Commissioned by Napp Pharmaceuticals Limited

This consensus discussion was commissioned by Napp Pharmaceuticals Limited in partnership with Guidelines in Practice. Napp Pharmaceuticals Limited has reviewed the supplement for factual accuracy, to ensure it is fair and balanced, and to ensure its compliance with appropriate regulations. The sponsorship fee included the honoraria for the contributors. Please see bottom of page for full disclaimer.

20180531 Asthma consensus

BTS/SIGN and NICE guidelines on asthma: similarities and differences and the implications for best practice in the pharmacological management of asthma in adults in primary care

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Consensus group members

  • Professor James Chalmers (chair), Professor of Respiratory Research and Consultant Respiratory Physician, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee
  • Dr Kevin Gruffydd-Jones, GP Principal, Box Surgery, Corsham
  • Dr Steve Holmes, GP, The Park Medical Practice, Shepton Mallet; PCRS-UK education lead
  • Vikki Knowles, Respiratory Nurse Consultant, Guildford and Waverley CCG; PCRS-UK executive member
  • Dr Anna Murphy, Consultant Respiratory Pharmacist, University Hospitals of Leicester NHS Trust; Visiting Professor at De Montfort University.

 

Introduction

In 1999, the British Thoracic Society and Scottish Intercollegiate Guidelines Network (BTS/SIGN) published their first joint guideline on asthma, with the aim of providing clear guidance for clinicians on how to manage patients with asthma using evidence-based methods.1 The BTS/SIGN guidance has been updated regularly since then, with the most recent update, SIGN 153, released in September 2016.1 NICE published its first guideline on asthma, NICE Guideline 80, in November 2017.2,3

Although the NICE and BTS/SIGN guidelines are broadly similar in the advice given, there are important differences in content and emphasis, and the BTS/SIGN guideline covers some topics not considered or only mentioned peripherally by NICE and vice versa. 

Where BTS/SIGN aim to cover the majority of clinical questions in the management of asthma including special situations such as asthma in pregnancy and the management of acute exacerbations, NICE has a more limited focus in terms of content compared with BTS/SIGN. The NICE guidance excludes any mention of biologics, which are covered separately by technology appraisals,4–6 likely due to the publication timeline, as only omalizumab would have been licensed when the initial NICE process for this guideline began. The NICE guidance includes the additional element of a health-technology appraisal, which evaluates the cost-effectiveness of interventions for healthcare systems.3 While the BTS/SIGN guidance might be considered a pragmatic best practice guideline for immediate implementation, the NICE guidance is more aspirational in nature, considering how CCGs and acute trusts may look to manage asthma in the near future.

Despite broad similarities between the two guidelines, the main differences are substantial and in areas of particular importance to primary care clinicians—namely diagnosis and prescribing. The availability of two guidelines with different recommendations for the management of asthma in the UK is potentially confusing. Healthcare professionals may feel pressured to implement the more aspirational NICE guidance, as it is perceived to have greater influence and policymakers see NICE guidance as an opportunity for standardisation. 

An expert consensus group was therefore convened to:

  • discuss the implications of similarities and differences between the latest BTS/SIGN and NICE guidance
  • develop consensus recommendations to support healthcare professionals understand and implement best practice in the pharmacological management of asthma in adults in primary care.

Healthcare professionals should note that the guidelines differ on definitions for adults, with BTS/SIGN using 12 years as a threshold compared with 17 years in the NICE guideline;1,3 for the purposes of these consensus recommendations, the age of adults has not been precisely defined, as children do not transition into adults overnight, and prescribers are therefore encouraged to use their clinical judgement and to refer to the relevant summary of product characteristics for licensed indications. 

Diagnosis

Correct diagnosis of asthma is critical to ensure patients receive appropriate and effective pharmacological treatment. Both BTS/SIGN and NICE recognise that diagnosis must be made on a clinical basis due to the absence of consistent gold standard diagnostic criteria.1,2 Both sets of guidelines recommend carrying out a structured clinical history and examination. NICE emphasises the need for objective testing (e.g. with lung function testing/exhaled nitric oxide testing) whereas BTS/SIGN states that a diagnosis can be made in people with a high probability of asthma who have a positive symptomatic response to a trial of therapy (e.g. 6–8 week course of inhaled corticosteroids [ICS]) without necessarily carrying out formal objective tests. The BTS/SIGN guideline also indicates that evidence of airway reversibility increases the probability of asthma.1

Neither the BTS/SIGN nor the NICE diagnostic algorithm have been prospectively tested or compared. NICE conducted a pilot of its diagnostic algorithm in seven practices and found that even with objective testing a definitive diagnosis could not be made in 20% of cases.7

The consensus group was therefore concerned that clinicians should not interpret NICE guidance to mean that clinical judgment is not required in making the asthma diagnosis. While it is desirable to have objective evidence of asthma, where this is not possible or practical, a positive response to a trial of therapy (response should be evaluated using a validated questionnaire such as the Asthma Control Questionnaire, Asthma Control Test, or Royal College of Physicians 3 Questions)1 and evidence of reversibility is pragmatically considered sufficient evidence to make an asthma diagnosis. 

Consensus recommendations—diagnosis:

  • Asthma should be diagnosed based on a structured clinical history and examination, with use of objective tests to confirm the diagnosis wherever possible
  • Consider treatment with inhaled corticosteroids for patients with a high probability of asthma—a positive response to a trial of therapy (evaluated using a validated questionnaire) and evidence of reversibility is considered sufficient to support a diagnosis of asthma.

Treatment options 

NICE advocates the use of short-acting beta2 -agonist (SABA) monotherapy in its treatment algorithm in some patients.3 BTS/SIGN recommends that a SABA is used as short-term reliever therapy for all patients with symptomatic asthma, but acknowledges that occasional SABA therapy may be the only treatment required for certain patients. The BTS/SIGN guideline removed the emphasis for starting treatment with SABA monotherapy, partly as a response to the National Review of Asthma Deaths, which identified SABA monotherapy as a potentially preventable contributor to asthma death,8 and partly in recognition of the inflammatory nature of the disease and the need for anti-inflammatory therapy. The apparent discrepancy between the two guidelines is not as significant as the algorithms might suggest. In essence, both guidelines accept the use of SABA monotherapy for people with infrequent short-lived wheeze. The consensus group noted that clinicians may not always read the accompanying guideline text and that the presence of SABA monotherapy in the algorithm of the NICE guideline may encourage ongoing and inappropriate use of SABA monotherapy. 

Additional concerns about SABA monotherapy include the risk of downregulation of beta-receptors through excessive beta-agonist use, which may worsen airway hyperresponsiveness.9 Some patients who complain of ‘occasional wheeze’ will report more persistent asthma symptoms when a more detailed history is taken, making prescribing of ICS more appropriate. Furthermore, patients often do not return for follow up if initial treatment is effective and so will continue to use a SABA to manage symptoms without the opportunity for clinicians to address the underlying disease process with an ICS. Overall, therefore, in the absence of evidence that one class is superior to the other, early prescribing of ICS to address the inflammatory process10 is preferred over SABA reliever monotherapy, which should be avoided.

Consensus recommendations—SABA monotherapy versus early ICS

  • Prescribe ICS as initial therapy for patients with asthma
  • Avoid use of SABA as monotherapy.

ICS=inhaled corticosteroid; SABA=short-acting beta2 -agonist

First add-on therapy to ICS

Both the BTS/SIGN and NICE guidelines recommend ICS as the first-line preventer drug for adults,1,3 starting with a low dose (the BTS/SIGN guideline includes a table that categorises ICS by low, medium, and high dose1). The guidelines also recommend a stepwise approach if asthma remains uncontrolled; however, their approach to add-on strategies for patients uncontrolled on ICS differ.

Before adding in a drug or switching drugs at any step of the pathway, healthcare professionals should return to the basics (Box 1), checking that the patient is using their ICS inhaler regularly, as patients often stop taking asthma drugs when they feel better and restart when symptoms return. It is also important to check their inhaler technique to make sure that they are using their device correctly.

In patients with uncontrolled asthma despite low‑dose ICS, BTS/SIGN recommend adding an inhaled long‑acting beta2 -agonist (LABA) first,1 while NICE recommends adding an oral leukotriene receptor antagonist (LTRA).3 Use of an LTRA instead of a LABA would represent a major change to current UK practice, as adding a LABA has been regarded as best practice for more than a decade. There is extensive evidence from controlled trials and systematic reviews to support the additional benefit of adding a LABA in patients on ICS with poorly controlled asthma in terms of improving lung function and symptoms, and decreasing asthma attacks, and ICS/LABA is generally the most appropriate choice.1 BTS/SIGN recommend trying ICS/LABA for a month and to stop the LABA if there is no improvement.1 This is in line with international guidance such as GINA, although GINA recommends therapeutic trials of 2–3 months.11

Box 1: The basic principles of asthma management

  • Deliver patient education at every opportunity
  • Drug choice should be personalised, taking into account the requirements of patients with different phenotypes including patients:
    • who smoke
    • who are resistant to corticosteroid treatment
    • with Samter’s triad of asthma, aspirin sensitivity, and rhinitis
    • co-morbidities who may need higher doses or to step up earlier in the pathway
  • Discuss and agree drug and inhaler device choice with the patient
  • Check and optimise adherence at every opportunity
  • Check and optimise inhaler technique at every opportunity
  • Put in place a personalised asthma action plan and update this when treatment changes
  • Where multiple inhalers are required, prescribing one type of inhaler (i.e. either drug powder devices or aerosols) will help maintain inhaler technique and improve adherence
  • Monitor use of reliever inhalers:
    • patients should ideally use less than one reliever inhaler per year with consistent good control
    • patients should ideally use no more than six inhalers per year (the use of more than 12 inhalers is a high risk factor for death).

Adding an LTRA to ICS can also improve asthma control in some patients, but head-to-head comparisons of ICS/LABA and ICS/LTRA suggest that an ICS/LABA combination is more effective.12 NICE acknowledges that patients are more likely to experience exacerbations with an LTRA, but its cost-effectiveness analysis suggests that even after taking into account poor control of symptoms and consequently a potential increase in exacerbations, an LTRA is still more cost effective than a LABA at this step.3 In practice, a LABA is likely to be added rather than replacing the LTRA, which is unlikely to be cost effective.

One potential disadvantage of ICS/LTRA treatment is possible non-adherence with ICS treatment as these two medications are taken separately. Patients taking an ICS/LABA combination who feel that they are deriving benefit from the LABA will at least continue taking the ICS as part of their combination inhaler, and those in England will only have to pay one prescription charge. Internet-savvy patients who see reports about some side-effects potentially linked to LTRAs, including nightmares and suicidal thinking and behaviour (which is very rare),13 may also be tempted to stop taking the LTRA without returning for follow up.

In the opinion of the consensus group, it is likely that a LABA will be preferred for some patients, while others may respond better to an LTRA. In practice, it is important to individualise choice of add-on therapy for each patient based on a detailed clinical history. Overall, continuing with the current practice of adding in LABA to ICS is the preferred step-up option for most patients, particularly those with a history of exacerbations. All patients should be followed up within 4–8 weeks at which point the LABA should be discontinued and the patient switched to another drug class if the LABA is not contributing to control of symptoms. In some specific patient groups, an LTRA might be more appropriate as first-line add-on to ICS, including people who would prefer a tablet over an inhaled medicine. It is unknown which particular patient groups are likely to respond to an LTRA but some clinicians show a preference for using this therapy in younger adults.

An LTRA might also be useful for patients with Samter’s triad of asthma, aspirin sensitivity, and rhinitis, although evidence around the efficacy of LTRAs in people with asthma and allergic rhinitis is equivocal, with disappointing results in randomised clinical trials (RCTs) but a reduced risk of asthma exacerbations in observational studies. Intranasal steroids remain the first-line treatment for allergic rhinitis,14 although there is some research that would suggest an LTRA is as effective as antihistamines.15

The choice of treatment should be discussed and agreed with the patient. Regardless of the drug class prescribed, it is important to go back to basics (see Box 1), checking adherence, checking and optimising inhaler technique, managing patient expectations, and reinforcing patient education at every opportunity. Where multiple inhalers are required, prescribing one type of inhaler (meter dose inhaler or dry powder) may help maintain inhaler technique and improve adherence.16–18

The patient should be reviewed for symptom control — the best indicator of future exacerbations — after 4–8 weeks, which allows sufficient time to determine whether the LABA has improved control of symptoms. If the patient still has suboptimal symptom control, it is important to not just add additional drugs but to assess if the current treatment has contributed to symptom control or reduced exacerbations and to consider stopping treatments that are not effective.

Consensus recommendations—add-on therapy to ICS

  • Before stepping up:
    • check that the patient has been correctly diagnosed
    • check that patients are responding to the current medication
    • check and optimise adherence and inhaler technique
    • address smoking cessation where appropriate
    • manage any correctable trigger factors
    • manage any significant co-morbidities
  • ICS therapy should not be discontinued
  • Choice of LABA or LTRA should be tailored to the patient:
    • a LABA is generally preferred to an LTRA if the goal is symptom control in order to reduce exacerbations
    • an LTRA may be a good option for patients with atopy and associated nasal disease particularly in patients with Samter’s triad of asthma, aspirin sensitivity, and rhinitis
    • discuss treatment with the patient, using this time to educate—emphasise the importance of adherence and correct inhaler technique—and respond to any concerns
  • Once the treatment choice is made, review the patient after 4–8 weeks and check for symptom control, which is the best indicator of future exacerbations
  • Before adding in another therapy for patients with suboptimal control, assess if the current treatment has contributed to symptom control or reduced exacerbations and consider stopping treatments that are not effective.

ICS=inhaled corticosteroid; LABA=long‑acting beta2‑agonist; LTRA=leukotriene receptor antagonist

Maintenance fixed-dose combination treatment and maintenance and reliever therapy

The BTS/SIGN guideline states that maintenance and reliever therapy (MART) can be considered for adults aged ≥18 years with a history of asthma exacerbations on moderate-dose ICS or ICS/LABA.1 The NICE guideline gives MART greater prominence, suggesting it as add-on therapy for patients uncontrolled on low-dose ICS/LABA, although it does acknowledge in subsequent recommendations that some patients will be prescribed a fixed-dose combination (FDC) rather than MART.3

A Cochrane review found that MART reduces the risk of asthma exacerbations in comparison with fixed dose maintenance ICS and separate relief medication.19 However, some patients, and indeed clinicians, find the concept of MART difficult to grasp given the long-established use of separate reliever and preventer inhalers, and the drug options licensed for MART currently are limited.

The MART approach is unlikely to be suitable for all patients, particularly while drug choices remain limited. However, MART offers a further alternative to adding in another drug or increasing to high-dose ICS in patients with exacerbations despite an FDC with moderate-dose ICS (as stated in the BTS/SIGN guideline). It may also be useful for patients who have poor adherence with preventers and FDCs, capitalising on patients’ preferred use of relievers to ensure they take some ICS to address the underlying inflammation. A MART regimen is also an attractive option for adolescents and younger patients, who seem to be more open to this newer concept of asthma management and for whom carrying just a single inhaler for prevention and relief may be appealing. The group felt that for suitable patients the MART approach was likely to offer benefits in terms of reduced exacerbations but requires careful patient selection.

From a practical perspective, additional use of the MART inhaler when needed as a reliever—usually two extra doses per day in RCTs20— may mean that an inhaler will not last the full month expected for an FDC inhaler. It is therefore important that the use of a MART regimen is highlighted in the patient’s notes and in their personalised asthma action plan to ensure they can refill their MART script as needed and do not have to revert to relying on a blue reliever inhaler, which can lead to them losing confidence in MART and reluctant to be without a reliever for reassurance (it is expected that patients on a MART regimen would generally require an extra inhaler every 3 months). The action plan should also be updated so that it does not include increasing doses of salbutamol. 

Consensus recommendations—FDC and MART regimens

  • Use a regimen that both the clinician and the patient are comfortable with
  • Check the licensed indications for different combination inhalers as not all products are licensed for a MART regimen
  • Consider MART for patients:
    • with a history of exacerbations or poor symptom control on moderate-dose ICS, in preference to a FDC with high-dose ICS
    • who are confident and adept at self-managing their asthma
  • Ensure patient notes and action plan record the treatment regimen in order to monitor use of medications including reliever use.

FDC=fixed-dose combination; MART=maintenance and reliever therapy; ICS=inhaled corticosteroid

Stepping down treatment

Stepping down is a vital part of the management of asthma but is often overlooked in practice. NICE provides minimal guidance on the topic, stating that prescribers should consider decreasing maintenance therapy when a person’s asthma has been controlled with their current maintenance therapy for ≥3 months but noting that no studies are large enough or sufficiently robust to provide clear guidance.3 It states that medicines should be stopped or the dose reduced in an order that takes into account the clinical effectiveness when introduced, side effects and the person’s preference, but without providing much practical guidance on how to achieve this.3 The BTS/SIGN guideline is similarly vague, also focusing on lack of evidence over practicalities.1

When stepping down is attempted, it is often abandoned as patients and physicians lose confidence if patients start to feel worse. This is a major barrier to stepping down, so it is important for patients and prescribers alike to bear in mind that some patients do lose control and will have to step back up, but that it is important to balance this risk with the risk associated with unnecessary long‑term use of high doses of ICS. Patients may step down their treatment of their own accord if they do not expect to achieve this with the support of their clinician. The clinician should work with patients to determine the best approach to stepping down treatment in a structured manner, accepting that a further treatment change may be necessary if symptoms return. Going back to the basics (see Box 1), including checking and optimising adherence and inhaler technique, can increase confidence when stepping down.

The standard criteria for considering stepping down treatment are:

  • 3–6 months of stability
  • no history of exacerbations or asthma-related admissions in the past 12 months.

Patients with severe asthma, a history of ‘brittle asthma’ or patients with previous failed stepdown attempts should be discussed with a specialist before attempting stepdown.

The consensus group generally agreed that exacerbations are a marker of poor asthma control and therefore stepping down should be avoided in anyone who has had exacerbations in the past 12 months. Some patients are more symptomatic during winter than summer, while others have worse control in summer, so it is worth considering the usual pattern and timeframe of symptoms when evaluating disease stability and considering whether it is an appropriate time to step down.

Patients taking high-dose ICS are key targets for stepping down treatment, while maintaining control at the lowest dose possible as ICSs are the cornerstone of therapy. The main strategy is therefore to reduce the ICS dose incrementally through a 50% reduction, stepping down first from high- to moderate-dose ICS and then from moderate- to low-dose ICS. Stepping down directly from high- to low- dose ICS should be avoided as it is more likely to result in loss of control. It is more challenging to switch from low-dose ICS plus LABA to ICS monotherapy as evidence suggests an increased risk of exacerbation and loss of control after LABA withdrawal,21 so caution is advised if attempting withdrawal of LABA. Patients’ action plans should be updated with the agreed step-down strategy, which should include a step-up option so they know they can increase the dose if control seems to be slipping.

Consensus recommendations — stepping down treatment

  • Consider stepping down treatment if the patient
    • has had 3–6 months of stability and
    • no history of exacerbations or asthma related admissions in the last 12 months
    • no past history of severe or brittle asthma
  • Work with patients to agree a plan for stepping down:
    • use positive language (e.g. ‘I would like to reduce your treatment slightly because your asthma is well controlled’)
  • Accept that some patients will lose control and need to be stepped up again and manage patient expectations from the start and discuss this with them
  • Check and optimise inhaler technique and emphasise the need for good adherence
  • Step down from high-dose to moderate-dose ICS and then from moderate- to low-dose ICS to minimise the risk of losing control
  • Update the action plan so that the patient knows they can step back up at any time.

Concluding comments

The addition of the new NICE guidance in the UK has brought some confusion to the management of asthma given some striking differences from the long-established and widely implemented BTS/SIGN guideline. Healthcare professionals may feel pressurised to follow NICE guidance, thus the key differences between the diagnosis and drug choices at some stages, will only add confusion and inconsistencies for those managing asthma in primary care. 

The consensus panel broadly agreed that the UK should aim to have a single asthma guideline with clear evidence‑based recommendations. In the meantime, the BTS/SIGN guideline is generally regarded as more pragmatic and better suited to implementation in current UK practice.

There is general agreement that the management of asthma in the UK is suboptimal and esoteric arguments about FeNO algorithms risks distracting clinicians from the issue that many patients still do not receive basic management such as appropriate preventer therapy, appropriate inhaler technique training, asthma action plans, and monitoring.

The consensus recommendations in this document should provide some clarity for prescribers in areas of contention, as well as offering some practical guidance around key components of asthma care (Box 1).

Useful resources

Conflicts of interest

James Chalmers (chair)—has received consultancy and speaker fees from Napp Pharmaceuticals Limited.

Kevin Gruffydd-Jones—has spoken on behalf of and acted as a consultant for AstraZeneca UK Limited, Boehringer Ingelheim Limited, GlaxoSmithKline UK, Mundipharma/Napp Pharmaceuticals Limited, Novartis Pharmaceuticals UK Ltd, and Pfizer Limited.

Steve Holmes—has received funding to attend advisory boards and to speak at meetings on behalf of AstraZeneca UK Limited, Beximco Pharma UK Limited, Boehringer Ingelheim Limited, Chiesi Limited, GlaxoSmithKline UK, Johnson and Johnson Ltd, Mundipharma/Napp Pharmaceuticals Limited, Novartis Pharmaceuticals UK Ltd, Nutricia, Orion Pharma (UK) Limited, Pfizer Limited, Sandoz Limited, Teva UK Limited, and Trudell Medical International.

Vikki Knowles—has received consultancy and speaker fees from AstraZeneca UK Limited, Boehringer Ingelheim Limited, Napp Pharmaceuticals Limited, Nutricia, Pfizer Limited, and Teva UK Limited.

Anna Murphy—has received consultancy payments from AstraZeneca UK Limited, Boehringer Ingelheim Limited, Chiesi Limited, Napp Pharmaceuticals Limited, Novartis Pharmaceuticals UK Ltd, and Roche Products Limited.

Acknowledgements

Jemma Lough, Medical Writer, drafted the article in this supplement, which was reviewed by the members of the consensus group.

References

  1. BTS/SIGN. British guideline on the management of asthma. SIGN 153. Edinburgh: SIGN, 2016. www.sign.ac.uk/sign-153-british-guideline-on-the-management-of-asthma.html
  2. National Guideline Centre. Asthma: diagnosis and monitoring of asthma in adults, children and young people. NICE Guideline 80. NICE, 2017. Available at: www.nice.org.uk/guidance/ng80/evidence
  3. National Guideline Centre. Chronic asthma management. NICE Guideline NG80. NICE, 2017. Available at: www.nice.org.uk/guidance/ng80/evidence
  4. NICE. Omalizumab for treating severe persistent allergic asthma. Technology Appraisal 278. NICE, 2013. Available at: www.nice.org.uk/ta278
  5. NICE. Mepolizumab for treating severe refractory eosinophilic asthma. Technology Appraisal 431. NICE, 2017. Available at: www.nice.org.uk/ta431
  6. NICE. Reslizumab for treating severe eosinophilic asthma. Technology Appraisal 479. NICE, 2017. Available at: www.nice.org.uk/ta479
  7. White J, Paton J, Niven R et al. Thorax 2018; 73: 293–297.
  8. Levy M, Andrews R, Buckingham R et al. Why asthma still kills: The national review of asthma deaths (NRAD) confidential enquiry report. London: Royal College of Physicians, 2014. Available at: www.rcplondon.ac.uk/projects/outputs/why-asthma-still-kills
  9. Johnston S, Edwards M. Thorax 2009; 64 (9): 739–741.
  10. Haahtela T, Selroos O, O’Byrne P. ERJ Open Res 2015; 1 (1). pii: 00022-2015. eCollection 2015 May.
  11. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2018. Available at: ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention
  12. Chauhan B, Ducharme F. Cochrane Database Syst Rev 2014, Issue 1. dx.doi.org/10.1002/14651858.CD003137.pub5
  13. Dr Reddy’s Laboratories. Montelukast 10 mg film-coated tablets—summary of product characteristics. May 2017. www.medicines.org.uk/emc/product/3494/smpc
  14. Brozek J, Bousquet J, Baena-Cagnani C; Global Allergy and Asthma European Network; Grading of Recommendations Assessment, Development and Evaluation Working Group. J Allergy Clin Immunol 2010; 126 (3): 466–476.
  15. Wilson A, O’Byrne P, Parameswaran K. Am J Med 2004; 116 (5):338–344.
  16. Bosnic-Anticevich S, Chrystyn H, Costello R et al. Int J Chron Obstruct Pulmon Dis 2016; 12: 59–71.
  17. Levy M, Dekhuijzen P, Barnes P et al. NPJ Prim Care Respir Med 2016; 26: 16017.
  18. van Palen, Klein J, van Herwaarden C et al. Eur Respir J 1999; 14 (5): 1034–1037.
  19. Cates C, Karner C. Cochrane Database Syst Rev 2013; (4): CD007313. doi: 10.1002/14651858.CD007313.pub3.
  20. Kuna P, Peters M, Manjra A et al. Int J Clin Pract 2007; 61 (5): 725–736.
  21. Ahmad S, Kew K, Normansell R. Cochrane Database Syst Rev 2015; (6): CD011306. doi: 10.1002/14651858.CD011306.pub2

UK/FLUT-K-18050b 

Date of preparation: August 2018

This consensus discussion was commissioned by Napp Pharmaceuticals Limited in partnership with Guidelines in Practice. Napp Pharmaceuticals Limited has reviewed the supplement for factual accuracy, to ensure it is fair and balanced, and to ensure its compliance with appropriate regulations. The sponsorship fee included the honoraria for the contributors. The views and opinions of the contributors expressed in this publication are not necessarily those of Guidelines in Practice, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.