CME (August 2003)
Monthly Self-Study Series

An Update on the Ambulatory Care of Childhood Asthma

Dr. Ng Kwok Keung, Daniel
Consultant Paediatrician
Department of Paediatrics
Kwong Wah Hospital

Dr. Lau Rebecca Becca Chaw
Intern, Department of Paediatrics
Kwong Wah Hospital

Introduction

Asthma is a worldwide health problem causing significant morbidity and mortality. It is the leading cause of absenteeism. Over the past 2 decades, Hong Kong has witnessed a significant increase in the prevalence of asthma which was found to be 12.4% among 13-14 year old teenagers, and 9.2% among the 6-7 year old in 1995.

Clinical Features

The characteristics of asthma are not specific to asthma only, nor is there a specific test available for diagnosing the disease, thus our clinical definition rests on the following findings: Recurrent cough +/- Wheeze +/- shortness of breath in a setting suggestive of atopy, with other diagnoses excluded. Other common clinical features include chest tightness or chest pain.

In children, cough is sometimes the sole manifestation of asthma. Cough in asthma is often distressing but unproductive. It is induced by upper respiratory tract infection, cold air, exercise, active or passive cigarette smoking, and aero-allergens. Cough at night-time and/or early morning exacerbation is common. Clinical signs are often absent between attacks, although for chronic asthmatics, there may be Harrison's sulci and an increase in chest AP diameter from air-trapping. Associated atopic features, i.e. allergic rhinitis, eczema, allergic conjunctivitis and urticaria provide the evidence of atopy in an individual child.

Other diseases can also cause the same pattern of recurrent chest symptoms as asthma and must be excluded before a diagnosis of asthma can be made. A comprehensive history from the patient and caregivers is crucial.

Doctor must looked for "Red Flag" symptoms such as weight loss, vomiting, prolonged fever, recent family history of pulmonary TB, clubbing, cyanosis, serous otitis media or stridor. Alternative diagnoses must be investigated thoroughly if these symptoms are found.

Investigations

Most investigations are available to the family practitioners. If PTB is suspected, a Mantoux test is mandatory.

Pulmonary Function Tests
Spirometry helps with the assessment of airway function and disease severity. In older children (> 6 year old) who are able to perform the technique correctly, asthma can be confirmed if there is a 15% increase in FEV1, or 20% in PEF, after administration of an inhaled Beta2-agonist. An alternative is a peak flow meter which is a simple and economical way to measure the PEFR. A diurnal variation of > 20%, with dipping in the early morning and peaking in the late afternoon, or an improvement by 20% after administration of a Beta2-agonist is considered diagnostic.

Exercise Tests
Physical exercise tests, inhalation of metacholine or histamine are commonly used to measure airway hyper-responsiveness (AWH). Almost all asthmatics have airway hyper-responsiveness which is exacerbated by respiratory infections or allergens, whilst treatment with anti-inflammatory agents can decrease but not normalize the hyperresponsiveness.

Up to 70-80% of untreated asthmatic school children exhibit exercise-induced bronchoconstriction secondary to a drying effect and heat loss which occur with movement of large volumes of air exchange during vigorous exercise. For infant, excitement, giggling and crying are exercise equivalent.

Exercise induced asthma can be evaluated by exercise testing. 6 minutes of exercise at 80% of maximal heart rate (220 minus age) is required. Peak symptoms occur after 8-15 minutes of exercise, there is a decrease in FEV1 of at least 10% after exercise, spontaneous recovery in around an hour with a refractory period up to 3 hours after exercise. In comparison, exercise in healthy non-asthmatics increases FEV1. When measured in a standardized way, the degree of AWH correlates with the severity of asthma. It is one of the first abnormalities to emerge and last to resolve after treatment by corticosteroids.

Skin Prick Tests
The allergens of the greatest importance are house dust mites, moulds, pollen and animal protein. Avoidance of these allergens leads to a reduction in severity, whilst exposure can cause prolonged increase in inflammation. In Hong Kong, the densely high rise housing makes it difficult to expose bedding to direct UV sun light which can kill the mites and the high humidity is conducive to mold formation. Allergy skin testing together with positive and negative control is a cost-effective and safe way to identify allergens. It is rare for childhood asthmatics to develop anaphylaxis although medical practitioners must be familiar with its treatment, i.e. subcutaneous adrenaline (0.01 ml/kg of 1 in 1,000 adrenaline). A strongly positive reaction becomes clinically important if it is associated with symptoms on contact with the allergen. Exposure in sensitized patients leads to eosinophilia that can be demonstrated in nasal smears and sputum.

Sputum, Blood and Urine Tests
The normal range for sputum eosinophils is < 2.5%. Sputum eosinophilia arises in asthmatics, making it more sensitive and specific for the diagnosis of asthma than blood or urine markers. In some studies, the degree of sputum eosinophilia was shown to correlate with the clinical severity of the disease. Like exhaled NO (eNO), sputum counts increases with airway inflammation and decreases with use of anti-inflammatory agents. Induced sputum may also be useful in diagnosing associated conditions such as gastroesophageal reflux by identifying fat-laden macrophages.

The most common blood markers are eosinophils and eosinophil cationic protein (ECP). While these markers respond to factors known to induce airway inflammation, they have poor disease specificity and are less sensitive than sputum counts. They can also be influenced by external factors such as smoking.

Urinary eosinophil peroxidase offers a less invasive alternative to serum ECP, while urinary leukotrienes require further evaluation.

Imaging
At initial diagnosis, every patients should have a chest radiograph (CXR) done. Hyperinflation, peri-bronchial cuffing and mild peri-hilar infiltrates can be seen in asthma, while transient generalized infiltrates can be noticed during acute attacks. Other radiographic findings, e.g. dilated bronchi or air-fluid level, which are not consistent with a diagnosis of asthma would dictate a CT thorax. CXR is not required for every acute attack unless there is clinical suspicion of pneumothorax, atelectasis or other pathology.

Chronic rhinosinusitis frequently co-exists with asthma and they may aggravate one another. Nasal endoscopy and CT scanning can readily identify the disease in those with a history of persistent nasal blockage and loss of smell.

Gastroesophageal reflux may lead to night-time exacerbations and post-prandial worsening of asthma. It occurs in up to 50-60% of asthmatic children. Thus it is worth ordering a pH study if asthma is suspected as some studies have shown an improvement in 70% of affected patients after anti-reflux therapy.

Exhalation Tests
Nitric oxide, carbon monoxide and hydrocarbons are gases in exhaled air. Exhaled NO (eNO), the most extensively gas investigated, has been used to assess airway inflammation. The levels of eNO increased with asthma exacerbation as well as exposure to allergens which are factors known to increase inflammation. Anti-inflammatory agents reduce eNO levels and reduction in eNO may occur 6 hours after nebulised corticosteroids, preceeding improvement in symptoms, FEV1, or sputum eosinophilia.

Classification of Asthma by Severity and Control

The Global Initiative on Asthma proposed a 4-step grading of severity, i.e. intermittent, mild persistent, moderate persistent and severe persistent. However, we found the 5-step grading by the National Asthma Council in Australia more useful in clinic setting.

Infrequent episodic asthma
This refers to occasional intermittent attacks of wheeze and breathlessness with recurrence less than every 4 weeks. Each attack may be mild, moderate or severe. Exacerbation may occur only after exposure to specific allergens, with viral respiratory infections or after exercise. This accounts for 75% of asthma in children.

Frequent episodic asthma
The pattern is similar to infrequent episodic asthma, but the interval between episodes is shorter, less than 4 weeks. The children have only minimal symptoms (e.g. mild exercise-induced wheeze) in between episodes.

Mild persistent asthma
This is defined by the occurrence of daytime symptoms more than once per week but less than once daily or nocturnal asthma more than twice per month. Diurnal peak flow variability is generally in the range of 20-30% whilst FEV-1 is usually normal.

Moderate persistent asthma
These patients have daily symptoms or nocturnal asthma symptoms more than once per week. Exacerbation occurs more than once per week that affects activity or sleep. Diurnal PEFR variability is generally more than 30% and FEV-1 is less than 80% of predicted value.

Severe persistent asthma
This is defined by continuous symptoms. The PEF variability is more than 30% and FEV-1 is less than 60% of predicted value.

Management

Despite the unpredictability of asthma, most cases can be controlled with appropriate management and follow-up. Management consists of prevention, education, monitoring progress and treatment, with education about the nature of the disease process and symptoms recognition being the cornerstone. In the majority of patients, the family practitioner should be the primary care provider.

Self-monitoring of symptoms and medication use in conjunction with the use of an action plan and regular medical review by a doctor were all shown to lead to significant reduction in hospitalizations, emergency department visits and time loss from school.

The most basic and valuable aspect of monitoring is symptom diary. Patients evaluate symptoms with physical activity, night-time awakenings, missing school, need for rescue medications and any side-effects of medications (Table 4). Most children over the age of six are able to use a peak flow meter, a record of at least 2 readings per day allows diurnal fluctuation to be observed and provides an early indication of changes in lung function. This is important as children generally have poor perception of dyspnoea.

An individualized asthma action plan should be drawn up for each individual patient to guide the patient towards appropriate management of asthma exacerbation (Table 5). Instructions and layout must be clear and simple. It should be carried by children and understanding on the use of the plan must be assured. This empowers the patient or their carers to know how to manage symptoms, enabling life-threatening attacks to be dealt with calmly.

During each visit, height, weight and blood pressure measurements are taken to monitor possible side effects of ICS. Symptoms and signs are rechecked, and the asthma diary is assessed for severity and control. Inhaler technique should also be tested at each visit.

There are many reasons why control management may be difficult to achieve. Non-compliance, poor technique/ inappropriate delivery device, exposure to triggers, and other aggravating factors such as sinus disease or reflux are among the commonest.

Adherence to prescribed treatment depends on many factors. One main factor is the number of doses per day. The level of adherence dropped from 71% in BD dosing to 35% in TDS dosing and to 18% in QID dosing. Other factors include absence of immediate benefits, denial of disease existence or fear of being different from peers. It is most difficult to attain in adolescents who often assert themselves and deny asthma symptoms. Family practitioners should be prepared to counsel them at length and set short-term objectives, e.g. to excel in the basketball match next week, instead of focusing on long term lung function which is of no concern to most adolescents.

The most important factor leading to improved adherence is a trusting doctor-patient relationship. Good communication allows patients to tackle changes in symptoms with confidence, knowing that medical support is available should it be required. It also allows a realistic expectations of treatment.

Drug Treatment

Traditionally drug treatment falls into two groups: Preventers - which have an anti-inflammatory effect and Relievers - which act through bronchodilatation. However this classification is now not strictly true.

Preventers

Any child who fits the criteria of having frequent episodic or persistent asthma should be started on a preventer. If one is already on regular preventer with poor control as evidenced by use of a reliever more than 3 times per week, the dose of preventer should be increased or additional therapy added as the break-through symptoms indicate inadequate control (Figure 1).

Inhaled Corticosteroids

Inhaled corticosteroids (ICS) are the mainstay for long-term treatment of asthma. In their usual doses (< 800 mcg/day), there are no major therapeutic difference between different ICS. Early treatment is important for symptom control and to prevent irreversible changes that can lead to permanent airway obstruction, remodeling, and hyperresponsiveness. Long-term studies on growth produced conflicting results. Linear growth study in mild-moderate asthmatics by the Childhood Asthma Management Program (CAMP) compared budesonide, nedocromil and placebo over a period of 4-6 years. The mean height gain was statistically significantly lower (1.1cm in 4.3 years) in the budesonide group than the placebo group whilst no difference was observed between nedocromil group and placebo group. This difference was related to the decrease in height velocity in the first year whilst no difference was observed in subsequent years. However, the projected final height was similar between budesonide and nedocromil group. Factors which are likely to affect the impact on growth include total dose of corticosteroids, delivery device and technique, genetic predisposition, age, compliance and even asthma severity.

For those with moderate-to-severe persistent asthma, a step-down approach is adopted. Starting with either a high dose of ICS, e.g. 800 mcg per day or ICS in addition to long-acting bronchodilater to alleriate symptoms related to inflammation (and confidence of the patient), it will gradually tail off after good control (i.e. both clinical and spirometry values) is achieved for 6 months.

Strategies to limit the unwanted effects of ICS are summarized in Table 6. As evening exposure to ICS possibly enhances growth suppression, some practitioners advise that one dose should be given in the morning. When symptoms are insufficiently controlled, add-on therapies should be considered rather than doubling the ICS dose.

Cromolynes
Sodium cromoglycate has been available for over 30 years. Its advantage was its excellent safety profile, but its efficacy was in doubt as no difference was identified between sodium cromoglycate and placebo in well-controlled studies.

Nedocromil is a new cromone that blocks mediator release from mast cells and appears to reduce survival time of eosinophils, inhibit their action and release of mediators. It is given at 8 mg twice a day from a pressurized metered-dose inhalers. It was regarded as one of the first line preventers in most asthma treatment guidelines. The recent CAMP study found nedocromil effective in reducing the number of emergency medical visits and use of prednisolone, but was similar to placebo in other endpoints.

Methylxanthines
Theophylline has been used for over 60 years yet its complete operating mechanism is still unclear. It is a non-specific phosphodiesterase inhibitor that inhibit the breakdown of cyclic adenosine monophosphoate (CAMP). It has both bronchodilating and anti-inflammatory effects and is a cost-effective drug for treating mild to moderate asthma in children. Its decline in popularity is due to the need for dose determination via regular plasma concentration monitoring as well as a myriad of adverse effects, e.g. headache, tremor, nausea, vomiting and gastric irritation, and hyperactivity, attributable to its non-specific nature.

Leukotriene receptor antagonists (LTRA)
Leucotrienes are released from arachidonic acid by 5-lipoxygenase. These leucotrienes cause bronchoconstriction, plasma exudation and mucus secretion. The pathway is not blocked by ICS. LTRAs have bronchodilating and anti-inflammatory effects combined with an excellent safety profile. Montelukast is a prime example of LTRAs and it blocks the leucotriene-D receptor. It is superior to placebo, appears to have comparable efficacy to cromolyns but is less effective than inhaled corticosteroids.

For children aged 2-5, montelukast (4mg nocte) was found to reduce nocturnal and daytime asthma symptoms, use of systemic corticosteroids or bronchodilators. However, no difference was found in caregiver＊s global evaluation nor asthma-related quality of life. No significant adverse effects were identified.

For children aged 6-14, montelukast 5mg nocte was more effective than placebo. It was found to be better than inhaled sodium cromoglycate as well as reducing the post-exercise fall in FEV-1. A recent meta-analysis comparing LTRAs to ICS concluded that ICS provided better lung function and quality of life, as well as reduced symptoms, night awakenings and need for rescue B-agonist use, but the rate of asthma exacerbations was similar between the two.

LTRAs are more popular in the United States where paediatric asthma guidelines state they may be an alternative to low-dose ICS therapy in mild persistent asthma, and an effective add-on to ICS therapy in moderate persistent asthma treatment. The effectiveness of this approach in comparison to the addition of a long acting B-agonist to ICS has not been evaluated.

Long acting beta-agonists
Salmeterol and formoterol are available in both aerosol and an inhaled dry powder forms, They are approved for use in children aged over 6 years. They have no anti-inflammatory effect, but their bronchodilating effect lasts for 12 hours and there is also an inhibition of the late-phase allergen response for up to 34 hours. Formoterol has a rapid onset of action, similar to short-acting beta-2 agonist, whilst salmeterol has a delayed onset of action. Hence, salmeterol cannot be used as a reliever. Their long duration of action results from the high lipophilicity and higher affinity and selectivity at the beta-2 receptor.

Tolerance to the protective effect of LTRAs against exercise induced bronchoconstriction develops with regular use. Tolerance to the bronchodilator effects of short-acting beta-2 agonists was also demonstrated in some studies. However, regular ICS is not effective in preventing the development of tolerance.

Side effects such as tremor, palpitations and tachycardia due to the stimulation of beta-2 agonists in muscle cells are not common with inhaled beta-2 agonists. Specific use of LTRAs may mask continuing airway inflammation with consequently worsening of asthma over time.

Relievers

Short-acting B2 agonists, such as salbutamol or terbutaline, and ipratropium bromide provide rapid bronchodilatation. Improvement in symptoms occurs within minutes, but the effect is short-lived, and may require repeated dosing. In severe attacks, relievers may not alleviate symptoms and systemic steroids are required. Relievers may also be used before exercise in those with exercise induced bronchoconstriction.

Inhaled drug delivery systems

The aim is to deliver the medications into the respiratory tract with minimal deposition elsewhere. Only particles in the respirable range, i.e. between 1 to 5 micron, could be delivered to the lower respiratory tract. Different devices are suitable for different age group.

Fig 2. Age and Ability to Use Devices

The pressurized meter dose inhaler (pMDI) uses a propellant gas to generate an aerosol containing 1 to 5 μm sized particles. As a result of the ban on use of chlorofluorocarbon (CFC), new propellants, e.g. hydrofluoroalkane (HFA) or hydrofluorocarbon (HFC), are used. These new propellents are environmentally friendly and generate finer particles and improve efficacy. Hence, dosage adjustment is required to avoid overdose. MDI is technically difficult to use, requiring accurate timing, co-ordination and breath-holding to improve airway deposition. This is overcome by the addition of a spacer which allows holding of aerosol to be inhaled by 5 tidal breaths.

The breath-actuated pMDI, e.g Easi-Breathe (IVAX), does not require the same level of co-ordination, but the patient must have sufficient inspiration flow, 30 L/min to activate the device.

New plastic spacers have an electrostatic charge that reduces the available dose by 66% and should be primed with 10 actuations from the MDI before use or washed in detergent and allowed to drip dry. Steps for optimal delivery are shaking the pMDI, delivering actuations one at a time with administration just before inhalation, and clearance by 5 tidal breaths.

Dry powder inhalers (DPI), e.g. turbuhaler (Astra) or accuhaler (GSK) are small and convenient to use. An inspiratory flow of 40 to 60 L/min is necessary to create an aerosol. One main benefit of DPI is the absence of propellent that implies the absence of cold freon effect, i.e. reflex cough or cessation of inspiration upon impact of the cold puff from MDI on the oropharynx. DPI is the device of choice for children over the age of 6.

Nebulisers suspends liquid particles in a carrier gas, either room air or oxygen. The main benefit of nebulizer is its potent placebo effect of being seen to come out. However, it is just as effective as pMDI with spacer if equivalent dose is given. The main disadvantage is the long treatment of 5 to 10 minutes, especially in frightened children. Currently, the main role of nebulizer is to give continuous inhalation of bronchodilator in life-threatening asthma.

Prevention

Primary Interventions

Breast-feeding
A recent prospective cohort study from Australia of > 2000 6 year old children found a significant reduction in asthma who were exclusively breast fed for at least 4 months after birth.

Nutritional factors and obesity
In several studies a significant positive relationship was found between obesity and asthma, some have found this association only in females or being stronger in females. The hypothesis is that the increased consumption of highly processed food may have contributed to the increase in asthma prevalence, but evidence has thus far been inconclusive.

Family size
Studies have shown that with increasing numbers of siblings, children had less hayfever and atopic eczema, but the relationship between family size and asthma is less clear.

Animal exposure
Most reports show a protective effect from exposure to farm animals, while studies on exposure to household pets in early childhood have produced conflicting results.

Tobacco smoke exposure
Whilst in-utero exposure to tobacco smoke pre-disposes towards wheeze in early childhood, environmental exposure increases the risk of developing asthma by 37% up to the age of 6 and 13% after that if parents smoked.

Secondary Interventions

Secondary prevention could be used to prevent development of symptoms in sensitized but asymptomatic children. Definite evidence is lacking, but recent studies suggest that specific immunotherapy for pollen and house dust mite sensitized children, and infants with atopic dermatitis, may prevent or delay new sensitizations and asthma.

Tertiary Interventions

Environmental control, such as allergen avoidance, has been confirmed to have a beneficial effect in reducing airway inflammation and symptoms alike, but rapid relapse is found on re-exposure.

Conclusion

Childhood asthma is a common disease. Most cases could and should be managed effectively with medications available by the family practitioners/paediatricians in an ambulatory setting. Hence, it is imperative for medical practitioners to be acquainted with its management.

References

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