Clin. lmmunother.1996Feb; 5(2); 96-114 DISEASE _ _ _ _MANAGEMENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _- -_ _1_17_2-7039/96/0002-01141$09.50/0

© Adis Internatio nal Umited . All rig hts reserved.

Childhood Asthma How Best to Manage the Disease George Russell Medical Paediatrics, Royal Aberdeen Children's Hospital, Aberdeen, Scotland

Contents Summary .. ... . 1. What is Asthma? . . 2. Available Protocols. 3. Non-Drug Management 3.1 Education and Assessment 3.2 Avoidance of Triggers . . . 3.3 Immunotherapy . . . . . . . 3.4 Alternative, Complementary and Over-The-Counter Medicines. 4. Drugs in the Management of Childhood Asthma 4.1 Inhaled Drugs and Inhalation Devices . 4.2 Bronchodilators . . . . . . . . . . 4.3 Anti-Inflammatory Drugs . . . . . 5. Development of Treatment Protocols

Summary

96 97 97 97 97 99 102

102 102 103 103

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The effective management of asthma involves careful attention to family education and environmental, psychological and other triggers. However, the majority of patients will require drug treatment. The only bronchodilators in common use are p2-agonists and theophylline. In young children, the choice of an appropriate drug delivery system will frequently determine the choice of medication. For anti-inflammatory therapy, it seems prudent to adhere to the recommendation that children should be started on sodium cromoglycate (cromolyn sodium), and to use inhaled corticosteroids only when sodium cromoglycate has been unsuccessful. Although inhaled corticosteroids are absorbed systemically, their toxicity is limited and their benefits are more apparent than their adverse effects. An acute attack of asthma should be regarded as a failure of prophylactic treatment, and is an indication to review interval management.

Surprisingly, given the high and increasing prevalence of asthma,[l] there is no agreed definition of the diseaseP] To the respiratory physiologist, asthma is reversible airways disease[3] or bronchial hyperreactivity;[4] to the immunologist and allergist, it is allergic airways disease; to the molecular biologist and pathologist, it is inflamma-

tory airways disease.[5,6] Epidemiologists have applied various definitions; some exclude children who wheeze only in the presence of respiratory tract infection[7] (,wheezy bronchitis'), while others include wheezy bronchitis as a subset of asthma,[8] thus classifying virtually all wheezy children as asthmatic. The aggregation of different types of

Childhood Asthma

wheeze under the unitary diagnosis of asthma has encouraged the use of bronchodilator and antiinflammatory medication rather than antibiotics, but it has also served to obscure important differences between classical asthma and virus-associated wheeze,[91 not least of which is the much better prognosis of the latter group.!101

1. What is Asthma? Not every child with wheeze has asthma, and some asthmatic children do not wheeze at all, presenting instead with recurrent cough.llll In an attempt to resolve this confusion, Godfreyll21 proposed the following definition: 'Asthma in childhood is a disease characterised by wide variations over short periods of time in resistance to flow in intrapulmonary airways and manifest by recurrent attacks of cough or wheeze separated by symptom free intervals. The airflow obstruction and clinical symptoms are largely or completely reversed by treatment with bronchodilator drugs or steroids.'

2. Available Protocols The clinician seeking guidance on the management of asthma is spoiled for choice. Numerous personal,lI3- 151 nationalll6-181 and intemationa1lI9-211 guidelines have been published in recent years. It is unnecessary to recycle this advice here; instead, this review will focus on the individual components of asthma management, and will discuss the practical value of each.

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formance and interpretation of regular peak expiratory flow measurements,l 241 requires a high level of parental understanding and co-operation. An example of an action plan used in my clinic, based on a plan described for adult use,l 25 1is shown in figure 1. More detailed laboratory assessment of pulmonary function is beyond the scope of this paper, but for most everyday purposes peak expiratory flow, expressed either as percentage predicted or percentage personal best, is adequate. It also has the advantages that it is easily understood even by quite young patients, it is simple to perform, and it is cheap. Asthma education programmes involve a considerable investment of time, energy, skill and resources, and it is important to ensure that these are not wasted. In 1988, Howland et al.l 261 concluded from a review of the literature that such programmes had only a slight effect in reducing school absences and healthcare utilisation. However, carefully designed and implemented educational programmes have been shown to have beneficial effects on school attendance, emergency room visits, hospitalisation rates, bronchodilator usage and lung function .[27-29] In 1984, Lewis et al. calculated that the implementation of an asthma care training (ACT) programme resulted in healthcare savings of approximately $US 180 per child per year,l3°1

Table I. Objectives of asthma education plans

3. Non-Drug Management 3.1 Education and Assessment

Whichever approach to treatment is adopted, the most important, yet most frequently neglected, component of asthma management is patient and parent education, the objectives of which are summarised in table I. It is only when the family have an adequate understanding of the disease that they are likely to be fully competent in its management. In particular, the successful development of management plans,l22.23 1which usually involve the per© Adis International Limited. All rights reserved.

Understanding of disease process, leading to: .avoidance of known triggers .appropriate recognition and interpretation of symptoms and objective measurements such as peak expiratory flow Understanding of disease management, leading to: .appropriate and effective use of therapy, including inhalational devices .appropriate response to symptoms and objective measurements, particularly those requiring emergency intervention Reduction in morbidity, leading to: • increased participation in everyday activities • reduced school absence .enhanced self-esteem

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Peak Flow Meters in the Assessment and Management of Asthma The Peak Flow Meter is a simple instrument for measuring the speed at which air leaves the lungs. Day-to-day variations in peak flow are due mainly to variations in the size of the tubes (bronchi) in the lungs, so the peak flow is a good way of assessing the severity of asthma. The peak flow may be measured regularly to help in the diagnosis of asthma, when it is likely to show more than normal day-to-day variation, and perhaps also a fall in the morning value compared to the evening value - the 'moming dip.' Peak flow measurements can also be used to help decide how best to manage asthma as part of a 'Management Plan.' A commonly used management plan is as follows: 1. Find out your child's best normal peak flow. This is done by documenting the peak flow twice a day over a period of 2 or 3 weeks. Keep a note of the result. 2. Calculate the value of two-thirds, half and one-third of the best, and write down these results. 3. The results of peak flows measured when the child has asthma can then be used to decide on management: • If the peak flow is less than two-thirds of best, take extra bronchodilator (usually a blue inhaler). ideally through a large spacer or by nebuliser. If on inhaled steroids (usually a brown inhaler), double the dose.

• If the peak flow is less than half of best, start a short course of oral sterOids. • If the peak flow is less than one-third of best, medical advice should be sought - admission 10 hospital may be needed. The above is only an example of a management plan. Individual children will usually need to modify this broad plan to suit their own circumstances, based on experience with managing their own asthma.

Fig. 1. An example of an asthma action plan based on use of a peak flow meter.

The crucial task of family education is often delegated to nurses and other staff, in both hospital and office practice. For this to be successful, it is esSential that the instructors be fully educated in all aspects of the disease and its management, so that the advice they give, especially in response to spontaneous questions, is accurate and well informed, and does not perpetuate the many myths surrounding asthma and its treatment. There is much to be said for basing local programmes on the many programmes in the public domain which have already been evaluated and debugged; some American programmes are reviewed by Conboy.[31] © Adis International Limited. All rights reserved.

Asthma is a frightening, unpredictable and frequently disabling disease which interferes with normal daily activities, and will inevitably have psychological effects on the sufferer and his or her family.l32,33] Lask[34] emphasised the need 'to give due consideration to physical, psychological, and social factors both in assessment and management. , .. Possible emotional and social triggers should be sought, and both short term and long term reactions to attacks explored,' Discussion of these issues is an integral component of family education which should include the social, financial and psychological as well as the purely physical aspects of the disease. elin. Immunother. 1996 Feb; 5 (2)

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3.2 Avoidance of Triggers

The environmental factors associated with asthma will vary from place to place and from time to time, and due account must be taken of local factors.f 351 Some are easily identified and dealt with; for example, the effects of paint fumes can be reduced by the use of water-based paints for indoor decoration. Others are more difficult; for example, although numerous studies have associated damp housing conditions with asthma,[36-38] the remedy is primarily socio-economic. This section will include strategies for dealing with the 5 most frequent precipitants of wheeze identified by parents in 1994 in a survey (unpublished) of respiratory symptoms and atopy in over 4000 Aberdeen primary school children aged 8 to 12 years: • upper respiratory tract infection (73%) • exercise (41%) • cold weather (36%) • pets (21 %) • house dust (18%). 3.2. 1 Upper Respiratory Tract Infection

In general, the acquisition of upper respiratory tract infections must be regarded as a hazard of normal living, but young children, with little innate immunity, sometimes experience a seemingly endless succession of such infections. Although a few of these children will have minor immunological abnormalities, particularly IgG subclass deficiency,l39.40] the majority will be normal. Day nurseries and play groups are major sources of upper respiratory tract infection,[41,421 and, on occasion, I recommend the temporary withdrawal of the child from such establishments. Influenza vaccine should be considered for all children with severe asthma; the development of successful vaccines against other respiratory viruses, including respiratory syncytial virus, is awaited. It is emphasised that although virus infections are important triggers of asthmatic attacks, bacterial infections are not, and there is no place for the routine administration of antibiotics to asthmatic children simply because they happen to have a fever. There are, of course, occasions when bac© Adis International Limited. All rights reserved.

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terial infection complicates a virus infection or an asthma attack, but these should be suspected only on the basis of supporting evidence (bacteriology of respiratory secretions, acute phase reactants, etc.) before antibiotics are administered. 3.2.2 Exercise

It would be entirely inappropriate to advise the

avoidance of this particular trigger. Asthma need not prevent participation in competitive sport, and indeed asthmatic children should be encouraged to participate. Numerous asthmatics have competed at the highest levels, and Meltzer et aJ.f43] cite the fact that 67 asthmatic athletes were members of the US team in the 1984 Olympics, winning 41 medals between them. At a more modest level, numerous studies have shown that exercise programmes have a beneficial effect on asthmatic children, resulting in better tolerance of symptoms, fewer exacerbations requiring medical intervention, less school absenteeism, increased cardiovascular efficiency and enhanced self-esteem.f44-471 Swimming is particularly well tolerated by asthmatic children,r48] the warm humidified air around the pool being much less irritant to hyperreactive bronchi than cold, dry outdoor air, although there are occasional problems with pools using chlorine as an antiseptic. On the theoretical basis that inflammatory mediators are released in the course of exerciseinduced asthma, and that these are destroyed more rapidly than they are reconstituted, Godfrey[49] has recommended a 'warm-up' period before undertaking exercise. Although later studies failed to confirm the benefits of warm-up,[50] many asthmatic athletes claim that a 20-minute period of graduated exercise, including short sprints as well as more leisurely gymnastic activity, improves their tolerance of subsequent more strenuous activity. More often, however, bronchodilators will have to be used as 'premedication' before exercise - salbutamol (albuterol) is acceptable to all the international sports authorities. Alternative group activities can be arranged for those children for whom active participation in athletic activities holds no attraction. Although a comClin. Immunother. 1996 Feb; 5 (2)

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puter games group will have no beneficial effect on cardiovascular function or exercise tolerance, provided suitable multiplayer games are provided the psychological benefits of competition and participation will still accrue. 3.2.3 Allergen Avoidance

Contributing to a discussion on biological washing powders as allergens, F1indt[51] commented that 'it is particularly unfortunate when patients are symptomatically treated for asthma while they continue knowingly to be exposed to a specific allergen.' It is important therefore, at the first consultation with an asthmatic child, to try to uncover avoidable sources of allergic sensitisation, and to give advice on the avoidance of such exposure. Dust Mite Avoidance

The great majority of asthmatic children have positive skin test reactions to house dust mite,[52] although mite concentrations do not necessarily correlate with disease activity[53] and only occasionally can attacks be attributed directly to exposure to house dust. Nevertheless, measures to reduce exposure to house dust mite are widely advocated and have been shown to be effective in the management of asthma.!54-56] Detailed protocols for the reduction of exposure to house dust mite vary, but generally include the reduction of bedroom soft furnishings and floor coverings,[57] the enclosure of mattress, pillows and bedding in plastic (preferably 'breathable'[5S]), the use of synthetic or cotton fabrics which can withstand frequent laundering using a hot cycle,[59] regular vacuum cleaning of the bedroom when the child is absent, using a fine filter cleaner,[60] and damp dusting of furniture. In hot climates, air conditioning may be used to cool and dehumidify the air, making conditions less suitable for mites.[61] Air filters,[62] both mechanical and electrostatic, have been used, as have ionisers, although with little evidence of clinical benefit.!63] Acaracides, usually benzoyl benzoate or tannic acid derivatives, have been used but, although they reduce mite populations,[64] they do not always reduce symptoms.[65] I have used liquid nitrogen as an 'environmentally friendly' acaracide, with no success on formal evaluation,!66] al© Adis International Limited. All rights reserved.

though my patients continue to report anecdotal evidence of success with this technique which locally is available commercially. Pets

Cats enjoy an unenviable reputation as a source of sensitisation.!67.6S] The most important feline allergen[69] is a glycoprotein derived from saliva which, attached to respirable particles less than 21-Im in size, remains suspended in the air for prolonged periods and persists in the household environment for many months after the departure of the cat. Weekly bathing of the cat has been advised as an alternative to disposal,[70] although I have never personally encountered a cat who would permit any such indignity! It is reasonable to employ house cleaning regimens similar to those directed against house dust mite. However, pet antigens are not only present in the home; Munir et al.[71] found levels of both cat and dog antigen in schoolroom dust which they considered high enough to sensitise children and to induce asthma in children already allergic. Horses are also particularly allergenic but, fortunately, are generally easier to avoid. There is however one source of horse antigen which is not always apparent; I have come across several patients whose asthma has been exacerbated by the use of 'family heirloom' soft furnishings stuffed with horse-hair. It is sensible to advise against the introduction of any furry or feathery pet to the household of an asthmatic child, but I do not advise the removal of existing pets unless there is clear evidence that their presence is aggravating the condition. This reflects my own attitude to pets, and there is a sound argument for advising the total avoidance of all pets by all allergic asthmatics. Other Allergies

The list of substances to which allergy may develop is endless and is beyond the scope of this review. Many are easily identified from a careful history but others, particularly food allergy, are more difficult to elucidate, even with the help of few-foods diets or double-blind challenge tests.!72,73] Nevertheless, the identification and elimination of Clin. Immunother. 1996 Feb: 5 (2)

Childhood Asthma

offending foods can be highly rewarding.[74] There has been increasing interest in peanut allergy in recent years;P5] whether this reflects a true increase in prevalence remains to be seen but, in the experience of Bock and Atkins,[72] it was the third most frequent food antigen involved in food allergy, after egg and cow's milk. Allergen Avoidance in the Prevention of Atopic Disease

Although not strictly part of asthma management, it is appropriate at this point to include a brief discussion of allergen avoidance in preventing the onset of atopic disease. It is attractive to speculate that, in vulnerable infants, if allergen exposure predisposes to the development of asthma,[76] then allergen avoidance during early life might postpone or even prevent the subsequent development of atopic disease. Breast feeding has been effective in some studies,[77.78] but not in others,[79.80] possibly because of failure to control the maternal as well as the infant diet. In a recent study, careful control of maternal diet, combined with attempts to reduce exposure to inhaled allergens, produced a dramatic reduction in the development of asthma, eczema and food intolerance compared with controls.[81] Although further studies are required to determine the long term effects of such comprehensive allergen avoidance, it is reasonable to recommend this approach to concerned, allergy-prone families. 3.2.4 Climatic and Seasonal Factors

The effects of climate and season are difficult to elucidate in isolation from their effects on pollution and on the biotic environment. High pressure days with relatively stagnant air predispose to photochemical smog, dust mites thrive in the humidity and warmth of the late summer and autumn[82] and moulds flourish in damp cold conditions. In the UK, the 'asthma epidemic' of the early autumn is well recognised[83] and in New Orleans daily climatic changes influence the occurrence of asthma attacks.[84] In general, these influences are beyond control but on occasion, when a family has the option of moving to a different climatic zone, advice can be given that a warm dry climate can be helpful. © Adis International limited. All rights reserved.

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In Aberdeen, the main climatic condition which induces wheeze is the cold dry air of winter. I was impressed by Bar-Or's report of the efficacy of heat exchange masks in preventing wheeze in asthmatic children participating in mountain sports,[85] but have only occasionally been able to persuade children in my practice to use them. 3.2.5 AtmospheriC Pollution Outdoor Pollution

The current prevalence of wheeze amongst Aberdeen schoolchildren is 25.4% (unpublished observations), whereas in Southern China it is only 2.8%.[86] The reason for this difference is likely to lie amongst the many components that collectively comprise the Western life-style. An obvious candidate is atmospheric pollution, which is known to precipitate asthma attacks[8 71 but has not been shown convincingly to induce the asthmatic state; the absence of pollution in the Highlands of Scotland has not protected children from an unusually high prevalence of asthma, wheeze and bronchial hyperreacti vi ty. [88] The association between air pollution and acute respiratory morbidity is long established,[89] but the responsible pollutants have varied over the years with, in most urban areas, a fall in particulates and oxides of sulphur but a concomitant rise in oxides of nitrogen, ozone and hydrocarbons. The degree of pollution varies with local levels of industrialisation and car usage, climate and geography, and numerous studies have confirmed the relationship between atmospheric pollution and asthmatic exacerbations.l90-93 ] Effective measures to reduce this problem will necessarily depend upon politicoeconomic processes, which physicians can influence by drawing attention to the dangers of atmospheric pollution. Indoor Pollution

By far the most important indoor pollutant is exposure to tobacco smoke (including intra-uterine exposure[94]), which has been associated consistently with an increased prevalence of childhood asthma.l 95 ] It is clear therefore that parental smoking is to be discouraged, and time should be deClin. Immunother. 1996 Feb: 5 (2)

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voted to appropriate counselling of smoking parents and children. However, the importance of cigarette smoke should not detract from the importance of other indoor air pollutants, which include wood- and other biomass-burning stoves,[96] kerosene and gas used for cooking,[97-100] and a huge variety of occasional items ranging from mosquito coils and cockroaches[IOI] to chemicals used in furniture manufacturer 102] and interior decoration. [103] It cannot be assumed that parents will volunteer information on such items, and a well taken asthma history must probe deeply into possible environmental precipitants. 3.3 Immunotherapy

Immunotherapy[104] involves the administration to an allergic patient, usually by injection, of small but gradually increasing amounts of the relevant allergen, with a view to reducing the severity of the clinical reaction on subsequent exposure, a process sometimes known as hyposensitisation. It is not known how this process of hyposensitisation is brought about, but it is usually accompanied by the development of IgG, particularly IgG4, 'blocking' antibodies against the offending allergen,l105] as well as other changes in the clinical[106] and immunological[107] response to allergen. Immunotherapy has been particularly successful in bee and wasp venom allergy,[108] and has also been shown to be effective in pollen,l109] house dust,[1I0.1I1] pet,[106] and a variety of other allergiesJl12] Immunotherapy is not without its hazards, which at worst can amount to full-blown anaphylaxis.[l13] Although 2 seminal papers on immunotherapy appeared in The Lancet, Noon's paper introducing it in 1911 [114] and Frankland's paper confirming its success in the first double-blind, placebo-controlled trial of immunotherapy in 1954,[115] the publication of a report by the Committee on Safety of Medicines[1I6] detailing 26 deaths associated with immunotherapy has led to the virtual abandonment of this treatment in the UK. More recently, guidelines for its use have appeared,llI7] although these preclude its use in asthma because of the high prevalence of adverse reactions. These restrictions have © Adis International Limited. All rights reserved.

not been endorsed internationally, but it is clearly important in selecting patients for immunotherapy that offending allergens are carefully identified by skin, serological and provocation tests, that only unavoidable allergens are included in the vaccine, and that this potentially hazardous treatment is given only to patients with clinically significant symptoms. It is also important to give the injections in a setting where, in the event of an adverse reaction, particularly anaphylaxis, resuscitative facilities and appropriately skilled personnel are readily available. Since the demonstration of the success of intranasal immunotherapy for ragweed rhinitis,11I8] alternatives to injection therapy are under investigation. Oral[119] and inhaled l120 ] immunotherapy have produced significant clinical and immunological changes in house dust mite allergy and may in the future provide greatly simplified therapy for large numbers of patients. None of these products is licensed for general use. 3.4 Alternative, Complementary and Over-The-Counter Medicines

Asthma is a mysterious condition, subject to inexplicable relapses and remissions, vaguely associated with modern life-styles and environmental degradation, for which conventional medicine offers suppression rather than cure, frequently involving prolonged steroid therapy, evoking in the public mind images of disgraced muscle-bound athletes. It is hardly surprising therefore that parents frequently seek alternative advice, most of which is harmless if seldom effective, e.g. acupuncture,1121] ionisers,[63] or special vacuum cleaners,[I22] but which can on occasion involve dangerous reductions in conventional medicine. The interested reader is referred to the paper by Lane and Lane, which reviews the subject in meticulous detail. I 123]

4. Drugs in the Management of Childhood Asthma My personal practice is outlined in figure 2 and table II; these protocols have been in use in the Royal Aberdeen Children's Hospital for many Clin. lmmunother. 1996 Feb; 5 (2)

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Are symptoms frequent enough or severe enough to warrant regular prophylactic therapy?

No further action; continue intermiHent relief medication

dose aerosols that, because of poor inhaler technique, many patients were failing to derive maximum benefit from them.[124] For obvious reasons, this is more of a problem with young children, who are seldom proficient in the use of metered dose inhalers before the age of 7 years. The development first of dry powder inhalers, then spacers, then breath-actuated metered dose inhalers, and finally spacers with infant face-masks , has greatly simplified the delivery of inhaled medication, even to infants. However, there are some children under the age of 3 years who are unable to use any inhaler device other than a nebuliser. The ability to use one or other type of inhaler will often determine the drug to be used, particularly during the first few years of life. 4.2 Bronchodilators

Review severity: is regular nebuliser therapy warranted?

Consider adding theophylline, sustained release ~2-agonist, ipratropium bromide, cromoglycate or salmeterol

Use nebulised corticosteroid; If parental anxiety regarding steroids, use nebulised cromoglycate

At each stage, if successful, no further action required; If unsuccessful, then move on to neld stage Fig. 2. Drug protocol for interval management of asthma.

years and, although the details have been amended from time to time in the light of experience, the underlying principles have not changed for many years. The remainder of this review deals with the actions, adverse effects and place in therapy of the drugs used in these protocols. 4.1 Inhaled Drugs and Inhalation Devices

In general, the inhaled route is preferred for the administration of drugs for asthma, but it became apparent soon after the introduction of metered © Adis International Limited. All rights reserved.

The earliest drugs to become available for the management of asthma were bronchodilators. Most of the earlier drugs, such as epinephrine (adrenaline), ephedrine and nonselective ~-adrenergic agonists, are no longer in widespread use, leaving ~2-adrenergic agonists, xanthines and ipratropium as the principal bronchodilators. 4.2. '

~2-Ad,ene,gic

Agonists

In 1968, an increase in asthma deaths in UK was linked to the use of the nonselective ~-adrenergic agonist isoprenaline (isoproterenol).l125] The announcement of a new class of selective ~2adrenergic receptor agonists[ 126] was therefore timely, and heralded a new era in asthma management. ~2-Agonists are now firmly established as the most widely used bronchodilators. Administered by inhaler, they are used routinely in the management of mild asthmatic exacerbations and for the prevention of exercise-induced wheeze. As controlled release tablets, they are useful for nocturnal asthma and to complement the child's usual prophylaxis during upper respiratory tract infections. By nebuliser, ~2-agonists playa central part in the management of more severe asthmatic attacks (table II), although use of spacers with MDIs may give equally satisfactory or even better results.ll27] Salmeterol, an inhaled ~2-agonist with a elin. Immunother. 1996 Feb: 5 (2)

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Table II. Protocol for management of acute asthma Stage 1: mild attack (nebuliser and oral corticosteroid therapy) Nebuliser treatment Use oxygen as driving gas Give 2-hourly initially, reduce to 4-hourly as condition improves Up to 18 months, give salbutamol (albuterol) 2.Smg; if not effective, try ipratropium bromide O.Smg 18 months to S years, give salbutamol2.Smg Over S years, give salbutamol Smg Oral corticosteroid treatment On arrival on ward, as soon as asthma confirmed, give single dose of prednisolone 1 to 2 mg/kg up to maximum of 40mg Stage 2: moderate attack (initial intravenous therapy) Given if failure to respond to Stage I, or if moderately ill on arrival. Treat as Stage 1, plus: Intravenous corticosteroid Hydrocortisone 200mg intravenously stat, followed by 100mg intravenously every 6 hours. When patient is clearly recovering, replace by oral prednisolone 1 to 2 mglkg/day, up to maximum of 40 mg/day Intravenous bronchodilator Aminophylline 4 to S mg/kg intravenously stat over 20 min by syringe pump with cardiac monitoring, followed by 0.7 mg/kg/hour by continuous intravenous infusion (omit loading dose if patient has received oral theophylline during previous 12 hours) Stage 3: severe or unresponsive attack (intravenous salbutamol) If attack severe ab initio, or if poor response to Stage 2, add intravenous salbutamol at loading dose 4 ).lg/kg, followed by infusion 0.1 ).lg/kg/min , which may be doubled if necessary In addition: Consider antibiotic therapy, especially if patient is febrile or chest X-ray is abnormal (in practice, it is extremely rare to have to give an antibiotic to an asthmatic child) Don't forget to continue with basic supportive care (oxygen, fluids, nutrition), since by this stage the child may be in danger of exhaustion Stage 4: severe unresponsive attack (intensive therapy) When it becomes clear that an attack of asthma is severe and unresponsive, and before the patient is in severe respiratory failure, arrangements should be made for transfer to the intensive care unit. It is better to err on the side of safety by transferring the occasional patient unnecessarily, than to end up transferring a patient already on a ventilator

duration of action of about 12 hours, is useful in children with an inadequate response to inhaled corticosteroids. f128] I will make no attempt to review the huge volume of literature testifying to the success and safety of ~2-agonists , but recently a few notes of caution have been sounded. Regular Use of

~2-Agonists

Although illogical, it has been common practice to use ~2-agonists as prophylactics. The first warnings that this might be dangerous came from New Zealand,fI29 ] where fenoterol was implicated, and from Canada,l1 30] where salbutamol was implicated. The regular use of ~2-agonists is therefore controversialfI 31-134] and, until the argument is resolved, it is sensible to adhere to the established practice of using them to relieve symptoms on an intermittent basis. © Adis International Limited. All rights reserved.

Fenoterol

Fenoterol differs from the other ~2-agonists in several respects. It has bronchodilator activity when applied to the nasa1 fI35] and oral fl36] mucosae, and at equipotent doses it has more undesirable cardiac and biochemical adverse effects than salbutamol. fI 37 ,1 38] More importantly, it has figured heavily in the controversy surrounding the 'epidemic' of asthma mortality in New Zealand fl39 ] and, although the case against fenoterol is by no means undisputed,fI40 ] the fall in asthma mortality which followed the reduction in fenoterol usage fl41 ] makes it unlikely that anyone in the future will seek unequivocal experimental proof that the association was causal. I no longer use it. 4.2.2Ipratropium Bromide

Ipratropium bromide is an inhaled anticholinergic agent which blocks parasympathetic reflex Clin. Immunother. 1996 Feb; 5 (2)

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bronchoconstriction.1142 ] It is less potent than ~2agonists, but because of its different mode of action its effects may be complementary and in some children it can be a useful adjunct to therapy. When the response to ~2-agonists is unsatisfactory, ipratropium should be tried. It is available as a metered dose aerosol in combination with salbutamol, which I find useful in a small number of 'difficult' asthmatic children. Because of suggestions that wheezy infants responded to ipratropium but not to salbutamol,1143.144] ipratropium has been widely used in infants. However, infants do respond to ~2-agonists,1145.146] although the bronchodilator of choice in this age group remains to be determined. Because ipratropium is effective in many younger children,1147] I still include it in my protocol (table II), as an alternative or adjunct to ~2-agonists. 4.2.3 Xanthines

Theophylline, the most widely used xanthine, is rapidly absorbed and has a short half-life,1148] which led to the introduction of sustained release formulations.!149] Unfortunately, the pharmacokinetics of these formulations are influenced unpredictably by diet,1150.151] febrile illness l152 ] and the concomitant administration of other drugs.! 153. 154] Numerous studies have confirmed the efficacy of theophylline,l155.156] although there are problems with its use. With an effective serum concentration in the range of 5 to 15 mg/L, and acute toxic effects occurring at levels as low as 20 to 25 mg/L, serum monitoring is necessary. Formulae are available to establish the 'correct' dose,1157] but in practice this usually takes several attempts and monitoring should be repeated as the child grows and during acute febrile illnesses. Most instances of acute theophylline toxicity (vomiting, tachycardia and central nervous system excitation, including convulsions) could be avoided by diligent monitoring of serum concentrationsl158J and, in the case of patients receiving intravenous aminophylline, by careful attention to the patient's drug history. Theophylline concentrations in the therapeutic range may induce nausea and vomiting which may interfere with compliance. Like caffeine, theophyl© Adis International limited. All rights reserved.

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line relaxes the lower oesophageal sphincter, predisposing to gastro-oesophageal reflux l159 ] which is itself an important cause of recurrent wheeze.!160] Insomnia and adverse effects on behaviour l161 ] and learning l162 ] have been reported, although prospective studies have shown that these are generally subtle l163 ] or even undetectable.!I64] Depression has been reported,1165] possibly explaining its effects on cognitive function.l 166] As a sprinkle preparation, theophylline is useful in younger children. 1167 ,168] Given at bed-time it may relieve nocturnal symptoms,1169] and its use may reduce the need for higher than normal doses of inhaled corticosteroids. Theophylline has been shown to have antiinflammatory effects l170 ] at serum concentrations of roughly half those required to produce bronchodilation,1171] a finding which, if of clinical value, would reduce the frequency of serum or salivary monitoring, greatly simplifying its use in children. Given intravenously, aminophylline has long been used in the management of acute asthma, I 172] but its place is now severely limited by the success and safety of nebulised ~2-agonists and systemic corticosteroids.l173.175] I would be unhappy about ventilating an asthmatic child without first exhausting all pharmacotherapeutic options, and aminophylline therefore retains a place in my protocol (table 11).

4.3 Anti-Inflammatory Drugs In many children, asthma can be managed quite adequately with the intermittent use of bronchodilators. However, children requiring frequent bronchodilator therapy (which I interpret as meaning on most days) should be started on prophylactic anti-inflammatory medication. My protocol for the interval management of asthma is given in figure 1. 4.3. 1 Sodium Cromoglycafe (Cromolyn Sodium) The first anti-inflammatory drug to be introduced for childhood asthma was sodium cromoglycate.1176.177] Although some treatment failures occurred early in the course of treatment,f I78 ] tachyphylaxis was not observed. It has a steroidsparing effect;f179 ] at my own clinic there were 12 Clin . Immunother. 1996 Feb: 5 (2)

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children on continuous corticosteroid or corticotrophin treatment when sodium cromoglycate was introduced; of these, 7 were able to discontinue steroids and 3 more were able to reduce their dosage by more than 50%. Early studies suggested that cromoglycate was particularly useful in exerciseinduced asthma,[180] and its prophylactic effects were said to be comparable with those of theophylline[181 .182] and beclomethasone,[183] although given in combination with beclomethasone there appeared to be no additive effect.[184] Given by nebuliser, it is a tedious but effective treatment for wheezy preschool children.l 185 ] Sodium cromoglycate is an unusually safe drug; the most frequent complaints relate to the taste, which some children find unpleasant, and to local irritation, often inducing cough or even bronchospasm. In a few cases, allergic and idiosyncratic reactions have occurred, most frequently resulting in bronchospasm. There has never been any suggestion that it might interfere with adrenal function or growth; therefore, with widespread public anxiety regarding the safety of corticosteroids, it remains the first drug of choice in the prophylaxis of asthma in childhood (fig . I) , a considerable achievement for a drug which has been in use for more than a quarter of a century and whose mode of action is still not fully understood . 4.3.2 Ketotifen

Ketotifen is an orally absorbed antihistamine that also inhibits histamine release.l 186 ] Early uncontrolled trials in childhood asthma gave extremely favourable results,[187.188] but, as Warner and Goldsworthy[189] pointed out, the trend to spontaneous improvement with increasing age necessitates carefully controlled studies. Some controlled trials have given encouraging results,[190,191] suggesting an efficacy comparable with that of sodium cromoglycate,l192] but others have failed to demonstrate any significant benefit.l193-195] This led Sarsfield[1 96] to conclude that ketotifen could not be recommended for children. The place for this drug is clearly limited, but I am in no doubt that it is sometimes effective[197] and, given its excellent safety record,[198] it is worthy of trial in younger © Adis International Lirnited. All rights reserved.

children with asthma too mild to warrant the inconvenience of nebulised drugs (table II). Outwith this small but important therapeutic niche, I never use it. 4.3.3 Inhaled Corticosteroids

It is logical to use corticosteroids in a disease characterised by inflammation of the airways, and to select for this purpose corticosteroids with high levels of topical activity, high affinity for pulmonary epithelium and rapid hepatic detoxication after systemic absorption.l 199 ] In the UK, beclomethasone dipropionate and budesonide are licensed for use in children in doses of up to 400 mg/day, and fluticasone in doses of up to 200 mg/day. Other corticosteroid molecules are available in other parts of the world. Inhaled corticosteroids are highly effective in childhood asthmaPOO-202] and early studies demonstrated apparent freedom from adverse effects. [203-205] Nevertheless, it was recommended that in children inhaled steroids should be given only when treatment with sodium cromoglycate was un successful,[206] a view which persists because of lingering anxieties about potential adverse effects and which is reflected in my protocol (fig. 1). These anxieties have centred on:[207] • • • • •

adrenal suppression bone metabolism growth cataract oropharyngeal candidiasis. Several early workers looked for and failed to find any evidence of adrenal suppression in children on inhaled corticosteroidsp08-210] but more recent work has demonstrated dose-related adrenal suppression.l 211 ,212] In spite of these laboratory findings, there is no evidence that any patient has ever come to any harm as a result of adrenal suppression caused by inhaled corticosteroids. The literature on bone metabolism has been inconsistent,[213-216] but the subject is currently under active investigation and, until clear answers are obtained, it seems sensible to follow the advice of Toogood and Hodsman[217] and titrate the dosage Clin. Immunother. 1996 Feb; 5 (2)

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to the lowest level needed to maintain optimum control. Research on the effects of inhaled steroids on growth is bedevilled by the fact that asthma itself has an adverse effect on growth, [218,219] but the majority of studies have failed to show that inhaled steroids have any effect on growth.[22o.223] However, recent studies using knemometry, an extremely accurate method of assessing short term growth, have shown convincing growth retardationJ224,225] The long term implications of these findings are unclear, as asthmatic children who have had inhaled corticosteroids achieve final adult heights within the range predicted from the heights of their paren ts J226] Posterior subcapsular cataract has now been looked for in 3 substantial series of children on inhaled steroidsY27-229] and it is clear that this complication rarely if ever occurs in patients receiving corticosteroids only by the inhaled route, Oropharyngeal candidiasis is seldom a problem in children,[230] and has never in my experience led to the withdrawal of treatment. Most other adverse effects seem to be idiosyncratic and therefore unpredictable. They include behavioural disorders[231] and symptoms of hyperadrenalismP32] Inhaled corticosteroids are recommended for all children in whom cromoglycate has failed. Because it tends to be more reliably effective than cromoglycate, it is frequently used as the first antiinflammatory of choice but, given the concerns about potential toxicity, it seems reasonable to follow the traditional practice of trying cromoglycate first (fig. \) , An exception is in younger children, for whom 3 or 4 daily nebulisations of cromoglycate are often unacceptable, and the twice-daily dosage regimen of nebulised budesonide, the only corticosteroid currently available for nebulisation, is preferred. When starting inhaled steroids, it is my practice to try to attain control as rapidly as possible by using the full maximum recommended dosage, subsequently lowering it to find the minimum necessary. Not every child will respond to conventional dosages, especially younger childrenJ233,234] Be© Adis International Limited. All rights reserved,

fore using higher dosages, alternative treatments should be considered (fig. I); my personal preference at this point is to introduce salmeteroUl28] A final use for inhaled corticosteroids is in children with persistent cough, some of whom may have asthma, The clinical evaluation of these children is difficult, and Parks et aU235] have stated that it should include a short trial of oral corticosteroids, My own practice is to use an inhaled corticosteroid and, if there is no response to the maximum recommended dosage after 1 month, to consider that asthma has been excluded, Fluticasone propionate is the most recently marketed inhaled corticosteroid, It exhibits high topical potency and negligible bioavailability,[236] Given at half the dosage level of beclomethasone and budesonide, it has so far been shown to have no effect on growth[237,238] and is otherwise well tolerated and effectivepo2,239] Whether this early experience will be translated into greater safety at higher than normal doses remains to be seen, but it is my current practice to use fluticasone for all children not controlled on beclomethasone or budesonide at a daily dosage >800llg, Inhaler technique is particularly important for inhaled corticosteroids; the total dosage and the adverse effects may be reduced by appropriate choice of inhalation device,[240,241] and by mouth rinsing.[242] 4.3.4 Systemic Corticosteroids

Systemic corticosteroids were introduced into the management of asthma over 35 years ago,[243] but it soon became apparent that this otherwise successful new treatment caused significant adverse effects including, in children, dosage-related growth impairment.[244] This is followed, on cessation of therapy, by slow and variable catchup.[245] Systemic corticosteroids are given mainly as oral prednisolone although, since children so frequently vomit when ill, it is sensible to give intravenous hydrocortisone if the asthma is severe. Although reducing courses were popular in the past,[246] they may well be unnecessary[247] and it has been shown in acute childhood asthma that a Clin , Immunother, 1996 Feb; 5 (2)

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3-day course,[248] or even a single dose,[249] of prednisolone will hasten recovery and reduce the need for hospital care. This does not mean that longer courses are never required; in the management of acute asthma, oral corticosteroids should be continued until the child is symptomatically better and lung function (usually peak expiratory flow) has returned to at least 80% of predicted or personal best. Since the introduction of inhaled corticosteroid therapy, prolonged systemic therapy is seldom necessary. Nevertheless, every paediatric asthma clinic includes patients whose asthma is resistant to all other forms of treatment and whose wellbeing can be maintained only by gi ving regular systemic steroids. There are 2 possible strategies to minimise adverse effects. The first, but seldom used, approach is to use corticotrophin, on which growth[250] and hypothalamo-pituitary-adrenal func. [251] are preserved. The second, and simpler, tlOn strategy is to give prednisolone on alternate mornings.l 252 ] It is essential to ensure, before starting regular steroid therapy, that every other aspect of treatment has been reviewed and, once treatment is instituted, that the patient is kept under regular review to ensure that the dosage is minimised.

5. Development of Treatment Protocols The treatment protocols illustrated in this paper have been developed with 4 guiding principles in mind: (i) Bronchodilators should not normally be used as prophylactics. (ii) Where there is a choice of medication longer established or potentially safer drugs should be used in preference to newer or potentially more dangerous drugs. (iii) The investigation of an asthmatic attack should be kept to a minimum (table III). In particular, chest radiography should be restricted to children with tachypnoea, tachycardia or localised chest signs persisting after treatmentP53] (iv) An asthmatic attack, or the frequent use of bronchodilators, should be regarded as a failure of preventive and anti-inflammatory treatment. It is © Adis International Limited. All rights reserved.

Table III. Monitoring and investigating the acute asthmatic attack. Senior advice should be obtained if in any doubt regarding assessment or management Stage 1: all patients Peak flow recording on all children post-nebulisation

~5

years, including pre- and

Stage 2: moderate attack Cardiac monitoring Pulse oximetry Blood gases if arterial oxygen saturation oxygen

$90%, or if patient on

Stage 3: severe or unresponsive attack Continuous pulse oximetry and regular blood gases Chest x-ray pneumothorax or other extrapulmonary air? consolidation or collapse? Urea and electrolytes - keep a close eye on fluid balance

essential, following an acute attack or the need to prescribe greater than usual quantities of bronchodilator, to take the opportunity to review interval management, and to ensure that there are adequate arrangements for the further assessment of the patient's progress. In older children, peak flow recordings can be helpful in assessing progress, but in preschool children one has to rely on symptoms which can, if necessary, be recorded regularly in an 'asthma diary.' In the long term, one would hope that insight into the factors which have led to the current 'epidemic' of childhood asthma would provide a rationale for effective prophylactic measures. Meantime, based on our understanding of the inflammatory process in asthma, several new drugs, such as the antileukotriene agents, are under active development but none is yet available for clinical use. We must therefore continue to make the best of existing medication, on which virtually all children can be adequately controlled provided that careful attention is paid to family education, identification of personal triggers and effective clinical review.

Acknowledgements I wish to thank my wife Jill for her help in the preparation of this manuscript.

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Correspondence and reprints: Dr George Russell, Department of Medical Paediatrics, Royal Aberdeen Children's Hospital, Cornhill Road, Aberdeen AB9 2ZG, Scotland.

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