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Asthma: beyond the guidelines
ARTICLE IN PRESS Current Paediatrics (2004) 14, 336–346
www.elsevierhealth.com/journals/cuoe
Asthma: beyond the guidelines Donald Payne, Sejal Saglani, Ranjan Suri, Pippa Hall, Nicola Wilson, Andrew Bush* Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
KEYWORDS Asthma; Eosinophil; Airway inflammation; Neutrophil; Corticosteroid; Steroid resistance; Adolescence; Adherence
Summary Although most children with asthma can easily be treated, a small minority have symptoms resistant to conventional therapy. Such children mandate a detailed re-evaluation. Alternative diagnoses should be considered, as well as factors which co-exist with asthma and may exacerbate the condition or be mistaken for uncontrolled asthma. Other important issues are the appropriateness of the drug delivery device; adverse environmental factors, including persistent allergen exposure and environmental tobacco smoke; and psychological factors, which include adherence to treatment. Finally, we suggest a detailed systematic approach to address the individual phenotype: for example, persistent airway eosinophilia, neutrophilia, or non-inflammatory. The protocol includes non-invasive measurement of airway inflammation and reactivity before and after systemic steroids, with bronchoscopy, lavage and biopsy at the end of the course. This approach leads us to develop an individual treatment plan. The validity of this approach needs to be tested in larger studies. & 2004 Elsevier Ltd. All rights reserved.
Practice points *
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If a child with asthma is not responding to simple treatment, is this because the child does not have asthma? If the problem is truly asthma, it is important to ask what it is about this child and the asthma which makes it resistant to therapy. There are several different phenotypes of difficult asthma, with different underlying
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*Corresponding author. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel.: þ 44 351-8232; fax: þ 44 351-8763. E-mail address: [email protected] (A. Bush). 0957-5839/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2004.04.010
causes and potentially different therapeutic approaches. Consider separately the possible contributions of bronchial hyper-reactivity, airway inflammation, and persistent airflow limitation to symptom persistence in severe asthma. Poor adherence to therapy, and overperception of symptoms, are important causes of apparent therapy-resistant asthma symptoms. Fibreoptic bronchoscopy should be considered in therapy-resistant asthma to determine underlying mechanisms and hence a logical treatment plan.
ARTICLE IN PRESS Asthma: beyond the guidelines
Table 1
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Initial approach to the child with ‘asthma beyond the guidelines’.
Possible problem
Examples
1. Not asthma at all? 2. Asthma plus?
Other diagnosis (Table 2) Rhinitis, upper airway disease Gastro-oesophageal reflux Psychological or environmental factors Metered dose inhaler without spacer Lack of attention to detail Inappropriate use of nebulizers Passive or active smoking Allergen exposure in allergic child Poor adherence Stress Dysfunctional breathing patterns Hidden gains
3. Wrong drug delivery device?
4. Environmental factors? 5. Psychological factors?
Research directions *
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What are the mechanisms of the steroidresistant, persistent airway inflammation in some cases of severe asthma, and what contributions are made by adverse environmental factors such as persistent allergen exposure and cigarette smoke? What are the mechanisms (smooth muscle, neural?) of persistent airway hyper-reactivity without residual inflammation? What is the relationship between airway inflammation and structural airway changes (remodelling); does inflammation drive remodelling, or are they parallel processes? Multicentre studies are required to determine whether a phenotypic approach to severe asthma is worthwhile.
Introduction The vast majority of children with asthma can safely be managed with low-dose inhaled corticosteroids, sometimes supplemented with a longacting b2 agonist or leukotriene receptor blocker. There are clearly structured guidelines on how to escalate and step down management.1 The guidelines industry can be criticized for the paucity of evidence generated over the past 15 years compared with the number of position papers produced, but nonetheless, despite the lack of evidence at many key points, most children are successfully managed by current strategies. How-
ever, by the time Steps 4 and 5 have been reached, the semi-logical progression of steps is replaced by a haphazard approach in which different medications are tried in a seemingly random and increasingly desperate sequence. Our definition of the older child with asthma ‘beyond the guidelines’ is a child with asthma non-responsive to high-dose inhaled steroids (Z1 mg/day fluticasone or equivalent) plus a failed trial of long-acting b2 agonists and leukotriene receptor antagonists.2–4 However, the referral of a child with such severe asthma should prompt a complete and systematic reevaluation (Tables 1 and 2). The commonest reasons for failure to respond to asthma treatment are: firstly, the child does not have asthma (in this respect, one important diagnostic confusion is that in many other respiratory conditions, for example chronic lung disease of prematurity and cystic fibrosis, there is a degree of airway reactivity which is to some extent bronchodilator-responsive), and secondlyFand not infrequentlyFasthma treatment is not being taken. This paper describes our systematic approach to children with apparently intractable asthma and includes an attempt to bring some logic to therapeutic trials when standard (Steps 1–3) therapy has failed.
Diagnostic approach Not asthma at all Children who do not have asthma do not benefit from asthma medications, and the possibility that the diagnosis is wrong is the first consideration. The differential diagnosis of asthma in childhood encompasses virtually the whole of paediatric
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Table 2
D. Payne et al.
Non-asthmatic causes of wheeze.
Upper airway diseaseFadenotonsillar hypertrophy, rhinosinusitis, postnasal drip Congenital structural bronchial diseaseFcomplete cartilage rings, cysts, webs Bronchial/tracheal compressionFvascular rings and sling, enlarged cardiac chamber, lymph nodes enlarged by tuberculosis or lymphoma, congenital thoracic malformations Endobronchial diseaseFforeign body, tumour Oesophageal/swallowing problemsFreflux, incoordinate swallow, laryngeal cleft or tracheo-oesophageal fistula Causes of pulmonary suppurationFcystic fibrosis, primary ciliary dyskinesia, any systemic immunodeficiency including agammaglobulinaemia, severe combined immunodeficiency MiscellaneousFbronchopulmonary dysplasia, congenital or acquired tracheomalacia, pulmonary oedema
Table 3 Points to seek in the history suggesting alternative diagnoses.
Table 4 Points to seek on examination suggesting alternative diagnoses.
Is the child/family really describing wheeze? Upper airway symptomsFsnoring, rhinitis, sinusitis Symptoms from the first day of life Very sudden onset of symptoms Chronic moist cough/sputum production Worse wheeze or irritable after feed, worse lying down, vomiting, choking on feeds Any feature of a systemic immunodeficiency Continuous, unremitting or worsening symptoms Disappearance of symptoms when asleep
Digital clubbing, signs of weight loss, failure to thrive Upper airway diseaseFenlarged tonsils and adenoids, prominent rhinitis, nasal polyps Unusually severe chest deformity (Harrison’s sulcus, barrel chest) Fixed monophonic wheeze Stridor (monophasic or biphasic) Asymmetric wheeze Signs of cardiac or systemic disease
respiratory medicine (Table 2), and is beyond the scope of this article. However, a few key points can be highlighted. Particular points in the history and physical examination are listed in Tables 3 and 4 Much confusion has resulted from different uses of the word ‘wheeze’. Careful studies using a video of respiratory noises have established that many different noises are identified as wheeze by parents, and many of these noisesFsuch as upper airway cracklingFare highly unlikely to be due to asthma or respond to asthma therapies.5–8 True wheeze is not an essential diagnostic feature of asthma, but its complete absence should prompt a careful diagnostic review. Symptoms which are truly from day one of life, and not just from the first viral cold in a young baby, always merit investigation, and suggest congenital lung disease or primary ciliary dyskinesia.9,10 The very sudden onset of symptoms should suggest a foreign body, and the possibility sought by direct questions;11 diagnosis may be delayed, even by many decades. Chronic productive cough, persisting between viral colds and without remission, may be a feature of the catarrhal child or asthma, but is far more likely to be due to chronic bronchial sepsis with or without bronchiectasis, and should be investigated as such. Delayed diagnosis is frequent for cystic fibrosis (10% undiagnosed until adult life;12,13 there may be other suggestive features such as diarrhoea,
nasal polyps or rectal prolapse), primary ciliary dyskinesia (mixed upper and lower airway disease; neonatal onset of symptoms9,10) and hypogammaglobulinaemia. Although H-type fistula is usually diagnosed early, late presentation has been well described.14 A careful inspection of the chest radiograph, including locating the side of the aortic arch15 and the shape of the flow volume loop, may give a clue that the problem is large airway obstruction and not asthma. These tests should be a routine part of the initial assessment. Further investigations should be targeted to eliminate specific conditions, rather than applied in a blanket fashion to all asthmatics.
Asthma plus Continuing symptoms wrongly attributed to asthma These children are particularly difficult to sort out, as although often they undoubtedly do have asthma, the persistence of symptoms is not related to uncontrolled asthma. Conditions which may mimic asthma or co-exist with it are rhinosinusitis and gastro-oesophageal reflux disease. These conditions may cause symptoms wrongly attributed to asthma.
ARTICLE IN PRESS Asthma: beyond the guidelines
Contributory factors to difficult asthma It is implicit in difficult asthma that factors other than lower airway inflammation may be operative. These factors include rhinitis, reflux, psychological issues, and adverse environmental effects (see below). The relationship between upper and lower airway is complex and has recently been reviewed.16 Although the precise contribution of rhinitis to asthma in an individual may be unclear, it would seem reasonable to treat any upper airway disease on its own merits: for example, house dust mite avoidance in sensitized children, oral antihistamines and topical nasal steroids for allergic rhinitis, and prolonged antibiotic courses for chronic infective rhinosinusitis. In our practice it is unusual, however, for these measures to result in complete disappearance of asthma that was previously troublesome. The relationship between the oesophagus and the lung is also complex. Lung disease can cause reflux; reflux can cause lung disease; or reflux may be of no clinical significance. Reflux is frequently found during the work up of severe asthma; however, our experience in the older child is that treatment of reflux rarely results in much improvement in the asthma. Reflux can cause asthma-like symptoms, broadly speaking, by two mechanisms: aspiration of gastric contents into the lung, and oesophageal acid-induced reflex airway constriction. The reason for the disappointing results of anti-reflux therapy on asthma (as opposed to gastrointestinal symptoms) in older children may be due to the fact that, in contrast to younger children, aspiration is rare, and aggressive antiinflammatory therapy has blocked the airway response to oesophageal acidification. In infancy, anti-reflux therapy may be more successful, perhaps because corticosteroids are (rightly) used more cautiously. Certainly an empirical trial in this age group if the history is suggestive is entirely reasonable.
Drug delivery devices Inappropriate selection or wrong use of inhalers and other drug delivery devices are common even in a specialist clinic.17 Common pitfalls are the use of metered dose inhalers without a spacer, in the na.ıve belief that the child can co-ordinate breathing at a young age; persistence of the use of masks when children aged three and above (and even some younger ones) can use a mouthpiece; or the discarding of ‘babyish’ spacers by adolescents. If
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spacers are used, then the inhaler should be shaken before every activation; the child should inhale from the spacer without delay after inhaler activation; and the spacer efficiency should be maximized by washing it once a week in ordinary washing up liquid and leaving it to drain dry without prior rinsing.18,19 A common myth is that the use of a mask and spacer in a crying child maximizes lung drug deposition; in fact, the reverse is the case.20 If nebulizers must be used (and there are really very few indications in asthma) then a mouthpiece or a tight-fitting mask is essential; hopefully waving the nebulizer cup somewhere near the child’s face is a waste of time. A detailed evaluation of inhaler technique is an essential part of the work up of the difficult asthmatic.
Environmental factors A comparison of children with difficult asthma with another group whose asthma was well controlled demonstrated a significantly greater prevalence of adverse environmental features in the former.21 The two commonest factors are cigarette smoke (either active or passive exposure) and aeroallergensFusually from petsFto which the child is sensitive. The effects of passive smoking in exacerbating respiratory disease are well known;22 smoke may also induce a state of relative steroid insensitivity (see below). Although there is debate as to whether primary prevention in the high-risk groups is best achieved by ruthlessly eliminating allergens or saturating the environment with them, there can be no doubt that in the already sensitized child allergen exposure causes worsening asthma and a state of relative steroid resistance (see below). Even repeated low-dose allergen challenge, insufficient to cause worsening of lung function, causes deterioration of bronchial hyperreactivity and worsening airway inflammation manifest by increased eosinophils and EG2-positive eosinophils in induced sputum.23 Cat-sensitive children attending school classes where 420% of the other children have pet cats develop a pattern of symptoms similar to occupational asthma, that is, progressive worsening during the week, with improvement at the weekends and during the holidays.24 The identification of the problem is relatively easy, but dealing with it is more difficult; the English in particular are lovers of animals to the point of folly. The role of the home environment (‘Can I have a letter for the Housing, Dr?’) is hotly debated.25,26 That poor housing conditions are undesirable is indubitable, but that they cause or
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worsen asthma is much more contentious. In general, a home visit by an experienced respiratory nurse is often informative in uncovering adverse environmental effects on the child.
Psychological factors This is another huge subject, which can only briefly be discussed here. Ignoring the mind, and treating the child as merely a pair of lungs, will inevitably result in many failures. It is an area that requires a very sensitive approach. Children are often afraid that discussing psychological factors carries the implication that their symptoms are thought not to be genuine; it may be wise to begin by stating that it is definitely accepted that the symptoms are genuine, and no question of fabrication arises. Using the analogy of stress-induced diarrhoea, a phenomenon familiar to most, may be helpful; the diarrhoeal stool is obviously not a figment of the imagination, but clearly not the result of an organic bowel disease. A neutral question like ‘some people find that stress is a factor that contributes to asthma; is that a factor you think may be important?’Fafter asking specific questions about other triggersFmay be a good way to introduce the topic. When talking to adolescents, it is important to spend part of the consultation with them alone, separate from their parents. Confidentiality between the health professional and the patient needs to be established, and once this is done it provides the opportunity for adolescents to talk more freely about their concerns.27 Speaking to adolescents separately also enables them to begin to take more responsibility for their asthma and its treatment.
Adherence to treatment The two commonest causes of apparent steroidresistant asthma are wrong diagnosis (above, Table 2) and not taking the treatment. Doctors are notoriously poor in predicting which patients are compliant. The measurement of prednisolone and cortisol levels in a child who is supposed to be taking oral prednisolone may be illuminating. A therapeutic trial with depot triamcinolone may reveal that the so-called steroid-resistant asthma disappears. Adherence is an issue which requires very sensitive handling, trying to explore the reasons for reluctance to take treatment in a ‘no blame’ manner. Often the help of a psychologist is essential.
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Stress Thankfully, the days of blaming asthma totally onto stress and low moral fibre have gone. However, the importance of stress should not be forgotten. The first study to show an effect of stress on airway inflammation compared the sputum eosinophil response to allergen challenge at the time of examinations with that during a less stressful term, and showed that there was a more marked induced sputum eosinophilia during stress.28 Another study appeared to show that stress ameliorated asthma in women who were studied while they were recounting stressful experiences.29 More work is needed, but the possibility of presumably neural driven inflammation worsening asthma as a result of psychological stress should not be discounted.
Dysfunctional breathing patterns This is a huge topic, and encompasses such disparate syndromes as vocal cord dysfunction (adduction of the vocal cords in inspiration or expiration or both30), hyperventilation syndromes, and habit/honk cough. The key feature in the history is the complete disappearance of the symptoms during sleep, quite unlike asthma. These syndromes may co-exist with mild asthma. Management involves weaning off the excessive therapy and the assistance of a physiotherapist, speech therapist or clinical psychologist as appropriate.
Hidden gains These may accrue to the child or family. School avoidance may arise because of prolonged absence due to asthma, and may preclude successful therapy unless specifically tackled. The avoidance of unpleasant situations, such as a cross-country run, may be another factor, with which at least one of the authors has considerable sympathy. Parents may gain financial benefit from having a child with severe asthma, including disability living allowance and rehousing. Rarely, a diagnosis of Munchausen syndrome by proxy may need to be considered.
A phenotypic approach? If attention to the factors above have failed to resolve the problem, then we proceed to more invasive assessment of the problem before starting on more toxic or inconvenient therapies. We have developed a protocol (Table 5) to try to determine a rational approach to severe asthma, predicated
ARTICLE IN PRESS Asthma: beyond the guidelines
Table 5
The difficult asthma protocol.
1.
Physiological measurements
2.
Non-invasive inflammatory and other markers
3.
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Visit 1
Visit 2n
Visit 3
Spirometry
Spirometry, including response to b2 agonist Assess symptoms Exhaled nitric oxidew
Spirometry, including response to b2 agonist Assess symptoms Exhaled nitric oxidew
Sputum induction RAST or skin prick tests as appropriate
Sputum induction Cortisol assay
Invasive studies
Prednisolone assay (unless given triamcinolone) Bronchoscopy, bronchoalveolar lavage, and bronchial biopsy
RAST, radioallergosorbent test. n Between visits 2 and 3 the patient is prescribed a course of systemic corticosteroids (preferably a single intramuscular injection of triamcinolone 80 mg, or oral prednisolone 40 mg daily for 2 weeks). w The role of exhaled nitric oxide in categorizing asthma is still unclear.
on the belief that there are many different reasons why asthma may be resistant to therapy.3,4 The protocol is a compromise between what is scientifically ideal and what is ethically acceptable; for example, it might be preferable to bronchoscope the child both before and after the course of oral steroids. Instead, we felt it correct to rely on induced sputum to determine airway cellularity before the course of steroids, accepting that some will have too severe an airflow obstruction for this to be attempted, and that in 20% of children over 12 years old (more in younger children) it will not be possible to obtain a sample. At the first visit (when the patient is enrolled, and after a full assessment has been performed), a diary card is supplied to confirm continuing symptoms. Home peak flow monitoring is generally so poorly performed that we have stopped using it as a clinical tool in this context.31 At the second visit, noninvasive measurements of airway inflammation are performed, and the child is given a single intramuscular injection of a depot preparation of triamcinolone. At visit three, 2 weeks later, the non-invasive measurements are repeated and a fibreoptic bronchoscopy performed, with bronchoalveolar lavage and airway biopsy. We do not perform transbronchial biopsy. The safety of this approach has been evaluated and found to be acceptable.2 The different phenotypes which we have recognized so far are summarized in Table 6, and discussed in detail below. One aim of this protocol is to determine how good the child’s lung function can become. We assume that a depot injection of triamcinolone, followed by inhaled
high-dose b2 agonist, is sufficient to correct any reversible element, but this remains to be tested.
Steroid-sensitive asthma The largest single phenotype is the child who becomes completely asymptomatic, with normal lung function, and with no airway inflammation on airway biopsy and lavage.32 In this situation we plan to reduce the oral steroids to the minimum dose which controls symptoms and (ideally) non-invasively measured inflammation. If prednisolone cannot be reduced to a level where side effects are minimal or tolerable, we would use a steroid sparing agent, usually cyclosporin. However, our experience has been that these agents seem to work less well in this group than in the steroidresistant asthmatics (below). Children requiring high-dose steroids to control asthma are also assessed as far as is possible for causes of secondary steroid resistance.
Steroid-resistant, eosinophilic asthma This phenotype comprises biopsy, lavage or induced sputum evidence of eosinophilic inflammation in children who remain symptomatic.4 In some of these steroid-resistant children we have found abnormalities of steroid receptor binding and translocation of the steroid–receptor complex from cytoplasm to nucleus. It must be said that these measurements are not easy to interpret, and remain in the domain of research.
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Table 6
Summary of proposed difficult asthma management, at the conclusion of the protocol.
Clinical scenario
Presumptive diagnosis
Suggested action
1.
Continued airflow obstruction, no inflammation, no reversibility to b2 agonists
Presumed obliterative bronchiolitis, or remodelling secondary to chronic inflammation, etc.
Inspiratory and expiratory CT scan Use minimum treatment which maintains lung function
2.
Continued airflow obstruction, no inflammation before or after steroid therapy, but with reversibility to b2 agonists
Presumed steroid-resistant, non-inflammatory bronchial reactivity
Look for causes of secondary steroid resistance (environment, etc.) Continuous subcutaneous terbutaline treatment
3.
Persistent eosinophilic inflammation, with either or both of airflow obstruction and symptoms
Presumed steroid partial or complete resistance
Look for causes of secondary steroid resistance Treat with either prolonged highdose steroids or steroid sparing agent Consider using computerized drug delivery device to confirm adherence
4.
Persistent eosinophilic inflammation, with no airflow obstruction or symptoms
Lagging of clearance of inflammation Risk of ongoing remodelling despite no symptoms
Observe closely with repeated spirometry and non-invasive measures of inflammation
5.
Presumed inflammation completely resolved with steroids (normal lung function, no symptoms)
Steroid-sensitive asthma, but requiring high-dose treatment
Look for causes of secondary steroid resistance Taper steroids to level at which symptoms are controlled without side effects, or steroid sparing agent
6.
Persistent non-eosinophilic inflammation
Presumed other inflammatory mechanisms (other cells, e.g. neutrophilic inflammation; neurogenic mechanisms)
Reduce steroid treatment to minimum level needed to control eosinophilic inflammation Consider macrolide therapy, 5lipoxygenase inhibitor, or theophylline if neutrophilic inflammation
7.
Apparently normal lung function, no inflammation, but reported ongoing symptoms
Poor symptom perception
Exercise test or methacholine challenge with Borg scale
Psychological problems Not asthma at all
Review by psychologist
The causes of steroid resistance are a subject of controversy. The commonest cause is failure to adhere to steroid treatment. Congenital steroid deficiency, characterized by a very low number of steroid receptors of normal binding affinity, is very rare.33 Secondary steroid resistance is much more common, and is usually characterized by a normal or increased number of steroid receptors, with reduced affinity for glucocorticoid. One putative mechanism is via allergen drive in a sensitized
subject, which causes increased interleukin (IL)-2 and -4 release from white cells, which in turn modulates steroid resistance.34 This underscores the need for attention to the environment and allergic sensitization in these children. Another (not necessarily mutually exclusive) cause of steroid resistance is a switch in the phenotype of a subunit of the steroid receptor to a phenotype with reduced affinity.35 Studies in adults have documented that cigarette smoking causes relative
ARTICLE IN PRESS Asthma: beyond the guidelines steroid resistance36,37 and, by analogy, passive smoking may be a factor in children. Animal experiments suggest that latent viral infection is a mechanism to be considered.38 Our own studies (submitted for publication) suggest that the mechanism of persistence is not persistence of the characteristic Th2 drive, based on the absence of typical Th2 signature cytokines such as IL-4 and IL-5 in bronchial biopsies. However, the true mechanism remains to be elucidated. We elect to treat these children with alternative anti-inflammatory therapies, usually cyclosporin. The protocol has been published elsewhere;39 briefly, meticulous attention to details of monitoring drug levels and renal function is essential. We would attempt a minimum of a 3-month trial of treatment if tolerated, and, if the response is good, try to wean the dose of steroids (initially oral, then inhaled) to the minimum dose tolerated.
Steroid-resistant, non-eosinophilic inflammatory phenotype asthma There have been a number of induced sputum and bronchial biopsy studies in which a neutrophil dominated or exclusive phenotype has been reported.40 This phenotype may account for around half the burden of asthma at all ages.41 These patients are symptomatic and poorly responsive to steroids. What is unclear is the role of the neutrophil in this phenotype. Possibilities include: (1) that it is the effector cell for this type of asthma; (2) that the presence of neutrophils merely reflects the effects of corticosteroids prolonging neutrophil survival by delaying apoptosis;42 or (3) that neutrophils are a beneficial response to an unknown stimulus (for example an occult infection), and it is the unknown stimulus which is driving the asthmatic symptoms. What are lacking are studies which demonstrate that reducing airway neutrophil count leads to an improvement in symptoms. Possible agents to reduce airway neutrophilia, assuming this to be desirable, are largely used on an empirical basis, in the absence of knowledge as to which neutrophil chemoattractants are important in driving airway neutrophilia. These would include reducing the synthesis of leukotriene (LT) B4, or blocking its receptor when suitable agents become available; blocking IL-8 production with a macrolide antibiotic;43 or accelerating neutrophil apoptosis with oral theophyllines.44 Anecdotally, we have treated patients with neutrophil-dominated asthma with a 6-month trial of azithromycin, using the same protocol as for our cystic fibrosis
343 work;45 some but not all children with this picture have shown an apparently dramatic response, although whether as a placebo effect is not clear. This is an unresearched phenotype, and more data are needed before firm recommendations can be made.
Non-inflammatory, persistent BHR Children with this phenotype have no evidence of residual airway inflammation on bronchoscopy, BAL and biopsy at visit two. However, they remain symptomatic, and have marked acute bronchodilator reversibility. The molecular basis of this phenotype is unclear. It would seem illogical to treat such children with ever more potent antiinflammatory therapies. This group have usually already tried high-dose inhaled and often oral longacting b2 agonists without success. We have used continuous subcutaneous infusion of terbutaline with some success in this group.46 This is a demanding therapy, but deemed worthwhile by the children who respond. The child carries a syringe pump in a waist bag; the needle is placed under the skin of the abdomen, and changed every one to two days, rotating the site of insertion. We start with a low dose (generally 2.5 mg over 24 h) and increase as high as 10 mg/24 h depending on symptoms and any side effects. Education and support from a really experienced respiratory nurse is essential. When symptom control has been obtained, we reduce the dose of oral and then inhaled corticosteroid as tolerated, monitoring airway inflammation with non-invasive techniques. It is unlikely that this is a pure non-inflammatory phenotype, and we would not anticipate being able to stop inhaled corticosteroids altogether; more plausible is that underlying airway inflammation is more easily treated than BHR. The role of abnormal smooth muscle function or neural control of the airways has not been investigated in this phenotype.
Persistent eosinophilic inflammation with no symptoms We have seen this phenotype in the context of our severe asthma protocol. The phenotype has been described best in a group of young adults who to all clinical intents and purposes have outgrown their asthma.47 They are off all therapy and have a normal lifestyle, and would be discharged from the clinic. However, detailed investigation in this group has shown persistent airway eosinophilia on biopsy. The interpretation of this finding is difficult, and
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management recommendations are purely conjectural. In the context of difficult asthma, we would treat the child as for steroid-sensitive asthma (above).
Asthma phenotypes in the older child with severe asthma: summary We have proposed a largely pathological classification of severe asthma in childhood as a means for rationalizing treatment. There is still much work to be done to try to work out the relationship between airway pathology and some clinical phenotypes, for example Types 1 and 2 brittle asthma. We have tested the utility of this approach in fewer than 100 patients, and even with this degree of detailed investigation it is not possible to treat all children successfully. Hence bigger studies are needed to confirm whether the invasive and expensive tests are worthwhile.
Persistent airflow limitation This can be part of many of the asthma syndromes described above. In pure form, such as an undiagnosed obliterative bronchiolitis secondary to previous adenoviral or other viral infection, or aspiration syndromes, there is no evidence of airway inflammation or BHR at either visit, and no change in lung function during the steroid trial. Treatment is reduced until evidence of BHR or inflammation appears. Usually therapy can be discontinued completely.
Particular problems in infancy and the preschool years
Poor perception of symptoms There is a big literature on both over-reporting and under-perception of symptoms in asthma, which will only be summarized here. Over-reporting may lead to overtreatment. The problem may lie with the child, the family, or both. Older children may complain that they get exercise-induced asthma, whereas in reality they are simply unfit; a formal exercise test may clarify this point. A methacholine challenge with a visual analogue score of perceived breathlessness may reveal either a perception of marked breathlessness with little change in spirometry, or more worryingly, no perception of breathlessness in the face of progressive airflow obstruction.48 There is some evidence that treatment with inhaled steroids may increase the perception of symptoms,49 and also that at least some of those prone to acute severe deteriorations have a blunted symptom perception.50 This group in particular may benefit from regular monitoring of peak flow at home. Table 7
There are several different wheezing phenotypes in preschool children (Table 7), and many of them are non-inflammatory and respond poorly to inhaled steroids. These have been reviewed in detail elsewhere;51 space precludes doing justice to them here. Some phenotypes (in particular virus-associated wheeze and post-bronchiolitic cough and wheeze) have their roots antenatally, with maternal smoking, atopy and hypertension of pregnancy resulting in reduced airway calibre, which can be detected soon after birth,52–54 and before a first viral infection.55–59 It may be necessary to accept that some symptoms do not respond to any treatment, and that they will improve with time.60–62 This seemingly nihilistic approach is preferable to vast increases in useless and potentially toxic therapy, and may in fact be welcome to parents who have become disillusioned with medications which fail to work.
Phenotypic characterization of pre-school asthma syndromes.
Preschool asthma syndrome
Inflammatory component
Extent of BHR (bronchial hyper-reactivity)
Extent of PAL (persistent airflow limitation)
1. Chronic lung disease of prematurity 2. Post-bronchiolitis 3. Virus-associated wheeze 4. Atopy-associated wheeze 5. Obliterative bronchiolitis 6. Non-atopy-associated, later onset wheeze
?(probably none)
þ
þ (antenatal)
? (probably none) þ (probably often eosinophilic) –
þ þ
þ (antenatal) þ (antenatal) þ (probably antenatal and postnatal) þ (postnatal)
?present, ?type
Probably present
–
þ (probably at least postnatal)
ARTICLE IN PRESS Asthma: beyond the guidelines
Summary and conclusions There are no easy answers when dealing with asthma beyond the guidelines. A systematic evaluation will reveal whether treatment is completely wrong, the child does not have asthma at all, or there are major, previously unappreciated, psychological factors. If this is not the case, meticulous attention to the detail of all aspects of conventional treatment may improve matters. If this fails, we believe that a phenotypic approach, using a structured protocol and including a bronchoscopy, is clinically justified, and preferable to haphazardly shuffling through different treatments. The validity of this approach, as with much that we do in paediatric respirology, requires justification by further studies.
References 1. British Thoracic Society, Scottish Intercollegiate Guidelines Network (SIGN). British guideline on the management of asthma. Thorax 2003; 58 (Suppl 1): i1–94 2. Payne DNR, McKenzie SA, Stacey S, et al. Safety and ethics of bronchoscopy and endobronchial biopsy in difficult asthma. Arch Dis Child 2001;84:423–6. 3. Payne DNR, Wilson NM, James A, et al. Evidence for different subgroups of difficult asthma in children. Thorax 2001;56:345–50. 4. Payne DNR, Adcock IM, Wilson NM, et al. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001;164:1376–81. 5. Cane RS, Ranganathan SC, McKenzie SA. What do parents of wheezy children understand by ‘wheeze’? Arch Dis Child 2000;82:327–32. 6. Cane RS, McKenzie SA. Parents interpretation of children’s respiratory symptoms on video. Arch Dis Child 2001;84: 31–4. 7. Elphick HE, Sherlock P, Foxall G, et al. Survey of respiratory sounds in infants. Arch Dis Child 2001;84:35–9. 8. Saglani S, Payne DN, McKenzie S, Bush A. Relationship between parental reported symptoms, video questionnaire and bronchoscopy findings in preFschool children with troublesome respiratory symptoms. Thorax 2003; 58(Suppl 111):iii12. 9. Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J 1998;12:982–8. 10. Coren ME, Meeks M, Buchdahl RM, et al. Primary ciliary dyskinesia (PCD) in childrenFage at diagnosis and symptom history. Acta Paediatrica 2002;91:667–9. 11. Puterman M, Gorodischer R, Lieberman A. Tracheobronchial foreign bodies: the impact of a postgraduate educational program on diagnosis, morbidity and treatment. Pediatrics 1982;70:96–8. 12. Cystic Fibrosis Foundation. Patient Registry 1996 Annual Data Report, Bethesda, MD, August 1997. 13. Gan K-H, Geus WP, Bakker W, et al. Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years. Thorax 1995;50:1301–4.
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14. Danton MH, McMahon J, McGuigan J, Gibbons JR. Congenital oesophageal respiratory tract fistula presenting in adult life. Eur Respir J 1993;6:1412–4. 15. Payne DNR, Lincoln C, Bush A. Lesson of the week: right sided aortic arch in children with persistent respiratory symptoms. Br Med J 2000;321:687–8. 16. de Benedictis FM, Bush A. Hypothesis paper: rhinosinusitis and asthmaFepiphenomenon or causal association? Chest 1999;115:550–6. 17. Kamps AW, van Ewijk B, Roorda RJ, Brand PL. Poor inhalation technique, even after inhalation instructions, in children with asthma. Pediatr Pulmonol 2000;29:39–42. 18. Janssens HM, Devadason SG, Hop WC, et al. Variability of aerosol delivery via spacer devices in young asthmatic children in daily life. Eur Respir J 1999;13:787–91. 19. Pierart F, Wildhaber JH, Vrancken I, et al. Washing plastic spacers in household detergent reduces electrostatic charge and greatly improves delivery. Eur Respir J 1999; 13:673–8. 20. Iles R, Lister P, Edmunds AT. Crying significantly reduces deposition of aerosolized drugs in infants. Arch Dis Child 1999;81:163–5. 21. Ranganathan SC, Payne DN, Jaffe A, McKenzie SA. Difficult asthma: defining the problems. Pediatr Pulmonol 2001;31: 114–20. 22. Cook DG, Strachan DP. Health effects of passive smokingF 10: summary of effects of parental smoking on the respiratory health of children and implications for research. Thorax 1999;54:357–66. 23. Sulakvelidze I, Inman MD, Rerecich T, O’Byrne PM. Increases in airway eosinophils and interleukin-5 with minimal bronchoconstriction during repeated lowFdose allergen challenge in atopic asthmatics. Eur Respir J 1998;11:821–7. 24. Almqvist C, Wickman M, Perfetti L, et al. Worsening of asthma in children allergic to cats after indirect exposure to cat at school. Am J Respir Crit Care Med 2001;163:694–8. 25. McKenzie S. ‘Can I have a letter for the housing, doctor? ’ Arch Dis Child 1998;78:505–6. 26. Paton J. Commentary. Arch Dis Child 1998;78:506–7. 27. Sawyer SM. Adolescence: the transition between child and adult life. Eur Respir Mon 2002;19:42–59. 28. Liu LY, Coe CL, Swenson CA, et al. School examinations enhance airway inflammation to allergen challenge. Am J Respir Crit Care Med 2002;165:1062–7. 29. Laube BL, Curbow BA, Fitzgerald ST, Spratt K. Early pulmonary response to allergen is attenuated during acute emotional stress in females with asthma. Eur Respir J 2003; 22:613–8. 30. Crowley S, Goldberg D, Argent A, Bush A. Discordant noises in children with asthma. Clin Child Psychol Psychiatry 1998;3:613–9. 31. Redline S, Wright EC, Kattan M, et al. Short term compliance with peak flow monitoring: results from a study of inner city children with asthma. Pediatr Pulmonol 1996;21:203–10. 32. Payne DNR. The pathology of difficult asthma in children. MD thesis, University of Cambridge, 2003. 33. Payne DN, Hubbard M, Mckenzie SA. Corticosteroid unresponsiveness in asthma: primary or acquired. Pediatr Pulmonol 1998;25:59–61. 34. Nimmagadda SR, Szefler SJ, Spahn JD, et al. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am Rev Respir Crit Care Med 1997;155:87–93. 35. Leung D, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increase expression of glucocorticoid receptor beta. J Exp Med 1997;185:1567–74.
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36. Chalmers GWE, Macleod KJ, Little SA, et al. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57:226–30. 37. Chaudhuri R, Livingston E, McMahon AD, et al. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308–11. 38. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001;164:S71–5. 39. Coren M, Rosenthal M, Bush A. The use of cyclosporin in corticosteroid dependant asthma. Arch Dis Child 1997;77: 522–3. 40. Wenzel SE, Szefler SJ, Leung DYM, et al. Bronchoscopic evaluation of severe asthma. Am J Respir Crit Care Med 1997;156:737–43. 41. Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643–8. 42. Meagher LC, Cousin JM, Seckl JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996;156:4422–8. 43. Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol 2001;31:464–73. 44. Yasui K, Hu B, Nakazawa T, et al. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J Clin Invest 1997;100:1677–84. 45. Equi A, Balfour-Lynn I, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomized, placebo-controlled crossover trial. Lancet 2002;360: 978–84. 46. Payne DNR, Balfour-Lynn I, Biggart EA, et al. Subcutaneous terbutaline in children with chronic severe asthma. Pediatr Pulmonol 2002;33:356–61. 47. van den Toorn LM, Overbeek SE, de Jongste JC, et al. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2002;164:2107–13. 48. Kifle Y, Seng V, Davenport PW. Magnitude estimation of inspiratory resistive loads in children with life-threatening asthma. Am J Respir Crit Care Med 1997;156:1530–5. 49. Salome CM, Reddel HK, Ware SI, et al. Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am J Respir Crit Care Med 2002;165:15–21.
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50. Veen JC, Smits HH, Ravensberg AJ, et al. Impaired perception of dyspnoea in patients with severe asthma: relation to sputum eosinophils. Am J Respir Crit Care Med 1998;158:1134–41. 51. Bush A, Price JP. Childhood asthma syndromes. In: Gibson GJ, Geddes DM, Costabel U, Sterk P, Corrin B, editors. Respiratory medicine. 3rd ed.. London: Saunders; 2003. p. 1396–414. 52. Lodrup-Carlsen KC, Jaakkola JJ, Nafstad P, Carlsen KH. In utero exposure to cigarette smoking influences lung function at birth. Eur Respir J 1997;10:1774–9. 53. Stick SM, Burton PR, Gurrin L, et al. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060–4. 54. Young S, LeSouef PN, Geelhoed GC, et al. The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N Engl J Med 1991;324: 1166–73. 55. Martinez FD, Morgan WJ, Wright AL, et al. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med 1988;319:1112–7. 56. Morgan WJ, Martinez FD. Risk factors for developing wheezing and asthma in childhood. Pediatr Clin N Am 1992;39:1185. 57. Tager IB, Hanrahan JP, Tostesan TD, et al. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am Rev Respir Dis 1993;147:811–7. 58. Young S, O’Keeffe PT, Arnot J, Landau L. Lung function, airway responsiveness, and respiratory symptoms before and after bronchiolitis. Arch Dis Child 1995;72:16–24. 59. Turner SW, Young S, Landau LI, Le Souef PN. Reduced lung function both before bronchiolitis and at 11 years. Arch Dis Child 2002;87:417–20. 60. Brooke AM, Lambert PC, Burton PR, et al. The natural history of respiratory symptoms in preschool children. Am J Resp Crit Care Med 1995;152:1872–8. 61. Oswald H, Phelan PD, Lanigan A, et al. Childhood asthma and lung function in mid-adult life. Pediatr Pulmonol 1997;23:14–20. 62. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541–5.
www.elsevierhealth.com/journals/cuoe
Asthma: beyond the guidelines Donald Payne, Sejal Saglani, Ranjan Suri, Pippa Hall, Nicola Wilson, Andrew Bush* Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
KEYWORDS Asthma; Eosinophil; Airway inflammation; Neutrophil; Corticosteroid; Steroid resistance; Adolescence; Adherence
Summary Although most children with asthma can easily be treated, a small minority have symptoms resistant to conventional therapy. Such children mandate a detailed re-evaluation. Alternative diagnoses should be considered, as well as factors which co-exist with asthma and may exacerbate the condition or be mistaken for uncontrolled asthma. Other important issues are the appropriateness of the drug delivery device; adverse environmental factors, including persistent allergen exposure and environmental tobacco smoke; and psychological factors, which include adherence to treatment. Finally, we suggest a detailed systematic approach to address the individual phenotype: for example, persistent airway eosinophilia, neutrophilia, or non-inflammatory. The protocol includes non-invasive measurement of airway inflammation and reactivity before and after systemic steroids, with bronchoscopy, lavage and biopsy at the end of the course. This approach leads us to develop an individual treatment plan. The validity of this approach needs to be tested in larger studies. & 2004 Elsevier Ltd. All rights reserved.
Practice points *
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If a child with asthma is not responding to simple treatment, is this because the child does not have asthma? If the problem is truly asthma, it is important to ask what it is about this child and the asthma which makes it resistant to therapy. There are several different phenotypes of difficult asthma, with different underlying
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*Corresponding author. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel.: þ 44 351-8232; fax: þ 44 351-8763. E-mail address: [email protected] (A. Bush). 0957-5839/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2004.04.010
causes and potentially different therapeutic approaches. Consider separately the possible contributions of bronchial hyper-reactivity, airway inflammation, and persistent airflow limitation to symptom persistence in severe asthma. Poor adherence to therapy, and overperception of symptoms, are important causes of apparent therapy-resistant asthma symptoms. Fibreoptic bronchoscopy should be considered in therapy-resistant asthma to determine underlying mechanisms and hence a logical treatment plan.
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Table 1
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Initial approach to the child with ‘asthma beyond the guidelines’.
Possible problem
Examples
1. Not asthma at all? 2. Asthma plus?
Other diagnosis (Table 2) Rhinitis, upper airway disease Gastro-oesophageal reflux Psychological or environmental factors Metered dose inhaler without spacer Lack of attention to detail Inappropriate use of nebulizers Passive or active smoking Allergen exposure in allergic child Poor adherence Stress Dysfunctional breathing patterns Hidden gains
3. Wrong drug delivery device?
4. Environmental factors? 5. Psychological factors?
Research directions *
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What are the mechanisms of the steroidresistant, persistent airway inflammation in some cases of severe asthma, and what contributions are made by adverse environmental factors such as persistent allergen exposure and cigarette smoke? What are the mechanisms (smooth muscle, neural?) of persistent airway hyper-reactivity without residual inflammation? What is the relationship between airway inflammation and structural airway changes (remodelling); does inflammation drive remodelling, or are they parallel processes? Multicentre studies are required to determine whether a phenotypic approach to severe asthma is worthwhile.
Introduction The vast majority of children with asthma can safely be managed with low-dose inhaled corticosteroids, sometimes supplemented with a longacting b2 agonist or leukotriene receptor blocker. There are clearly structured guidelines on how to escalate and step down management.1 The guidelines industry can be criticized for the paucity of evidence generated over the past 15 years compared with the number of position papers produced, but nonetheless, despite the lack of evidence at many key points, most children are successfully managed by current strategies. How-
ever, by the time Steps 4 and 5 have been reached, the semi-logical progression of steps is replaced by a haphazard approach in which different medications are tried in a seemingly random and increasingly desperate sequence. Our definition of the older child with asthma ‘beyond the guidelines’ is a child with asthma non-responsive to high-dose inhaled steroids (Z1 mg/day fluticasone or equivalent) plus a failed trial of long-acting b2 agonists and leukotriene receptor antagonists.2–4 However, the referral of a child with such severe asthma should prompt a complete and systematic reevaluation (Tables 1 and 2). The commonest reasons for failure to respond to asthma treatment are: firstly, the child does not have asthma (in this respect, one important diagnostic confusion is that in many other respiratory conditions, for example chronic lung disease of prematurity and cystic fibrosis, there is a degree of airway reactivity which is to some extent bronchodilator-responsive), and secondlyFand not infrequentlyFasthma treatment is not being taken. This paper describes our systematic approach to children with apparently intractable asthma and includes an attempt to bring some logic to therapeutic trials when standard (Steps 1–3) therapy has failed.
Diagnostic approach Not asthma at all Children who do not have asthma do not benefit from asthma medications, and the possibility that the diagnosis is wrong is the first consideration. The differential diagnosis of asthma in childhood encompasses virtually the whole of paediatric
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Table 2
D. Payne et al.
Non-asthmatic causes of wheeze.
Upper airway diseaseFadenotonsillar hypertrophy, rhinosinusitis, postnasal drip Congenital structural bronchial diseaseFcomplete cartilage rings, cysts, webs Bronchial/tracheal compressionFvascular rings and sling, enlarged cardiac chamber, lymph nodes enlarged by tuberculosis or lymphoma, congenital thoracic malformations Endobronchial diseaseFforeign body, tumour Oesophageal/swallowing problemsFreflux, incoordinate swallow, laryngeal cleft or tracheo-oesophageal fistula Causes of pulmonary suppurationFcystic fibrosis, primary ciliary dyskinesia, any systemic immunodeficiency including agammaglobulinaemia, severe combined immunodeficiency MiscellaneousFbronchopulmonary dysplasia, congenital or acquired tracheomalacia, pulmonary oedema
Table 3 Points to seek in the history suggesting alternative diagnoses.
Table 4 Points to seek on examination suggesting alternative diagnoses.
Is the child/family really describing wheeze? Upper airway symptomsFsnoring, rhinitis, sinusitis Symptoms from the first day of life Very sudden onset of symptoms Chronic moist cough/sputum production Worse wheeze or irritable after feed, worse lying down, vomiting, choking on feeds Any feature of a systemic immunodeficiency Continuous, unremitting or worsening symptoms Disappearance of symptoms when asleep
Digital clubbing, signs of weight loss, failure to thrive Upper airway diseaseFenlarged tonsils and adenoids, prominent rhinitis, nasal polyps Unusually severe chest deformity (Harrison’s sulcus, barrel chest) Fixed monophonic wheeze Stridor (monophasic or biphasic) Asymmetric wheeze Signs of cardiac or systemic disease
respiratory medicine (Table 2), and is beyond the scope of this article. However, a few key points can be highlighted. Particular points in the history and physical examination are listed in Tables 3 and 4 Much confusion has resulted from different uses of the word ‘wheeze’. Careful studies using a video of respiratory noises have established that many different noises are identified as wheeze by parents, and many of these noisesFsuch as upper airway cracklingFare highly unlikely to be due to asthma or respond to asthma therapies.5–8 True wheeze is not an essential diagnostic feature of asthma, but its complete absence should prompt a careful diagnostic review. Symptoms which are truly from day one of life, and not just from the first viral cold in a young baby, always merit investigation, and suggest congenital lung disease or primary ciliary dyskinesia.9,10 The very sudden onset of symptoms should suggest a foreign body, and the possibility sought by direct questions;11 diagnosis may be delayed, even by many decades. Chronic productive cough, persisting between viral colds and without remission, may be a feature of the catarrhal child or asthma, but is far more likely to be due to chronic bronchial sepsis with or without bronchiectasis, and should be investigated as such. Delayed diagnosis is frequent for cystic fibrosis (10% undiagnosed until adult life;12,13 there may be other suggestive features such as diarrhoea,
nasal polyps or rectal prolapse), primary ciliary dyskinesia (mixed upper and lower airway disease; neonatal onset of symptoms9,10) and hypogammaglobulinaemia. Although H-type fistula is usually diagnosed early, late presentation has been well described.14 A careful inspection of the chest radiograph, including locating the side of the aortic arch15 and the shape of the flow volume loop, may give a clue that the problem is large airway obstruction and not asthma. These tests should be a routine part of the initial assessment. Further investigations should be targeted to eliminate specific conditions, rather than applied in a blanket fashion to all asthmatics.
Asthma plus Continuing symptoms wrongly attributed to asthma These children are particularly difficult to sort out, as although often they undoubtedly do have asthma, the persistence of symptoms is not related to uncontrolled asthma. Conditions which may mimic asthma or co-exist with it are rhinosinusitis and gastro-oesophageal reflux disease. These conditions may cause symptoms wrongly attributed to asthma.
ARTICLE IN PRESS Asthma: beyond the guidelines
Contributory factors to difficult asthma It is implicit in difficult asthma that factors other than lower airway inflammation may be operative. These factors include rhinitis, reflux, psychological issues, and adverse environmental effects (see below). The relationship between upper and lower airway is complex and has recently been reviewed.16 Although the precise contribution of rhinitis to asthma in an individual may be unclear, it would seem reasonable to treat any upper airway disease on its own merits: for example, house dust mite avoidance in sensitized children, oral antihistamines and topical nasal steroids for allergic rhinitis, and prolonged antibiotic courses for chronic infective rhinosinusitis. In our practice it is unusual, however, for these measures to result in complete disappearance of asthma that was previously troublesome. The relationship between the oesophagus and the lung is also complex. Lung disease can cause reflux; reflux can cause lung disease; or reflux may be of no clinical significance. Reflux is frequently found during the work up of severe asthma; however, our experience in the older child is that treatment of reflux rarely results in much improvement in the asthma. Reflux can cause asthma-like symptoms, broadly speaking, by two mechanisms: aspiration of gastric contents into the lung, and oesophageal acid-induced reflex airway constriction. The reason for the disappointing results of anti-reflux therapy on asthma (as opposed to gastrointestinal symptoms) in older children may be due to the fact that, in contrast to younger children, aspiration is rare, and aggressive antiinflammatory therapy has blocked the airway response to oesophageal acidification. In infancy, anti-reflux therapy may be more successful, perhaps because corticosteroids are (rightly) used more cautiously. Certainly an empirical trial in this age group if the history is suggestive is entirely reasonable.
Drug delivery devices Inappropriate selection or wrong use of inhalers and other drug delivery devices are common even in a specialist clinic.17 Common pitfalls are the use of metered dose inhalers without a spacer, in the na.ıve belief that the child can co-ordinate breathing at a young age; persistence of the use of masks when children aged three and above (and even some younger ones) can use a mouthpiece; or the discarding of ‘babyish’ spacers by adolescents. If
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spacers are used, then the inhaler should be shaken before every activation; the child should inhale from the spacer without delay after inhaler activation; and the spacer efficiency should be maximized by washing it once a week in ordinary washing up liquid and leaving it to drain dry without prior rinsing.18,19 A common myth is that the use of a mask and spacer in a crying child maximizes lung drug deposition; in fact, the reverse is the case.20 If nebulizers must be used (and there are really very few indications in asthma) then a mouthpiece or a tight-fitting mask is essential; hopefully waving the nebulizer cup somewhere near the child’s face is a waste of time. A detailed evaluation of inhaler technique is an essential part of the work up of the difficult asthmatic.
Environmental factors A comparison of children with difficult asthma with another group whose asthma was well controlled demonstrated a significantly greater prevalence of adverse environmental features in the former.21 The two commonest factors are cigarette smoke (either active or passive exposure) and aeroallergensFusually from petsFto which the child is sensitive. The effects of passive smoking in exacerbating respiratory disease are well known;22 smoke may also induce a state of relative steroid insensitivity (see below). Although there is debate as to whether primary prevention in the high-risk groups is best achieved by ruthlessly eliminating allergens or saturating the environment with them, there can be no doubt that in the already sensitized child allergen exposure causes worsening asthma and a state of relative steroid resistance (see below). Even repeated low-dose allergen challenge, insufficient to cause worsening of lung function, causes deterioration of bronchial hyperreactivity and worsening airway inflammation manifest by increased eosinophils and EG2-positive eosinophils in induced sputum.23 Cat-sensitive children attending school classes where 420% of the other children have pet cats develop a pattern of symptoms similar to occupational asthma, that is, progressive worsening during the week, with improvement at the weekends and during the holidays.24 The identification of the problem is relatively easy, but dealing with it is more difficult; the English in particular are lovers of animals to the point of folly. The role of the home environment (‘Can I have a letter for the Housing, Dr?’) is hotly debated.25,26 That poor housing conditions are undesirable is indubitable, but that they cause or
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worsen asthma is much more contentious. In general, a home visit by an experienced respiratory nurse is often informative in uncovering adverse environmental effects on the child.
Psychological factors This is another huge subject, which can only briefly be discussed here. Ignoring the mind, and treating the child as merely a pair of lungs, will inevitably result in many failures. It is an area that requires a very sensitive approach. Children are often afraid that discussing psychological factors carries the implication that their symptoms are thought not to be genuine; it may be wise to begin by stating that it is definitely accepted that the symptoms are genuine, and no question of fabrication arises. Using the analogy of stress-induced diarrhoea, a phenomenon familiar to most, may be helpful; the diarrhoeal stool is obviously not a figment of the imagination, but clearly not the result of an organic bowel disease. A neutral question like ‘some people find that stress is a factor that contributes to asthma; is that a factor you think may be important?’Fafter asking specific questions about other triggersFmay be a good way to introduce the topic. When talking to adolescents, it is important to spend part of the consultation with them alone, separate from their parents. Confidentiality between the health professional and the patient needs to be established, and once this is done it provides the opportunity for adolescents to talk more freely about their concerns.27 Speaking to adolescents separately also enables them to begin to take more responsibility for their asthma and its treatment.
Adherence to treatment The two commonest causes of apparent steroidresistant asthma are wrong diagnosis (above, Table 2) and not taking the treatment. Doctors are notoriously poor in predicting which patients are compliant. The measurement of prednisolone and cortisol levels in a child who is supposed to be taking oral prednisolone may be illuminating. A therapeutic trial with depot triamcinolone may reveal that the so-called steroid-resistant asthma disappears. Adherence is an issue which requires very sensitive handling, trying to explore the reasons for reluctance to take treatment in a ‘no blame’ manner. Often the help of a psychologist is essential.
D. Payne et al.
Stress Thankfully, the days of blaming asthma totally onto stress and low moral fibre have gone. However, the importance of stress should not be forgotten. The first study to show an effect of stress on airway inflammation compared the sputum eosinophil response to allergen challenge at the time of examinations with that during a less stressful term, and showed that there was a more marked induced sputum eosinophilia during stress.28 Another study appeared to show that stress ameliorated asthma in women who were studied while they were recounting stressful experiences.29 More work is needed, but the possibility of presumably neural driven inflammation worsening asthma as a result of psychological stress should not be discounted.
Dysfunctional breathing patterns This is a huge topic, and encompasses such disparate syndromes as vocal cord dysfunction (adduction of the vocal cords in inspiration or expiration or both30), hyperventilation syndromes, and habit/honk cough. The key feature in the history is the complete disappearance of the symptoms during sleep, quite unlike asthma. These syndromes may co-exist with mild asthma. Management involves weaning off the excessive therapy and the assistance of a physiotherapist, speech therapist or clinical psychologist as appropriate.
Hidden gains These may accrue to the child or family. School avoidance may arise because of prolonged absence due to asthma, and may preclude successful therapy unless specifically tackled. The avoidance of unpleasant situations, such as a cross-country run, may be another factor, with which at least one of the authors has considerable sympathy. Parents may gain financial benefit from having a child with severe asthma, including disability living allowance and rehousing. Rarely, a diagnosis of Munchausen syndrome by proxy may need to be considered.
A phenotypic approach? If attention to the factors above have failed to resolve the problem, then we proceed to more invasive assessment of the problem before starting on more toxic or inconvenient therapies. We have developed a protocol (Table 5) to try to determine a rational approach to severe asthma, predicated
ARTICLE IN PRESS Asthma: beyond the guidelines
Table 5
The difficult asthma protocol.
1.
Physiological measurements
2.
Non-invasive inflammatory and other markers
3.
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Visit 1
Visit 2n
Visit 3
Spirometry
Spirometry, including response to b2 agonist Assess symptoms Exhaled nitric oxidew
Spirometry, including response to b2 agonist Assess symptoms Exhaled nitric oxidew
Sputum induction RAST or skin prick tests as appropriate
Sputum induction Cortisol assay
Invasive studies
Prednisolone assay (unless given triamcinolone) Bronchoscopy, bronchoalveolar lavage, and bronchial biopsy
RAST, radioallergosorbent test. n Between visits 2 and 3 the patient is prescribed a course of systemic corticosteroids (preferably a single intramuscular injection of triamcinolone 80 mg, or oral prednisolone 40 mg daily for 2 weeks). w The role of exhaled nitric oxide in categorizing asthma is still unclear.
on the belief that there are many different reasons why asthma may be resistant to therapy.3,4 The protocol is a compromise between what is scientifically ideal and what is ethically acceptable; for example, it might be preferable to bronchoscope the child both before and after the course of oral steroids. Instead, we felt it correct to rely on induced sputum to determine airway cellularity before the course of steroids, accepting that some will have too severe an airflow obstruction for this to be attempted, and that in 20% of children over 12 years old (more in younger children) it will not be possible to obtain a sample. At the first visit (when the patient is enrolled, and after a full assessment has been performed), a diary card is supplied to confirm continuing symptoms. Home peak flow monitoring is generally so poorly performed that we have stopped using it as a clinical tool in this context.31 At the second visit, noninvasive measurements of airway inflammation are performed, and the child is given a single intramuscular injection of a depot preparation of triamcinolone. At visit three, 2 weeks later, the non-invasive measurements are repeated and a fibreoptic bronchoscopy performed, with bronchoalveolar lavage and airway biopsy. We do not perform transbronchial biopsy. The safety of this approach has been evaluated and found to be acceptable.2 The different phenotypes which we have recognized so far are summarized in Table 6, and discussed in detail below. One aim of this protocol is to determine how good the child’s lung function can become. We assume that a depot injection of triamcinolone, followed by inhaled
high-dose b2 agonist, is sufficient to correct any reversible element, but this remains to be tested.
Steroid-sensitive asthma The largest single phenotype is the child who becomes completely asymptomatic, with normal lung function, and with no airway inflammation on airway biopsy and lavage.32 In this situation we plan to reduce the oral steroids to the minimum dose which controls symptoms and (ideally) non-invasively measured inflammation. If prednisolone cannot be reduced to a level where side effects are minimal or tolerable, we would use a steroid sparing agent, usually cyclosporin. However, our experience has been that these agents seem to work less well in this group than in the steroidresistant asthmatics (below). Children requiring high-dose steroids to control asthma are also assessed as far as is possible for causes of secondary steroid resistance.
Steroid-resistant, eosinophilic asthma This phenotype comprises biopsy, lavage or induced sputum evidence of eosinophilic inflammation in children who remain symptomatic.4 In some of these steroid-resistant children we have found abnormalities of steroid receptor binding and translocation of the steroid–receptor complex from cytoplasm to nucleus. It must be said that these measurements are not easy to interpret, and remain in the domain of research.
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D. Payne et al.
Table 6
Summary of proposed difficult asthma management, at the conclusion of the protocol.
Clinical scenario
Presumptive diagnosis
Suggested action
1.
Continued airflow obstruction, no inflammation, no reversibility to b2 agonists
Presumed obliterative bronchiolitis, or remodelling secondary to chronic inflammation, etc.
Inspiratory and expiratory CT scan Use minimum treatment which maintains lung function
2.
Continued airflow obstruction, no inflammation before or after steroid therapy, but with reversibility to b2 agonists
Presumed steroid-resistant, non-inflammatory bronchial reactivity
Look for causes of secondary steroid resistance (environment, etc.) Continuous subcutaneous terbutaline treatment
3.
Persistent eosinophilic inflammation, with either or both of airflow obstruction and symptoms
Presumed steroid partial or complete resistance
Look for causes of secondary steroid resistance Treat with either prolonged highdose steroids or steroid sparing agent Consider using computerized drug delivery device to confirm adherence
4.
Persistent eosinophilic inflammation, with no airflow obstruction or symptoms
Lagging of clearance of inflammation Risk of ongoing remodelling despite no symptoms
Observe closely with repeated spirometry and non-invasive measures of inflammation
5.
Presumed inflammation completely resolved with steroids (normal lung function, no symptoms)
Steroid-sensitive asthma, but requiring high-dose treatment
Look for causes of secondary steroid resistance Taper steroids to level at which symptoms are controlled without side effects, or steroid sparing agent
6.
Persistent non-eosinophilic inflammation
Presumed other inflammatory mechanisms (other cells, e.g. neutrophilic inflammation; neurogenic mechanisms)
Reduce steroid treatment to minimum level needed to control eosinophilic inflammation Consider macrolide therapy, 5lipoxygenase inhibitor, or theophylline if neutrophilic inflammation
7.
Apparently normal lung function, no inflammation, but reported ongoing symptoms
Poor symptom perception
Exercise test or methacholine challenge with Borg scale
Psychological problems Not asthma at all
Review by psychologist
The causes of steroid resistance are a subject of controversy. The commonest cause is failure to adhere to steroid treatment. Congenital steroid deficiency, characterized by a very low number of steroid receptors of normal binding affinity, is very rare.33 Secondary steroid resistance is much more common, and is usually characterized by a normal or increased number of steroid receptors, with reduced affinity for glucocorticoid. One putative mechanism is via allergen drive in a sensitized
subject, which causes increased interleukin (IL)-2 and -4 release from white cells, which in turn modulates steroid resistance.34 This underscores the need for attention to the environment and allergic sensitization in these children. Another (not necessarily mutually exclusive) cause of steroid resistance is a switch in the phenotype of a subunit of the steroid receptor to a phenotype with reduced affinity.35 Studies in adults have documented that cigarette smoking causes relative
ARTICLE IN PRESS Asthma: beyond the guidelines steroid resistance36,37 and, by analogy, passive smoking may be a factor in children. Animal experiments suggest that latent viral infection is a mechanism to be considered.38 Our own studies (submitted for publication) suggest that the mechanism of persistence is not persistence of the characteristic Th2 drive, based on the absence of typical Th2 signature cytokines such as IL-4 and IL-5 in bronchial biopsies. However, the true mechanism remains to be elucidated. We elect to treat these children with alternative anti-inflammatory therapies, usually cyclosporin. The protocol has been published elsewhere;39 briefly, meticulous attention to details of monitoring drug levels and renal function is essential. We would attempt a minimum of a 3-month trial of treatment if tolerated, and, if the response is good, try to wean the dose of steroids (initially oral, then inhaled) to the minimum dose tolerated.
Steroid-resistant, non-eosinophilic inflammatory phenotype asthma There have been a number of induced sputum and bronchial biopsy studies in which a neutrophil dominated or exclusive phenotype has been reported.40 This phenotype may account for around half the burden of asthma at all ages.41 These patients are symptomatic and poorly responsive to steroids. What is unclear is the role of the neutrophil in this phenotype. Possibilities include: (1) that it is the effector cell for this type of asthma; (2) that the presence of neutrophils merely reflects the effects of corticosteroids prolonging neutrophil survival by delaying apoptosis;42 or (3) that neutrophils are a beneficial response to an unknown stimulus (for example an occult infection), and it is the unknown stimulus which is driving the asthmatic symptoms. What are lacking are studies which demonstrate that reducing airway neutrophil count leads to an improvement in symptoms. Possible agents to reduce airway neutrophilia, assuming this to be desirable, are largely used on an empirical basis, in the absence of knowledge as to which neutrophil chemoattractants are important in driving airway neutrophilia. These would include reducing the synthesis of leukotriene (LT) B4, or blocking its receptor when suitable agents become available; blocking IL-8 production with a macrolide antibiotic;43 or accelerating neutrophil apoptosis with oral theophyllines.44 Anecdotally, we have treated patients with neutrophil-dominated asthma with a 6-month trial of azithromycin, using the same protocol as for our cystic fibrosis
343 work;45 some but not all children with this picture have shown an apparently dramatic response, although whether as a placebo effect is not clear. This is an unresearched phenotype, and more data are needed before firm recommendations can be made.
Non-inflammatory, persistent BHR Children with this phenotype have no evidence of residual airway inflammation on bronchoscopy, BAL and biopsy at visit two. However, they remain symptomatic, and have marked acute bronchodilator reversibility. The molecular basis of this phenotype is unclear. It would seem illogical to treat such children with ever more potent antiinflammatory therapies. This group have usually already tried high-dose inhaled and often oral longacting b2 agonists without success. We have used continuous subcutaneous infusion of terbutaline with some success in this group.46 This is a demanding therapy, but deemed worthwhile by the children who respond. The child carries a syringe pump in a waist bag; the needle is placed under the skin of the abdomen, and changed every one to two days, rotating the site of insertion. We start with a low dose (generally 2.5 mg over 24 h) and increase as high as 10 mg/24 h depending on symptoms and any side effects. Education and support from a really experienced respiratory nurse is essential. When symptom control has been obtained, we reduce the dose of oral and then inhaled corticosteroid as tolerated, monitoring airway inflammation with non-invasive techniques. It is unlikely that this is a pure non-inflammatory phenotype, and we would not anticipate being able to stop inhaled corticosteroids altogether; more plausible is that underlying airway inflammation is more easily treated than BHR. The role of abnormal smooth muscle function or neural control of the airways has not been investigated in this phenotype.
Persistent eosinophilic inflammation with no symptoms We have seen this phenotype in the context of our severe asthma protocol. The phenotype has been described best in a group of young adults who to all clinical intents and purposes have outgrown their asthma.47 They are off all therapy and have a normal lifestyle, and would be discharged from the clinic. However, detailed investigation in this group has shown persistent airway eosinophilia on biopsy. The interpretation of this finding is difficult, and
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management recommendations are purely conjectural. In the context of difficult asthma, we would treat the child as for steroid-sensitive asthma (above).
Asthma phenotypes in the older child with severe asthma: summary We have proposed a largely pathological classification of severe asthma in childhood as a means for rationalizing treatment. There is still much work to be done to try to work out the relationship between airway pathology and some clinical phenotypes, for example Types 1 and 2 brittle asthma. We have tested the utility of this approach in fewer than 100 patients, and even with this degree of detailed investigation it is not possible to treat all children successfully. Hence bigger studies are needed to confirm whether the invasive and expensive tests are worthwhile.
Persistent airflow limitation This can be part of many of the asthma syndromes described above. In pure form, such as an undiagnosed obliterative bronchiolitis secondary to previous adenoviral or other viral infection, or aspiration syndromes, there is no evidence of airway inflammation or BHR at either visit, and no change in lung function during the steroid trial. Treatment is reduced until evidence of BHR or inflammation appears. Usually therapy can be discontinued completely.
Particular problems in infancy and the preschool years
Poor perception of symptoms There is a big literature on both over-reporting and under-perception of symptoms in asthma, which will only be summarized here. Over-reporting may lead to overtreatment. The problem may lie with the child, the family, or both. Older children may complain that they get exercise-induced asthma, whereas in reality they are simply unfit; a formal exercise test may clarify this point. A methacholine challenge with a visual analogue score of perceived breathlessness may reveal either a perception of marked breathlessness with little change in spirometry, or more worryingly, no perception of breathlessness in the face of progressive airflow obstruction.48 There is some evidence that treatment with inhaled steroids may increase the perception of symptoms,49 and also that at least some of those prone to acute severe deteriorations have a blunted symptom perception.50 This group in particular may benefit from regular monitoring of peak flow at home. Table 7
There are several different wheezing phenotypes in preschool children (Table 7), and many of them are non-inflammatory and respond poorly to inhaled steroids. These have been reviewed in detail elsewhere;51 space precludes doing justice to them here. Some phenotypes (in particular virus-associated wheeze and post-bronchiolitic cough and wheeze) have their roots antenatally, with maternal smoking, atopy and hypertension of pregnancy resulting in reduced airway calibre, which can be detected soon after birth,52–54 and before a first viral infection.55–59 It may be necessary to accept that some symptoms do not respond to any treatment, and that they will improve with time.60–62 This seemingly nihilistic approach is preferable to vast increases in useless and potentially toxic therapy, and may in fact be welcome to parents who have become disillusioned with medications which fail to work.
Phenotypic characterization of pre-school asthma syndromes.
Preschool asthma syndrome
Inflammatory component
Extent of BHR (bronchial hyper-reactivity)
Extent of PAL (persistent airflow limitation)
1. Chronic lung disease of prematurity 2. Post-bronchiolitis 3. Virus-associated wheeze 4. Atopy-associated wheeze 5. Obliterative bronchiolitis 6. Non-atopy-associated, later onset wheeze
?(probably none)
þ
þ (antenatal)
? (probably none) þ (probably often eosinophilic) –
þ þ
þ (antenatal) þ (antenatal) þ (probably antenatal and postnatal) þ (postnatal)
?present, ?type
Probably present
–
þ (probably at least postnatal)
ARTICLE IN PRESS Asthma: beyond the guidelines
Summary and conclusions There are no easy answers when dealing with asthma beyond the guidelines. A systematic evaluation will reveal whether treatment is completely wrong, the child does not have asthma at all, or there are major, previously unappreciated, psychological factors. If this is not the case, meticulous attention to the detail of all aspects of conventional treatment may improve matters. If this fails, we believe that a phenotypic approach, using a structured protocol and including a bronchoscopy, is clinically justified, and preferable to haphazardly shuffling through different treatments. The validity of this approach, as with much that we do in paediatric respirology, requires justification by further studies.
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