Indian J Pediat 51:

333-340, 1984

Symposium--Resplratory D i s e a s e Bronchial asthma in children J.O. Warner, M.R.C.P

Asthma is the commonest chronic disease of childhood. Whilst most pediatricians have a fairly clear picture of what constitutes asthma, the condition has eluded a universally acceptable, comprehensive and precise definition despite many attempts. It is most simply defined as that state characterised by partial obstruction of airways, reversible with time either spontaneously or as a result of treatment. Clinically it is characterised by episodes of cough, sensations of chest tightness, dyspnoea and wheezing. However, any condition which results in narrowing of intrathoracic airways can present with cough and wheeze. Thus, before launching into the treatment of asthma, it is necessary to consider alternative diagnoses. Whilst the aphorism, "all that wheezes is not asthma" is as true in children as in adults, the commonest errors is failure to diagnose asthma in recurrently wheezy infants. Most alternative diagnoses will be obvious from a clinical history, examination and chest radiograph.

Spectrum of iUness There is an enormous variation in the severity of the disease, from the very mild and infrequent to severe crippling disease and occasional deaths. The Melbourne Prospective Study classified asthmatics into four groups based on an assessment at 14yr.l Grade A (6-7% of the population) had less Consultant Pediatrician, Brompton Hospital. London.

than five attacks, usually in mid-childhood from four to eight years and would usually not have been labelled as asthma. However, these children have similar frequencies of atopy and increased bronchial lability as other groups and upto 50 percent have redeveloped symptoms later in adolescence or early adult life. Grade B (6-7% of the population) h a d mild episodic asthma with three to four attacks per year from three to ten years of age with most going into spontaneous remission before adolescence. However, rather more of these children have had a recurrence of symptoms in late adolescence. Thus, it would be truer to say that the asthmatic grows out of the pediatrician rather than out of the disease. Grade C asthmatics (4-5% of the population) had continuing asthma at 14yr and often had an early age of onset. Grade D (0.5% of the population) had chronic severe perennial asthma with remissions of less than one month. The sex ratio progressed from a male to female of 1:1 in Grade A to 4:1 in Grade D. As the ratio for severe asthma is closer to 1:1 in adults there must be more males who have a remission and more females with persistent probJems orwho develop asthma for the first time as adults. The Melbourne Study suggested that early age of onset, frequent severe or prolonged attacks in the first year of life was rather more likely to be associated with severe asthma in the Grades C and I) categories.

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Mortality The majority of deaths will occur in the Group D asthmatics. Fortunately, in children fatalities are rare, but five per 100,000 asthmatic children die each year in Britain. Iqais is only 6 percent of that due to accidents in the same age group. There is no doubt that some of these asthma deaths could be avoided if the severity of disease was appreciated and appropriately treated. Chronic perennial severe asthmatics may complain little about acute attacks and cope reasonably well despite having grossly abnormal lung function. Such patients have very little respiratory reserve and are most at risk of sudden death at night or in the early morning. For some reason, as yet not elucidated, prolonged sleep is associated with greater susceptibility to decrease airways calibre and thus more severe asthma. Unfortunately, none of the therapies currently available totally abolishes this phenomenon. Until this is sorted out there will always be occasional unavoidable deaths. 2

Pathogenesis There are two basic defects which can usually be easily demonstrated in asthmatic children, bronchial hyper-reactivity and the atopic constitution.

Bronchial lability or hyper-reactivity: The sine qua non of asthma is bronchial lability. This is the susceptibility of the airways to react excessively with air-flow limitation due to smooth muscle spasm after exposure to various stimuli. The most obvious clinical stimulus is exercise, but inhalation of histamine, acetylcholine, prostaglandin F2, sulphur dioxide, cold air and many other non-specific factors could have a similar effect. Up to 90 percent of asthmatic children

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will have a positive exercise test with a greater than 15 percent fall in peak expiratory flow rate after six minutes of running, and this provides a very useful screening test if the diagnosis is in doubt. 3

Atopic constitution: Ninety to 95 percent of asthmatic children will have the propensity to develop Type 1 hypersensitivity to common environmental antigens such as the house dust mite, grass pollen, animal danders etc. This is most easily demonstrated by prick skin testing. 1 There is a strong familial tendency to produce this reaction, although other family members, even with positive skin tests, may not have asthma. Hayfever, eczema, gastrointestinal food intolerance and urtic--ia may manifest in 50 percent of the relatives 4 in any combination.

Pathology Whilst the bronchial hyper-reactivity results in bronchospa',-n with hypertrophy and hyperplasia ot ~.nooth muscle, the other essential ingredient of air-flow limitation is an inflammatory reaction. In patients dying from asthma the small airways are plugged with thick, viscid mucus, often forming casts. There is hyperplasia of goblet cells and basement membrane, sloughing of epithelium and submucosal infiltration with eosinophils, lymphocytes, mast cells and neutrophils. 5 Examination of sputum from athmatics will often reveal an excess of eosinophils, Charcot-Leyden crystals (degranulation products of eosinophils), Curshman spirals (small airway casts) and respiratory epithelium with villi.

Evaluation of patients Histom~: Most infants present with loud

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wheezing and tachypnoea often persisting for days or weeks and particularly exacerbated by viral infection. However, most remain well and thrive despite the very loud wheeze. Some do not go on to have frank asthma, but others will and it must be remembered that 80 percent of children will have their first symptoms before five years, 30 percent before three and 18 percent before one. I A small proportion of infants, often with eczema and a family history of atopy, have serious attacks of asthma leading to rapid development of respiratory failure. They usually have chronic severe asthma of the Grade D variety, subsequently. 9 Established asthmatics have clear-cut attacks associated with such factors as viral infection, exercise, emotional disturbance, l~iughing, exposure to dust, animals or pollens and cold air. They may have overt wheezing and coughing, but some are only aware of coughing. Particular attention should be paid to nocturnal symptoms. Fifty per cent have current or previous eczema and most also have symptoms of allergic rhinitis. Apparently excessive respiratory infections so often called "wheezy bronchitis" are common, but it is often difficult to distinguish whether these are true lower respiratory infections or just asthma triggered by upper respiratory tract infections. Only few have genuine lower respiratory tract infections, including pneumonias, probably because of a more profound underlying immuno-deficiency. In taking a history specific questions should be asked on known allergen exposure, such as to pets. The association of symptoms with physical agents, such as temperature, humidity, tobacco smoke, sprays and other fumes, should be elicited. The type of housing may also influence allergic disease. Such factors as age of property, prox-

imity to water-ways, type of heating, carpeting, furniture and bedding may be important. A family history should include both indirect and direct questioning, particularly for allergic disease and other disorders associated with immune deficiency. In considering the environment of the child it should be remembered that he or she will spend an appreciable time during the day at school or out of doors. Timing of symptoms in relation to such locations will be important.

Physical signs: The stigmata of atopic disease are often apparent and a typical atopic facies is often described. The patient often has discoloration and swelling of the eyelids, a transverse nasal crease due to the nose constantly being rubbed up and down and mouth-breathing due to rhinitis obstructing the nasal airway. The nasal mucosa can easily be examined using an auriscope and the pale, swollen inferior turbinates due to allergic rhinitis easily seen. Serous otitis media with a conductive deafness is a quite frequent associate, on. Red, runny eyes with blepharitis and a cobble-stoned conjunctiva will indicate allergic conjunctivitis. The skin should be carefully examined, particularly in the flexures and the scalp. Hypopigmentation may indicate areas of previous skin disease. Occasionally allergic children may manifest dermatographism. The bowed sternum, spinal kyphosis and Harrison's sulci will all be signs of chronic respiratory distress. Some patients with more severe chronic disease will be under weight and growth Stunted with delayed adolescence and therefore, accurate anthropometry is essential. Investigations: A routine chest radiograph is necessary to exclude other diseases. Prick skin testing is safe and a satisfactory way of

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highlighting the atopic constitution. A few allergens with phenol saline and 1 percent histamine as negative and positive controls respectively~ should be used. Over the age of three years it should be possible to measure peak expiratory flow rate using a simple, cheap device which should be in every doctor's kit, namely a Wright mini peak flow meter. In a wheezy child measurement before and after bronchodilator will clinch the diagnosis. Between episodes an exercise test will highlight lability. Alternatively the child can make regular records of the peak flow over a short period to demonstrate the variability so characteristic of asthma. This can be recorded on a simple diary card together with symptoms and treatment administered. Blood counts, biochemical tests, IgE, and E antibody measurements whilst interesting are rarely helpful in the management of the patient. Where relevant bronchial challenge with allergens will aid specific allergy diagnosis if this is considered necessary to guide treatment. Sputum cytology may be of value to children with productive coughs and where the diagnosis is in doubt. Lung function testing beyond frequent peak flow measurements is unlikely to provide any more information except in the severe asthmatics. In these cases measurement of lung over-inflation and small airway obstruction may provide some indication of response to treatment if monitored sequentially.

Differential diagnosis Bronchiolitis." An acute episode of wheezing in association with fever in an infant may be acute bronchiolitis or the first attack of asthma associated with a viral infection. Ultimately the distinction is probably not critical and there is still controversy about the associations between the two diseases. It

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is clear that babies with genuine respiratory syncytial virus induced bronchiolitis have a incidence of recurrent wheezing over the subsequent four to five years, even if they do not have straightforward atopic asthma. Furthermore, the treatment of the acute episode will be symptomatic whatever the cause.

Aspiration: In infancy inhalation of milk into the respiratory tract results in chemical bronchitis and thus recurrent or persistent wheezing. A history of vomiting, choking on feeds, or respiratory distress during or shortly after feeds should alert the clinician to this diagnosis. In toddlers and older children foreign body inhalation is occasionally missed in the acute stages only to present later with persistent wheezing. A history of choking, particularly on peanuts should always be followed up with radiography and bronchoscopy. Cystic fibrosis." Infants with cystic fibrosis and chest infection frequently present with cough and wheezing. Most children with this recessively inherited condition will also have failure to thrive by the time they develop respiratory infections. This will be obvious provided weight and height are accurately measured and plotted on appropilate centile charts. Eighty-five percent will have evidence of pancreatic insufficiency with steatorrhea. Mediastinal lesions." Mediastinal glands, cysts and tumours may partially compress the large airway and cause wheezing. Primary tuberculosis should be excluded by tuberculin tests and chest radiograph.

Management of asthma Because there is an enormous spectrum

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of severity of disease the management must be tailored to the individual case and severity must be assessed before treatment is commenced. As responses to treatment are different in infants below 18 months they will be considered separately. All sensible avoidance of precipitating factors should be recommended. This will primarily involve advice on reducing exposure to house dust mite and animal danders. House dust mite elimination techniques are occasionally of value and include the use of synthetic materials for bedding, removal of soft toys from the bed, regular vacuuming of the mattress and preferably enclosing the mattress in a plastic cover, and irritants, such as cigarette smoke, is important. As emotion plays an important role in potentiating problems it is imperative that the child and family should be helped to gain a realistic understanding and acceptance of the condition. This can usually be achieved by the pediatrician, but occasionally specialist family psychotherapy may be needed. 6 Where children have other atopic problems these may also require treatment. Whilst antihistamines are usually not of value in asthma, they may be very helpful in reducing the pruritus of eczema and the nasal symptoms of allergic rhinitis. Asthma under 18 months

Most wheezing in infancy is preceded by an upper respiratory infection, but as this is virtually always viral in origin antibiotics are not required. The wheeze is often loud and persistent, but in most cases causes very little distress and therefore infants can manage very well without any treatment. This approach is often difficult to sell to the parents.

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Unfortunately, beta agonists, even by nebuliser are often ineffective in this age group, although nebulised ipratropium bromide (Atrovent) does sometimes temporarily releave acute airflow obstruction. Oral theophyllines as an elixir are sometimes helpful, but doses must be carefully estimated (theophylline maximum 5 mg per kg per dose six hourly, or choline theophyllinate-maximum 8 to 10 mg per kg per dose eight hourly). Theophylline should never be administered rectally as absorption is erratic and may lead to toxic complications. Only the very severe acute cases will require short courses of steroids and such children will probably require hospital admission for the severity of disease. Frequcnt episodes may be controlled by regular theophylline medications, but if further prophylaxis is required nebulised sodium cromoglycate 2 ml three to four times daily may be effective. In the very occasional infant with frequent severe wheezing, long term-alternate day oral steroids together with regular bronchodilator may become necessary. Asthma over 18 months

MiM episodic asthma: Children with mild, episodic asthma will grow normally, miss little school and will have minimal or no lung function abnormality between attacks. Most will be satisfactorily treated with beta zspecific agonist preparations orally for individual attacks. Inhaled beta agonist drugs will of course be more effective and for younger children most appropriately administered as Salbutamoi by rotahaler (200 ug up to a maximum of four hourly). When children are sufficiently well coordinated a pressurised aerosol can be used.

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Frequent episodic asthma: Where attacks have become relatively frequent it will be necessary to administer regular therapy. Here the choice lies between regular theophylline preparations, preferably in slow-release form, or sodium cromoglycate, either by nebuliser in the very young and poorly co-ordinated children, or spinhaler. Current trials suggest that the pressurised aerosol form of sodium cromoglycate is not as effective as the spinhaler in children. The sodium cromoglycate should be taken at least three and preferably four times daily. Most failures of this treatment are due to failure to use the inhaler correctly, which is sometimes difficult for small children. Time spent in education on inhaler usage is invaluable. The dose of theophylline preparation must be tailored to the individual patient. Thus for slow-release theophylline it is l0 to 12 mg per kg per dose twice daily. Having used either theophyllines or sodium cromoglycate as necessary it will then also be possible to use beta against preparations as necessary for any acute exacerbations. Chronic perennial, or severe episodic asthma: Where regular sodium cromoglycate or theophyllines fail to control the asthma it will be necessary to use steroids. There is little to be gained from continuing with sodium cromoglycate once this has been ineffective. Thus use of potent topically active steroid preparations, such as beclomethasone dipropionate by inhalation has dramatically impoved the management of severe asthma. These can be administered either by pressurised aerosol or rotahaler. In younger children the latter mode of delivery is usually preferred. These preparations should be administered regularly two to four times daily depending on the severity of the disease. Only a very small number of cases will require regular oral steroids, preferably

Vol. 51, No. 410 given as prednisolone on alternate days to reduce the major side-effect of growth stunting. Where steroids, either by inhalation or any other route, are used beta agonist preparations should always be given regularly in addition. One of the important effects of steroids is to facilitate the bronchodilator response and this should be capitalised upon .7

Immunotherapy : This consits of a graded series of increasing doses of allergen, usually administered by subcutaneous injection. It should be reserved for those allergic factors which cannot be eliminated and that can be demonstrated to play a major role in producing asthma. Patients controlled on simple and safer conventional therapy should not be considered for immunotherapy. In practice only pollen and the house dust mite have been convincingly shown to have any benefit and these only in carefully selected patients, following appropriate bronchial challenge studies. 8 Other therapies: There is no evidence to support the use of air filters or ionisers. No controlled study has yet validated the use of hypnosis or acupuncture. There is no indication to use sedation, cough suppressants, mucolyticus or antihistamines. Physiotherapists can most usefully train children to use their inhalers correctly. Controlled breathing and relaxation may be of value during acute exacerbations, although no trials have ever been conducted to support this contention. Postural drainage is rarely necessary and pos~ral coughing is disadvantageous as this may exacerbate bronchospasm. Encouragement to participate in all physical activities is important. Whilst swimming is less likely to induce bronchospasm properly designed activities outside the swimming pool, particularly

WARNER : BRONCHIAL ASTHMA IN CHILDREN

when combined with appropriate medications, will be equally unlikely to produce wheezing. Acute-severe

asthma

Acute exacerbations of asthma have been termed status asthmaticus, but this is an illdefined state and the term is probably best avoided. Acute attacks are potentially lethal and therefore great care is required in assessment and if the attack is considered severe the patient will require treatment with full intensive care facilities. Initial assessment is based primarily on the degree of distress which will be indicated by recession, the use of accessory muscles and tachypnoea. Any degree of disturbance of affect or consciousness may indicate a severe abnormality of blood gases. Tachycardia and a (Pulsus) paradoxus of greater than 20 mrrtof mercury and poor air entry on auscultation of the lung fields indicates a severe attack. Where ever possible an attempt should be made to measure the peak expiratory flow rate. A dose of a beta agonist (salbutamol or terbutaline) by nebuliser should be administered immediately and the clinical state reassessed over the succeeding five to ten minutes. A response which must be documented objectively, preferably with the use of the peak flow meter, will allow admission to an open pediatric ward. Provided the air entry is equal in both lung fields there is probably no need for a chest radiograph. The child must be reassessed regularly and if there is a relapse within four hours then it will be clear that nebulised beta agonists alone will not be enough to control the attack and intensive care will be required. Oxygen should be administered to all cases initially at a concentration of 40 percent. However, as there is no concern about

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chronic CO 2 retention concentrations upto 100 percent may be used if necessary. Having failed to respond to inhaled beta agonists, intravenous therapy will be required. Provided the patient has not received theophylline preparations in the previous 12 h aminophylline should be administered at a dose of 5.6 mg per kg given slowly over 20 min. Thereafter a continuous infusion of 0.9 mg per kg per hour should be maintained. If such drugs have been used within the previous 12 h it should be possible to get an urgent measurement of the blood level so that doses can be judged accordingly. In the meantime intravenous salbutamol l0 ug per kg can be given and followed with a continuous infusion of 0.25 ug per kg per minute. In our experience this infusion can be increased considerably if necessary, but as with all treatments at this stage intensive monitoring is required. If there is a response to therapy at this stage it may be possible to avoid doing an arterial blood gas, but where ever it is not possible to judge the severity of the attack or in very ill patients, arterial gases are mandatory. Intravenous hydrocortisone in a dose of 4 mg per kg every three to four hours will also be required. The vast majority of patients will respond to this treatment within four to six hours, but therapy should be maintained for at least 24 to 48 h before slowly converting to an oral and inhaled regime. If there is no response to the aminophylline it is possible to combine this with salbutamol, either by nebuliser or intravenously. It is very rare for a patient to progress to respiratory failure and require ventilation. This is more likely to occur in infants. The decision of institute ventilation is a clinical one, but will be strongly indicated by a PA C O 2 of greater than 65 mm of mercury and rising, particularly if associated with decreased air entry, cyanosis in 40 percent

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oxygen, depressed level of consciousness or p o o r muscle tone. T h e intubation s h o u l d be d o n e u n d e r anesthetic a n d muscle relaxation is best achieved with p a n c u r o n i u m b r o m i d e which will not p r o d u c e histamine release as with some other more regularly used muscle relaxants. O t h e r general measures will include m a n a g e m e n t o f hydration. Whilst dehydration m a y occur because o f p o o r fluid intake a n d evaporative loses from the airways during prolonged attacks, over h y d r a t i o n can h i n d e r recovery because p u l m o n a r y e d e m a is easily precipitated. Therefore, intravenous fluids should be calculated as between 100 and 125 percent o f n o r m a l daily requirements as 4.3 percent Dextrose in a fifth normal saline. C h i l d r e n o n steroids m a y require additional potassium based on electrolyte estimations. It is worthwhile correcting an acidosis if the p H falls below 7.25. T h e metabolic c o m p o n e n t can be corrected using the formula: base deficitXweight in kg )<0.15, to indicate the n u m b e r o f m m o l o f s o d i u m b i c a r b o n a t e to give by slow infusion. Antibiotics are not required routinely in acute exacerbations o f asthma.

k n o w n as a N e b u h a l e r , has a valve incorporated which may allow its use in small children. Nebulisers with appropriate air compressors m a y be necessary in very small children who are u n a b l e to use any form of simple inhaler. T h e y are only very rarely required in older children on a domiciliary basis, where it can be p r o v e d that this form of delivery produces greater degrees of b r o n c h o d i l a t i o n than a simple device. In conclusion, asthma is very c o m m o n affecting up to 20 p e r c e n t o f the c h i l d h o o d population. It is nearly always associated with the presence o f allergy and bronchial hyper-reactivity. Severity ranges from the very mild occasional attacks to a severe life threatening problem. F o r the vast majority o f patients it should be possible to control their attacks with fairly simple treatment, resulting in minimal absences from school and participation in all n o r m a l activities. G r e a t care is required in the m a n a g e m e n t of acute exacerbation which are potentially lethal, but the spectre o f the chronic severe asthmatic with growth stunting and chest deformity should be vision from the past.

Inhalers: T h e r e are now a bewildering

array o f delivery devices to administer i n h a l e d medications. Simple pressurised aerosols require good c o o r d i n a t i o n to be used optimally~ Ideally the child should relax to the end tidal position and then take a long,-slow inhalation starting just before actuation o f the aerosol. At full inspiration the child should m a i n t a i n a ten second breath hold. This p r o c e d u r e is often impossible for small children. T h e y usually find it easier to use a rotahaler. However, it is still necessary for the child to generate a reasonable inspiratory flow. It has recently been shown that placing a spacer device between pressurised aerosol and the patient improves the delivery and the latest model,

References

I. McNicol, Williams HB" Spectrum of asthma in children, l.Br Med J 4: 7, 1973 2. Stablebith DE: Death from asthma. Thorox 38: 801, 1983 3. Godfrey S: Exercise testing in children. W.B. Saunders Co. Ltd.. London 1974 4. Edbrs-Lubs ML: Allergy in 7000 twin pairs. Acta Allergologica 26: 249. 1971 5. Dunnill MS, Massarella GE, Anderson JA: A comparison of the quantitative anatomy ofthe bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and emphysema. Thorax 24: 176, 1969 6. Lask B, Mathew D: Childhood asthma-a controlled trial of family therapy. Arch Dis Child 54: 116, 1979 7. Clark TJH: Steroids in asthma. Adis Press Aukland N 2. 1983 8. Warner JO: Hyposensation in asthma: a review. J Roy Soc Med 74: 60, 1981