Table of Contents

HK J Paediatr (New Series)
Vol 2. No. 2, 1997

HK J Paediatr (New Series) 1997;2:153-158

C. Elaine Field Lecture

Airway Inflammation and Its Treatment in Wheezy Children

JF Price


The Evidence for Airway Inflammation

It is possible that Hippocrates was the first to describe asthma in children as a distinct entity. In an essay entitled Airs Waters and Places he wrote "Children are liable to convulsions and asthma which are regarded as divine visitations and the disease itself as sacred". It is interesting that he referred to asthma in the same context as epilepsy, emphasising the paroxysmal nature of both conditions. This concept of asthma as an intermittent paroxysmal condition has persisted until modern times. Henry Hyde Salter, an physician practising in London during the mid 19th century was an asthma sufferer himself and his writings show considerable insight into the disease. He was one of the first to hint at the concept of bronchial hyperactivity. In his treatise "On Asthma its Pathology and Treatment" published in 1859 he wrote, "...it is clear that the vice of asthma consists not in the production of any special irritant but in the irritability of the part irritated". By the end of the 19th century airway inflammation, particularly mucous plugging and eosinophil infiltration had been recognised in patients dying of asthma.1 Throughout the first half of the 20th century bronchial smooth muscle spasm continued to be considered the most important component of airway obstruction in asthma; with additional inflammatory pathology contributing to asthma death. Fibreoptic bronchoscopy without anaesthesia opened up new possibilities for investigating the pathology of asthma. Bronchial lavage and bronchoscopic biopsy revealed a previously unsuspected infiltrate of inflammatory cells, damage to the epithelium and deposition of collagen beneath the basement membrane, in apparently well asthmatic patients. A worrying discovery was that airway remodelling could occur in adults with long-standing but symptomatically mild asthma. The infiltrate of mast cells, eosinophils and Iymphocytes is seen in bronchial biopsies from adult asthmatic patients with symptoms of less than a years duration. Almost all descriptions of the histopathology of airway inflammation in asthma have been in adults. Fibreoptic bronchoscopy is possible in children but there are ethical considerations which restrict its use in the very young. Our understanding of the mechanisms of airway inflammation in children is therefore very limited. Nevertheless evidence of an inflammatory response in the airways of children with asthma was obtained 20 years ago. Two children with a history of long-standing asthma were investigated by lung biopsy because of unexplained chest radiograph abnormalities. The biopsies showed a picture of airway inflammation which had previously only been described in children dying of asthma.2 Although our knowledge of the pathological changes in the early stages of asthma is rudimentary, there is indirect evidence of an inflammatory response in the airways of atopic asthmatic children as young as two years. This has been obtained by measurement of Eosinophil Cationic Protein (ECP) and Eosinophil Protein X (EPX) which are products of activated eosinophils detectable in blood and urine.3 Although there is a relationship between asthma symptoms, atopy and increased blood levels of ECP4 the test is not sensitive or specific enough to use in clinical practice. We must still rely on clinical judgement, frequency and severity of symptoms and tests of lung function between asthma attacks to decide when to start anti-inflammatory therapy.

The most potent anti-inflammatory agents available are the corticosteroids and inhaled corticosteroids provide the most effective treatment for asthma at all ages. However the questions when to start inhaled steroid therapy in asthmatic children, what should be the starting dose, and whether inhaled steroids induce undesirable long term side effects are controversial issues.

Inhaled Steroids - When to Start?

There is little disagreement that children over the age of four with frequent persistent symptoms need regular anti-inflammatory therapy. The question is whether those in whom symptoms are mild and lung function only slightly deranged have the type of underlying inflammation which would benefit from inhaled steroid treatment. Elevated ECP has been reported in symptomatic children receiving only intermittent bronchodilator therapy but the authors of this particular study did not quantitate the severity or duration of symptoms.4 Until recently the view taken by the British Thoracic Society and most International Guidelines for asthma management has been that a child fulfilling the clinical criteria to start regular preventive therapy should first be given a trial of sodium cromoglycate. If symptoms are severe or cromoglycate fails to control the asthma an inhaled steroid should be prescribed. However the revised British Thoracic Society guidelines published in 1997 5 and the Global Initiative For Asthma guidelines published by the American National Institutes of Health in 1995 6 have recommended that a low dose (100-400mcg day) of inhaled steroid be considered as an alternative to cromoglycate at first introduction of anti-inflammatory prophylaxis.

Some biopsy studies have indicated that in mild disease there is mast cell and eosinophil activation but relatively little T lymphocyte involvement. This may possibly explain the efficacy of cromoglycate at the milder end of the asthma spectrum.7 However it is unlikely that adequate asthma control will be achieved with cromoglycate in more than two thirds of school age children with frequent symptoms.8 Cromolyns seem less effective in pre-school than in older children, perhaps because of difficulties with administering sufficient doses to the lung.9 The need to take cromoglycate four times a day also poses problems with compliance; this is much poorer if inhaled medication is prescribed four times a day compared with twice a day.10 Rapid improvement in symptoms and lung function are seen at low doses (100-200mcg/day) of inhaled steroid in most children with moderately severe asthma.11-12 Relatively few published studies have compared the efficacy of low doses of inhaled steroid with sodium cromoglycate at first introduction of anti-inflammatory therapy. A recent trial however has shown substantially greater improvement in symptoms and lung function over an eight week period in children treated with 100 mcg fluticasone propionate per day compared with 20mgs sodium cromoglycate per day. The asthmatic children recruited to this study were 4-12 years old and had never received anti-inflammatory treatment before.13 There is no evidence that early introduction of treatment with cromoglycate influences the long term course of childhood asthma. On the other hand a Danish prospective, controlled, but not randomised trial suggests there may be long term benefit to lung function when inhaled steroids are started within two years of onset of asthma. This is an important study but more work needs to be done because the baseline lung function of the children recruited indicated quite wide variation in severity of disease at entry and the doses of inhaled steroid used generally exceeded 400 mcg/day.14

Inhaled Steroids - How Much and for How Long?

Our current understanding of the mode of action of corticosteroids argues for starting treatment with a high dose which is then reduced as soon as the asthma is controlled.15 This view is reflected in recent asthma guidelines.5 It has been suggested that if a large initial dose is given, the total dose of inhaled steroid used in the long term may be reduced.14 However there is some dispute about what is meant by asthma control and what constitutes a high dose of inhaled steroid in children. Symptoms of asthma can be controlled in most children with an initial dose of 100-200 mcg per day.11,13 Table I lists other parameters which might be used to judge asthma control. The only well planned study in children which has looked at the dose response relationship between inhaled steroids and several of these parameters suggests that for symptoms and PEFR the dose response plateau is indeed reached at 100-200 mcg per day.12 The idea that the plateau of the dose response curve for symptoms is quite low is also supported by a study of high versus low starting dose of nebulised budesonide. Wheezy infants and pre-school children treated with 250 mcg of budesonide per day took the same time to become asymptomatic as those treated with 1000 mcg per day.16 For exercise induced asthma, a measure of non specific bronchial reactivity, the plateau for the dose response curve is at a higher level. About 50% of maximal inhibition is seen at 100mcg budesonide per day but 80% of maximum inhibition is seen at a dose of 400 mcg per day.12 It is possible that a higher dose still is required for maximum inhibition of airway inflammation but there seems little justification for starting beclomethasone or budesonide in a dose of more than 800 mcg per day or fluticasone in a dose of more than 400-500 mcg per day. If the high dose regime is employed it is very important to try to reduce the dose as soon as possible and certainly within three months.

Table I Measures of Asthma "Control"
* symptoms
  elicited in the outpatient clinic
  recorded on a diary card at home
* lung function
  PEFR recorded on a diary card at home recorded in the outpatient clinic
  measured in the lung function laboratory
* bronchial reactivity
  specific eg. histamine / methacholine challenge
  non-specific eg. exercise challenge
* airway inflammation
  indirect - inflammatory markers measured in blood, urine, respiratory secretions, exhaled air
  direct - bronchial lavage I bronchial biopsy

Having decided to start treatment with inhaled steroids in children, when should we stop? A large multicentre well controlled study conducted in the Netherlands has demonstrated progressive improvement in symptoms and lung function, and cumulative reduction in bronchial reactivity during two years continuous administration of inhaled steroid.17 When treatment was withdrawn lung function and bronchial reactivity returned to pre-treatment levels over the ensuing six months.18 These important studies suggest that inhaled steroid treatment suppresses rather than ablates airway inflammation. The children who participated in these trials were 7-16 years of age at entry. One can speculate that had anti-inflammatory treatment been introduced at an earlier age the treatment effects may have been more permanent. A reasonable practical approach once inhaled steroid therapy has been started, is to review asthma symptoms and if possible lung function at three monthly intervals; if the child becomes virtually asymptomatic with little requirement for bronchodilators the dose of inhaled steroid can be halved. Discontinuing the inhaled steroid and treating only with an intermittent bronchodilator can be considered if the child is asymptomatic for at least three months when taking not more than 100 mcg/day. If symptoms recur this will convince both parent and doctor of the continuing need for inhaled steroid treatment.

Inhaled Steroids - Are They Safe ?

Pharmacotherapy in asthma is a balance of efficacy of the drugs used against safety to the patient. The relationship between efficacy and safety with inhaled steroids can be described by their respective dose response curves. The assessment of safety is inseparable from the assessment of efficacy and clinically relevant safety data refers therefore to the dose of inhaled steroid required to control asthma. The risk of adverse or systemic effects will continue to increase after the plateau for maximal efficacy has been reached. Data in normal subjects or where the dose given is in excess of that needed to control the asthma must therefore be interpreted with caution.

Adrenal axis
In some children 400mcg of beclomethasone dipropionate (BDP) causes suppression of nocturnal19 and daytime20 plasma cortisol and output of cortisol metabolites in urine.21 Comparisons between inhaled steroids have been confused by differences in duration and delivery of the drug, patient groups and methodology for assessing HPA suppression. For example morning plasma cortisols have not been affected by 400mcg/day of fluticasone propionate (FP) but this dose has been shown to lower nocturnal urinary cortisol output.22 It is probable that FP and budesonide (BUD) have less effect on the HPA axis than BDP. A decrease in diurnal release of glucocorticoids in children taking inhaled steroids becomes clinically important only if the adrenal gland loses its capacity to respond to stimulation. For example Bisgaard et al demonstrated dose related suppression of 24 hour urine free cortisol but normal adrenal responses to ACTH in asthmatic children treated with 200-800mcg of BDP or BUD.23

In practice either a single morning cortisol or a cortisol creatinine ratio measured on a timed morning urine sample is the easiest screening test for HPA axis function. For research purposes 24 hour urine cortisol metabolites are probably more reliable. If adrenal suppression is suspected this can be confirmed by a low dose ACTH stimulation test.

Bone metabolism
Bone metabolism is assessed either by measuring markers of bone formation and resorption or by physical measurement of bone density. Normal age related variation in bone formation and resorption is not well established. Data in asthmatic children is scarce but one study has suggested that children with asthma, irrespective of their treatment, may have lower osteocalcin levels than children without asthma.24 Only a small number of short term, cross sectional studies have looked at the effects of inhaled steroid on bone metabolism in asthmatic children. The results of measurement of markers of bone formation and resorption have tended to give conflicting results.25-30 However studies of bone density assessed by dual energy X-ray absorptiometry have consistently shown no detrimental effects of inhaled steroids.24,31-35 This is reassuring but before we can draw firm conclusions we need long term longitudinal data.

Lower leg growth
The knemometer allows very precise measurement of lower leg length. Measurements are normally performed twice a week and lower leg growth calculated in mm/week by linear regression.

A small number of centres have employed knemometry to assess the effect of inhaled steroids on short term growth in children with asthma. No systemic activity, judged by slowing of lower leg growth rate, has been demonstrated in children taking less than 400mcg/day of inhaled steroid.36-41 The apparatus is expensive but it is a more sensitive index of systemic activity of inhaled corticosteroid than 24 hour urine free cortisol excretion.42 Measurement of lower leg growth has no place in routine management but provides a valuable means for comparing different compounds and methods of delivery.

Long term growth
There are a number of pitfalls to growth assessment in asthmatic children receiving inhaled steroid therapy. Growth in length both in healthy children and those with chronic disease occurs by discontinuous bursts interspersed with quite long growth free periods. A half of normal prepubertal children show seasonal variation in height velocity. These patterns of growth probably explain the lack of correlation between short term and long term growth rate.43 A slow tempo of growth often associated with late onset of puberty is a characteristic of asthma which is independent of disease severity or treatment.44-45 In spite of this most children with asthma, with the possible exception of those with very severe disease, attain a normal final height.46-47 Frequency of symptoms or the degree of asthma control has an important influence on growth rate.48 Accurate measurement of height and height velocity requires a good quality stadiometer that is regularly serviced and calibrated and proper training of the anthropometrist.49 The most useful way to express growth rate is by the use of height velocity standard deviation scores (HVSDS):

HVSDS = height velocity - mean height velocity
-------------------------------------
standard deviation

where the mean height velocity and the standard deviation are taken from a population of children of the same age and sex as the patient.

Many studies have been published but few have taken into account all these confounding variables. Nevertheless the data in school children with frequent or persistent asthma have been consistent and are summarised by a meta analysis.50 Unlike oral corticosteroids, inhaled steroids given in appropriate doses, do not cause clinically important growth suppression. On the other hand there are reports of growth retardation when asthmatic children have been treated with 5-10 times the recommended dose of inhaled steroid.51 Inhaled steroids are increasingly being used to treat asthma in pre-school children. There are few studies of the effect of inhaled steroids on growth in the very young but the results of those that have been published are reassuring.52-53 The use of inhaled steroids in mild asthma is more controversial. There is one report of growth suppression in children treated with 400mcg/day of BDP for seven months. Most of the children recruited to this trial had infrequent symptoms provoked by viral infections and would not have fulfilled standard criteria for starting regular anti-inflammatory therapy.54 By contrast a study in children who did fulfil these criteria demonstrated that treatment for one year with l00mcg/day FP was not associated with growth suppression while providing good asthma control.55

Wheezing in Infancy

Wheezing illness is very common in the first year of life affecting about one third of all infants. However 60% of wheezy infants will cease to wheeze before school age. The vulnerability of some infants to wheezing illness is almost certainly related to the calibre and function of their airways rather than to airway inflammation.56 Even in children of atopic parents, for whom the risk of airway inflammation and asthma is high, persistence of wheezing into the second decade is five times more likely if the onset is after rather than before the age of 2.57 At the moment we are unable to distinguish wheezy babies who will remit from those who will continue to wheeze. It follows that without specific, sensitive and non invasive markers of airway inflammation we must apply different rules to wheezy infants when deciding whether to start inhaled steroid therapy. Moreover the results of trials of inhaled steroids in the first two years of life have been less consistent than in older children (Table II)16,58-61 Safety issues are therefore very important. During the first postnatal year, growth in length is largely dependent on nutrition, so inhaled steroids probably have little adverse influence on growth velocity. On the other hand the bulk of alveolar multiplication takes place during the first 18 months after birth. Studies in rodents have shown that daily administration of dexamethasone during the neonatal period is associated with reduced alveolar septation.62 Of course intraperitoneal dexamathasone administered to newborn rats is very different from inhaled steroid administered to human infants. Nevertheless this is an area which needs further study and in the meantime we should be cautious about the use of inhaled steroids during the first year of life. The dilemma we face is that if we apply the rules for introducing inhaled steroids in older children to wheezy infants we shall almost certainly treat many who will remit spontaneously. But if we treat none of them we shall be ignoring some who by the age of 6 will show quite marked deterioration in lung function.56 The common sense approach is to treat only those infants who have severe persistent wheezing and to have a slightly lower threshold for introducing inhaled steroids in infants with a strong personal or family history of atopy.

Unfortunately there is no evidence that sodium cromoglycate administered by nebuliser has any beneficial effect in wheezy infants.63 Ketotifen may prevent or delay the onset of wheezing in infants with atopic dermatitis64-65 and its use is justified in infants with mild wheezing. Ketotifen has not proved useful in young children with more severe wheezing.66

Table II Trials of Inhaled Corticosteroids in Wheezy Infants
REF. DRUG DOSE
mcg/day
N AGE
months
PLACEBO RESULT
Spacer
58 BUD 300 24 4-17 YES +
59 BDP 400 38 5-18 YES -
             
Nebuliser
60 BUD 1000 23 3-17 YES -
61 BUD 1000 40 6-30 YES +
16 BUD 250/1000 102 6 - 48 NO +
BUD = budesonide
BDP = beclomethasone dipropionate

Conclusions

The increasing evidence of an inflammatory response in the airways of young children with asthma justifies lowering our theshold for starting treatment with inhaled steroids. Given our inability to detect airway inflammation non invasively and to predict persistence of wheezing, a higher threshold for starting inhaled steroids should be applied to wheezy infants than to older children. There are theoretical reasons for starting with high doses and reducing when asthma is controlled but convincing evidence for long term benefits of this practice is not yet available. Some systemic absorption is seen with all the currently available inhaled steroids if sufficiently large doses are administered. Data obtained in normal subjects or in children who in clinical practice would not require treatment with inhaled steroids should be interpreted with great care. The overwhelming evidence is that clinically important systemic effects are rare when inhaled steroids are used in appropriate dosage. Most childhood asthma can be controlled with not more than 400mcg/day of inhaled steroid. Measurement of growth is part of asthma management but data collected for less than a year is liable to error or misinterpretation. Children with severe asthma in whom doses 800mcg or more of inhaled steroid per day are required should be supervised in paediatric units which have the facilities to monitor for adrenal and growth suppression. As a general rule growth retardation in asthmatic children is more likely to be the result of undertreatment than overtreatment.


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