Precision Medicine: What are the Key Parameters for Diagnosing Severe Asthma?
Part 2 of our Precisely Speaking blog series that explore how precision medicine can be applied to enhance diagnostic accuracy, particularly using spirometry and other testing methods.
What are some of the most informative parameters for asthma diagnosis and why?
Taking an accurate history can give clinicians reliable clues into the nature of a patient’s condition. For instance, waxing and waning symptoms that worsen with exposure to certain triggers including cold air or viruses might raise the clinical suspicion for asthma, whilst prolonged exposure to other allergens may be responsible for a type of severe asthma known as allergic asthma. Often symptoms dramatically improve following a sustained trial of inhaled corticosteroids, which in itself can be supportive evidence for asthma. Other times, it may be less clear as respiratory symptoms could be attributable to heart failure, or COPD. Severe asthma is defined as that which requires high dose controller therapy or disease that becomes uncontrolled when such therapy is reduced or withdrawn, which is why asthma management is crucial in evaluating treatment decisions. Although there is no gold standard test for diagnosing asthma, the use of multiple investigations can certainly increase the likelihood of accurate diagnosis. The three key tenets of asthma include reversible airflow obstruction, airway hyperresponsiveness and bronchial inflammation.
Conventional spirometry is useful in severe asthma where patients are more likely to demonstrate severe asthma symptoms like airway obstruction and air trapping compared to those with less severe disease. Demonstrating reversible airflow obstruction with bronchodilator therapy is a sensitive marker for asthma with a positive result traditionally defined as >12% and >200ml improvement in forced expiratory volume in 1 second (FEV1) following short acting beta agonist. Patients with bronchodilator reversibility have poorer asthma control and greater type 2 inflammation. Secondly, assessing airway hyperresponsiveness can be done by performing bronchial challenge testing with an indirect agent such as mannitol to induce a 10% or 15% fall in FEV1. Compared to direct challenge tests using methacholine or histamine, indirect agents are more sensitive for diagnosing asthma and less related to airway geometry. In this regard, the degree of airway hyperresponsiveness also directly correlates to the severity of asthma.
Serial pulmonary function testing such as assessing peak flow variability over time can also be helpful. Generally, demonstrating a peak flow variability ≥20% between the highest and lowest readings (ideally four measurements per day) is considered supportive of an asthma diagnosis.
However, in many asthma patients with severe asthma, spirometry can be misleadingly normal and so-called small airways disease can be missed. In simple terms, spirometry measures the calibre of the medium to larger airways, corresponding to generations 1 to 7 of the bronchial tree. Spirometry is not considered a sensitive tool for evaluating the smaller airways, defined as those less than 2mm in diameter and interestingly comprising >98% of the cross-sectional area of the lungs. Characterisation of generations 8 to 23 of the bronchial tree is possible using a tool such as airway oscillometry. It has been shown in studies that the small airways are more closely related to type 2 inflammation and poorer asthma control. Eosinophilic asthma is linked specifically to type 2 inflammation. In addition to being able to access the smaller airways, oscillometry further provides an alternative option to spirometry in patients where performing a forced expiratory manoeuvre might not be realistic, such as in children, or in people with very severe respiratory disease. Similar to above, oscillometry can be used instead of or as a complementary diagnostic test to spirometry to measure bronchodilator response and airway hyperresponsiveness.
Lastly, airway inflammation can be quantified using FeNO testing which has the advantage of being a point-of-care breath test and is useful for detecting the eosinophilic phenotype that is present in ≥80% of patients with asthma. As well as being a sensitive marker of inhaled corticosteroid adherence, FeNO is also useful in predicting severe asthma exacerbations that require oral corticosteroids, and now plays a key role in helping clinicians determine subsequent biologic decisions. Severe eosinophilic asthma requires novel therapies targeting interleukin-5 or its receptor. Severe persistent asthma highlights the importance of personalized treatment strategies.
What top tips would you share for using spirometry, oscillometry, FeNO in lung function tests in clinic testing?
One of our initial priorities when performing any lung function test should be to ensure standardised collection of data by trained individuals so that accurate interpretation and translation into clinical practice can occur. Testing for spirometry is standardised by international American Thoracic Society (ATS) guidelines to ensure values meet acceptability, usability, and repeatability criteria. There are also ATS guidelines for FeNO testing and European Respiratory Society (ERS) technical standards for oscillometry.
Before interpreting individual values for the various tools, it might be worth understanding some nuances. For example, our circadian rhythm plays an important role in lung function variability. In people without asthma, it has been shown before that FEV1 can vary by about 70ml during the day, with this effect being closer to 170ml in those with mild-to-moderate asthma. For people with severe asthma this within-day variability is thought to be even higher. To put this into perspective, 170ml closely approaches the minimal clinically important difference for FEV1 of 230ml and therefore those who interpret lung function should always consider what time the test was performed. To further illustrate this point, it is thought that lung function peaks in the early afternoon whereas conversely, symptoms are worst at around 4am. Previous studies looking at eosinophil counts in bronchoalveolar lavage, corresponding to airway inflammation, demonstrated a two-to-three-fold increase at 4am versus 4pm.
Treating asthma, especially in patients with severe asthma, presents unique challenges. Difficult to treat asthma may remain uncontrolled despite high doses of controller medications, often due to factors like coexisting health conditions, poor inhaler technique, and persistent triggers.
Apart from the effect of time, clinicians might also wish to consider the impact of weight gain over time on lung function, with this topic being particularly relevant in our post-covid clinical practice. From the current evidence base, it has been suggested that a higher body mass index results in considerable mechanical compression on the airways, translating into worse spirometry and airway oscillometry measurements. Indeed, elevated BMI is considered a treatable trait in persistent asthma.
Finally, if the data is available, clinicians should try not to rely on one value at a single point in time. For example, a patient with severe asthma attending the specialist clinic with an FEV1 of 80% predicted might previously have had an FEV1 of 100% or equally 65% predicted. The first case would probably be cause for concern whereas the latter scenario may be consistent with a good treatment response.
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About our Vital Insights guest
Dr Rory Chan (MBChB PhD) is a Consultant Respiratory Physician and Senior Clinical Lecturer at NHS Tayside and University of Dundee. His specialist area of research relates to precision medicine in severe asthma, and he has published articles in top respiratory and allergy journals including AJRCCM, ERJ, JACI and Allergy. He is also an Editorial Board Member at the journal CHEST