Introduction – the clinical pathology of asthma
Asthma may be defined clinically as a syndrome of variable airway obstruction and bronchial hyper-responsiveness. These fundamental abnormalities may result in a variety of symptoms that vary in prominence between patients and may be overlain by diurnal variability of symptoms (worse in the early morning when natural cortisol is low) and by the fact that exogenous trigger factors can be identified in some, but not all, patients and can vary between patients. Thus, it is not clear if asthma is driven and triggered exclusively by external environmental stimuli or whether the disease partly reflects inherent disorders of those components of the airways that regulate resistance to airflow, principally the bronchial smooth muscle but also the epithelial and submucosal linings, which, when oedematous, can reduce the internal calibre of the airways. The key clinical features of asthma include:
Variable airway obstruction. Airway obstruction in cases of asthma, as measured by spirometry, may vary spontaneously from no obstruction to a severe obstruction in minutes or hours and improves after suitable therapy. Breathlessness and impaired exercise tolerance in asthmatics arise from the increased ventilatory effort required to move air in and out of abnormally narrow airways and from obstruction of the small airways. This causes ‘gas trapping’ in the alveoli, which, in turn, results in hyperinflation of the chest and reduced tidal volume. Airway obstruction also results in a feeling of tightness in the chest, which may be perceived as wheeze.
Non-specific bronchial hyper-reactivity. This refers to the tendency of the smooth muscle cells of asthmatic airways to constrict in response to a very wide variety of non-specific (that is, non-immunological) environmental as well as pharmacological stimuli that do not cause clinically significant bronchoconstriction in non-asthmatics (e.g. cold air, smoke, exercise, aerosol sprays, dust, etc.). The mechanism of this remarkable phenomenon remains obscure. It is further exacerbated by excessive mucus production and oedema of the airways mucosa, both of which further narrow the internal airway lumen, increasing the degree of obstruction produced by a given degree of smooth muscle constriction. Bronchial hyper-reactivity causes excessive coughing and contributes to bronchospasm. Again, different stimuli may provoke bronchospasm in different patients.
Epidemiology of asthma
Surveys based on asking patients questions regarding their asthma symptoms or their doctor’s diagnosis of asthma suggest that asthma affects 5–16% of people worldwide.1 Rates vary widely in different countries, partly reflecting ethnic and environmental effects on the prevalence of asthma and partly diagnostic standards. The prevalence of asthma has greatly increased in the past 50 years but now appears to be stabilizing, particularly in countries such as the UK, where the prevalence is relatively high.2 Asthma is a major health cost in many countries; for example, 18 billion US dollars was spent on adult asthmatics alone in the USA in 2005.3 Much of this cost arises from patient emergency visits and hospital admissions, although the cost of medications is forming an increasingly large proportion of the total costs.
Birth cohort studies confirm that asthma often begins in childhood, although there is diagnostic confusion since clinical symptoms of the disease, particularly wheezing, are non-specific to this age group and most often reflect transient viral infections. Even when asthma symptoms are not prominent in early childhood, there is a greater number of symptoms earlier in life in newly diagnosed young adults.4 Nevertheless, some cases of asthma are diagnosed later in life, especially when triggered by occupational sensitizing agents. The strongest predictor of severe and persistent symptoms is the development of irreversible bronchial obstruction,5 which is fortunately rare in the asthmatic population as a whole. In affluent societies, sensitization to multiple aeroallergens during preschool years is associated with increased risk of severe asthma,6 although, in poorer countries, where asthma may also be highly prevalent, this association is less clear,7 suggesting that distinct aetiological mechanisms of the disease may predominate in different environments and that coexisting atopy is not a sine qua non for asthma development.
Investigation and monitoring in asthma
Many countries publish national asthma management guidelines readily available via the internet [e.g. British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) for the UK8 and National Institutes of Health guidelines for the USA9]. The Global Initiative for Asthma (GINA) guidelines10 are compiled by an international body of asthma physicians and all guidelines are updated regularly. All guidelines advocate regular assessment of asthma control and describe steps to improve control, if necessary.
Diagnosis of asthma
Asthma should be neither missed nor inappropriately diagnosed. As emphasized above, at least 50% of preschool children who exhibit symptoms of wheezing while suffering from a cold will not go on to develop asthma.11 In children, the likelihood of the diagnosis of asthma is increased by a history of typical chest symptoms (e.g. wheeze, cough, chest tightness) that are frequent and recurrent, vary across the day (worst in the early morning), are triggered by factors other than chest infections (such as exercise, allergens and emotions) and occur in the absence of colds. Detection of audible wheezing on examination and a personal and/or family history of atopic disease increase the likelihood of asthma. Children who wheeze only with colds or who have an isolated cough, especially when wet and productive, or a normal-sounding chest or normal lung function when ‘symptomatic’ are less likely to have asthma. If the diagnosis is in doubt, demonstration of reversible airways obstruction is helpful, as most children over the age of 5 years can perform lung function tests. The BTS/SIGN criteria for objective asthma diagnosis are as follows:
more than 20% diurnal variability for > 3 days per week for 2 weeks in a peak expiratory flow (PEF) diary;
an increase in PEF of 20% [or 15% with a 200 ml improvement in forced expiratory volume in 1 second (FEV1)] after taking short-acting beta (β)2-agonists or a 6-week course of inhaled or oral steroids (30 mg prednisolone daily for 2 weeks);
a fall in FEV1 or PEF of 20% after a 6-minute run (children);
positive histamine/methacholine/mannitol challenge test.
Any one of these BTS/SIGN features is diagnostic and, in addition, symptomatic patients with airway obstruction generally have a FEV1/forced vital capacity (FVC) ratio of < 70%, but this is not specific for asthma.
Ultimately, the diagnosis may depend on a favourable response to a trial of therapy. Watchful waiting is also a legitimate course of action if the diagnosis is in doubt.
In adults, the diagnosis is suggested by typical symptoms and confirmed by the demonstration of variable airway obstruction. Onset of symptoms after childhood always suggests the possibility of occupational asthma and, again, a chronic productive cough, absence of chest signs or normal lung function when symptomatic, voice disturbance and symptoms only with colds make the diagnosis less likely, whereas concomitant features such as a long smoking history (> 20 pack-years) or cardiac disease suggest alternative or additional causes of breathlessness.
It is critical to document the diagnosis of asthma objectively before commencing any treatment. This is usually based on simple spirometric measurements made before and after taking a bronchodilator (or exercise in children) or on home PEF measurements made in a diary, but may occasionally require gold standard histamine, methacholine or mannitol challenge measurements in a hospital laboratory (occasionally with very young children, it is justifiable to make the diagnosis by trial of therapy, as above). If the diagnosis of asthma has not been documented in this way, or is not obviously confirmed by the past medical history, it is prudent to doubt it until such proof is available. This may involve stopping existing anti-asthma treatment followed by watchful waiting.
Monitor patients regularly with the aim of maintaining disease control
All guidelines assert that ‘perfect’ asthma control is feasible in most patients. Studies such as the GOAL study12 have affirmed that ≥ 70% of asthmatics can be perfectly controlled if sufficient ‘conventional’ treatment is delivered to the airway. Most of these patients will be managed entirely in primary care and will seldom, if ever, have to visit a hospital. A small minority of patients never attain disease control with full dosages of conventional medications and these patients are usually managed jointly with secondary/tertiary care professionals. The GINA guidelines present a useful categorization of asthma control, as shown in Table 1, while the strategy for drug management of asthma according to the UK BTS/SIGN guidelines is summarized in Figure 1. The strategy proposed by guidelines is to step up treatment if asthma is not controlled and to step down treatment if it has remained controlled for a reasonable period of time (3–6 months). The ‘starting step’ of treatment should be roughly aligned to the initial degree of disease control. In general, when stepping down therapy, inhaled steroids should be reduced by 25–50%. With patients at step 3 and above, oral or inhaled steroids should first be reduced to step 2 levels before discontinuing steroid-sparing add-on therapies such as long-acting β-agonists or leukotriene receptor antagonists. These can then also be stopped provided that the disease control is maintained.
Adequate assessment of asthma control
Although it is important that patients step down therapy if asthma remains controlled, many patients remain symptomatic because they are undertreated. One cause of this is poor appreciation of current disease control. When assessing this, a single lung function measurement and a perfunctory ‘How have you been since last time?’ is not enough. Most asthma physicians are now adopting objective assessments of asthma control. One good test that is suitable for adults and children aged ≥ 12 years is the Asthma Control Test (ACT), in which the patient answers five short questions about asthma control,each with a score of up to 5 points, and a total score of 25 representing perfect control. In a study in primary care from 2009,13 the authors found that an ACT score of ≥ 20 quite accurately predicted ‘controlled’ asthma, as defined by GINA in Table 1, whereas a score of ≤ 19 indicated less than perfect control. It is simple to incorporate such tests into asthma reviews in order to assess asthma control properly.
Assessment of patients with poor asthma control
When symptoms attributed to asthma do not improve as expected when patients are reviewed, it is helpful to consider the five possible causes presented here as questions in rough order of their importance in confounding asthma control.
Is the patient taking the prescribed treatment at all? Studies suggest that, even in patients outwardly compliant with treatment, only about 30–50% of prescribed inhaled medication is actually taken and not necessarily at the appropriate time.14,15 Poor compliance may arise from poor understanding, fears about taking medications, physical or psychiatric disease or stressful personal circumstances (poverty, family conflict, homelessness, drug addiction as well as many others). It is not always within the power of the physician to address all of these, but the GINA guidelines make reference to a wealth of national resources that may help patients burdened by such circumstances. There is evidence that the key to compliance, at least in some patients, is the promotion of guided self-management, which may incorporate provision of a written asthma action plan, which empowers the patient to assume responsibility for keeping his or her own disease under control and sets shared goals with his or her health professional, and provides a sympathetic ear about problems and expectations. There is also abundant evidence that guided management improves health outcomes.
Does the patient like his or her inhalers and is he or she using them properly? Poor inhaler technique is an extremely common cause of failure to achieve asthma control. It is not enough to ‘go through the motions’ of inhaler technique with patients in a perfunctory way, as subtle problems that may go unnoticed by the uninitiated can reduce delivery of inhaled drugs by as much as 90%. Some patients cannot use particular devices because of factors such as age, disability and inadequate lung function. Even when patients can, in theory, use a particular device, errors of technique are known to be occur frequently.15 With pressurized, metered dose inhalers (pMDIs), two of the most critical errors are failure to coordinate inhalation with actuation of the device16 and inhaling the aerosol too quickly.17 The former may be overcome by using a breath actuated device or a spacer and the latter can be improved with training.18 With dry powder inhalers (DPIs), successful aerosolization of the dry powder depends on both the velocity and the acceleration of the inhalation manoeuvre, which, in turn, requires rapid and forceful inhalation.18 Evidence suggests that many of these errors may be detected and patients taught to correct them, at least temporarily, with coaching. With this in mind, various aids have appeared designed to help patients to use inhalers correctly and efficiently. A selection of these includes:
The 2Tone device (Canday Medical, Newmarket, UK) teaches patients to inhale from pMDIs at the correct speed. Training with this device improved asthma outcomes and quality of life.16
The Turbutest (AstraZeneca, Lund, Sweden) measures patients’ ability to generate sufficient peak inspiratory flow when using the Turbohaler and also reminds them to prime the device first by rotating the base, both of which are critical errors that can greatly reduce drug delivery. Turbutesting a large group of adult asthmatics revealed that 33% generated inadequate peak inspiratory flow when using the Turbohaler,19 although none had reported difficulty in using it beforehand.
The In-CheckDial (Clement Clark International, Harrow, UK) simulates the resistance of a number of DPIs and checks that the patient can generate adequate peak inspiratory flow. In a group of child asthmatics who were apparently experienced with use of the Turbohaler, testing revealed adequate peak inspiratory flow (> 60 l/min) in only 68%.20
The Mag-Flow Inhaler (Fyne Dynamics Ltd, Essex, UK) flow indicator provides visual feedback that the patient has inhaled adequately quickly through a variety of DPIs such as the Turbohaler, Accuhaler, Handihaler and Novolizer.
The Aerosol Inhalation Monitor (Vitalograph, Buckinghamshire, UK) is designed for pMDI training and checks coordination of actuation of the device with inhalation and also provides feedback on optimal speed of inhalation.
Other devices are also available. It is critical when managing asthma to ensure that all inhaler devices are being used properly by the patient and repeated and careful training is essential. Rationalization of dosing regimens and inhaler devices to minimize the number of different devices used seems sensible, but, above all, it is essential that the physician goes that extra mile to look into inhaler technique highly critically, with the use of aids wherever possible.
Have other possible asthma-exacerbating factors been eliminated? Passive smoking increases the risk of asthma exacerbation in children while active smoking increases the risk of persisting disease in teenagers. There is little organized evidence that giving up smoking increases long-term asthma control, although there is better evidence that smoking induces resistance to asthma treatment. Global allergen avoidance measures, particularly of household perennial allergens such as pet dander and house dust mites, has not been shown to improve asthma control in the long term in population studies and cannot be generally recommended; nevertheless, particular allergens may exacerbate asthma in particular patients and in these cases avoidance is mandatory. Asthmatic patients very frequently have concomitant seasonal and/or perennial allergic rhinitis, which should always be treated. Whenever asthma control is lost, consider exposure to new allergens, including occupational allergens, as a possible cause. In a small minority of asthmatics, aspirin and related cyclooxygenase-1 inhibitors may cause acute exacerbation of disease. β-Blockers administered orally or intraocularly may produce severe bronchospasm and should generally be avoided completely in asthmatics except perhaps in hospital after acute coronary events. Obesity has recently been associated with asthma, although the cause/effect relationship, if one exists, is still obscure. The UK BTS/SIGN guidelines recommend weight reduction in patients with a high body mass index. Gastro-oesophageal reflux can exacerbate asthma, especially in children, and asthma sometimes improves when the reflux is corrected. Many women notice that their asthma is worse perimenstrually. Asthma control may improve, worsen or remain unchanged in pregnancy.
Is the diagnosis correct? Clear documentation of variable airway obstruction before commencement of treatment is reassuring, but in situations when this is not available and symptom control does not improve as expected after commencing anti-asthma medication (which is regularly used and efficiently delivered to the airways), it may be appropriate to reconsider the diagnosis, perhaps with discontinuation of treatment with watchful waiting and further investigation. In children, poor symptom response to a trial of asthma therapy is very much against a diagnosis of asthma and the differential diagnosis includes bronchiolitis, inhaled foreign body, vocal cord dysfunction, developmental abnormalities of the upper airway, recurrent aspiration and chronic sepsis (cystic fibrosis or congenital immune deficiency or ciliary dysfunction). In adults, the differential diagnosis includes cystic fibrosis, bronchiectasis, inhaled foreign body, tracheobronchomalacia, recurrent aspiration, chronic obstructive pulmonary disease, congestive cardiac failure, tumours impinging on the central airways, vocal cord dysfunction and obstructive bronchiolitis.
Is there additional morbidity? Asthma may be complicated by, or occur in association with, other morbidities, as described above. This may limit the capability of anti-asthma drugs to effect complete control of symptoms.
In summary, health care professionals should aim to empower patients to manage their asthma and abolish symptoms. For the vast majority of patients, this is a realistic aim but success depends on strict adherence to the cycle of asthma assessment (Figure 2), especially when asthma control is not achieved. Critical points in the cycle include examination and re-examination of compliance and inhaler technique. Even using the cycle, some patients never get better and may be referred to specialist colleagues to explore other avenues of treatment.
Organization of care for asthma patients
Most asthma begins in childhood and most patients will be referred by their parents or guardians to their local primary care physician for the diagnosis, investigation and monitoring of their symptoms. Once the diagnosis has been established as described above, routine care of asthmatics is often delegated to specialist teams, such as asthma specialist nurses within primary care. It is the task of these professionals to enforce the five key questions of asthma control on a regular basis and to provide liaison with other community specialists such as school nurses, particularly when there are comorbidities such as severe allergy to manage.
In the UK and other countries, there are governance and financial incentives for primary care physicians to keep a register of all the asthmatics in their catchment area and to ensure that everyone is monitored regularly, although, obviously, this cannot be more frequently than every 6 months or so. This would normally be through a visit to a specialist nurse for assessment of the five key questions and adjustment oftherapy up or down, if appropriate. In addition, during the course of monitoring, all patients must be taught self-knowledge of their disease, as emphasized above. They should be familiar with PEF monitoring as a marker of deterioration of the disease and have a clear plan of what to do should this occur. Many of these asthma action plans are sponsored by local and national asthma charities as well as patients’organizations. Such organizations also provide a forum for information, support and mutual interaction for asthma sufferers and their families.
In addition to ‘routine’ monitoring, patients are also singled out for assessment if they require unplanned care, such as by turning up at a hospital emergency department, if they are admitted to hospital with an acute exacerbation of disease or if they do not renew their anti-asthma prescriptions as often as they should according to their prescribed dosages, suggesting poor compliance.
Patients with forms of the disease that are more difficult to control, or in whom the diagnosis is still uncertain, may be referred to a respiratory specialist or allergist, often in a hospital setting where there are better facilities for lung function testing, diagnosis of comorbidities such as allergies or bronchiectasis, and other services such as radiology and physiotherapy. Care is often collaborative with the primary care physician.
Patients with very severe forms of the disease may be referred on from specialist physicians in secondary care to strategically localized tertiary care referral services which typically provide a ‘one-stop shop’ for the full assessment of asthmatics with severe and unrelenting symptoms or frequent, severe exacerbations despite undergoing maximal conventional therapy. In addition to the facilities provided by specialist consultants, such centres will typically have facilities for pioneering therapies such as new biologicals and thermoplasty and a greater range of specialists able to address specific problems such as vocal cord dysfunction. Such centres are also typically hubs of research and contributors to national disease databases that allow monitoring of disease trends on a national basis.
Drug treatment of asthma
Asthma is associated with chronic inflammation of the bronchial mucosa and, although the relationship between this inflammation and the clinical pathology of asthma (variable airways obstruction and hyper-responsiveness) is still not understood, conventional anti-asthma therapy has been directed at reducing it through the use of topical (inhaled) corticosteroids (ICSs) and reducing bronchospasm with β-adrenergic agonists, which may be short or long acting. An overview of recommended asthma management is shown in Figure 1 and further detail is available in the BTS/SIGN guidelines.
Inhaled corticosteroid therapy
Inhaled corticosteroid monotherapy achieves successful control of mild/moderate persistent asthma in a significant proportion of patients. Generally, the dose–response curve of ICS is relatively flat for a number of outcome measures, and for many patients the therapeutic benefits of high-dosage versus low-dosage ICS may be marginal.21,22 Nevertheless, for the majority of patients, even at low dosages, ICS therapy rapidly improves clinical symptoms and measures of airways obstruction and hyper-responsiveness23 and in the long term reduces the frequency and severity of exacerbations24 as well as the risk of death from asthma.25 Thus, guidelines all agree that ICS therapy is the most effective current controller therapy for asthma in adults and children of all ages. Several studies26–28 have also confirmed that withdrawal of ICS therapy in stable asthmatics, who were previously deemed to require it for disease control, increases the risk of relapse in the short term. Thus, all asthma guidelines stress the point that ICS therapy is not curative and must be maintained if needed. In many children, clinical symptoms regress and it is legitimate to discontinue therapy.
Inhaled corticosteroid versus cysteinyl leukotriene receptor antagonist (LTRA) monotherapy for mild persistent asthma
Cysteinyl leukotrienes, produced by a variety of inflammatory cells implicated in asthma, are powerful bronchoconstrictors and also increase mucus secretion and oedema in the bronchial mucosa. They amplify inflammation through their chemoattractive effects on inflammatory cells such as eosinophils. Consequently, in addition to causing bronchodilatation, leukotriene receptor antagonists (LTRAs) have also been shown to have anti-inflammatory properties in cases of asthma.29,30 Four studies involving both adults and children with mild persistent asthma compared therapy with LTRA and low-dosage ICS.31–34 It was found that both drugs improved most asthma outcomes, but ICS therapy was significantly superior for most outcomes (asthma control, lung function and inflammatory biomarkers).
Despite these studies, LTRAs are widely used outside the UK as monotherapy for mild, persistent asthma, especially in children. Furthermore, guidelines are curiously ambivalent about the use of LTRAs as monotherapy instead of ICS in mild persistent asthma. The GINA guidelines10 suggest that LTRAs can be an alternative form of treatment for mild cases of persistent asthma in adults, but also that, when used alone as a controller, their effects are inferior to those of ICS and cannot replace this treatment in patients already on ICS without risking loss of control of asthma.35,36 For children, no specific comment is made about their use as monotherapy, although inferiority to low-dose ICS therapy is implied.31,37 The EPR3 guidelines,9 based on evidence from five placebo-controlled trials,31,32,37–39 also assert that ICS therapy is superior to other single, long-term control medications but nevertheless conclude that, in both adults and children, LTRA monotherapy is an ‘alternative, not preferred’ treatment. The BTS/SIGN guidelines state that LTRA therapy is not as effective as ICS as monotherapy and suggest that LTRAs can be used in children < 5 years old in whom ICS cannot be used. Despite what the guidelines say, most clinicians would conclude from all of these studies that LTRAs should be used as monotherapy for mild persistent asthma only as a last resort when ICS cannot be used, for whatever reason. The reasons for their continuing popularity as monotherapies in practice in some countries are not clearly defined but may relate to perceived problems with giving ICS to children or using inhaler devices in this age group.
Inhaled corticosteroids versus theophylline monotherapy for mild persistent asthma
Theophylline is a rather weak, non-specific inhibitor of phosphodiesterase that elevates cyclic AMP concentrations in airway smooth muscle and immune cells, resulting in modest bronchodilatation and inhibition of inflammatory cells. Theophylline has limited effectiveness when given as monotherapy in adult asthmatics40 but is more effective than placebo at relieving symptoms in children.41 Several studies (e.g. Yurdakul et al.42) and a Cochrane meta-analysis43 have shown that ICS therapy is more effective than theophylline for monotherapy of mild, persistent asthma. In addition, the US guidelines do not recommend the use of theophylline in children up to the age of 11 years, while acknowledging that it may be contemplated on economic grounds or when compliance with inhaled medication is poor.
Beyond inhaled corticosteroids alone – further therapeutic options (1): addition of a long-acting β2-agonist (LABA)
In adults with mild persistent asthma insufficiently controlled with moderate dosages of ICS alone, all guidelines agree that adding a long-acting β2-agonist (LABA), rather than further increasing ICS dosages initially, is the preferred course of action. Addition of a LABA to a daily regimen of ICS reduces day and night symptoms, improves lung function, reduces rescue medication usage, reduces exacerbations and achieves clinical control of asthma in more patients, more rapidly and at a lower final dosage of inhaled ICS than increased dosages of ICS given alone.12,44–49 There is a paucity of studies on the effects of LABAs in children, particularly under the age of 5 years. Although the UK guidelines still recommend LABAs as the first-line add-on therapy to ICS in children from the age of 5 years, the GINA guidelines recommend LTRAs as an alternative and the US guidelines conclude that there is insufficient evidence at present to know whether adding in a LABA or increasing ICS dosages is best. All guidelines agree that LABAs should never be given without ICS. This follows a study50 reporting a small but significant excess of deaths in asthmatics receiving daily treatment with salmeterol compared with placebo added to their usual asthma therapy, the implication being that masking of symptoms with LABAs while avoiding ICS is potentially dangerous. For this reason, combination inhalers containing ICS and a LABA, although no more or less effective than taking the two drugs in separate inhalers, are preferable when prescribing LABAs because they ensure that LABAs can never be taken without ICS.
In addition, it is important to note that many patients with mild, persistent asthma are adequately controlled on ICS therapy alone. In these patients, adding in a LABA is of no additional benefit.51,52 The UK guidelines stress the fact that in patients with stable asthma controlled by ICS, no intervention has been shown to reduce this requirement. Consequently, physicians should not be tempted to use combination therapy too hastily.
Beyond inhaled corticosteroids alone – further therapeutic options (2): addition of a leukotriene receptor antagonist (LTRA)
Several studies53,54 have confirmed that that LTRAs are also sparing of ICS. A Cochrane meta-analysis55 comparing the addition of a LABA with the addition of a LTRA in asthmatics who were inadequately controlled on moderate to high dosages of ICS reported that LABAs were superior to LTRAs in preventing exacerbations requiring systemic steroid therapy, improving lung function and reducing symptoms and the use of rescue medication. Thus, the major guidelines recommend LABAs as a first line add-on therapy before LTRAs in adults and older children, although, in infants, in whom there is a paucity of evidence of the effectiveness of LABAs, a LTRA would seem a more legitimate alternative.
Beyond inhaled corticosteroids alone – further therapeutic options (3)
Beyond using inhaled ICS therapy with a LABA or LTRA, all guidelines become vague because of lack of extensive evidence about the management of patients who retain chronic, severe symptoms despite moderate dosages of ICS with a LABA and/or a LTRA. Most guidelines advocate increasing inhaled ICS dosages to the maximum level (essentially that which may have systemic effects equivalent to low dosages of oral corticosteroids) and experimenting with one or more of the anti-asthma drugs discussed here, hopefully to investigate their individual and combined impact on symptoms and disease control. It is particularly important to scrutinize compliance, inhaler technique and comorbidity in these therapy-resistant patients. Ultimately, patients may have to be maintained on regular oral corticosteroids such as prednisolone or prednisone, which is undesirable because systemic corticosteroid therapy is more likely to cause systemic unwanted effects (weight gain, osteoporosis, hypertension, diabetes). Such patients should be maintained on maximal inhaled therapy, which minimizes the need for these systemic corticosteroids and maximizes the chance that they can be discontinued again in the future.
Future possibilities for asthma care
Therapy for severe asthmatics who retain symptoms despite taking medications reliably remains a challenge. The emphasis now is on searching for ‘endotypes’ of asthma – subcategories of the disease with common pathogenetic/molecular mechanisms to which new treatments may be specifically addressed. Omalizumab, a humanized, monoclonal immunoglobulin G anti-immunoglobulin E (IgE) antibody that binds to the constant region of IgE and thereby prevents it from binding to high- and low-affinity IgE receptors on cells such as mast cells and basophils, has been effectively used in atopic asthmatics to reduce the number of acute disease exacerbations in both children56 and adults;57 however, it is less impressive in reducing everyday symptoms and enabling reduction of anti-asthma medication. About 20% of treated patients do not respond for reasons that are still not clear, as its precise mechanism of action is unknown. There has existed circumstantial evidence for many years that eosinophils play a role in asthma pathogenesis and that strategies targeting interleukin-5, the cytokine that acts specifically on eosinophil precursors in the bone marrow to promote their development and ingress into tissues, are of benefit at least in a subgroup of severe asthmatics and, again, most obviously in reducing disease exacerbations.58 Similar studies targeting interleukin-4 and interleukin-13, cytokines that can switch B cells to IgE synthesis and promote mucus secretion and remodelling of asthmatic airways, which may, in turn, cause irreversible obstruction, have been less impressive, although subgroups of patients do appear to respond.59 The problem with this ‘try it and see’ approach is that these molecular targets have not yet been clearly tied to the fundamental clinical pathology of asthma described above. Future research will hopefully clarify these issues.
Another approach to the management of chronic severe asthma has been to reduce the bulk of hypertrophied smooth muscle in the airway using thermal energy applied in an outpatient setting through a bronchoscope. Initial data are promising60 in terms of reducing disease exacerbations in severe asthmatics although the procedure is time-consuming and it remains to be clarified whether or not the benefits outweigh any possible longer-term effects of the procedure and whether or not the procedure is cost-effective overall.
Hyper-responsiveness of asthmatic bronchial smooth muscle cells to a wide range of agonists is clearly unlikely to reflect upregulation of receptors for every possible agonist. More sense has been made of this phenomenon recently from the observation that asthmatic bronchial smooth muscle cells abnormally express proteins that regulate intracellular calcium homoeostasis and, thereby, the resting intracellular free calcium concentration. Thus, smooth muscle cells regulate the force with which they will respond to any stimulus that causes a transient intercellular calcium flux, which, in turn, triggers contraction. For example, deficiency of expression of the sarcoplasmic/endoplasmic reticulum calcium-transporting ATPase protein has recently been implicated61 in raising baseline intercellular calcium in asthmatic smooth muscle cells. Another protein that regulates intracellular calcium in smooth muscle cells is the calcium-sensing receptor: a pleiotropic G-protein-coupled receptor that plays a fundamental role in mineral ion metabolism.62 Although extracellular calcium ions are the physiological ligand for this receptor, it is also activated by a range of polycations elevated in asthma such as poly-l-arginine, poly-l-lysine and spermine. The receptor may be antagonized by drugs that are already in existence. Interestingly, eosinophil basic proteins, such as eosinophil cationic protein, are also polycations and, if eosinophil basic proteins have the propensity to ‘reset’ resting intracellular calcium in asthmatic airway smooth muscle cells, this would provide the first clear link between eosinophilic inflammation in asthma and one of the cardinal facets of its pathophysiology.