Summary

Asthma and related wheezing disorders are very common in the childhood period. In Hong Kong, approximately 10% of children suffer from asthma. Recently published longitudinal studies have provided important information regarding the natural history of different phenotypes of wheezing disorders in the early childhood period. Advances in both technical equipment and the skills available have enabled us to measure various parameters of lung function even in preschool children and infants. With the improvement in the methodology of non-invasive monitoring of airway inflammation such as exhaled nitric oxide measurement, it is now possible to monitor asthma treatment objectively in addition to the patient's reported severity of symptoms. Although the currently available medications are highly effective in controlling the disease in most asthmatic children, under-treatment remains a significant problem. With further understanding of the underlying genetic determinants of asthma and the variable responses to drug therapy, it may be possible to stratify our asthmatic population. In doing so, the most appropriate combination treatment according to their genetic makeup may be prescribed in the not too distant future.

摘要

哮喘和其他喘鳴病在兒童期很常見。香港約有10%的兒童患有哮喘。最近出版的一個縱向研究，提供了不同種類喘鳴病早期兒童自然發展史的重要資料。由於科學儀器和技術的進步，我們能夠量度各種不同的肺功能參數，甚至學令前或嬰兒也可以測量。採用非侵入性監控氣管炎的方法，例如，量度呼出一氧化氮的濃度，可以在分析病人主觀症狀的嚴重程度的基礎上，客觀地監控哮喘病的治療情況。雖然現有藥物可以很有效地控制哮喘絕大部份兒童哮喘，但治療不足還是一個重要的問題。深入研究哮喘的致病和對不同藥物的遺傳基因後，在不久的將來，我們可以依照病的遺傳因子，給予針對性的混合治療。

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Introduction

Wheezing is a very common complaint in early childhood. It is also one of the most important presenting symptoms of a child with asthma. There are many other conditions however which can result in airway obstruction and wheezing that the physician in his or her daily practice should be aware of.

The diagnosis of childhood asthma and related wheezing conditions are primarily based on the clinical history and the physical examination. A broad knowledge of the possible differential diagnoses and an exhaustive clinical history including frequency and severity of the symptoms, exacerbating factors, response to treatment, and family history of atopy are of paramount importance in helping to confirm this diagnosis. On physical examination, one should be looking for signs of chronic lung disease due to poorly controlled asthma or other stigmata suggestive of an alternate diagnosis such as bronchiectasis. In selected patients further investigations may be needed to differentiate asthma from other wheezing disorders or chronic respiratory conditions.

Over the past 2 decades, several large longitudinal studies have been performed and these have provided important information regarding the natural history of various childhood wheezing disorders. Significant advances in lung function testing in young children have also been seen. Both short and long term clinical trial results have provided evidence for the formulation of treatment guidelines to help clinicians in the selection of the best possible care for children with asthma and wheezing disorders. In this paper, we will review the recent advances in the treatment and monitoring of these disorders.

Differential diagnoses and phenotypes of childhood wheezing disorders

The differential diagnosis for recurrent wheezing disorder in early childhood is numerous. Practitioners often find making a definitive diagnosis challenging. Acute bronchiolitis is one of the more common diagnoses in early childhood.¹ A child under the age of 2-year-old, may have recurrent episodes of acute bronchiolitis and the cause could be any of the common respiratory viruses, such as respiratory syncytial virus, influenza virus, parainfluenza virus, rhinovirus and adenovirus. Most children get infected either from their elder siblings, school or nursery. Asthma in early childhood is a common condition. As documented by the International Study of Asthma and Allergies in Childhood (ISAAC), the current prevalence of asthma in children in Hong Kong is approximately 10%.^2-4 Accumulating evidence has demonstrated an increase in its prevalence especially in affluent countries.^2-5 Numerous hypotheses have been proposed to explain this increasing trend. These include early-childhood infections and hygiene,⁶ allergen exposure,^7,8 environmental pollution,^9,10 diet and obesity,¹¹ maternal smoking and perinatal risk factors.^12,13 Meanwhile, there is an uncertain relationship between viral infections, episodes of childhood wheezing and true asthma.^14-16 Indeed, it is essential to diagnose asthma early, so that the appropriate treatment can be offered, which may possibly prevent irreversible airway remodeling.^17-20 Risk factors such as atopic history, genetic or familial factors, prematurity should be identified.^21-27 Chart reviews can be surprisingly helpful, as some of the typical features of asthma, such as the pattern of exacerbation, recurrent wheezy attacks, good response to bronchodilator treatment may then be observed.

Different phenotypes of wheezing illness in early childhood, with its variable prognosis and determinants have been described in recently published epidemiological studies. Particularly, two distinct phenotypes of wheezing illness in children up to the age of 6 years old have been identified.^5,28 The transient early wheezer is characterised by the resolution of wheezing symptoms by 3 years of age. These children have been noted to have preexisting reduced lung function shortly after birth, which is probably due to congenitally smaller airway. These children are also more likely to have a mother who smoked during pregnancy. However, the persistent wheezer whose wheezing attacks persist beyond the first 3 years of life tends to have a normal pulmonary function during the first year of attack but this then decreases by the age of 6. These children are more likely to have other atopic diseases or a positive family history of atopy.

An asthma prediction index was derived based on the data from these longitudinal studies. The major criteria for childhood asthma are: a parental diagnosis of asthma and a personal diagnosis of eczema. The minor criteria are: a personal diagnosis of allergic rhinitis, wheezing apart from upper respiratory infections and blood eosinophilia (4%). Early wheezers (having wheezing within the first three years of life) with at least one major or two minor criterias will have a risk of 2.6-5.5 times likelihood of active asthma between ages 6 and 13 compared to those without.²⁹

For childhood asthmatics not responding to the appropriate anti-asthma treatment, an alternative diagnosis should be considered such as gastro-esophageal reflux disease, immunodeficiency syndrome, foreign body aspiration, and pulmonary infection (pertussis and tuberculosis). Rarely, wheezing in childhood can be due to congenital heart disease with heart failure and structural abnormalities such as vascular malformations and a mediastinal mass.

Investigations for children with wheezing disorders

Certainly, there is no substitute for a good history in clinical medicine. Laboratory tests are sometime required to provide further evidence to support the clinical diagnosis. It should be noted that the majority of asthmatic patients will not need any further investigations if the history and physical examination clearly points towards this diagnosis. Investigations are useful in those who do not respond to appropriate anti-asthma treatment.

In selected cases, laboratory testing can provide means for objectively evaluating the severity and progress of the disease. Asthma that starts in early childhood is commonly associated with atopy. Allergy skin-prick test, measurement of IgE levels and various cellular mediators of inflammation and biomarkers in exhaled breath or sputum at time of onset and before steroid treatment may be helpful in confirming the diagnosis. An abnormal level is supportive of the diagnosis of asthma. These useful tools may also be used to predict the persistence of asthma symptoms in the very young wheezer.

Skin-prick test

The basic principle of this test is to detect the presence of specific IgE bound to the surface of mast cells and basophils.³⁰ A positive test is defined as a local wheal and flare response on the skin where the allergen is applied and absorbed via a pricked epidermis. Although this test is rapid and sensitive, several studies have shown that the reproducibility of response is variable.^30-33 Thus, repeated measurements are needed for the highly suspicious cases who has an initial negative test result. In Hong Kong, many asthmatic children (over 80%) are skin-test positive to common aero-allergens such as house dust mites and cockroach.³⁴

Serum IgE

Serum total IgE is elevated in the majority of patients with atopic disease.³⁵ Serum IgE is extremely low at birth but rises significantly during the first few years of life. The adult level is reached when the child is around 5 years of age. However, the "normal" range of IgE varies widely. Its level depends on the genetic background of the patient as well as the environmental factors. Whilst a level of <20kU/l virtually excludes atopy, a level of >180kU/l makes the diagnosis likely. However, other conditions can also have an elevated IgE level e.g. parasitic infections, Wiskott Aldrich syndrome, hyper-IgE syndrome, aspergillosis, and Hodgkin's lymphoma.

The evaluation of serum-specific IgE by RAST or RIA is less sensitive than skin prick test (SPT). However, this test is extremely valuable for patients who are not suitable for SPT, such as those with extensive eczema, severe allergic reaction provoked by the allergen use in a previous SPT, an inability to stop antihistamine medication and those with dermographism. The serum of the patient is collected and specific IgE in the serum will bind to the allergen. The complex can then be detected by various methods, such as Anti-IgE tagged with enzyme, radioisotope or fluorescein. Its concentration can then be determined by specific counters. As the elevation of IgE is generally associated with atopy, these tests may be useful in supporting the diagnosis of asthma in recurrent wheezers.

Exhaled nitric oxide

Nitric oxide is synthesised by nitric oxide synthase (iNOS). This is an inducible enzyme found in various tissues, including the respiratory epithelium. It is significantly up regulated in the bronchial epithelium of steroid naive asthmatics. In addition, the amount of exhaled nitric oxide (NO) is markedly elevated in patients with acute exacerbation of asthma. Following appropriate steroid treatment, this level will drop significantly.³⁶ Contrary, only minimal iNOS activity is detectable in healthy subjects. Thus, exhaled NO is a useful surrogate marker in asthma and can be used to monitor the response to treatment and detection of subclinical deterioration. Nevertheless, elevation of exhale NO is not specific for asthma, diseases such as pneumonia, fibrosing alveolitis have also been shown to have increased level of exhaled NO.

Usually children over 6 years of age are able to maintain a steady exhaled flow rate to allow the NO analyser to detect a plateau level. The only other limitation is the cost of the NO analyser.

Bronchial reactivity testing

The response to gradually escalating doses of histamine or methacholine is measured by conventional spirometry to determine the bronchial reactivity.³⁷ This form of testing is easily performed in older children and adults. However, its use in young children is limited. Furthermore, satisfactory spirometry can be very difficult to obtain in preschool children. Moreover, the interrelationships of bronchial hyper-responsiveness (BHR) and the diagnosis of asthma and asthma symptoms are very complex. Studies have found that clinical asthma and BHR do not always coexist. Normal healthy subjects can have a positive BHR response. Therefore, one needs to interpret these results in relation to other clinical parameters of that specific patient.

Sputum induction

Sputum induction by hypertonic saline has been extensively applied in research studies of asthma. The expectorated sputum can be analysed for the composition of various non-epithelial cells such as eosinophils, and the concentration of various immune mediators and cytokines.³⁸ Many studies have shown a strong correlation between biomarkers of inflammation measured in the induced sputum and lung function. Currently it is mainly a research tool. However this may become more widely available in the future as one of the non-invasive methods to monitor control in asthmatic children.

Spirometry and plethysmography

Spirometry has been widely used as an outcome measure of asthma for older children and adults. With the use of an interactive computer-animated system, successful spirometry with reliable results can be performed in the preschool age.³⁹ Furthermore, new computerised and validated equipment is now available to perform whole-body plethysmography in infants and children under 3 years of age.⁴⁰ With the "squeeze" technique, adult-type of lung function study (flow-volume loop) is now possible for the young infant. The current research effort has been directed at establishing the normal reference of the various parameters obtained by the use of such a new equipment.⁴¹ This equipment is, however, expensive and requires a team of experienced personnel to operate as well as to interpret the test results. Hopefully in the not too distant future, these tests will be available in our everyday clinical practice.

Asthma genetics

As mentioned before, different wheezing phenotypes in the early childhood period have been noted. Some children have transient wheezing while atopic asthma tends to persist into adulthood. This observation suggests that the development of asthma requires a strong interplay between the underlying genetics factor and the surrounding environment. In the past decades, there have been many research projects directed at determining the predisposing genotypes for various wheezing disorders.^23,42,43 The genes that have been implicated in the pathogenesis of asthma include the cytokine genes encoded on chromosome 5, the T-cell receptor gene (chromosome 6) as well as the high-affinity IgE receptor gene (chromosome 11). Hopefully in the near future, advances in molecular research will provide us with ways to determine the wheezing phenotype of an affected patient in early childhood. Furthermore, pharmacogenetic studies have already shown that different patients will respond differently to the same medication.⁴⁴ Clarification of the role a patient's genetics may have in contributing to their treatment response will enable us in the future to prescribe the best individualised treatment for every patient.

Treatment

As wheezing disorder in early childhood is a complex heterogenous syndrome, the natural history for an individual patient will be difficult to predict. However, in the majority of cases, there is a tendency towards natural resolution of the wheezing illness, particularly in early childhood. Symptomatic treatment with bronchodilator and controller therapy for recurrent symptoms remains the cornerstone of treatment for this condition.

The treatment of asthma in children is not always straightforward. Therefore, many regional and international authorities have provided evidence-based treatment guidelines to facilitate optimal treatment of this condition.⁴⁵ However, there are a number of important barriers to optimal treatment especially in young children and infants. The use of inhalers in young children is often very difficult without proper education and supervision. There are several major concerns including the variability of the actual dose of inhaled corticosteroids which are delivered to the lungs, parental concerns with regards to the side effect of steroid treatment and the lack of objective evaluation of treatment response. Furthermore, parents tend to underestimate the degree of disability in their asthmatic children such that under treatment remains a major problem.^46,47 Whatever controller therapy is prescribed, the parents must be given clear instructions on how to use the device properly. Detail explanation of why the affected child needs the controller medication on a daily basis is also important.

Inhaled corticosteroids (ICS) are the main stay of treatment in childhood asthma. The preference for their use has decreased due to parental reservations about potential side effects, fear of dependency and difficulty in administration. ICS has long been recommended as one of the first line therapies for persistent asthma. The GINA guidelines have provided a step-wise approach and this is summarised in Tables 1 and 2. Asthmatics are classified into different categories of severity (intermittent or persistent asthma) according to their symptoms and lung function results. There have been several longitudinal studies confirming the long term safety of inhaled corticosteroid. No significant effects have been noted on final adult height or on the bone density of those children treated.^48-50 The majority of asthmatic children can be well controlled with 400 of ICS daily.

The other options of controller therapy include leukotriene modifier, inhaled cromoglycate and theophylline. There now exists an abundant amount of encouraging clinical evidence regarding the use of oral leukotriene antagonist for the treatment of childhood asthma. Leukotrienes are the product of oxidative metabolism of arachidonic acid by lipoxygenase. Cystenyl-leukotrienes can cause smooth muscle contraction, increase vascular permeability, increase mucus production and promote infiltration of inflammatory cells into the airway. These effects are relevant to the pathophysiology of asthma development.Leukotriene-modifier has been shown to be an effective way of controlling asthma inflammation in those with childhood asthma. Furthermore, it has been found to be useful in treating exercise-induced bronchoconstriction, nocturnal asthma, and asthma due to occasional exposure to antigens.^51,52 Montelukast is the most widely prescribed leukotriene-modifying agent. This oral medication can be administered once daily and the safety profile is comparable to any other controller agent. Some parents may prefer this form of treatment over inhaled medications.

Cromolyn and nedocromil have been advocated as a possible alternative treatments for asthma because of the relative absence of side effects. However, these are not as effective as ICS and the cost is higher than a low dose ICS. Furthermore, sodium cromoglycate has to be given 3 to 4 times daily and this may be difficult for most parents.

Another alternative of long-term controller therapy is theophylline. The popularity of this drug has decreased in the recent decade because of the availability of other effective medications such as ICS and leukotriene-modifying agents. In particular, the narrow therapeutic window and the necessity of frequent monitoring of its serum levels makes it difficult to use in many young children.

Long acting b₂-agonists are recommended as one of the most effective add-on therapies for older children with asthma that is not adequately controlled with 400 to 800痢 of ICS.⁴⁵ Formoterol and salmeterol are the two currently available long acting b₂-agonists. A recent trial which involved children with moderate persistent asthma has demonstrated better control with the addition of formoterol as compared to doubling the dose of ICS.⁵³ Although there are an increasing number of studies for the use of long acting b₂-agonists in younger children, the exact role of this drug in the preschool age group remains to be defined.^54,55

Conclusion

Asthma and wheezing disorders are among the most common reasons for hospitalisations and doctor's visits in young children. The prevalence of this group of disorders appears to be on the increase. There have been significant advances in our understanding of the natural history of the various phenotypes of wheezing disorders. With the improvement in medical technology and equipment, we can now accurately assess the lung function of young children. An increasingly number of non-invasive tests are also now available such as the measurement of exhaled nitric oxide which will help in airway inflammation monitoring. In conclusion, all of these with the addition of the medications currently available should enable a near normal life style to be achieved without excessive restrictions in the majority of asthmatic children. However, under diagnosis and under treatment of this common condition is still prevalent. Continuous medical education for both professionals and the public is important in improving the control of this illness in the affected child.

Key messages

1. One in ten children in Hong Kong has asthma.
2. There are two major phenotypes of wheezing disorder in young children. One is associated with other atopic disorders and children with this phenotype tend to have persistent symptoms as they grow older.
3. Transient wheezing in early childhood is associated with viral infections.
4. Advances in lung function testing and non-invasive measurement of inflammatory markers has enabled us to monitor a subgroup of children with severe persistent asthma.
5. For childhood asthma, low-dose inhaled corticosteroid has been documented to be highly effective with minimal side effects.
6. Under-treatment continues to be a major problem resulting in sub-optimal care of asthma in young children.

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References