Introduction
What is asthma?
Asthma In older people
The NICE Guideline (NG80)
Fractional exhaled nitric oxide
Recommendations
Differences and agreements between NICE and BTS/SIGN
Discussion
References

 

Introduction

NICE refers to asthma as “a chronic inflammatory respiratory disease that can affect people of any age, but often starts in childhood.” With an increasingly ageing population, projections have suggested a that there may be a 20% increase in the number of older adults with asthma by 2030.

In November 2017, NICE issued guidance entitled: “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; 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% of cases 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, however with the appropriate treatment can be reversible.”1

Though it may often start in childhood, asthma can develop at any age. With an increasingly ageing population, projections have suggested a that there may be a 20% increase in the number of older adults with asthma by 2030.6

A study by the Centre For Disease Control and Prevention in the US in 2015 found that asthma prevalence is highest in the 45-64 age group (8.4% having diagnosis of asthma).7

Unlike children, comorbidities are more likely to present in asthmatics over the age of 65 and so presentation and diagnosis may present additional complexities not present in younger age groups (eg. differentiating asthma from other diseases such as COPD and CCF).

Increasingly there is a consensus that the term asthma should be seen as an umbrella condition, with identification of different endotypes of asthma helping to guide treatment to individual patients.9 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) inflammation suggesting that response to pharmacological intervention may differ between these groups. The neutrophilic endotype, which is a distinct disease entity defined by a specific biological mechanism (mediated by Th17), is more common in older asthmatics10 and may require treatment with regular antibiotics in addition to regular inhaled medications.

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, 1410 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.

 

Table 1. Asthma-COPD Overlap Syndrome8

Described in patients over the age of 40

  • Persistent airway limitation
  • Prior history of asthma or large bronchodilator reversibility
  • Affects quarter of patients with COPD
  • Affects third of patients with asthma
  • Worse symptoms and higher numbers of exacerbations, lower quality of life and higher hospital admission rates than asthma or COPD alone

 

Asthma In older people

As mentioned above, the prevalence of asthma in the 45-64 year age group is the same as the 0-18 year age group overall and there is suggestion of both under- and overdiagnosis at all ages. A study of 180 patients over the age of 55 years revealed that, whilst many cases do indeed begin in childhood, 46% had been diagnosed after the age of 40 years.11 Due in part to comorbidities, adults over the age of 65 have, as a group, the highest rate of admission via emergency departments for asthma (25%) when compared to asthma across all age-groups (7.9%) as well as the longest inpatient stays.12

Presentation to primary and secondary physicians of the older asthmatic patient presents some significant differences to those in the younger age groups. Uniquely, fatigue is reported as a presenting symptom of asthma, even in the absence of respiratory symptoms.13 Symptoms such as breathless, wheeze and cough may be attributed by the individual as a natural age-related change and to the physician can present multiple differentials of diagnosis (COPD, gastro-oesophageal reflux disease (GORD), heart failure) all of which may coexist in the same individual.

 

The NICE Guideline (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 suggests 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. It should be noted that FEV1/FVC decreases with ageing and low levels of good quality evidence in older people for spirometry as an effective diagnostic tool.

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

 

Figure 1. NICE Guideline Algorithm A

 

Fractional exhaled nitric oxide

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.14 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.

The use of FeNO and its position in the NICE algorithm, despite the moderate diagnostic accuracy in the 2017 systematic review, is still controversial; an earlier systematic review and meta-analysis suggested that the use of FeNO in isolation could lead to false positives and negatives in diagnosis.15

When the draft guidance was issued in Jan 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 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. It is yet to be seen whether such measures can be efficiently implemented in the NHS at the present time.

 

Recommendations

  • 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 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.
  • 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 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 Maintenance and reliever therapy (MART) regime. This 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).
  • If asthma remains uncontrolled consider increasing the ICS to a moderate maintenance dose and seek advice from a healthcare professional with expertise in asthma.

 

Figure 2. NICE algorithm 2017. Summary of NICE Pharmacological Treatment

 

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 short-acting beta2 agonist (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.

Both guidelines also differ at the next stage after the introduction of ICS. NICE recommends a trial of a leukotriene receptor antagonist (LTRA), with the drug being stopped and replaced by a long acting beta agonist (LABA) if there is no benefit seen. SIGN is 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 makes 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.16 The BTS notes that starting and stopping oral tablet therapy may have an effect on adherence to inhaler use and compliance. This may be a particular problem in older persons, who might already be experiencing a degree of polypharmacy from treatment of other conditions. In addition, there are well recognised polymorphisms in the response to

LTRAs17 meaning that a variable response may be seen in patients for genetic reasons.

                                                                               

Table summarising difference in NICE/SIGN guideline management

  Step 1 Step 2 Step 3 Step 4 Step 5

Adult
BTS/SIGN

Low-dose ICS

+LABA

Increase ICS to medium dose +/- stop LABA if not beneficial +/- consider adding LTRA /SR theophylline etc.

Consider trial of ICS to high dose

Consider addition 4th drug – LTRA/SR Theophylline/LAMA/beta-agonist tablet

Refer

PO steroid daily

Consider other treatments

Refer

Child
BTS/SIGN

Very low dose ICS (or LTRA under 5 yrs)

+LABA (unless <5yrs in which case + LTRA)

Review LABA and continue or stop

Increase to low-dose ICS

Consider LTRA

Consider trial of increase ICS to medium dose

Consider adding SR theophylline

Refer

PO steroid daily

Consider other treatments

Refer

Adult
NICE

SABA +/- low dose ICS if symptoms require at presentation

+LTRA and review 4-8 weeks

+LABA and review LTRA

MART Regime

Consider increasing ICS to moderate dose

Increase to high dose ICS, or

Trial of additional drug (LAMA or theophylline), or

Refer

5-16yrs NICE

SABA +/- paediatric low dose ICS if symptoms require at presentation

+LTRA and review 4-8 weeks

+LABA and review LTRA

MART Regime Consider increasing to moderate paediatric dose if not improving on MART

Refer, and consider increasing ICS to high paediatric dose, or

Consider additional drug eg. theophylline)

<5yrs NICE

SABA and consider 8 week trial of paediatric moderate dose ICS if symptoms require at presentation

Stop ICS after 8 weeks and review

If symptoms resolve and reoccur <4 weeks start paediatric low dose ICS

If symptom s resolve and reoccur >4/52 repeat 8 week trial

+LTRA

If not better stop LTRA and refer

                                

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 Custovic18using 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 eight 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 makes 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.16

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 emergency department 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.

Dr Matt Doyle
GP

 


References

1. NICE Guideline NG80. Asthma: diagnosis, monitoring and chronic asthma management https://www.nice.org.uk/guidance/ng80 (accessed 10/06/18)

2. BTS / SIGN Guideline 2016. https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssign-british-guideline-on-the-management-of-asthma/ (accessed 10/06/18)

3. http://www.pulsetoday.co.uk/clinical/more-clinical-areas/respiratory-/confusion-over-asthma-diagnosis-as-gold-standard-guidelines-contradict-nice/20031575.article (accessed 10/06/18)

4. National Review of Asthma Deaths 2014. https://www.rcplondon.ac.uk/projects/national-review-asthma-deaths (accessed 10/06/18)

5. Looijmans-van den Akker I, van Luijn K, Verheij T. Overdiagnosis of asthma in children in primary care: a retrospective analysis Br J Gen Pract 2016; 66(644):  e152-e157

6. Mather M Aging in the United States. Population Bull 2015; 70: 1-17

7. Summary Health Statistics. https://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2015_SHS_Table_A-2.pdf

8. Leung JM, Sin DD. Asthma-COPD overlap syndrome: pathogenesis, clinical features and therapeutic targets. BMJ 2017; 358: j3772

9. Asthma Endotypes and an Overview of Targeted Therapy for Asthma, Front Med (Lausanne) . 2017; 4: 158

10. Braman SS. Asthma in the elderly: a comparison between patients with recently acquired and long-standing disease. Am Rev Respir Dis 1991; 143: 336-40

11. Baptist J, Hao W, Karamched KR, et al. Distinct Asthma Phenotypes Among Older Adults with Asthma Allergy. Clin Immunol Pract 2018; 6: 244–49

12. http://www.cdc.gov.nhcs/data/ahcd/nhames_emergency/2014_ed_web_tables.pdf

13. Baptist J. Age-specific factors influencing asthma management by older adults. Qual Health Res 2010; 20:117-24

14. http://dx.doi.org/10.1136/thoraxjnl-2017-211189

15. Korevaar DA, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Resp Med 2015; 3(4): 290–300

16. White J, Paton JY, Niven R on behalf of the British Thoracic Society, et al Guidelines for the diagnosis and management of asthma: a look at the key differences between BTS/SIGN and NICE Thorax 2018; 73: 293–97

17. Wang Z, Pianosi P, Keogh K, et al. The Clinical Utility of Fractional Exhaled Nitric Oxide (FeNO) in Asthma Management Comparative Effectiveness Reviews, No. 197.Rockville (MD): Agency for Healthcare Research and Quality (US)

18. Lancet Child Adolesc Health 2017; 1: 114–23