C. Elaine Field Lecture
Airway Inflammation and Its Treatment in Wheezy Children
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.
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.
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.
Lower leg growth
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
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
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.
1. Ellis AG. The pathology and anatomy of bronchial asthma. Am J Med Sci 1908;136:407-29.
2. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978;2:407-21.
3. Zimmerman B, Enander I, Zimmerman R, Ahlstedt S. Asthma in children less than five years of age: eosinophils and serum levels of the eosinophil proteins ECP and EPX in relation to atopy and symptoms. Clin Exp Allergy 1994;24:149-55.
4. Koller DY, Herouy Y, Gotz M, et al. Clinical value of monitoring eosinophil activity in asthma. Arch Dis Child 1995;73:413-17.
5. The British Guidelines on Asthma Management: 1995 Review and Position Statement. Thorax 1997;52 Suppl 1.
6. Global Strategy for Asthma Management and Prevention. NHLBI/WHO Workshop Report. 1995; National Institutes of Health, USA. No.95-3659.
7. Holgate ST. The inflammation-repair cycle in asthma: possible new biomarkers of disease activity. Eur Respir Rev 1996;6:32,4-10.
8. Furukawa CT, Shapiro GG, Bierman CW, Kraemer MJ, Pierson WE. A double blind study comparing the effectiveness of cromolyn sodium and sustained release theophylline in childhood asthma. Pediatrics 1984;74:453-9.
9. Cogswell JJ. Simpkiss MJ. Nebulised sodium cromoglycate in recurrently wheezy pre-school children. Arch Dis Child 1985;60:736-8.
10. Coutts JAP, Gibson NA, Paton JY Measuring compliance with inhaled medication in asthma. Arch Dis Child 1992;67:332-3.
11. MacKenzie' CA, Weinberg EG, Tabachnik E, et al. A placebo controlled trial of fluticasone propionate in asthmatic children. Eur J Pediatr 1993;152:856-60.
12. Pedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children. A dose response study. J Allegy Clin Immunol 1995;1:29-33.
13. Price JF, Weller PH. Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study). Respir Med 1995;89:363-8.
14. Agertoft L, Pedersen S. Effects of long term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-81.
15. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Comparison of a beta against terbutaline with an inhaled steroid in newly detected asthma. N Eng J Med 1991;325:388-92.
16. Wennergren G, Nordvall SL, Hedlin G, et al. Nebulised budesonide for the treatment of moderate to severe asthma in infants and toddlers. Acta Paediatr 1996;85:183-9.
17. Van Essen Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months treatment with inhaled corticosteroid and/or beta-2-agonist on lung function, airway responsiveness and symptoms in children with asthma. Am Rev Respir Dis 1992;146:547-54.
18. Waalkens HJ, Van Essen-Zandvliet EE, Hughes MD, et al. Cessation of long term treatment with inhaled corticosteroid (budesonide) in children with asthma results in deterioration. Am Rev Respir Dis 1993;148:1252-7.
19.Law CM, Marchant JL, Honour JW, Preece MA, Warner JO. Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate. Lancet 1986;i:942-4.
20. Doull IJM, Donovan SJ, Wood PJ, Holgate ST. Bloodspot cortisol in mild asthma: the effect of inhaled corticosteroids. Arch Dis Child 1995;72:321-4.
21. Priftis K, Milner AD, Conway E, Honour JW. Adrenal function in asthma. Arch Dis Child 1990;65:838-40.
22. Clark DJ, Clark RA, Lipworth BJ. Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic children. Thorax 1996;51:941-3.
23. Bisgaard H, Nielsen MD, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol 1988;81:1088-95.
24. Konig P, Hillman L, Cercantes C, et al. Bone metabolism in children with asthma treated with inhaled beclomethasone. J Paediatrics 1993:122:219-36.
25. Sorva R, Turpeinen M, Juntunen-Backman K, Karonen SL, Sorva A. Effects of inhaled budesonide on serum markers of bone metabolism in children with asthma. J Allergy Clin Immunol 1992;90:808-15.
26. Wolthers OD, Juul A, Hansen M, Muller J, Pedersen S. The insulin-like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide. Acta Paediatr 1995;84:393-39790:808-15.
27. Le Bourgeois M, Cormier C, Kindermans C, Souberbielle JC, Garabedian M, de Blic J, Scheinmann P. Inhaled beclomethasone and bone metabolism in young asthmatic children: A six month study. J Allergy Clin Immunol 1995;96:565-7.
28. Agertoft L, Pedersen S. Bone growth and collagen markers in children treated with fluticasone propionate and budesonide. Eur Respir J 1996;9(Suppl 23):295s.
29. Birkebaek NH, Esberg G, Andersen K, Wolthers O, Hassager C. Bone and collagen turnover during treatment with inhaled dry powder budesonide and beclomethasone dipropionate. Arch Dis Child 1995;73:524-7.
30. Doull I, Freezer N, Holgate S. Osteocalcin, growth and inhaled corticosteroids: a prospective study. Arch Dis Child 1996;74:497-501.
31. Kinberg KA, Hopp RJ, Biven RE, Gallagher JC. Bone mineral density in normal and asthmatic children. J Allergy Clin Immunol 1994;94:490-7.
32. Baraldi E, Bollini MC, De Marchi A, Zacchello F. Effect of beclomethasone dipropionate on bone mineral content assessed by X-ray densitometry in asthmatic children: a longitudinal evaluation. Eur Respir J 1994;7:710-4.
33. Agertoft L, Pedersen S. Bone densitometry in children treated for 3-6 years with high dose inhaled budesonide. Eur Respir J 1993;6(Suppl 17):261s.
34. Mattinati LC, Bertoldo F, Gasperi E, Micelli S, Boner AL. Effect on cortical and trabecular bone mass of different anti-inflammatory treatments in preadolescent children with chronic asthma. Am J Respir Crir Care Med 1996;153:232-6.
35. Hopp RJ, Degan JA, Phelan J, Lappe J, Gallagher GC. Cross sectional study of bone density in asthmatic children. Pediar Pulm 1995;20:189-92.
36. Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double blind trial. Brit Med J 1991;303:163-5.
37. Wolthers OD, Pedersen S. Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids. Pediatrics 1992;89:839-42.
38. MacKenzie CA, Wales JKH. Growth of asthmatic children. Brit Med J 1991;303:416.
39. Wolthers OD, Pedersen S. Short term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child 1993;68:673-6.
40. Bisgaard H. Systemic activity of inhaled topical steroid in toddlers studied by knemometry. Acta Paediatr 1993;82: 1066-71.
41. Agertoft L, Pederesn S. Short term lower leg growth in children during treatment with fluticasone propionate and budesonide. A dose response study. Poster. American Thoracic Society Conference, Seattle May 20-24 1995.
42. Wolthers OD, Pedersen S. Measures of systemic activity of inhaled glucocorticosteroids in children: a comparison of urine cortisol excretion and knemometry. Respir Med 1995;89:347-9.
43. Karlberg J, Low L, Yeung CY. On the dynamics of the growth process. Acta Paediatr 1994;83:777-8.
44. Ferguson AC, Murray AB, Wah-Jun T. Short stature and delayed maturation in children with allergic disease. J Allergy Clin Immunol 1982;69:461-6.
45. Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986;61:1049-55.
46. Martin AJ, McLennan LA, Landau LI, Phelan PD. The natural history of childhood asthma to adult life. Brit Med J 1980;280:1397-400.
47. Shohat M, Shohat T, Kedem R, Mimouni M, Danon YL. Childhood asthma and growth outcome. Arch Dis Child 1987;62:63-5.
48. Ninan T, Russell G. Asthma, Inhaled corticosteroids and growth. Arch Dis Child 1992;67:703-5.
49. Preece MA. Measurement of the effects of drugs on growth. Eur Respir Rev l993;313:317-20.
50. Allen DB, Mullen M, Mullen B. A meta analysis of the effect of oral and inhaled corticosteroids on growth. J Allergy Clin Immunol 1994;93:967-76.
51. Todd G, Dunlop K, McNaboe J, Ryan MF, Carson D, Shields MD. Growth and adrenal suppression in asthmatic children treated with high dose fluticasone propionate. Lancet 1996;348:27-9.
52. Varsano I, Volovitz B, Malik H, Amir Y Safety of 1 year of treatment with budesonide in young children with asthma. J Allergy Clin Immunol 1990;85:914-20.
53. Ruiz RGG, Price IF. Growth and adrenal responsiveness with budesonide in young asthmatics. Respir Med 1994;88:17-20.
54. Doull IJM, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am I Respir Crit Care Med; 151:1715-9.
55. Price JF, Russell G, Hindmarsh PC, Weller PH, Heaf DP, Williams AJ. Growth and one years treatment with fluticasone propionate or sodium cromoglyacte in asthmatic children. Pediatr Pulmonol 1997:(in press)
56. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-8.
57. Sporik R, Holgate ST, Cogswell JJ. Natural history of asthma in childhood - a birth cohort study. Arch Dis Child 1991;66:1050-3.
58. Noble V, Ruggins NR, Everard ML, Milner AD. Inhaled budesonide for chronic wheezing under 18 months of age. Arch Dis Child 1992;67:285-8.
59. Stick SM Burton PR, CLough JB, et al. The effects of inhaled beclomethasone dipropionate on lung function and histamine responsiveness in recurrently wheezy infants. Arch Dis Child 1995;73:327-32.
60. Van Bever JP. Schuddinck L. Wojciechowski M, Stevens WJ. Aerosolized budesonide in asthmatic infants. Pediatr Pulmonol 1990;9:177-80.
61. De Blic J, Delacourt C, Le Bourgeois M, et al. Efficacy of nebulised budesonide in treatment of severe infantile asthma. J Allergy Clin Immunol 1996;98:14-20.
62. Massaro D, Teich N, Maxwell S, Massaro GD, Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest 1985;76:1297-305.
63. Furfaro S, Spier S, Drblik SP, Turgeon JP, Robert M. Efficacy of cromoglycate in persistently wheezing infants. Arch Dis Child 1994;71:331-4.
64. Iikura Y, Naspitz CK, Mihura H. et al. Prevention of asthma by ketotifen in infants with atopic dermatitis. Ann Allergy 1992;68:233-6.
65. Neijens HJ, Knol K. Oral prophylactic treatment in wheezy infants. Immunol Allergy Pract 1988;10:17-23.
66. Loftus BG, Price JF Long term placebo controlled trial of ketotifen in the management of pre-school children with asthma. J Allergy Clin Immunol l987;79:350-5.
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