Precision Medicine: What do Different Asthma Diagnosis Test Types Tell Clinicians?

Diagnosing asthma involves a variety of tests to understand the condition better and tailor the treatment accordingly. There are a range of test types that may be used to assess lung function and airway inflammation. Allergy tests are crucial in identifying potential triggers that may exacerbate asthma symptoms, providing a comprehensive view of a patient's overall health and potential allergens. Additionally, blood tests play a significant role in evaluating eosinophilic asthma by determining the levels of eosinophils and IgE, which are indicators of the severity of asthma. These tests are essential in guiding effective treatment options. 

Spirometry 

Spirometry is one of the most widely used lung function tests for adults in clinic. It measures how much air a person can inhale and exhale, which helps in assessing lung function. The test involves patients performing a forced expiratory manoeuvre to obtain values including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow rate between 25% and 75% of FVC (FEF25-75) as well as FEV1/FVC ratio. A diagnosis of obstructive airways disease such as in asthma or chronic obstructive pulmonary disease can be supported by an FEV1 <80% predicted and an FEV1/FVC <0.70. Alternatively restrictive airways limitation can be demonstrated by commensurate reductions in both FEV1 and FVC but a subsequently preserved FEV1/FVC ratio, as can sometimes be seen with interstitial lung disease and severe obesity. FEF25-75, a measure of mid-expiratory flow, is less commonly used but has been shown to be a more sensitive measure of small airways disease. 

In addition to absolute spirometry indices, examination of the flow volume loop (FVL) can yield useful additional information. The FVL is a plot of inspiratory and expiratory flow on the Y-axis against volume on the X-axis during the forced expiratory manoeuvre. It demonstrates characteristic appearances in obstructive and restrictive conditions as well as in upper airway obstruction. 

Oscillometry 

Asthma can be particularly tricky to diagnose since the main spirometry values are often entirely normal at the time of testing. Oscillometry is another type of pulmonary function test that can be particularly useful in diagnosing asthma when spirometry results are normal. In this regard, the small airways are more accurately assessed using airway oscillometry, a physiological tidal breathing test that superimposes sound or air waves to measure lung impedance. It has the additional advantage of being effort independent and therefore is especially useful in paediatric or elderly patients or those with severe respiratory disease who might otherwise not be able to perform a forced manoeuvre. 

The first component of impedance is resistance typically measured at 5Hz (R5) as total airway resistance or 20Hz (R20) as large airway resistance. Subtracting R20 from R5 (R5-R20) has been shown through computational modelling to correspond closely with small airway resistance. The second measurable component of impedance is reactance (X) which itself is reflective of capacitance and inertance. Capacitance describes the elasticity of the airways whereas inertance reflects the mass-inertive forces of the moving air column. Reactance can be assessed commonly at 5Hz (X5) or across a range of frequencies as the area under the reactance curve (AX). Recently airway oscillometry ratios (R5-R20 divided by R5) as the ratio between peripheral to total airway resistance, have been shown to correspond to worse symptom control and a greater frequency of exacerbations in patients with persistent asthma. It has been demonstrated that for R5-R20, AX and R5-R20/R5, values exceeding ≥0.10kPa/L/s, ≥1.0kPa/L and ≥19% respectively represent severe small airway dysfunction in patients with moderate-to-severe asthma.  

FeNO test 

Fractional exhaled nitric oxide is a point of care asthma test that can be used to measure the degree of eosinophilic airway inflammation. It is closely linked to asthma exacerbation rates and can also be used as a marker of adherence to inhaled corticosteroid therapy. The American Thoracic Society guidelines recommend general cut points to denote high, medium or low FeNO as >50ppb, between 25 and 50ppb and <25ppb respectively. FeNO increases with height, age and sex, and levels can be increased by more than 60% by eating nitrogen-rich foods. Conversely, it can be reduced by corticosteroids, bronchoconstriction and smoking. In addition to its association with exacerbation risk, FeNO levels also predict poor lung function and longitudinal lung function decline. Moreover, high FeNO levels have previously been shown to be associated with superior exacerbation reduction in response to asthma biologics including omalizumab, mepolizumab, dupilumab and tezepelumab. 

Home PEF/FEV1  

There is considerable value in being able to remotely monitor patients with asthma with home spirometry. Home PEF/FEV1 monitoring is particularly valuable for patients who have already had asthma diagnosed and need to monitor their condition remotely. A good example was during the recent COVID-19 pandemic when face to face consultations were being minimised. Even in the absence of a pandemic, clinic spirometry is not always available due to pre-existing limitations such as appointment times, trained staff and equipment shortages, and an inability to monitor lung function at a static time point if the patient is unwell. On the contrary, home spirometry also has its limitations and cannot entirely substitute clinic tests. Conventionally there is low adherence to monitoring, poor technique that may or may not improve with coaching and even variability between devices. These conclusions have recently been confirmed in a large post hoc analysis comparing home versus clinic spirometry, but further research is indicated. 

Blood eosinophils/imaging & CT, questionnaires 

In addition to blood eosinophils and imaging, doctors often perform allergy tests to identify potential triggers for asthma symptoms. Peripheral blood eosinophils are mediated by interleukin-5 and are closely associated with severe asthma exacerbation risk. Furthermore, they predict response to biologics that target this pathway including reslizumab, mepolizumab and benralizumab. One of the main points to bear in mind is that blood eosinophils exhibit considerable variability over time in patients with severe asthma and therefore a single low value should always be repeated at a later date. 

High resolution CT (HRCT) imaging has been used successfully in recent years to identify pulmonary (mucus plugging and bronchial wall thickness) and extrapulmonary features (mediastinal lymph nodes and paraspinal muscle density) relating to asthma phenotypes. Historically, mucus plugging was thought to only play an important role in fatal asthma. However, in recent years, we now know it is associated with type 2 inflammation (as blood eosinophils, FeNO and total IgE), worse lung function (as spirometry) and greater severe exacerbation frequency. Bronchial wall thickness, on the other hand, has also been shown to correspond to worse lung function (as spirometry and airway oscillometry), higher levels of blood eosinophils and severe asthma exacerbation risk. A recent publication has reported on the relationship between worse spirometry, airway oscillometry and greater total IgE levels in asthma patients with larger mediastinal lymph nodes. Finally, paraspinal muscle density, which is a surrogate for skeletal muscle adiposity, has been associated with longitudinal spirometry decline and worse airway oscillometry in women with persistent asthma. 

A physical exam is also crucial in evaluating a patient's overall health and signs of asthma. Common questionnaires that are used in clinical practice and in research to assess symptom control include the asthma control questionnaire (ACQ) and the asthma control test (ACT). ACQ is a 7-point questionnaire that enquires about asthma symptoms, bronchodilator use and spirometry FEV1, although shortened versions have also been validated. The minimal clinical important difference (MCID) is 0.5 units, with values of <0.75 units denoting optimal control and ≥1.5 units representing poorly controlled asthma. ACT consists of 5 questions with a maximum score out of 25. Poor asthma control is observed with a score of ≤19 and the MCID is 3 units. The mini-asthma quality of life questionnaire (mini-AQLQ) is an abbreviated form of the AQLQ and consists of 15 questions with a MCID of 0.5. 

Combining investigations / Multi-diagnostic approach for diagnosing asthma 

Combining various diagnostic methods helps to accurately diagnose asthma and determine its severity, including moderate persistent asthma. 

Ultimately, the investigations discussed aid the clinician in making an asthma diagnosis or help predict key outcomes such as exacerbation risk. Instead of relying on one or two tests, there is a strong reason for combining investigations. For example, the triple type 2 signature characterised by concomitant FeNO≥25ppb, blood eosinophils ≥300 cells/µl and allergy as total IgE ≥100kU/L has been shown to be significantly associated with increased asthma exacerbation frequency and worse FEF25-75. Conversely, the triple type 2 low phenotype is associated with better spirometry. 

Likewise, combining pulmonary function modalities as spirometry or oscillometry with type 2 biomarkers results in a greater likelihood for detecting worse symptom control and exacerbations in asthma. Furthermore, when amalgamating imaging features, the triple radiological phenotype characterised by mucus plugging, bronchial wall thickness and larger mediastinal lymph nodes, is associated with greater allergy burden and more frequent exacerbations.  Combining imaging features and other diagnostic methods helps to diagnose asthma more accurately. 

Ready to take your asthma management approach to the next level with precision medicine? 

Understanding what different diagnostic test types reveal can help tailor treatments to each patient’s unique needs. Dive deeper into the world of precision medicine by exploring our comprehensive resources on asthma diagnostics or contact our experts and allow us to enhance your clinical practice today with personalised care designed to lead to better outcomes for your patients. 

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