NICE guidelines review: asthma

In November 2017, NICE issued guidance titled Asthma: diagnosis and monitoring of asthma in adults, children and young people.¹ The history of the guideline development was attached to a degree of controversy over the recommendation to significantly increase the use of fractional exhaled nitric oxide (FeNO) as a diagnostic and monitoring tool when the draft guideline was first released in 2015.

In 2016, the British Thoracic Society (BTS) and Scottish Intercollegiate Guideline Network (SIGN) had released their joint revised guideline,² emphasising their previous approach of using a positive response to a trial of treatment to make the diagnosis in primary care. Dr Steve Holmes, the RCGP Lead for Respiratory Medicine, was quoted in Pulse magazine at the time, saying: “NICE extrapolated to suggest a diagnosis of asthma should not be made in primary care unless we have reversibility spirometry and an elevated FeNO. Whereas the BTS/SIGN draft recognises that there is enormous variation among people in the way their asthma presents and a good clinician balances the science with more of a clinician’s artistic skills and experience to draw the full picture of the patient’s condition and do what is best for the patient.”³

Both guidelines refer to the importance of the NRAD (National Register of Asthma Deaths) report published in 2014.⁴ This report reviewed 3,554 deaths in the UK in the 12-month period from February 2012, and excluded a significant number on the basis of age (>75years), lack of information or incorrect diagnoses; 195 of these cases were felt to be truly deaths from asthma, and in each case their medical records over the two years prior to death were examined.

The enquiry noted the following key points:

• 45% died having not sought medical assistance
• 57% were not under specialist care in the year before death
• 47% had had a hospital admission in the previous year
• 10% died within 28 days discharge from hospital
• 21% had attended an Emergency Department in the 12 months before death; 10% had attended more than once.⁴

A number of recommendations were subsequently made by the report, which noted the common absence of asthma management plans, specialist review, overuse of short-acting beta-agonists (SABA), and made the suggestion of incorrect diagnosis in 10%. Several other studies have suggested the possibility of overdiagnosis, with one report in the British Journal of General Practice⁵ suggesting that more than 50% of children with a diagnosis of asthma were overdiagnosed.

What is asthma?

The NICE guideline introduction refers to asthma as “a chronic inflammatory respiratory disease. It can affect people of any age, but often starts in childhood. Asthma is a variable disease which can change throughout a person’s life, throughout the year and from day to day. It is characterised by attacks (also known as exacerbations) of breathlessness and wheezing, with the severity and frequency of attacks varying from person to person. The attacks are associated with variable airflow obstruction and inflammation within the lungs, which if left untreated can be life-threatening, but with the appropriate treatment can be reversible.”¹

Increasingly, there is a consensus that the term asthma should be seen as an umbrella condition, with identification of different endotypes (a disease entity defined by a specific biological mechanism) of asthma helping to guide treatment to individual patients.⁶ The two best recognised and described of these are the T-helper type 2 (Th2)-high and Th2-low endotypes of severe asthma. The former is characterised by the presence of eosinophilic inflammation in the airways and the latter with other cell types (neutrophilic or paucigranulocytic) suggesting that response to pharmacological intervention may differ between these groups.

Data from Asthma UK suggests that 5.4 million people in the UK have asthma, with it now being the most common chronic condition in the UK affecting over a million children. In 2016, 1,410 people died from asthma in the UK and there is an overall annual cost to the NHS of treating and managing care for asthmatic patients exceeding £1 billion.

The NICE Guideline on asthma (NG80)

The guideline makes the usual recommendations of a structured clinical history, with particular focus on:

• Wheeze, cough or breathlessness and any daily or seasonal variation in these symptoms
• Any triggers that make symptoms worse
• A personal or family history of atopic disorders.

The most essential change from previous guidance is that NICE suggest a specific algorithm of objective testing should be used to diagnose asthma. Previous guidance had utilised peak flow variability and spirometry to help guide diagnosis. Both these tests have relatively low sensitivity and high specificity in asthma, making them more useful as “rule in” than “rule out” for the condition.

In children under 5 with suspected asthma, the advice is to treat symptoms based on observation and clinical judgement, and to perform objective tests when the child reaches 5 years of age. If they remain unable to perform testing at 5 years, NICE suggest trying again every 6-12 months until satisfactory results are obtained.

Fractional exhaled nitric oxide (FeNO)

FeNO has a much higher specificity and sensitivity for the diagnosis of asthma than other objective testing. A 2017 systematic review found that FeNO has moderate diagnostic accuracy for asthma.⁹ In the studies considered by the NICE guideline development group (GDG), they found the FeNO showed moderate to high sensitivity and high specificity in children and young people aged 5-16 years and high sensitivity and specificity in adults, depending on the cut-off level used.

When the draft guidance was issued in January 2015, the inclusion of FeNO testing was identified as needing investment in both training and equipment in primary care; a potential barrier to implementing the guidance. As a result the guideline was paused with a feasibility study performed (Appendix Q, https://www.nice.org.uk/guidance/ng80/evidence/appendices-a-r-pdf-4656178048) in primary care to assess the implementation of the guidance. FeNO was noted to be expensive to implement, but  there was both positive clinician and patient acceptance with the test. A suggestion of a “hub and spoke” model was raised to aid diagnosis in primary care with a sharing of costs across geographical regions.

Summary of NICE pharmacological treatment recommendations

Children over 5 years of age, young people and adults

• Unless symptoms suggest that there is an immediate need for maintenance therapy (asthma-related symptoms three times a week or more, or causing waking at night), the guideline recommends offering a short-acting beta2 agonist (SABA) as reliever therapy initially and then a low-dose ICS (inhaled corticosteroid) as first-line maintenance therapy if the symptoms are uncontrolled with a SABA alone
• Leukotriene receptor antagonist (LTRA) should be offered to adults aged 17 and over as the next step, with consideration of LTRA in the 5-16 age group and planned review after 4-8 weeks
• If control is still not achieved, the LTRA should be reviewed and cessation considered before introducing a long acting beta agonist (LABA) in combination with the ICS
• If asthma remains uncontrolled on low dose ICS and LABA as maintenance therapy, consider changing the ICS/LABA to a maintenance and reliever therapy (MART) regime. MART is a form of combined ICS and LABA treatment in which a single inhaler, containing both ICS and a fast-acting LABA, is used for both daily maintenance therapy and the relief of symptoms as required. MART is only available for ICS and LABA combinations in which the LABA has a fast-acting component (for example, formoterol).¹
• If asthma remains uncontrolled consider increasing the ICS to a moderate maintenance dose and seek advice from a healthcare professional with expertise in asthma

Children under 5 years of age

• Offer a SABA as reliever therapy for symptom relief alongside all maintenance therapy
• Consider an 8-week trial of a paediatric moderate dose ICS if symptoms indicate the need for maintenance therapy (asthma-related symptoms three times a week or more, or causing waking at night) or suspected asthma is uncontrolled with a SABA alone
• After 8 weeks, stop ICS treatment and monitor the child’s progress:
• If symptoms did not resolve during the trial period, consider alternative diagnosis
• If symptoms resolved then recurred within 4 weeks of stopping ICS treatment, restart the ICS at a paediatric low dose as first-line maintenance therapy
• If symptoms resolved but recurred beyond 4 weeks after stopping ICS treatment, repeat the 8 week trial of a paediatric moderate dose of ICS
• If suspected asthma is uncontrolled, consider the addition of an  LTRA to the ICS
• If suspected asthma is uncontrolled on a paediatric low-dose ICS and LTRA as maintenance therapy, stop the LTRA and refer the child to a healthcare professional with expertise in asthma.

Differences and agreements between NICE and BTS/SIGN

Both the current NICE guidance and the BTS/SIGN guideline stress the importance of a structured clinical history, with the latter guideline taking a slightly broader approach suggesting the inclusion of atopic status and previous consultations into consideration.

Both feature spirometry with caution, stressing that it is not useful for ruling out asthma as it has generally low sensitivity (both guidelines suggesting around a quarter of patients will have obstructive spirometry).

One of the most significant differences is in the various stages of pharmacological management. BTS/SIGN, in light of the findings of the NRAD report of 2014 which identified that a proportion of those suffering fatal asthma attacks were using monotherapy with a SABA, recommends a low-dose inhaled corticosteroid (ICS) as the first stage of treatment, cautioning against the use of a SABA in isolation. In contrast, the NICE guideline makes the following recommendations:

1.6.1 Offer a SABA as reliever therapy to adults (aged 17 and over) with newly diagnosed asthma

1.6.2 For adults (aged 17 and over) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone

1.7.1 Offer a SABA as reliever therapy to children and young people (aged 5 to 16) with newly diagnosed asthma

1.7.2 For children and young people (aged 5 to 16) with asthma who have infrequent, short-lived wheeze and normal lung function, consider treatment with SABA reliever therapy alone.¹

Both guidelines also differ at the next stage after the introduction of ICS. NICE recommend a trial of an LTRA, with the drug being stopped and replaced by a LABA if there is no benefit seen. SIGN are in agreement with most international guidance with the move to a combination inhaler as the next step after introduction of ICS.

The full NICE guideline backs up this decision due to the lower cost of LTRAs versus LABA. In an article published in Thorax, the BTS make the reasonable point that this cost benefit is only retained if the LTRA is stopped prior to stepping up to a LABA in addition to the ICS.⁷ They note that starting and stopping oral tablet therapy may have an effect on adherence to inhaler use and compliance. In addition, there are well recognised polymorphisms in the response to LTRAs,⁸ meaning that a variable response may be seen in patients for genetic reasons.

Discussion

Primary care in the UK now has two active peer-reviewed guidelines for the diagnosis and management of asthma. The significant differences between these documents are likely to lead to confusion in managing patients in both diagnosis and the steps of pharmacology at all ages.

In July 2017, the Lancet published a study by Professors Angela Simpson and Adnan Custovic¹⁰ using follow-up data from the Manchester Asthma and Allergy Study group, a population-based, birth cohort study of 1,184 children. They looked at the diagnostic value of the three of the objective tests individually and then tested the proposed NICE algorithm in symptomatic children at 13-16 years of age follow-up.

Their findings were startling; an FEV1:FVC of less 70% was only found in 10 of 630 children (2%), bronchodilator reversibility (BDR) was seen in only 54 children (9%) and they noted that, as the algorithm places spirometry first, only 8 of these children would have progressed to being tested for BDR.

FeNO was found to be the most sensitive test among children with symptoms, but they noted that performing spirometry first can reduce FeNO by up to 25% in patients both with and without asthma. Lung function guidelines of the American Thoracic Society and European Respiratory Society recommend that FeNO is performed before spirometry for this reason.

In their discussion, the authors conclude that there is an urgent need for evidence about the value of these different tests in paediatric asthma and “until such evidence is available, the proposed NICE guidance of asthma diagnosis should not be implemented in children”.

In their own assessment of the differences between the guidelines, the BTS make the comment that “it is clear that close scrutiny of the evidence base shows that there is often more in common between the guidelines than might appear at first glance” and their article makes for helpful and instructive reading to help understand the differences and the rationale behind them.⁸

Whilst confusion exists, a combined guideline approach is essential for primary care, using the resources available to them locally, objective testing where possible and regular review of patients. The recommendations of the NRAD report in 2014 below are vital in moving towards better care for adults, children and young people of such a common disease.

• Every hospital and GP surgery should have a designated asthma lead
• Refer to specialist service if:
• more than two courses of steroids in the last 12/12 (injectable or oral)
• BTS step 4/5 in treatment (800mcg inhaled steroid daily / oral steroids daily)
• Follow up in secondary care for anyone attending ED with asthma attack
• Follow up in primary care for anyone using >12 relievers over 12/12
• Annual review by healthcare professional with specialist training in asthma

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Dr M J Doyle MRCP (UK) MRCP (London) FRCGP, Indigo Medical, Jersey, Channel Islands

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References

1. NICE Guideline NG80
2. BTS / SIGN Guideline 2016
3. http://www.pulsetoday.co.uk/clinical/more-clinical-areas/respiratory-/confusion-over-asthma-diagnosis-as-gold-standard-guidelines-contradict-nice/20031575.article
4. NRAD 2014
5. Ingrid Looijmans-van den Akker, Karen van Luijn and Theo Verheij, Br J Gen Pract 2016; 66 (644): e152-e157. DOI: https://doi.org/10.3399/bjgp16X683965
6. Asthma Endotypes and an Overview of Targeted Therapy for Asthma, Front Med (Lausanne). 2017; 4: 158
7. http://dx.doi.org/10.1136/thoraxjnl-2017-211189
8. White J, Paton JY, Niven R on behalf of the British Thoracic Society, et al G Thorax 2018;73:293-297
9. Wang Z, Pianosi P, Keogh K, Agency for Healthcare Research and Quality (US); 2017 Dec
10. Lancet Child Adolesc Health 2017; 1: 114–23.