Diycult Asthma: Beyond the Guidelines

Arch Dis Child 1999;80:201–206 201 Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from PERSONAL PRACTICE

DiYcult asthma: beyond the guidelines

Ian Balfour-Lynn

The current guidelines for prophylactic treat- should be considered, some more rare than ment of paediatric asthma culminate in the others. Relevant investigations should be car- addition of regular oral corticosteroids after a ried out when the history or examination stepwise increase in treatment.1–3 However, suggests one of these other diagnoses (table 1). there are still a few patients whose asthma is In particular, the presence of finger clubbing is not controlled despite such maximal conven- incompatible with the lone diagnosis of tional treatment and these children are often asthma. An asthmatic child may be aVected by referred to a tertiary paediatric respiratory another condition that contributes to or centre. Childhood asthma has several manifes- worsens the asthma symptoms. In particular, tations and diVerent approaches may be gastro-oesophageal reflux should be looked for required for diVerent patterns of asthma. and treated although its significance is not Unfortunately, some of these children are diY- always clear.5 Immunodeficiencies should also cult to treat. These include infants with severe be excluded; an initial screen should include recurrent viral wheezing who respond poorly to serum immunoglobulins and IgG subclasses, medication but generally have a good progno- complement concentrations, and antibody re- sis. There are those said to have “brittle sponses to common antigens (diphtheria, teta- asthma”; this has been classified into those with nus, Haemophilus influenzae type b, and pneu- a wide peak flow variation despite maximal mococcus) (Jones A, personal communication, treatment (type 1), and those who are well 1998). controlled in between attacks, which when they 4 occur are often sudden and severe (type 2). VOCAL CORD DYSFUNCTION This article concentrates on another group— Vocal cord dysfunction frequently mimics or children who have severe chronic background complicates asthma, and is characterised by a symptoms with acute exacerbations superim- paradoxical adduction of the vocal cords on http://adc.bmj.com/ posed. inspiration.6 The resultant airflow obstruction produces wheezing or stridor (usually loudest Confirming the diagnosis over the larynx), chest tightness, breathless- The first question when confronted by a child ness, and cough. Symptoms can be produced with severe symptoms despite conventional throughout the respiratory cycle, so they may treatment is: does the child really have asthma? be inspiratory, expiratory or both7 but they are

There are several alternative diagnoses that never present during sleep. Although patients on September 29, 2021 by guest. Protected copyright. with vocal cord dysfunction are usually women Table 1 Some of the alternative and concomitant diagnoses with relevant investigations for children aged 20–40 years, the condition is well presenting with diYcult asthma recognised in children and adolescents.8 There are often underlying psychological stresses but Diagnosis Investigations it is not factitious as patients do not consciously 6 Cystic fibrosis Sweat test, DNA analysis control the process. Patients with vocal cord Primary ciliary Ciliary brushings for structure and dysfunction have often been misdiagnosed with Department of dyskinesia function, nasal nitric oxide asthma (subsequently found to be unrespon- Congenital lung Paediatric Respiratory abnormalities Chest x ray, CT chest scan sive to bronchodilators and corticosteroids), Medicine, Royal Tracheobronchomalacia Flexible bronchoscopy but the condition may coexist with asthma.9 Brompton & Harefield Vascular ring Barium swallow Spirometry is poorly reproducible, but the NHS Trust; Bronchiectasis Chest x ray, CT chest scan Department of Obliterative flow–volume loop may show evidence of Paediatrics, Chelsea bronchiolitis CT chest scan, viral titres variable extrathoracic obstruction or be and Westminster Chest x ray, inspiratory and 7 expiratory chest imaging (older normal. Diagnosis is confirmed by laryngos- Hospital, London, UK Inhaled foreign body children), rigid bronchoscopy copy, which shows adducted cords relieved by I Balfour-Lynn Chest x ray, bronchoalveolar lavage sedation.7 Treatment evolves around a clear for fat laden macrophages, explanation of the syndrome, stopping unnec- Correspondence to: Recurrent aspiration radiolabelled milk scan Dr I Balfour-Lynn, Congenital heart Echocardiography, essary medication, speech therapy, and psycho- Department of Paediatric disease electrocardiography logical support. Medicine, Royal Brompton Vocal cord dysfunction Laryngoscopy & Harefield NHS Trust, Gastro-oesophageal 24 hour pH study or radiolabelled Sydney Street, London reflux milk scan Confirming the severity SW3 6NP, UK. Immune problems Immune function testing email: i.balfourlynn@ In many cases, severity can be gauged from the ic.ac.uk CT, computed tomography. history and physical examination. Simple 202 Balfour-Lynn

spirometry, which can be performed in the PSYCHOSOCIAL ASPECTS Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from outpatient clinic, will provide measures of It is not uncommon for psychosocial aspects to airflow limitation, and a look at the flow– play a large role in the wellbeing of a child and volume loop can be helpful. Day to day peak particularly an adolescent with asthma. DiY- flow variability is a useful measure assuming cult home circumstances may lead to a that the home diaries are accurate. Unfortu- worsening of symptoms and sometimes the ill- nately, experience shows that these diaries can ness is used as a weapon or a cry for help. It rarely be relied on, compliance is poor, and may even be the mechanism for school refusal. measurements are often fabricated.10 Formal Admission to hospital is often needed to assess lung function testing in a laboratory may also the true functional status of the child and to be necessary for full evaluation, and would gain an impression of family interactions, albeit include measures of airway resistance, lung in unfamiliar surroundings. As well as simple volumes and air trapping, bronchodilator observations from the nursing staV on the responsiveness, and the eVects of exercise. A ward, help can be enlisted from the clinical directly observed exercise test may be useful to psychologist, teachers and play leaders, and help diVerentiate whether it is the patient’s sometimes social workers. Psychosocial prob- perception of breathlessness, general muscle lems do not mean the child does not have fitness, or true exercise induced asthma that is asthma (a point that must be emphasised to the causing problems with exercise. Patients often child), but the severity of symptoms are often start to complain of breathing diYculties the out of keeping with the actual disease severity. minute they start exercising, in which case it is The asthma and psychological disturbance unlikely this is caused by asthma itself. must both be treated on their own merits with- Measurement of exhaled nitric oxide may also out necessarily deciding which is primary and which secondary. be used to monitor the eVects of corticosteroids on the underlying inflammation, although the usefulness of this measure is Reasons for treatment failure Assuming the patient genuinely has severe uncertain.11 12 It has been suggested that asthma responding poorly to treatment, it may assessment of bronchial hyperresponsiveness be possible to improve matters by simple (methacholine or histamine challenge) is the means. single most useful test of asthma severity,13 but in practice it is rarely useful in children. ALLERGENS AND OTHER AVOIDABLE FACTORS Inconsistencies with the clinical picture There may be allergens in the home that are should raise suspicions that the asthma severity providing a constant source of immunological is not as great as the child and his or her family stress to the airways. While house dust mites (and perhaps the referring doctors) perceive. are almost impossible to eradicate, their eVect The history should then be treated with may be reduced by various methods, including caution, and while reliable measures in the regular ventilation of the bedroom, mite proof examination include chest hyperinflation and allergen covers on bedding, and the use of an http://adc.bmj.com/ Harrison sulci, added sounds on auscultation eYcient vacuum cleaner with an adequate may not be genuine. Spirometry becomes filter.15 It is surprising how many asthmatic harder to interpret as measures are so eVort children live in homes with a multitude of furry dependent, although the shape of the flow– pets, and horse riding seems to be a favourite volume curve may give clues to poor eVort. pastime of teenage girls with severe asthma. Other measures that may be useful when the Rather than being dictatorial, it is best for the situation is in doubt include a straight and lat- families to come to decisions about removing

eral chest x ray for hyperinflation, and in pets themselves. This may be helped by on September 29, 2021 by guest. Protected copyright. extreme cases a ventilation–perfusion scan. providing objective evidence, and if the history During a prolonged exacerbation the latter is suggests worsening symptoms after exposure to likely to show patchy areas of ventilation– a particular animal, skin prick testing or RAST perfusion mismatch and a normal scan should (radioallergosorbent) testing for specific IgE raise suspicions. Doubts will also arise when a may be useful. Families should be warned that severely “symptomatic” child has a normal it may take up to six months for symptom bronchial challenge. These children are often improvement to be seen after the pet has been being overtreated, and as the perceived symp- removed.16 toms inevitably fail to resolve, the treatment Exposure to cigarette smoke at home and in regimen is increased further still resulting in the car may be a contributory factor, and a potentially serious side eVects. child with a serious disease does not always Another problem is poor perception and provide enough motivation for some parents to underestimation of symptom severity in a child stop smoking. It is worth considering whether who truly has severe asthma. A significant the adolescent asthmatic has started smoking number of patients with asthma (and their par- themselves. The issue of poor housing and ents) fail to recognise how serious the symp- damp in the home is controversial but may toms are, in both the acute and chronic contribute to symptoms.17 situation. This increases the risks of noncompliance and severe exacerbations. Reasons INAPPROPRIATE DEVICES for this lack of insight range from psychological It is surprising how often asthma control can be denial to a blunted perception of breathlessness improved by changing the device used to and airway obstruction intrinsic to some administer inhaled drugs. Watching the child’s patients.14 technique with their medicines is essential, and DiYcult asthma 203

time spent in retraining is well spent. Drug STEROID RESISTANCE Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from deposition in the lungs varies signiﬁcantly Steroid resistant asthma occurs in a small sub- according to the device; spacers are very set of patients with genuine asthma that fails to eVective18 so these are recommended for taking show a clinical response to high dose systemic twice daily prophylaxis. However, owing to corticosteroids that are genuinely taken. De- their size, spacers are inconvenient to carry spite adequate treatment, they have persistent around during the day, so dry powder inhalers airway obstruction and immune activation. are recommended as the next best thing, with Steroid resistant asthma has been recognised Turbohalers (Astra Pharmaceuticals, Kings for a while in adults and there are now reports Langley, UK) being the most eYcient.18 I never of a few children with the condition.22 23 The prescribe metered dose inhalers without a clinical deﬁnition for adults is failure to

spacer device. In fact the choice of device is improve morning FEV1 (forced expiratory vol- probably more important than the choice of ume in one second) by more than 15% drug, with the child’s age and coordination predicted after 14 days of 40 mg/day being the most critical factors. In addition, prednisolone.24 In children, there is no set defi- devices that are “uncool” will not be used at nition but 10 days of at least 15 mg twice a day school, and compliance can be improved by has been suggested as an adequate trial.25 giving the child a degree of choice. However, symptoms and persisting evidence of airway inflammation can occur in children with INADEQUATE DOSES relatively well preserved lung function. Use of regular systemic steroids may some- The steroid resistance is not necessarily gen- times be avoided with high enough doses of eralised; the patients are often Cushingoid inhaled corticosteroids. There is no room for despite lack of a local response in the lungs, so being timid, and fears of adverse eVects, they suVer the adverse eVects of corticosteroids particularly poor growth, should not lead to while receiving little clinical benefit.25 There inadequate treatment. Professor Charles are several mechanisms behind steroid resist- Brook, with his expertise on growth, is the first ance, both primary and secondary (acquired), to say, “asthmatics do not die of short stature”. which have recently been reviewed.24 26 If a However, equally there is no need to be child does not respond to a controlled cavalier; safety can be enhanced by delivery therapeutic trial, bronchial mucosal biopsy is through a spacer device combined with rinsing recommended to determine the cellular and the mouth afterwards, which will reduce oral inflammatory cytokine profiles.23 Less invasive absorption of the drug. Regular monitoring of methods such as induced sputum for inflam- growth and examination for cataracts19 is matory markers and exhaled nitric oxide levels recommended when using very high doses. can also be used. If this confirms unrestrained Deciding whether one inhaled corticosteroid is inflammation despite high dose systemic ster- truly safer or more eYcacious than another is oids, then alternative treatments should be diYcult to determine as, despite many claims, considered as there is little point in continuing

it is almost impossible for clinicians to judge with steroids. Complete steroid resistance is http://adc.bmj.com/ whether such claims are correct.20 Anecdotally, fortunately rare, but there is a group of patients switching to high dose ﬂuticasone propionate with reduced responsiveness to steroids has sometimes resulted in improved control. In (corticosteroid insensitive asthma) in which terms of other drugs, there is little evidence high doses of inhaled or systemic steroids are that giving doses of salmeterol above those needed to maintain adequate control. Finally, generally recommended leads to additional there is a group of patients requiring constant beneﬁt, although there are some anecdotal systemic corticosteroids for control (steroid

cases in which this has proved useful. dependent asthma). This last group is thought on September 29, 2021 by guest. Protected copyright. to have severe disease with profound airway 24 NON-ADHERENCE TO TREATMENT inﬂammation. There is little doubt that patients do not take their medication as we think or hope. One study using electronic monitors attached to Therapeutic options inhaler devices has shown that more than 90% It may not be possible to reduce or stop of children exaggerated their use of inhaled systemic steroids, in which case they should be steroids, with a median use reported in diaries given in a way to enhance safety. Suppression of of 95% compared to actual electronically the hypothalamo–pituitary–adrenal axis is less- recorded use of 58%.21 Compliance was worse ened by taking the steroids in the morning, and in those who experienced an exacerbation if possible on alternate days. Prednisolone requiring oral steroids. Furthermore, compli- tends to be used and recent claims that ance does not improve with increasing disease deﬂazacort has a lower incidence of steroid severity and, worryingly, non-compliance often induced side eVects compared to prednisolone occurs with tacit approval from parents.21 have been revised at the request of the Reasons for non-adherence to long term medi- Medicines Control Agency.27 However, the fol- cation are multiple, including poor under- lowing are alternative forms of treatment that standing, fear of steroid side eVects, adoles- may allow reduction of steroids or at least lead cence, and a wish to be just like everyone else. to improved control. The assumption is that A patient approach from a multidisciplinary the child is already taking high dose inhaled

team, which the child and family must feel a steroids and oral steroids, a long acting â2 ago- part of, is the way forwards, although there are nist (salmeterol or eformoterol) and perhaps no guarantees of success. theophylline. 204 Balfour-Lynn

NEBULISED BUDESONIDE Sharp & Dohme Ltd, Hoddesdon, UK) is Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from In a double blind, placebo controlled study, 36 available for children over 6 years and has the children aged 10 months to 5 years who were advantage of being a once daily chewable dependent on oral steroids were given 2 mg/ tablet. The only published paediatric study was day nebulised budesonide or placebo.28 There multicentre and involved 336 children aged was a signiﬁcant reduction in oral steroids and 6–14 years.36 A signiﬁcant improvement in

an improvement in subjective symptom scores morning FEV1 was shown after eight weeks of in the active treatment group. However, the treatment with benefit seen after one day’s patients had not been taking inhaled steroids treatment. There were no diVerences in by other means and it is not clear whether adverse events between the drug and placebo budesonide administered by a spacer device groups, in particular there were no problems would have been equally eVective. With an with liver enzymes. Further studies are needed optimal nebuliser setup budesonide delivered to assess the long term safety profile of monte- by spacer is equipotent to that delivered by lukast. Zafirlukast (Accolate; Zeneca Pharma, nebuliser29 and, in practice, nebulisers are less Wilmslow, UK), a twice daily tablet, is also eYcient at drug deposition compared to available and licensed for children over 12 spacers.18 No study of nebulised budesonide years.37 These drugs are an exciting develop- has been carried out in steroid dependent older ment as they represent the first mediator children, but an open study in 42 adults given specific treatments for asthma. They have not 2 mg/day found that 55% were able to reduce yet been proved as steroid sparing agents in their oral steroid intake by a mean of 59%.30 It children, but inevitably if better control is is best to use a mouthpiece, but if a mask must achieved, steroid doses will be reduced. Within be used it should be tight fitting and children the next year, their therapeutic role in mild should be advised to wash their faces and rinse asthma may become clearer, but for now it is their mouths afterwards. The holes in the mask likely that their use will be restricted to the facing upwards towards the eyes should be stage before oral steroids are introduced—even covered and children should be reminded to though there is no evidence of their benefit in breathe through their mouths and not their this situation. noses. ORAL CYCLOSPORIN SUBCUTANEOUS TERBUTALINE Cyclosporin is an immunosuppressant used Continuous subcutaneous terbutaline and after organ transplantation that works by salbutamol have been shown to be useful in inhibiting T helper lymphocytes. The promi- some adults with severe chronic or brittle nent role of T lymphocytes in asthma has led to asthma.31 32 This form of treatment has been trials of cyclosporin in adults which showed used in acute severe infantile asthma33 and can improved lung function38 39 and a steroid spar- be quite eVective in the chronic phase in ing eVect.39 No trials have been carried out on children who are prepared to tolerate a children although its successful use in three of

subcutaneous needle. The intravenous prepa- ﬁve children on regular oral steroids has been http://adc.bmj.com/ ration (0.5 mg/ml) is administered by Graseby recently reported using 5 mg/kg daily.40 The pump (Graseby Medical Ltd, Watford, UK) at side eVects in adults include hirsutism, paraes- a starting dose of 5 mg/day. Systemic side thesia, mild hypertension, headaches, and eVects include tremor, hyperactivity, sinus tremor.38 39 The only concern in the paediatric tachycardia, palpitations, headache, and mus- report was hirsutism, which led to one girl cle cramps, although generally it is well stopping its use even though her steroid dose tolerated. Serum potassium should be moni- had been profoundly reduced. There is obvi-

tored owing to the theoretical possibility of ously a concern about renal impairment with on September 29, 2021 by guest. Protected copyright. developing hypokalaemia, although this is in long term use, so renal function must be care- fact rare.4 Local problems are more common fully monitored, and cyclosporin blood con- and include tender subcutaneous nodules and centrations maintained at 80–150 mg/l. A haematomas at the site of injection. It is advis- proper randomised trial is urgently needed as able to start this treatment in hospital for safety this drug has real potential in severe asthma. reasons, and to allow adequate time for Furthermore, nebulised cyclosporin is being educating the patient and family. It is often tried in some post-transplant patients, and this useful to start with saline for 48–72 hours and may oVer an improved risk–beneﬁt ratio over essentially perform an n = 1 single blind thera- systemic cyclosporin in asthma. peutic trial; this ensures any symptom improve- 34 ment is not simply a placebo eVect. INTRAVENOUS IMMUNOGLOBULIN Two small, open label studies found that infu- ORAL ANTI-LEUKOTRIENES sions of intravenous immunoglobulin (IVIG) Since the discovery of the leukotrienes and led to a reduction of oral steroids in children their role in asthma, there has been intense aged over 6 years.41 42 It was thought the IVIG activity to produce drugs that counteract their had an immunomodulatory role and, interest- eVects. This has been achieved by blocking ingly, serum IgE and skin test reactivity were leukotriene synthesis with enzyme inhibitors reduced in one study.41 A recent case report (5-lipoxygenase inhibitors, such as zileuton) or showed a reduction in markers of disease activ- interfering with binding of leukotrienes to their ity in peripheral blood as well as a decrease in receptors (receptor antagonists, such as monte- numbers of all cell types (especially CD3+, lukast, zaﬁrlukast) recently reviewed by Hor- CD4+, and activated CD25+ T lymphocytes) witz et al.35 Montelukast (Singulair; Merck, on bronchial biopsy.43 A recent randomised DiYcult asthma 205

placebo controlled trial in 31 children and 9 Newman KB, Mason UG, Schmaling KB. Clinical features Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from of vocal cord dysfunction. Am J Resp Crit Care Med 1995; adolescents was disappointing in that no 152:1382–6. benefit was seen in lung function, bronchial 10 Côté J, Cartier A, Malo J-L, Rouleau M, Boulet L-P. Com- 44 pliance with peak expiratory flow monitoring in home hyperreactivity, or symptom scores. There management of asthma. Chest 1998;113:968–72. was however a trend towards fewer total days of 11 Kharitinov SA, Yates DH, Chung KF, Barnes PJ. Changes upper respiratory tract infections, and the in the dose of inhaled steroid aVects exhaled nitric oxide levels in asthmatic patients. Eur Respir J 1996;9:196–201. eVect of IVIG may simply be to reduce viral 12 Byrnes CA, Dinarevic S, Shinebourne EA, Barnes PJ, Bush exacerbations. For this reason, it may be most A. Exhaled nitric oxide measurements in normal and asthmatic children. Pediatr Pulmonol 1997;24:312–18. useful in severe infant wheezing, although evi- 13 Woolcock AJ, Dusser D, Fajac I. Severity of chronic asthma. dence for this will be required. The main side Thorax 1998;53:442–4. 14 Nguyen B-P, Wilson SR, German DF. Patients’ perceptions eVects reported have been fever and head- compared with objective ratings of asthma severity. Ann aches, but it is a blood product and regular Allergy Asthma Immunol 1996;77:209–15. 15 Custovic A, Woodcock A. Allergen avoidance. BrJHosp intravenous cannulation is required. Med 1996;56:409–12. 16 Wood RA, Chapman MD, Adkinson NF, Eggleston PA. The eVect of cat removal on allergen content in household-dust ORAL METHOTREXATE samples. J Allergy Clin Immunol 1989;83:730–4. Methotrexate is an immunosuppressive and 17 McKenzie S. “Can I have a letter for the housing, doctor?” Arch Dis Child 1998;78:505–7. anti-inflammatory agent. 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Coexistence of glucocorticoid receptor and pharmacokinetic abnormalities: factors contributing to a gastrointestinal upset and transiently raised poor response to treatment with glucocorticoids in children liver transaminases.47 However, there are nu- with asthma. J Pediatr 1994;124:984–6. 23 Payne DNR, Hubbard M, McKenzie SA. Corticosteroid merous potentially serious adverse eVects asso- unresponsiveness in asthma: primary or acquired? Pediatr ciated with the drug (pulmonary fibrosis, Pulmonol 1998;25:59–61. 24 Barnes PJ, Pedersen S, Busse WW. EYcacy and safety of pneumonitis, hepatic cirrhosis, myelosuppres- inhaled corticosteroids: new developments. Am J Resp Crit sion), particularly when given in high doses. Care Med 1998;157:S1–53. 25 Kamada AK, Leung DYM, Szefler SJ. Steroid resistance in Low doses are relatively safe, and its use may be asthma: our current understanding. Pediatr Pulmonol 1992; considered in some children. 14:180–6. 26 Leung DYM, Szefler SJ. 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‘43 Vrugt B, Wilson S, van Velzen E, et al.EVects of high dose 45 Marin MG. Low-dose methotrexate spares steroid usage in Arch Dis Child: first published as 10.1136/adc.80.2.201 on 1 February 1999. Downloaded from intravenous immunoglobulin in two severe corticosteroid steroid-dependent asthmatic patients: a meta-analysis. insensitive asthmatic children. Thorax 1997;52:662–4. Chest 1997;112:29–33. 44 Niggemann B, Leupold W, Schuster A, et al. Prospective, 46 Stempel DA, Lammert J, Mullarkey MF. Use of methotrex- double-blind, placebo-controlled, multicentre study on the ate in the treatment of steroid-dependent adolescent asth- eVect of high-dose, intravenous immunoglobulin in chil- matics. Ann Allergy 1991;67:346–8. dren and adolescents with severe bronchial asthma. Clin 47 Guss S, Portnoy J. Methotrexate treatment of severe asthma Exp Allergy 1998;28:205–10. in children. Pediatrics 1992;89:635–9.

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