Introduction: the problem of poor asthma control

Asthma has a high prevalence throughout Europe and the industrialised nations, with increasing prevalence in developing economies probably as a consequence of life style changes.1,2 For a variety of (often correctable) reasons many people with asthma do not gain full control of their condition,3 and there are marked variations in outcomes of care between hospitals and between primary care practices.4,5 The only example of a systematic national approach to the management of asthma (in Finland) demonstrated significant patient benefit coupled with large cost savings.6 This programme was based on education of healthcare professionals and promotion of self-management, with the aim of achieving accurate diagnosis and high quality structured management.

The SIMPLES approach to poorly controlled asthma

SIMPLES is a structured approach to the review of a person with uncontrolled asthma which encompasses self-management education monitoring, lifestyle and pharmacological management and addressing support needs. See Table 1 for a summary of the components of SIMPLES.

Table 1 The SIMPLES approach to the primary care management of ‘difficult to manage’ asthma
Full size table

After a succession of structured reviews over a short time frame, most patients' asthma will have been brought under control. Those who have not achieved control by this process are identified as needing referral to specialist care for further evaluation. Some of these patients will have severe or atypical ‘therapy resistant’ asthma (see the first case study), some will have psychosocial problems which make it difficult for them to achieve asthma control (see the second case study) and some may prove to have an alternative diagnosis driving their symptoms.7 If the diagnosis is in doubt, spirometry performed while the patient is symptomatic should confirm reversible obstruction. Referral for a bronchial challenge test or assessment of airway inflammation may be needed.

Regular review and self-monitoring

Ideally monitoring should be undertaken both by a healthcare professional during regular planned and structured reviews, and by daily self-monitoring (of symptoms and/or peak expiratory flow, as preferred) by the patient. These overlap, of course, as self-monitoring should always be supported by the healthcare team during structured reviews at a frequency appropriate to the patient's needs.8 Ease of access in times of crisis is also important, to ensure that exacerbations are identified and treated early.

In order to self-monitor effectively the patient needs to have an accurate understanding of their condition after receiving education about various aspects of asthma and its management. The literature on self-management education stretches back over some thirty years. The single most consistent finding is that patients who receive structured education and have a written personalised plan have a significant reduction in exacerbations or hospital admissions.8

The advent of telehealth and internet-based applications may help improve outcomes by enabling real-time support for self-monitoring.9 A recent study of self-monitoring using traditional paper charts or recording data on a mobile phone and receiving instantaneous feedback did not demonstrate a difference in control between the groups, though patients in both groups demonstrated a clinically meaningful improvement in asthma control.10 Comprehensive internet-based guided self-management improved asthma control, with more patients achieving a clinically significant improvement than in the usual care group.11 Recently, the utility of mobile phone technology to identify exacerbations of asthma has been demonstrated.12 Improving technology may produce a digital solution which can be used to support patients with ‘difficult to control’ asthma in gaining and maintaining control.

Pharmacotherapy

Asthma guidelines recommend a stepwise approach to the treatment of asthma.13,14 The aim is to achieve and maintain control by stepping up treatment as necessary and stepping down when control is good. A decision to increase treatment should not be made until it has been confirmed that a person can demonstrate optimal inhaler technique, has access to and is taking their treatment as recommended, and is taking adequate measures to avoid allergens and triggers.15 Correcting these factors can often improve asthma control and prevent unnecessary escalation of treatment.16–19

Non-adherence to inhaled corticosteroids (ICS) is a common cause of poor asthma control.20 For many reasons (including lack of understanding of the roles of different forms of therapy, fear of steroids, financial concerns) only 30–70% of patients take preventative therapy as instructed.21 Many patients forget to take one or more doses each day or stop taking their preventative inhaler when they feel better, only to have a recurrence of asthma symptoms a few weeks later. Identification of non-adherence is fundamental to managing apparently refractory disease. Medication adherence can be improved by providing information on treatment, allaying fears, and negotiating with the patient as to how they can take their therapy taking into account their individual lifestyle.18,19

Resources

As part of an initiative on ‘difficult to manage asthma’,22 the International Primary Care Respiratory Group (IPCRG) has produced a desktop helper with the SIMPLES checklist and a number of other tools to support primary health care professionals in their daily practice. This and other useful resources are given in Table 1.boxed-text

Difficult to manage asthma in adults is a challenge.23 Even if this case history is not the most common among asthma patients in primary care practice it is still not unusual. The review of a patient with difficult to manage asthma includes evaluation of several factors: the SIMPLES approach provides a helpful checklist.

Medical history: co-existing conditions

It is important to review the clinical history. The patient is a non-smoker. Does she have any other co-existing conditions or co-morbidities which may have an impact on her asthma control?

  • Non-steroidal anti-inflammatory drugs and aspirin intolerance are recognised causes of severe asthma and often overlooked. In clinical practice it is not unusual that asthma patients have been prescribed an oral β-blocker for hypertension or ischaemic heart disease, or topical β-blockers for glaucoma which may worsen their asthma.

  • Cough may be an indicator of gastro-oesophageal reflux, but the relationship between reflux and poorly controlled asthma is not clear.24 Treatment with proton-pump inhibitors does not improve asthma control in patients with asymptomatic reflux.25

  • It is also important to consider allergic and non-allergic triggers which may worsen her asthma. Asthma and rhinitis frequently coexist and if this patient has symptoms of rhinitis it will be important to treat the rhinitis according to guidelines.26 This is important, as both rhinitis and asthma symptoms could be aggravated by allergies. Allergy testing may help confirm or refute a suspected allergic cause for her poor control.

  • Another cause which needs to be considered is occupational asthma,27 though this is unlikely in this lady who is a teacher.

  • Looking for dysfunctional breathing and other conditions such as vocal cord dysfunction and bronchiectasis is also important as they may contribute to asthma-like symptoms.28,29

Monitoring asthma control

Assessing the patient's asthma control is important. There are several tools which are easy to use — for example, the RCP 3 Questions30 — which have been tested in clinical practice.31 Other common validated questionnaires are the Asthma Control Test (ACT) with five questions assessing symptoms over the last four weeks,32 the Asthma Control Questionnaire (ACQ) with seven questions about symptoms in the last week,33 and CARAT, a 10-question test assessing the control of both allergic rhinitis and asthma in the last four weeks.34 In their clinical review in this issue of the PCRJ, Blakey et al. discuss the importance of not only assessing asthma control but also the future risk of asthma attacks.35

In this case, the patient's history of frequent exacerbations and frequent use of relievers not only indicate uncontrolled asthma but also a significant future risk of further exacerbations despite a high treatment level. Self-management education supported by a personalised asthma action plan and an emergency supply of oral steroids is an important aspect of this lady's care.8,13,14

In patients with difficult to manage asthma and persistent exertional breathlessness such as this lady it is important to look for fixed airflow obstruction (usually related to airway remodelling or smoking) which may not be responsive to treatment escalation.36 In this case, the post-bronchodilator FEV1 four years ago could not be reversed to normal suggesting that this might be a problem. Up-to-date spirometry would be helpful to assess any deterioration in fixed airflow obstruction.

Inhaler technique

This patient has uncontrolled asthma despite ‘step 3’ treatment,13,14 and she assures her doctor that she uses her inhalers regularly (although this should be confirmed by assessing the refill prescribing record, as patient report may be unreliable). There is evidence that many patients are unable to use their inhalers correctly, regardless of the device. Poor inhaler technique is associated with poor asthma control.37,38

Guidelines recommend that inhaler technique should be checked in all patients, particularly those with uncontrolled asthma,13,14 and this is highlighted in the SIMPLES tool. Inhaler technique training is a cornerstone in the management of all patients with asthma in order to ensure optimal therapy,39 with a range of different possibilities in the choice of inhaler.40

Pharmacotherapy

Before evaluating whether the patient is treated at the right step to achieve control, the SIMPLES approach recommends discussing both adherence and understanding of the treatment. The teacher in this case had no specific reasons for her poor control so a step-up in treatment should be considered. There are several treatment options at step 4: increasing ICS up to a daily dose of 1,000 μg fluticasone (FP) or equivalent, adding a leukotriene receptor antagonist (LTRA), or treatment with a theophylline.13,14 If a trial of additional treatment is ineffective it is important to stop the add-on treatment or reduce the dose of ICS to previous levels to minimise the risk of systemic side effects. Considering the safety profile of ICS is important. Doses up to 400 μg daily FP or equivalent are regarded as having minimal long-term side effects, whereas patients treated with higher doses of ICS for a longer period or with repeated courses of oral corticosteroids have an increased risk of steroid-related adverse effects.13,14

There is increasing evidence that abnormalities in the small airways may contribute to severity of disease. A recent systematic review showed that small-airways dysfunction was associated with worse asthma control and suggested that treatment with extra-fine particle ICS could improve symptoms and asthma control in those patients with small-airways disease.41 This may be another option for treatment in this lady.boxed-text

This man attends frequently for healthcare but when he does he is in crisis and it is often too late for primary care management alone. These emergency visits will inevitably focus on acute management but attempts should also be made to engage him in a follow-up visit in order to work through the reasons for his loss of control. Creating an opportunity for a holistic review should be a key aim, since planned care with a GP when asthma is stable can improve asthma control.42 UK standards now recommend booking a review by a GP within 48 hours of an unplanned asthma event.43 A key component of the review will be the provision of a personalised action plan.

In the presence of such complexity the use of the SIMPLES algorithm can support a comprehensive overview that can be followed up with focused appointments about the identified adherence and precipitating factors.

Smoking cessation

Smoking worsens asthma symptoms, increases exacerbations and hospitalisations and is associated with an increased risk of mortality.44,45 This man has received or is currently receiving pharmacotherapy for conditions known to worsen asthma such as nasal allergy and depression or anxiety, but there is no evidence that he has received smoking cessation medication and this may be a potential blind spot when considering treatment of exacerbating factors. The last recorded smoking status in this patient was six years previously with no record of an intervention to support his quit attempt. This could have been a result of his failure to attend planned care but could also be due to the health professionals' attitudes or beliefs about the effectiveness of smoking cessation in highly addicted smokers who persist despite the effect on their illness.46

Stopping smoking can both decrease the risk of future disease and help improve his current control.47 This man is at risk of fixed airways disease (COPD) because of the combination of poor control and smoking.48 In this (and at every appropriate) general practice consultation we need to provide brief advice using behavioural change techniques. This involves assessing current and past smoking, possibly monitoring carbon monoxide levels, advising on effects of continued smoking, explaining briefly how stop smoking treatments work and then initiating appropriate pharmacotherapy and arranging future support. Patients expect and are happy to be asked this in a healthcare setting.49

One of the benefits of stopping smoking — and an important factor to communicate to this man — is that lower doses of ICS may then be effective. Tobacco smoke inhibits the effect of steroids on airway inflammation so that smokers require escalating doses of ICS, putting them at risk of systemic steroid effects. His combined steroid use from nasal, inhaled and oral routes currently exceeds 1000 μg FP equivalent per day and he should therefore be provided with a steroid card. Whilst working with this man to help him quit smoking there is some evidence that other medicines such as LTRAs, inhaled anticholinergics and LABAs may improve asthma outcomes in smokers.50–53

Lifestyle factors

The SIMPLES checklist reminds us to explore lifestyle factors and for this man there is some evidence that his work may be important. He asks for a sick note at the same time as a crisis. A number of factors may play a part, such as work stress that may be exacerbating anxiety or depression, or he may have specific occupational exposure from which he needs to be removed. Removal from, or reduced exposure to, an occupational trigger should improve control (especially if it is initiated soon after the onset of sensitisation). It is important to balance the clinical benefit against the social or psychological harms that may arise from the risk of unemployment that follows a diagnosis of occupational asthma.54

Psychosocial problems

Depression is associated with difficult asthma and the record of citalopram prescribing suggests he has been treated for this condition. Support for this man therefore needs to be considered from a number of perspectives such as depression, work and smoking. We know that low levels of health-related quality of life in asthma are associated with current or past smoking history, severity of symptoms and absence from work.55 As a clinician it is possible to support him not just through direct medical care but also through signposting to support that may be available locally. This might include a counselling service, a health trainer, online and telephone support from organisations such as patient charities. However, patients may also have personal resources locally that they have not considered using. How can family, friends, neighbours or even work colleagues be utilised to support him? Has he told them what is happening and could you help him consider resources close to home?

Referral to the ‘difficult asthma’ clinic

When should a referral be made?

The substantial majority of patients with asthma can expect minimal breakthrough symptoms on standard doses of ICS therapy with or without additional add-on therapies. In the primary care setting, a ‘red flag’ strategy of proactively identifying and systematically reviewing patients who are prescribed treatment at Step 4 or 5,13,14 particularly those who fail to achieve symptom control or have recurrent ‘exacerbations’, should be applied. This will prevent inappropriate escalation of treatment and identify patients who should be assessed in more detail, both within the primary care setting or with referral to a difficult asthma service.

The small group of patients presenting with persistent asthma symptoms despite being prescribed high levels of treatment are often referred to as having ‘difficult asthma’. A pragmatic definition of difficult asthma is persistent respiratory symptoms despite treatment with a LABA and high dose ICS (≥1000 μg FP equivalent) which equates to people who remain symptomatic at step 4 or requiring treatment at step 5 of guidelines.13,14 It is important to differentiate the term ‘difficult asthma’ from ‘therapy-resistant asthma’ or ‘severe refractory asthma’; these latter terms encompass patients who are relatively treatment resistant and generally require high doses of steroid therapy or additional biological treatments to achieve control, whereas patients with ‘difficult asthma’ often have more therapy-responsive disease but may have different factors which cause them to have persistent symptoms.23,56,57

What can a ‘difficult asthma’ clinic offer?

The initial phase of assessment in a ‘difficult asthma’ clinic involves addressing the fundamental issues using a systematic approach, and a series of key questions about accuracy of diagnosis, medication adherence and inhaler technique, and potentially modifiable aggravating factors which should be considered before committing patients to further high dose treatment (see Table 2).

Table 2 Potentially modifiable aggravating factors which should be considered before escalating treatment
Full size table

In the ‘difficult asthma’ clinic, these issues are systematically identified and managed by the multi-disciplinary team;23,56,57 this can include trials of therapy along with more detailed investigation such as detailed lung function, high resolution CT scanning, measures of airway inflammation (e.g. induced sputum, exhaled nitric oxide), psychological assessment and management with either medication or clinical psychology input, echocardiography, cardiopulmonary exercise testing, plus other investigations as required. Clinical assessment with spirometry during an episode of worsening symptoms can help to distinguish patients with worsening asthma from other conditions causing increased breathlessness, as this can sometimes be the reason for acute events unresponsive to asthma treatment.

Specific conditions

Specific problems such as vocal cord dysfunction, dysfunctional breathing, and bronchiectasis will be managed with appropriate multi-disciplinary input, along with optimisation of asthma therapy (if appropriate) to try and achieve symptom control.

After thorough evaluation and management, some patients will have ‘refractory asthma’, which is defined as persisting asthma symptoms despite adherence with high dose treatment. These patients often have a propensity to asthma exacerbations, with frequent use of courses of oral corticosteroids despite prescription of add-on therapies e.g. LTRAs or theophylline, and may require maintenance oral corticosteroids.58,59 In general, following systematic evaluation and a detailed assessment, between one-third and a half of patients with ‘difficult asthma’ will have therapy resistant disease, with other diagnoses, co-morbidities, non-adherence or psychosocial factors explaining symptoms in the others.19,56

Therapeutic options

There are a number of therapeutic options available in refractory asthma. For some patients, low dose maintenance oral corticosteroid therapy is well tolerated and effective, but for many, systemic steroid therapy either causes significant side-effects or does not produce disease control, and some patients display steroid insensitivity.

Current therapeutic options for such patients include:

  • Immunomodulatory corticosteroid-sparing drugs such as methotrexate, cyclosporin and gold. These agents have marked variability in efficacy, may result in significant adverse effects and benefits do not persist after stopping treatment.14 Guidelines recommend that these medications should be reserved for patients who have not responded to usual treatments, and that risks and benefits should be closely monitored.13,14

  • Omalizumab. This humanised monoclonal antibody reduces free IgE by almost 95% by blocking the binding of IgE to its specific high-affinity receptor.60 Over 50% of patients with refractory asthma have allergic IgE-mediated disease,59 and omalizumab is a therapeutic option for those patients with serum IgE levels in the range 30 to 1500 IU/ml. Anti-IgE therapy is recommended by guidelines for patients at step 513,14 and is administered by subcutaneous injection at 2- or 4-weekly intervals. Due to the high cost of this treatment, different countries have specific criteria to maximise benefit in selected populations of patients. Treatment should be initiated only after specialist assessment, should be monitored closely, and discontinued if it is not beneficial.

  • Inhaled long acting anti-muscarinic agents (LAMAs). Recent data with tiotropium shows some additional benefit in patients already prescribed LABA/ICS with persistent symptoms and airflow obstruction.61 In the next few years other ultra-long-acting LAMA and LABA preparations will become available and will require evaluation in severe asthma.

  • Bronchial thermoplasty is a technique that involves the delivery of radio frequency energy to the airways during bronchoscopy with the aim of reducing airway smooth muscle mass and responsiveness in asthma.62 Several studies have demonstrated efficacy and safety for this treatment in selected patients,63 but the degree and duration of benefit, and which patients with severe asthma will benefit most, remain to be clearly established.

  • Novel biological agents which will target ‘Th2 inflammation’ (elevated interleukin-4, interleukin-5 and interleukin-13) and are likely to be available in the next 2 – 3 years.64–66 Although there is likely to be some overlap with the population suitable for omalizumab, these new therapies are not specifically targeted at allergic disease. A ‘stratified’ approach to severe asthma, which focusses on targeting complex therapies at patients with the appropriate inflammatory phenotype is likely to be a core component of work in the severe asthma clinic in the future.67

  • Anti-fungal therapy may have a role in patients with chronic allergic bronchopulmonary aspergillosis (ABPA) and other fungally-sensitised severe asthma patients.68,69

How can the primary care physician help support care? — the ideal referral letter…

As with many conditions, the assessment and control of patients with difficult asthma can be optimised with a close cohesive partnership between primary and secondary care. Many of the initial questions around diagnosis, adherence and co-morbidity can be addressed in primary care and this detail can be covered in the referral letter. This will provide much of the information required in the initial assessment in the difficult asthma clinic. By way of example, a referral letter with much of the relevant detail is presented in Figure 1.

Figure 1
figure 1

An exemplar referral letter

Full size image

Conclusion

‘Difficult to manage’ asthma is not in itself a diagnosis but is a clinical problem which is clearly defined and which requires detailed assessment as outlined above. The SIMPLES approach, aligned with close co-operation between primary and specialist care, can identify this patient group, avoid inappropriate escalation of treatment, and streamline clinical assessment and management. Some patients will have severe refractory asthma. Novel therapies, many with companion disease biomarkers to allow targeting of these therapies to the correct patient, will be available in the difficult asthma clinic in the coming years.