around the attack should be reviewed in detail. Was the asthma plan followed, and should it be modified in any way? Was the attack monitored objectively with peak flow measurements, both by the family and also in the emergency care facility? Do the family understand the triggers for asthma, including smoking if this is a factor? Is their asthma undertreated  – baseline control may not have been as good as it should have been. Prescription uptake should be reviewed as a marker of adherence; for sure, merely collecting a prescription does not equate to inhaling the medication correctly, but failure to collect any prescription certainly does not inspire confidence in adherence! A big uptake of SABA canisters is another warning sign. Technique with the medication delivery device must be checked. There should be a review of previous attendances – is there a history of failing to bring the child, or psychosocial factors such as denial or disorganisation within the family? Should the child be referred for a specialist assessment? The importance of asthma attacks as a signal event cannot be overstressed.
What is very clear is that we can make a difference with proper management. The stellar example is from Finland, where attention to education of the families and professionals, and the aggressive use of ICS drove down asthma morbidity and mortality. Although pharmacological treatment costs rose, the overall cost of asthma, counting days lost from work and other health-care costs, and overall the fiscal burden of asthma fell.
Having been the basics of good asthma care covered above, the remainder of this review covers airways disease in special circumstances: Unexplained breathlessness on exercise, habit cough, the obese asthmatic and asthma complicating other airways diseases.
| Breathless on Exercise – but Is it Really Asthma?|| |
Exercise-induced bronchoconstriction is a common feature of poorly controlled asthma and usually comes on a few minutes after exercise. It is usually abolished by pre-exercise SABA and improvement of baseline asthma control. However, it is a cardinal error to assume that just because a child with even correctly diagnosed asthma is breathless, the cause of the breathlessness is asthma; it would be just as logical to assume firefighters are arsonists just because they are found at the site of fires. The differential diagnosis of exertional breathlessness is shown in [Table 4].
A common misdiagnosis is exercise-induced laryngeal obstruction (EILO), which may also complicate asthma. Typically, the symptoms of EILO are seen in high-achieving athletes and come on during exercise. Characteristically, the sound heard is stridor, not the expiratory polyphonic wheeze typical of asthma, and the pathophysiology is of vocal cord adduction or various types of laryngeal and supraglottic obstruction, which of course do not respond to asthma treatments. A video recording of an episode may be very informative. If direct confirmation of the diagnosis is needed, laryngoscopy can be performed during most exercise  (such as running and rowing, but perhaps not swimming!) and the laryngeal abnormalities demonstrated to the patient. EILO may also be late sequelae of neonatal laryngomalacia  and is also described in survivors of preterm delivery who have left recurrent laryngeal nerve damage secondary to surgical ligation of the ductus arteriosus in the neonatal period.
The most important survey of exercise-induced breathlessness was recently carried out in Norway. The authors performed a questionnaire study in 3838 adolescents; the prevalence of exercise-induced bronchoconstriction was 19.2%, and of EILO 5.7%. A sub-sample (n = 99 with exercise dyspnoea, n = 47 without) underwent standard treadmill exercise-induced bronchoconstriction and EILO tests (the latter including laryngoscopy on exercise). Nearly half the patients had neither exercise-induced asthma nor EILO, but many were being prescribed SABAs and other asthma medications; they were presumably deconditioned, but they were not more obese than the rest of the group. Six per cent of patients had isolated EILO, 5% had EILO and exercise-induced bronchoconstriction and the remainder had exercise-induced bronchoconstriction alone. The message of this large study is that exercise-induced asthma is overdiagnosed and, rather than escalating treatment for asthma when the patient complains of exercise dyspnoea, it is vital to understand the root cause of the problem.
| 'habit' Cough|| |
As discussed above, cough on its own is rarely if ever due to asthma, but it is often treated as such with escalating doses of ICS. A variant which is particularly prone to this is 'habit' (sometimes also called 'honk') cough. This is a repeated, loud and explosive cough, non-responsive to any medication, and quite unlike any cough relating to underlying disease. The key question is what happens when the child is asleep? Whereas asthma and most respiratory disorders are worse at night, the habit cough disappears completely. The initial step is to explain the nature of the symptoms, and stop any inappropriate medication. Very often the symptoms will respond to intervention from a skilled physiotherapist or speech therapist. Occasionally, they may be a manifestation of some deep-rooted problem, such as impending parental divorce, and then the intervention of a psychologist may be helpful.
| The Obese Breathless Child: Asthma or Not?|| |
Obesity is overtaking us as a major epidemic. Globally, in 2013, there were an estimated more than 42 million overweight children under age 5 years age, and it is estimated that this will rise to more than 70 million by 2025. The majority of overweight children live in developing countries; stunting is well known as being caused by poverty, but poverty also results in the consumption of cheap junk food, and hence obesity. Obesity may be part of a constellation of adverse factors, including smoking, poverty and overcrowding, and it may be difficult to determine causality of a particular factor.
Important information comes from the ISAAC study. They reported on 10,652 children aged 8–12 years from 16 affluent and 8 non-affluent centres, using ISAAC phase two methodology. Both being overweight (OR 1.14, 95% confidence intervals [CIs] 0.98; 1.33) and obese (OR 1.67, 1.25; 2.21) related to wheeze. Both being overweight and obese were associated with a reduction in forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC); −0.90 (−1.33%; −0.47%) for being overweight and −2.46% (3.84%; −1.07%) for being obese. There was no association with any other objective markers including atopy. The lack of association with atopy must mean either they were a reporting non-asthma sound, which is perfectly feasible, or the asthma of obesity is a different phenotype to the usual childhood atopic asthma. However, in another study, obese children with asthma were more likely to be admitted, and more likely to go to the intensive care unit, suggesting an association of obesity with asthma severity and/or treatment resistance. This latter was supported by data from the CAMP study, which suggested that obese asthmatic children had a worse response to ICS treatment than lean children.
There are increasing data that obese children may have an airway disease, but it is phenotypically different from atopic asthma. In a recent study, overweight and obese children had a lower FeNO (suggesting that airway eosinophilia was not a feature of their disease) and were less methacholine responsive, but reported increased β agonist use, worse asthma symptoms and more often reported breathlessness rather than wheeze as the primary symptom of an asthma attack. They less often reported cough and displayed poorer 'asthma' control and a distinct pattern of symptoms. The authors pointed out that the obese asthmatic may falsely attribute exertional dyspnoea to asthma rather than deconditioning, leading to excess rescue medication use, and clearly measuring what actually happens on exercise (bronchoconstriction vs. fatigue, above) is especially crucial in the obese.
There are pathophysiological data suggesting that obesity-asthma is a distinct condition. Dysanapsis is defined as normal flows in large lungs, so FEV1 is normal or high, and FVC is high, so the FEV1/FVC ratio is reduced. Airway length but not airway calibre is thought to be determined by lung size. The hypothesis that obesity may lead to dysanapsis was tested in six separate cohorts pooled (4 with longitudinal data). The authors calculated body mass index (BMI) and looked at asthma outcomes. Four thousand one hundred and twenty-one children, aged 6–20 years, 1084 of whom were dysynaptic, were studied. They found that obesity was associated with greater likelihood of dysanapsis, and this was associated with a lower FEV1 and higher total lung capacity, and with severe exacerbations (hazard ratio 1.95, 95% CIs 1.38–2.75) and use of systemic steroids (3.22, 2.05–5.14). The interpretation of these data is not easy, but these anatomical changes are not likely to be susceptible to ICS therapy. Whether obesity is associated with eosinophilic airway inflammation is controversial,, and again atopic status, blood eosinophil count and preferably exhaled nitric oxide should be measured before escalating treatment with ICS.
An interesting and novel concept is the airway as the target of systemic inflammation. Obesity and obstructive sleep apnoea are both pro-inflammatory states, and recent data suggested that interleukin-6 (IL-6) in particular could be an important mediator of airway damage. Two cohorts of adult patients were studied, a total of 636 in all. Blood IL-6 was measured as a marker of systemic inflammation and related to asthma outcomes. 111/138 IL-6 high asthmatics were obese, and 178/289 of obese asthma patients were IL-6 low. Metabolic dysfunction as measured by IL-6 was not exclusive to the obese, but irrespective of BMI, IL-6 high patients had worse outcomes, which were not mediated via type 2 inflammation.
The treatment of the airway disease of obesity should clearly start with weight reduction, either dietary, with the aid of pharmacotherapy  or with bariatric surgery. Three groups were compared in a longitudinal study in adults: Asthma and bariatric surgery (n = 27), bariatric surgery no asthma (n = 39) and asthma not treated with bariatric surgery (n = 12). Patients undergoing bariatric surgery lost weight, improved their FEV1 and small airway function (especially if they were asthmatic); those with asthma who underwent bariatric surgery improved airway hyper-responsiveness, but changes in inflammatory profile were merely minor reduction in airway mast cell numbers. As well as weight reduction, it is clearly essential to be clear (a) that the symptoms reported are truly due to an airway disease and (b) what are the treatable components of that airway disease.
| Asthma Plus – does it Exist?|| |
The final topic is how to answer the vexed question of diagnosing 'asthma' in the presence of another disease which may be airway based (e.g., cystic fibrosis) or systemic (e.g., sickle-cell anaemia). The question immediately becomes meaningless if the asthma label is abandoned and the airway disease is described in terms of its component parts. There are many causes of airway obstruction in childhood, some of which are summarised in [Table 5]. Hence, for example, instead of asking 'does this cystic fibrosis patient have evidence of asthma?', the proper question is does this cystic fibrosis patient have evidence of eosinophilic airway inflammation which would justify the prescription of ICS?'. This then guides the response – is the child atopic, what is the exhaled nitric oxide, what is the peripheral blood eosinophil count and are there eosinophils present in spontaneously expectorated or induced sputum. The same approach can be used in, for example, the survivors of preterm birth. Instead of asking 'do they have asthma?', the airway disease is characterised. This shows evidence of fixed and bronchodilator responsive airflow obstruction, but no evidence of type 2 inflammation., Hence, treatment should be with bronchodilators and not ICS. Similarly, with sickle-cell anaemia, our data  showed fixed airflow obstruction, but no increase in atopy, evidence of allergic sensitisation or elevation of exhaled nitric oxide, suggesting that the airway phenotype will be resistant to conventional asthma therapies. Thus, the approach of defining treatable components of airway disease rather than sterile debates about umbrella terms is an approach that is widely applicable in paediatric airway disease.
|Table 5: Some causes of airway obstruction in school age children, deconstructed and with proposed treatments|
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| Summary and Conclusions|| |
The term asthma has outlived its usefulness as an unqualified diagnosis, and the era of diagnosing and treating this disease with potent ICS without any objective diagnostic testing or monitoring should have long passed. This review proposes deconstructing the components of airway disease and identifying treatable and untreatable components to individualise treatments. Asthma attacks are important red flag events and should lead to a detailed review of all aspects of care. This approach is applicable to all forms of airway disease, including the vexed question of 'asthma' complicating other airway diseases such as cystic fibrosis and systemic disease such as sickle-cell anaemia and is the first step to personalised care of many airway diseases. Ultimately, the target should be to identify abnormal pathways driving disease, and use specific molecular treatments rather than non-specific anti-inflammatory medications such as ICS. However, while looking to the future of pathway-based, designer molecule therapy for individually characterised airway disease, it should never be overlooked that at the present time, asthma is a disease which kills children, and getting the basics of care right is essential.
Financial support and sponsorship
Andrew Bush is an NIHR Senior Investigator and additionally was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bush A, Fleming L. Is asthma overdiagnosed? Arch Dis Child 2016;101:688-9.
Looijmans-van den Akker I, van Luijn K, Verheij T. Overdiagnosis of asthma in children in primary care: A retrospective analysis. Br J Gen Pract 2016;66:e152-7.
Martin MJ, Wilson E, Gerrard-Tarpey W, Meakin G, Hearson G, McKeever TM, et al.
The utility of exhaled nitric oxide in patients with suspected asthma. Thorax 2016;71:562-4.
Bush A, Nagakumar P. Preschool wheezing phenotypes. Eur Med J 2016;1:93-101.
Bisgaard H, Jensen SM, Bønnelykke K. Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med 2012;185:1183-9.
Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al.
Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007;176:858-64.
Bossley CJ, Fleming L, Gupta A, Regamey N, Frith J, Oates T, et al.
Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol 2012;129:974-82.e13.
Bisgaard H, Hermansen MN, Bønnelykke K, Stokholm J, Baty F, Skytt NL, et al.
Association of bacteria and viruses with wheezy episodes in young children: Prospective birth cohort study. BMJ 2010;341:c4978.
Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC. Increased airway epithelial Na+absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004;10:487-93.
Kerem E, Bistritzer T, Hanukoglu A, Hofmann T, Zhou Z, Bennett W, et al.
Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med 1999;341:156-62.
Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, et al.
Treatable traits: Toward precision medicine of chronic airway diseases. Eur Respir J 2016;47:410-9.
Thompson M, Vodicka TA, Blair PS, Buckley DI, Heneghan C, Hay AD; TARGET Programme Team. Duration of symptoms of respiratory tract infections in children: Systematic review. BMJ 2013;347:f7027.
Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Pedersen TM, Vinding RK, et al.
Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: A randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016;4:19-26.
Cane RS, McKenzie SA. Parents' interpretations of children's respiratory symptoms on video. Arch Dis Child 2001;84:31-4.
Elphick HE, Sherlock P, Foxall G, Simpson EJ, Shiell NA, Primhak RA, et al.
Survey of respiratory sounds in infants. Arch Dis Child 2001;84:35-9.
Saglani S, McKenzie SA, Bush A, Payne DN. A video questionnaire identifies upper airway abnormalities in preschool children with reported wheeze. Arch Dis Child 2005;90:961-4.
Levy ML, Godfrey S, Irving CS, Sheikh A, Hanekom W, Bush A, et al.
Wheeze detection: Recordings vs. assessment of physician and parent. J Asthma 2004;41:845-53.
Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance of cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996;75:489-93.
Shields MD, Bush A, Everard ML, McKenzie S, Primhak R; British Thoracic Society Cough Guideline Group. BTS guidelines: Recommendations for the assessment and management of cough in children. Thorax 2008;63 Suppl 3:iii1-15.
Pavord ID, Agusti A. Blood eosinophil count: A biomarker of an important treatable trait in patients with airway disease. Eur Respir J 2016;47:1299-303.
Jochmann A, Artusio L, Robson K, Nagakumar P, Collins N, Fleming L, et al.
Infection and inflammation in induced sputum from preschool children with chronic airways diseases. Pediatr Pulmonol 2016;51:778-86.
Piacentini GL, Bodini A, Costella S, Vicentini L, Mazzi P, Sperandio S, et al.
Exhaled nitric oxide and sputum eosinophil markers of inflammation in asthmatic children. Eur Respir J 1999;13:1386-90.
Leuppi JD, Downs SH, Downie SR, Marks GB, Salome CM. Exhaled nitric oxide levels in atopic children: Relation to specific allergic sensitisation, AHR, and respiratory symptoms. Thorax 2002;57:518-23.
Redline S, Wright EC, Kattan M, Kercsmar C, Weiss K. Short-term compliance with peak flow monitoring: Results from a study of inner city children with asthma. Pediatr Pulmonol 1996;21:203-10.
Powell CV, White RD, Primhak RA. Longitudinal study of free running exercise challenge: Reproducibility. Arch Dis Child 1996;74:108-14.
Lex C, Payne DN, Zacharasiewicz A, Li AM, Nicholson AG, Wilson NM, et al.
Is a two-week trial of oral prednisolone predictive of target lung function in pediatric asthma? Pediatr Pulmonol 2005;39:521-7.
Sweeney J, Patterson CC, O'Neill S, O'Neill C, Plant G, Lynch V, et al.
Inappropriate prescribing of combination inhalers in Northern Ireland: Retrospective cross-sectional cohort study of prescribing practice in primary care. Prim Care Respir J 2014;23:74-8.
Sorkness CA, Lemanske RF Jr., Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al.
Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: The Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2007;119:64-72.
Lemanske RF Jr., Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, et al.
Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010;362:975-85.
Bush A, Saglani S. Management of severe asthma in children. Lancet 2010;376:814-25.
Bush A, Fleming L. Diagnosis and management of asthma in children. BMJ 2015;350:h996.
Kamps AW, van Ewijk B, Roorda RJ, Brand PL. Poor inhalation technique, even after inhalation instructions, in children with asthma. Pediatr Pulmonol 2000;29:39-42.
von Mutius E, Drazen JM. Choosing asthma step-up care. N Engl J Med 2010;362:1042-3.
Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, et al.
Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016;375:840-9.
Bush A, Frey U. Safety of long-acting beta-agonists in children with asthma. N Engl J Med 2016;375:889-91.
Bush A, Hedlin G, Carlsen KH, de Benedictis F, Lodrup-Carlsen K, Wilson N. Severe childhood asthma: A common international approach? Lancet 2008;372:1019-21.
Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al.
International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73.
Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, et al.
The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child 2009;94:780-4.
Kobayashi Y, Bossley C, Gupta A, Akashi K, Tsartsali L, Mercado N, et al.
Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest 2014;145:305-12.
Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest 2008;134:394-401.
FitzGerald JM. Targeting lung attacks. Thorax 2011;66:365-6.
Bush A, Pavord I. Following Nero: fiddle while Rome burns, or is there a better way? Thorax 2011;66:367.
O'Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW; START Investigators Group. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009;179:19-24.
Belgrave DC, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A. Trajectories of lung function during childhood. Am J Respir Crit Care Med 2014;189:1101-9.
Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010;182:627-32.
Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol 2011;46:393-400.
Waters V, Stanojevic S, Atenafu EG, Lu A, Yau Y, Tullis E, et al.
Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis. Eur Respir J 2012;40:61-6.
Sunther M, Bush A, Hogg C, McCann L, Carr SB. Recovery of baseline lung function after pulmonary exacerbation in children with primary ciliary dyskinesia. Pediatr Pulmonol 2016;51:1362-6.
Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al.
The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-6.
Chipps BE, Zeiger RS, Borish L, Wenzel SE, Yegin A, Hayden ML, et al.
Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2012;130:332-42.e10.
Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, et al.
A 10 year asthma programme in Finland: Major change for the better. Thorax 2006;61:663-70.
Davis RS, Brugman SM, Larsen GL. Use of videography in the diagnosis of exercise-induced vocal cord dysfunction: A case report with video clips. J Allergy Clin Immunol 2007;119:1329-31.
Maat RC, Hilland M, Røksund OD, Halvorsen T, Olofsson J, Aarstad HJ, et al.
Exercise-induced laryngeal obstruction: Natural history and effect of surgical treatment. Eur Arch Otorhinolaryngol 2011;268:1485-92.
Panchasara B, Nelson C, Niven R, Ward S, Hull JH. Lesson of the month: Rowing-induced laryngeal obstruction: A novel cause of exertional dyspnoea: Characterised by direct laryngoscopy. Thorax 2015;70:95-7.
Hilland M, Røksund OD, Sandvik L, Haaland Ø, Aarstad HJ, Halvorsen T, et al.
Congenital laryngomalacia is related to exercise-induced laryngeal obstruction in adolescence. Arch Dis Child 2016;101:443-8.
Røksund OD, Clemm H, Heimdal JH, Aukland SM, Sandvik L, Markestad T, et al.
Left vocal cord paralysis after extreme preterm birth, a new clinical scenario in adults. Pediatrics 2010;126:e1569-77.
Johansson H, Norlander K, Berglund L, Janson C, Malinovschi A, Nordvall L, et al.
Prevalence of exercise-induced bronchoconstriction and exercise-induced laryngeal obstruction in a general adolescent population. Thorax 2015;70:57-63.
Weinmayr G, Forastiere F, Büchele G, Jaensch A, Strachan DP, Nagel G; ISAAC Phase Two Study Group. Overweight/obesity and respiratory and allergic disease in children: International study of asthma and allergies in childhood (ISAAC) phase two. PLoS One 2014;9:e113996.
Carroll CL, Stoltz P, Raykov N, Smith SR, Zucker AR. Childhood overweight increases hospital admission rates for asthma. Pediatrics 2007;120:734-40.
Forno E, Lescher R, Strunk R, Weiss S, Fuhlbrigge A, Celedón JC; Childhood Asthma Management Program Research Group. Decreased response to inhaled steroids in overweight and obese asthmatic children. J Allergy Clin Immunol 2011;127:741-9.
Lang JE, Hossain MJ, Lima JJ. Overweight children report qualitatively distinct asthma symptoms: Analysis of validated symptom measures. J Allergy Clin Immunol 2015;135:886-93.e3.
Forno E, Weiner DJ, Mullen J, Sawicki G, Kurland G, Han YY, et al.
Obesity and airway dysanapsis in children with and without asthma. Am J Respir Crit Care Med 2017;195:314-23.
Desai D, Newby C, Symon FA, Haldar P, Shah S, Gupta S, et al.
Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med 2013;188:657-63.
van Huisstede A, Rudolphus A, van Schadewijk A, Cabezas MC, Mannaerts GH, Taube C, et al.
Bronchial and systemic inflammation in morbidly obese subjects with asthma: A biopsy study. Am J Respir Crit Care Med 2014;190:951-4.
Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, et al.
Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: A cross-sectional analysis of two cohorts. Lancet Respir Med 2016;4:574-84.
Coles N, Birken C, Hamilton J. Emerging treatments for severe obesity in children and adolescents. BMJ 2016;354:i4116.
van Huisstede A, Rudolphus A, Castro Cabezas M, Biter LU, van de Geijn GJ, Taube C, et al.
Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma. Thorax 2015;70:659-67.
Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, et al.
Lung function and respiratory symptoms at 11 years in children born extremely preterm: The EPICure study. Am J Respir Crit Care Med 2010;182:237-45.
Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005;171:68-72.
Carraro S, Piacentini G, Lusiani M, Uyan ZS, Filippone M, Schiavon M, et al.
Exhaled air temperature in children with bronchopulmonary dysplasia. Pediatr Pulmonol 2010;45:1240-5.
Chaudry RA, Rosenthal M, Bush A, Crowley S. Reduced forced expiratory flow but not increased exhaled nitric oxide or airway responsiveness to methacholine characterises paediatric sickle cell airway disease. Thorax 2014;69:580-5.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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