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Strategies for asthma management: what are the options?

Dr Runa Ali
BSc PhD FRCP
Consultant Physician in Respiratory Medicine and Allergy
London Chest Hospital
Barts and the London NHS Trust

Figures indicate that 1,400 people die from asthma each year in Britain, with 34% of these under the age of 65. This is because one in four of our asthma patients are undertreated. This article reviews the recent changes in guidelines for asthma and provides an understanding of the mechanisms of the condition.

Asthma is a major long-term condition affecting around 15% of our population, and the UK has one of the highest rates of asthma and allergic diseases in the world. The average primary care trust (PCT) will have around 45,000 patients with diagnosed asthma, costing around £4.5m per year for their care, and each PCT will have 400 or more emergency asthma admissions per year to hospital.

The British Thoracic Society (BTS) guidelines for asthma management were updated in May 2008 and revised further in June 2009.1 This article reviews the recent changes in the guidelines, discusses current controversies at Step 3, and provides an understanding of the mechanisms of asthma.

Asthmatic reactions
An asthmatic reaction may occur when an allergic individual who is carrying an antibody, immunoglobulin E (IgE), against an allergen, such as pollens or cat dander, inhales that substance. This causes mast cells in the airways to release inflammatory chemicals, including histamine causing an early (or acute phase) asthmatic reaction.

Typically, patients experience narrowing and swelling of the airways, leading to cough, breathlessness and wheezing. This happens immediately, peaking at 15 minutes and resolving within an hour. Some asthmatics experience a second wave of symptoms six hours later known as the late phase reaction, due to further inflammation. This can lead to bronchial hyperreactivity for a further week or more, where patients cough and wheeze in response to non-specific triggers.

Importance of controlling inflammation
Not all asthma is due to allergy. "Non-allergic" or "intrinsic" asthma tends to affect adults rather than children and adolescents; but even here, inflammation is a hallmark. Uncontrolled inflammation in either "intrinsic" or "extrinsic" (allergic) asthma causes recurrent symptoms and may also lead to chronic irreversible changes with microscopic re-sculpting of the airways (so-called "airway remodelling"). Permanent limitation of lung function and activity may occur.
So many of our patients are unaware that their preventer inhalers are anti-inflammatory treatments and that use of a blue inhaler alone will not protect against long-term damage.

Diagnosis
There are many definitions of asthma. The Global Initiative for Asthma (GINA) was formed in collaboration with the World Health Organization (WHO) and they term asthma as "a chronic inflammatory disorder of the airways, with airway hyper-responsiveness, recurrent episodes of wheezing, coughing and shortness of breath, widespread, variable and reversible airflow limitation". Because of the varying definitions available, the BTS acknowledge that diagnosis of asthma is a clinical one, relying on a combination of characteristic symptoms, backed up by suggestive changes in lung function tests.

History
An increased or decreased probability of asthma is suggested by certain features (Tables 1 and 2). Following this, spirometry should be performed to assess the presence and severity of airflow obstruction. Airflow obstruction is indicated by a Forced
Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity (FVC) ration of

[[Tab 1 asth]]

Reversibility testing with a bronchodilator and a trial of treatment are warranted in those with high probability, and also intermediate probability with an obstructive ratio (Figure 1). Reversibility testing involves measurement of the FEV1 (or PEF) and/or symptoms before and after 400 mg inhaled salbutamol. In other patients, or if there is an incomplete response to inhaled salbutamol, measure after either inhaled corticosteroids (200 mg twice daily beclomethasone equivalent for six to eight weeks) or oral prednisolone (30 mg once daily for 14 days). There should be >400 ml increase in FEV1 to indicate definite reversibility.

[[Fig 1 asth]]

Once you have completed your assessment, if you still remain uncertain about the diagnosis, consider specialist referral. The BTS guidelines provide a list of criteria to help you decide. If asthma is still suspected, the next step in secondary/tertiary care is a bronchial provocation test. This is a measure of airways hyperreactivity and involves the patient inhaling increasing concentrations of a nebulised bronchoconstrictor agent eg, histamine or metacholine and assessing for ≥20% decrease from the baseline FEV1.

Non-pharmacological management
Treatment is begun once the diagnosis of asthma is made. Don't forget to start with non-pharmacological strategies where appropriate, for example, smoking cessation, weight reduction and allergen avoidance if appropriate (see Resources for useful websites).

Pharmacological treatment
Drug treatment should be initiated at the step most appropriate to the severity of asthma, rather than Step 1. Control may be improved by stepping up further as needed. Remember to step down when control is good; and before making a change, check compliance with existing therapies, inhaler technique and eliminate trigger factors if appropriate.

Remember to tell patients to gargle after inhaled corticosteroids (ICS) and prescribe spacers for very high doses of ICS, to reduce oropharyngeal deposition and lessen the side-effects of oral Candida or hoarseness of the voice (from weakened vocal cords). Higher doses of ICS may be needed in smokers/ex-smokers due to impaired absorption across the lung. When prescribing fluticasone remember that it is twice as potent as the other ICS, so the dose is half that of beclomethasone or budesonide.

Step 3
The main change in guidance is that at Step 3, addition of a long-acting beta2-agonist (LABA), such as salmeterol or formoterol, is advised before going above a dose of 400 mg beclomethasone diproprionate (BDP) or equivalent per day.

This recommendation has been backed by the National Institute for Health and Clinical Excellence (NICE). Research has demonstrated that the increase in mean morning peak expiratory flow is significantly greater using a LABA and ICS than using a high dose of ICS.2 Furthermore, meta-analysis has indicated that addition of salmeterol to ICS significantly reduces the proportion of patients with an exacerbation.3

There is no difference in efficacy between use of a combination inhaler containing an ICS and LABA versus separate inhalers, but a combination device is more convenient and also guarantees LABAs are not taken alone, thus avoiding potential side-effects.

Current controversies at Step 3: what are the options?
Fixed dosing
The standard approach at Step 3 is fixed dosing with preventers, with clinician review to adjust treatment. This approach has proven efficacy as shown in the Gaining Optimal Asthma Control (GOAL) study, which examined whether GINA guideline-defined asthma control could be achieved using fixed dosing with either fluticasone propionate or salmeterol/fluticasone.4 The majority of the 3,421 patients achieved control with the greatest result - 75% - in patients in the combination group who had been on just a low dose of ICS before entering the study.

Adjustable maintenance dosing (AMD)
Adjustable maintenance dosing (AMD) regimens were developed as a means of minimising the overall amount of ICS used. In this method, the dose of the combination preventer is adjusted following a set protocol according to symptom severity by patients themselves. An additional short-acting beta2-agonist (SABA), such as salbutamol, is still provided as
reliever medication. Open label studies of AMD vs fixed-dose, both with budesonide/formoterol, have shown reduced asthma exacerbations with AMD.

However, the CONCEPT trial, which was a one-year, double-blind trial of 688 patients, found that fixed dose salmeterol/fluticasone had significantly greater increases in: symptom-free days, days free of rescue medication and morning PEF, and almost halved asthma exacerbation rate when compared to AMD of budesonide/formoterol.5 But the mean daily ICS consumption was higher in salmeterol/fluticasone group, suggesting that a critical minimum daily amount of maintenance therapy may be necessary to prevent exacerbations than can be delivered by AMD.   

SMART (single maintenance and reliever therapy)
This is the newest strategy available and mentioned in the BTS guidelines. In selected adult patients at step 3 who are poorly controlled or selected adult patients at step 2 (above BDP 400 mg/day who are poorly controlled), use of budesonide/formoterol in a single inhaler as a regular preventer treatment, plus additional use as a reliever (instead of an addtional SABA), can be considered.

Potentially, this is much more convenient for patients who can self-manage reliably and perhaps also for those non-adherent patients who would only ever use their blue inhaler and never receive any anti-inflammatory treatment. But is it effective? A Cochrane review in 2009 found SMART as effective as fixed dosing in controlling the exacerbation rate; however, a recent bronchoscopy study found less inflammation in the fixed dosing group.6 The debate continues …

Monitoring asthma in primary care
Once the diagnosis is establised, regular check-ups in primary care should include:

  • Symptomatic asthma control using the Royal College of Physicians (RCP) "three key questions".
  • Asthma Control Questionnaire or Asthma Control Test (ACT™).
  • A test of lung function (spirometry/PEF).
  • Exacerbation rate.
  • Inhaler technique.
  • Compliance (prescription refill frequency).
  • Bronchodilator reliance (prescription refill frequency)
  • Possession and use of a self-management plan/personal action plan.

Don't forget to step down your fixed dose patients. This is often not implemented, leaving some patients overtreated. Consider this in stable patients every three months, decreasing the dose of ICS by approx 25-50% each time.

If a trial of a drug is ineffective, stop the drug (or reduce dose to original dose if ICS). If uncontrolled on Step 4, prescribe daily steroid tablets in the lowest dose providing adequate control and maintain a high dose ICS at 2 mg/day. It is vital the patient is referred for specialist care at this stage and considered for other treatments to minimise the use of steroid tablets eg, omalizumab (Xolair®). This is a monoclonal antibody, given by subcutaneous injection, which binds to IgE in the blood, thus reducing the number of allergic asthmatic reactions.

Summary
Asthma affects a significant proportion of our population. Making the correct diagnosis is based on the presence of characteristic symptoms and variable airflow obstruction, with spirometry the preferred initial test. Treatment focuses on controlling inflammation and, at Step 3, adding in a LABA to ICS is the preferred choice. There are various ways of using a combination inhaler: fixed, adjustable or SMART dosing - but careful patient education is the key to success in all of these. l

References
1. British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN). British Guideline on the Management of Asthma. A national clinical guidelines. London: BTS; 2009.
2. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344(8917):219-24.
3. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320:1368-73.
4. Bateman ED, Boushey HA, Bousquet J et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 2004;170(8):836-44.
5. FitzGerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter, randomized, double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Clin Ther 2005;27(4):393-406.
6. Pavord ID, Jeffery PK, Qiu Y et al. Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol. J Allergy Clin Immunol 2009;123(5):1083-9.

Resources
British Thoracic Society
W: www.brit-thoracic.org.uk

British Society for Allergy & Clinical Immunology (for healthcare professionals)
W: www.bsaci.org

Allergy UK (for patients)
W: www.allergyuk.org