SAD, a complex and silent signature of asthma

SAD, a complex and silent signature of asthma

Research shows that small airways dysfunction (SAD) is present in 91% of patients with asthma and are involved across almost all disease severities. Patients with severe asthma are especially affected. Untreated SAD has been proposed as a contributing factor to inadequate disease control in 50%–60% of patients.1,2

Small airways (internal diameter ≤2mm or internal perimeter of ≤6mm) are located beyond the 7th and 8th generation of the tracheobronchial tree and account for >98% of the cross sectional area of the lung, ending in the alveolar sacs. They have no cartilage to support their structure and collapse easily on constriction.4,5

Asthma is characterised by chronic inflammation and airway hyper‐reactivity leading to cough, wheeze, difficulty in breathing and chest tightness. Recent studies show that inflammation is associated with bronchial hyper-responsiveness, worsening of asthma symptoms and increased exacerbations. Small airways are narrowed in patients with asthma as a result of inflammation.2,5

Postma et al describe SAD as ‘a complex and silent signature of asthma’. Small airways are considered ‘silent’ because of their relatively low impact on the whole resistance of the respiratory tree compared to larger airways.2,5

Assessing SAD

According to Postma et al although SAD is well recognised in asthma, its role in the severity and control of asthma is unclear. In the AssessmenT of smalL Airways involvemeNT In aSthma (ATLANTIS) study, the team investigated which combination of biomarkers, physiological tests and imaging markers best measure the presence and extent of SAD in asthma patients.2

The study is the most comprehensive evaluation of SAD to date and included 773 patients with a confirmed diagnosis of asthma, and 99 controls without airway obstruction, normal spirometry as well as airways responsiveness, and smoked for a maximum of 10 pack-years.2

Asthma patients’ disease had to be under control using any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than eight weeks before baseline, and they smoked for a maximum of 10 pack-years in their lifetime.2

Diagnosis had to be supported by objective evidence at baseline or during the past five years. Objective evidence included positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200mL within 30 min) after treatment with 400μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over seven days), or documented reversibility after a cycle (eg four weeks) of maintenance anti-asthma treatment.2

All participants were assessed using spirometry, body plethysmography, impulse oscillometry and multiple breath nitrogen washout. Patients with asthma were also assessed using questionnaires about disease control, asthma-related quality of life, as well as health status. Selected participants also underwent computed tomography (CT) scans.2

The team used structural equation modelling to assess the contribution of all physiological and CT variables to SAD in asthma patients. The results were used to define clinical SAD and CT SAD scores and to classify asthma patients into SAD groups. They compared asthma severity, control, and healthcare use during the past year by SAD score and by SAD group.2

SAD findings

Postma and team found that SAD was present in asthma of all severities and showed proportionally more structural and functional abnormalities with increasing clinical severity (Global Initiative for Asthma severity stages [GINA 5], see table 1).

Model-based clustering identified two clinical SAD groups. Patients in group 1 (n=452) had milder SAD compared to group 2. Patients in group 2 (n=312) had abnormal physiological SAD results compared to group 1. In addition group 2 patients had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1.

The authors found that the difference between the two clinical SAD groups was particularly clear with SAD measurements related to spirometry (see box 2) and impulse oscillometry (see box 3). They concluded that these two tests were the most effective in identifying SAD in clinical practice because they are easy to use.

Postma et al concluded that the clinical classification of SAD into two groups using impulse oscillometry and spirometry is meaningful given its association with GINA severity stages, asthma control, quality of life and exacerbations.

According to Zinellu et al, evaluating the functional and inflammatory impairment of small airways should be part of the routine evaluation of all asthma patients, and not just to measure disease severity. Assessment could help in identifying the clinical phenotype (see box 1) and guide treatment decisions.4

Box 1: Most common asthma clinical phenotypes11

Box 2: Spirometry

Spirometry is the most commonlyperformed lung function test in clinicalpractice. Spirometry should be used asthe first line investigation for asthma inadults and in children over five, accordingto the 2021 National Institute of Healthand Care Excellence guidance. A forcedexpiratory volume in one second to forcedvital capacity (FEV 1 /FVC) ratio of less than70% should be considered a positive test forobstructive airway disease. These patientsshould then be offered a bronchodilatorreversibility test, which measures the abilityto reverse obstruction in the airways byusing bronchodilators. An improvementin FEV 1 of 12% or more, together with anincrease in volume of 200ml or more, shouldbe considered a positive test. Postma etal identified spirometry tests of ForcedExpiratory Flow (FEF 25-72 and FEF 50 ) or adecrease in Forced Vital Capacity (FVC) asbest suited for SAD measurement. 2,9

Box 3: Impulse oscillometry

Recent studies have shown that impulse oscillometry is useful in diagnosing asthma and assessing control – especially in children. Impulse oscillometry measures airway resistance and reactance during tidal breathing. While conventional spirometry requires a forced expiratory manoeuvre, impulse oscillometry is an effort-independent and patient-friendly modality for evaluating lung function and peripheral airway dysfunction. Sound waves are superimposed on normal tidal breathing, and the disturbances in flow and pressure caused by the external waves are used to calculate parameters describing the resistance to airflow and reactive parameters that mostly relate to efficient storage and return of energy by the lung. Importantly, impulse oscillometry can differentiate small airway obstruction from large airway obstruction and is more sensitive than spirometry for peripheral airway disease.8,10

References

1. Van den Bosch, James AL, and Tiddens HAWM. Structure and function of small airways in asthma patients revisited. European Respiratory Review, 2021.

2. Postma DS, Brightling C, Baldi S et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study. Lancet Respir Med, 2019.

3. Carpaij OA, Muiser S, Bell AJ et al. Assessing small airways dysfunction in asthma, asthma remission and healthy controls using particles in exhaled air. ERJ Open Research, 2019.

4. Carr TF, Altisheh R, and Ziet M. Small airways disease and severe asthma. WAOJ, 2018.

5. Zinellu E, Piras B, Ruzitte GG et al. Recent Advances in Inflammation and Treatment of Small Airways in Asthma. Int J Mol Sci, 2019.

6. Enilari O and Sinha S. The global impact of asthma in adult populations. Ann Glob Health, 2019.

7. Parsons J and Mastronarde J. Asthma: Clinical Manifestations and Management. Pulmonary Advisor. https://www.pulmonologyadvisor.com/home/ decision-support-in-medicine/pulmonary-medicine/ asthma-clinical-manifestations-and-management/.

8. Desiraju K and Agrawal A. Impulse oscillometry: The state-ofart for lung function testing. Lung India, 2016.

9. NICE (2021). Asthma: diagnosis, monitoring and chronic asthma management. https://www.nice.org.uk/guidance/ ng80/chapter/Recommendations#objective-tests-fordiagnosing-asthma-in-adults-young-people-and-childrenaged-5-and-over

10. Park J-H, Lee JH, Kim H-J et al. Usefulness of impulse oscillometry for the assessment of bronchodilator response in elderly patients with chronic obstructive airway disease. J Thorac Dis, 2019.

11. GINA. Global Strategy for Asthma Prevention. https:// ginasthma.org/wp-content/uploads/2018/04/wms-GINA2018-report-V1.3-002.pdf SF