Why the committee made the recommendations
Although evidence on symptoms and signs of asthma was not reviewed for this guideline update, the committee emphasised the importance of taking a good clinical history in all their discussions of diagnosis. Evidence on objective tests was only included if it was carried out in people in whom asthma was suspected on clinical grounds. Therefore, the recommendations for diagnostic testing should only be applied when the history and examination findings support a diagnosis of asthma. The committee also noted that, depending on the mode of presentation, other diagnoses might be considered, but they confined their recommendations to confirmation or exclusion of asthma.
The committee reviewed evidence on tests of variation in airflow obstruction and markers of allergy separately for adults and children. They took into account the sensitivity and specificity of the various tests but did not base their recommendations on these measures alone. They noted that no test showed high enough values of both sensitivity and specificity to be diagnostic in all cases. However, some of them showed high specificity and were potentially useful as rule-in tests with a suitably high cut-off value. It was agreed that a combination of tests would be needed for most people.
When considering combinations of tests, the extent to which the available tests correlate with one another is important because there is less benefit in performing a test that gives similar information to a preceding one. Practical aspects were taken into account using the committee’s knowledge and experience. These included the availability of the tests, which varies considerably (in particular, bronchial challenge testing is not available in primary care and not readily available in secondary care), the ability of people to perform the tests, and the acceptability of the tests to the person, which is particularly relevant in younger children.
The committee also considered the cost of the available tests. However, no health economic study on the most cost-effective sequence or combination of tests was identified. Therefore, a health economic model was developed to help address this.
The committee discussed what cut-off values should be recommended for the tests. For some of the tests it was agreed that it was inappropriate to state a numerical value for an abnormal result. For example, normal ranges for blood tests may vary slightly between laboratories. Therefore, for eosinophil counts and IgE levels, a raised measurement (suggesting asthma) should be regarded as one above the upper end of the local reference range. There are also several standardised methods of performing bronchial challenge tests, and the definition of bronchial hyperresponsiveness will be dependent on the method used.
Spirometry should always be performed using an international standard protocol but the method of expressing reversibility after bronchodilator varies. Ideally this would be based on change in z-scores, but these are not measured by all spirometry equipment. Change in absolute values of FEV1 is arguably best given as the percentage change compared with the person’s predicted FEV1,and using this parameter a change of more than 10% is abnormal. Using the more traditional means of expressing the change as a percentage of the baseline FEV1, increased reversibility would be 12% or more in adults and children. In adults, the change should also be 200 ml or more. The committee agreed to include both ways of measuring reversibility in its recommendations.
An optimal cut-off value is also difficult to give for FeNO (fractional exhaled nitric oxide). There is good evidence that FeNO levels increase with age and with height, and ideally normal ranges would be available which correct for these factors. However, there are currently no standard charts and FeNO equipment does not give an age/height corrected output. Although not ideal, the committee agreed that they need to suggest a simple cut-off value. And because FeNO is the first, and possibly the only, test in the recommended sequences in both adults and children they agreed that the value should be reasonably high so that it would be specific, acknowledging that this sacrifices a degree of sensitivity. Cut-offs of 50 ppb in adults and 35 ppb in children were agreed.
No evidence was available for diagnostic tests in children under 5. The age at which a child can co-operate with tests will vary, but the committee agreed that it is usually necessary to manage these children pragmatically based on symptoms and signs only.
Adults
Several tests showed good specificity for asthma, with values over 80% for blood eosinophils, FeNO (cut-off values 40-50 ppb), peak expiratory flow (PEF) variability, bronchial challenge tests, and spirometry with bronchodilator reversibility. However, sensitivity was poor for most of these, and only FeNO and bronchial challenge tests showed values over 70%. Although bronchial challenge is the most accurate test, overall, it is more costly than others and is less readily available.
Using the health economic model, the most cost-effective diagnostic strategy was found to be a gradual rule-in approach. It facilitates a positive diagnosis of asthma in a broad population using relatively inexpensive tests and confines the more expensive bronchial challenge tests to the end of the sequence.
The committee agreed that a cheap and highly specific test to rule in asthma should start the sequence. This should be either an eosinophil count or a FeNO measurement, but both need care in interpretation. For example, a raised eosinophil count can occur for other reasons including other allergic diseases, and FeNO is also affected by allergic diseases, although only those that affect the airways. Both measurements are altered in smokers. However, if used correctly in the presence of a history suggesting asthma, they are good rule-in tests.
The second test in the sequence should be to measure spirometry with reversibility. This is a more specific test than it is sensitive, but it represents a test of airway function to complement a first test which reflects atopy and so both components of asthma will have been assessed.
The committee were aware that there can be delays in accessing spirometry and FeNO testing, and it is hoped that access will improve. However, if these tests are not available or there is a significant delay in obtaining them, the committee agreed it would be reasonable to use PEF variability as a substitute rule-in test.
If asthma is not diagnosed at this stage, the only additional investigation that offers sensitivity without losing significant specificity is a bronchial challenge test. The committee are aware that these tests are not easily available in many areas but reasoned that making a positive recommendation should encourage services to improve access. They also noted that methacholine challenge is more sensitive than mannitol but did not want to further limit the recommendation.
Children aged 5 to 16
The committee noted that diagnostic testing is harder in children as they may find some tests difficult to perform and be unwilling to have blood tests.
A separate health economic model was developed for children using children-specific diagnostic accuracy data and inputs. In children, testing for sensitisation to house dust mite via skin prick test or finding an elevated IgE both showed high sensitivity. Therefore, the diagnostic strategy was a rule-in–rule-out approach. This proved to be the most cost-effective in children as it considerably reduced the proportion of children reaching the last stage and needing an expensive bronchial challenge test.
The committee agreed that a cheap and highly specific test was needed first to rule in asthma. FeNO is a more acceptable first test in children than an eosinophil count because it avoids the need to take blood, and because a level of more than 35 ppb is reasonably specific for asthma in the presence of a suggestive history.
The model suggested that a sensitive test should come next to rule out asthma. However, the committee noted that some children would not be able to have a FeNO test because the equipment is not available in all primary care settings, or because a minority may not be able to perform the necessary expiratory manouevre. They were also concerned that an increasing proportion of children with asthma are non-atopic and therefore unlikely to have a raised FeNO level. However, these children may show bronchodilator reversibility (BDR). It was therefore agreed that it would be appropriate to use spirometry with BDR as a second test for those without an elevated FeNO, or as the first test in those in whom FeNO could not be measured. Although this does not follow our optimal model exactly, including BDR at this stage is still cost-effective.
In children with a suggestive history of asthma, both skin prick testing for sensitisation to house dust mite and measurement of total IgE are sensitive tests, and the committee agreed that one or the other should be done next. If the test is negative, asthma is highly unlikely and can be ruled out without resorting to bronchial challenge testing. Although taking blood for IgE is invasive, it does have the advantage that an eosinophil count could also be obtained, and if this is above 0.5 x 109 per litre, it would support a diagnosis of asthma.
The committee were aware that there can be delays in obtaining spirometry, FeNO measurements or skin prick testing, and that it may not be possible to get blood samples from some children. It is hoped that access to these tests will improve. But if the tests are not available or there is a significant delay in obtaining them, the committee agreed it would be reasonable to use PEF variability as a substitute rule-in test.
The best single test is a bronchial challenge test, but these are also not readily available and cannot be done in primary care. If there is still diagnostic doubt after performing other tests, the committee agreed that a referral to an asthma specialist should be made for a second opinion, including consideration of a challenge test.
Further research
Although there is evidence underpinning each of the tests included in the recommended diagnostic sequences for adults and for children aged 5 to 16 years, the committee acknowledged that the sequences themselves have not been tested. The clinical and cost-effectiveness of the recommended diagnostic process should be formally evaluated.
Children under 5
The main issue in this age group is differentiating asthma from symptoms caused by recurrent viral infections. The committee were aware of evidence outside the review of diagnostic tests showing that asthma is more likely than recurrent viral wheeze when the episodes are frequent or severe, when they occur in the absence of other signs of viral illness and when the child shows other evidence of atopy. On this basis, they agreed that young children with recurrent wheeze and features suggesting asthma should be treated empirically with a low dose of inhaled corticosteroid (ICS) for a period of 8 to 12 weeks. If this is ineffective in reducing wheezing episodes, assuming that the ICS has been given satisfactorily, a referral to a specialist to consider other diagnoses is appropriate. If the ICS is associated with improvement, this is not proof of asthma as viral wheezing can remit and relapse spontaneously, so the committee agreed that the ICS should be stopped. If symptoms then reappear within a few weeks, asthma is the more likely diagnosis and the ICS should be re-started.
In view of the difficulty in diagnosing asthma in this age group the committee also agreed that any child who had been admitted to hospital, or been taken to the emergency department twice or more, because of wheezing or breathlessness should be referred to a specialist respiratory paediatrician for advice on diagnosis and management.
How the recommendation might affect practice
The diagnostic tests recommended for both children and adults are not routinely carried out in current practice, with the exception of spirometry and reversibility testing, which is performed in some adults with suspected asthma. FeNO equipment is not available in some areas, but an eosinophil count and IgE level is easily obtainable everywhere. Bronchial challenge tests are not done in primary care and infrequently used in secondary care. The recommendations will increase the demand for challenge tests and initially there will be a capacity problem. Incorporating the recommended diagnostic sequences into clinical practice would therefore require significant investment. However, using the tests increases the accuracy of asthma diagnosis and will be cost-effective over time.
The recommendations for children under 5 are based on a pragmatic trial of treatment, as is current practice.
Full details of the evidence and the committee’s discussion are in:
Asthma pathway (BTS, NICE, SIGN) [SIGN 244]
