Review
Bronchodilator reversibility in chronic obstructive pulmonary disease: use and limitations

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Summary

The change in forced expiratory volume in 1 s (FEV1) after administration of a short-acting bronchodilator has been widely used to identify patients with chronic obstructive pulmonary disease (COPD) who have a potentially different disease course and response to treatment. Despite the apparent simplicity of the test, it is difficult to interpret or rely on. Test performance is affected by the day of testing, the severity of baseline lung-function impairment, and the number of drugs given to test. Recent data suggest that the response to bronchodilators is not enhanced in patients with COPD and does not predict clinical outcomes. In this Review we will discuss the insight that studies of bronchodilator reversibility have provided into the nature of the COPD, and how the abnormal physiology seen in patients with this disorder can be interpreted.

Introduction

Chronic obstructive pulmonary disease (COPD) is the term used to describe a persistent and generally progressive illness that results from a respiratory bronchiolitis, beginning in the most peripheral airways,1 and that is often accompanied by alveolar loss (emphysema).2 These pathological changes delay lung emptying at rest and even more so during exercise3 and are characterised by the presence of abnormal obstructive spirometry, customarily defined as a reduction in the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio to 0·7 or less. However, this criterion is inappropriate for use in elderly patients4 and has led some experts to advocate the use of an age-related lower limit of normal for this ratio.5, 6 The degree to which the FEV1 falls below the predicted normal value has been used as a marker of disease severity, although recent treatment guidance has emphasised the need to base decisions about management on clinical factors as well as spirometric impairment.7 Theoretically, spirometric data should be measured after an inhaled bronchodilator is given. This approach has been applied in recent international studies of COPD prevalence8, 9 and remains the recommended method to assess disease severity.7

Key messages

  • Small changes in FEV1 after a bronchodilator in individuals with mild chronic obstructive pulmonary disease (COPD) can challenge the diagnosis of COPD

  • The absolute change in FEV1 post-bronchodilator varies with the day of testing, the number of bronchodilator drugs used to test, and drug dose

  • The absolute increase in FEV1 post-bronchodilator is similar in individuals with moderate COPD and healthy smokers

  • The absolute increase in FEV1 post-bronchodilator decreases as baseline FEV1 decreases and so does the chance of being classified as reversible

  • Although the average number of reversible patients in a COPD population is stable over time, individuals change their reversibility status on repeat testing

  • Reversibility status does not identify patients with a different clinical course or response to treatment nor does it add to the baseline FEV1 in the prediction of patients with more rapid disease progression

  • In patients with clinical and spirometric evidence of COPD, reversibility testing adds little to management. However, in patients who have atypical clinical features, reversibility testing is still warranted

COPD differs from bronchial asthma, which is also associated with obstructive spirometry, because patients with COPD do not show substantial variability in lung function either spontaneously or in short-term response to treatment. However, this has not prevented many clinicians and investigators10 from trying to identify discrete phenotypes of patients with COPD who show a greater than anticipated change in spirometry after treatment with a short-acting bronchodilator drug. A positive response in the bronchodilator reversibility test has been suggested to identify differences in the clinical course and therapeutic response of patients with COPD that have not been prospectively established. Nobel prize-winning psychologist Daniel Kahneman noted that it is easier to substitute the answer to an easy question when a hard one is asked. 11 In this case, doctors have extrapolated their observation of an immediate change in lung function after administration of bronchodilators into an expectation that this will predict clinical outcome. We believe that there is now good evidence that this is not the case. The topic of bronchodilator reversibility in patients with COPD has been reviewed previously,12, 13 but recently published data allow this commonly used mode of testing to be set into a wider context. We clarify what can and cannot be ascertained with confidence from this widely used but surprisingly confusing test.

Section snippets

How to define bronchodilator reversibility

The term bronchodilator reversibility implies the complete or near complete correction of an obstructive spirometric abnormality. Such changes can occur in patients with bronchial asthma but are not always seen. Normalisation of spirometry after administration of a bronchodilator is not seen in patients with COPD unless the baseline FEV1 is close to the predicted normal value before the drug is given. In this case, a small absolute increase in FEV1 can mean that the post-bronchodilator value is

Drawbacks of reversibility tests in COPD

Large clinical studies have examined the usefulness and performance characteristics of bronchodilator reversibility testing across a wide range of COPD severities defined by spirometry.14, 17, 19, 20, 31, 33, 34, 35, 36, 37, 38 The table describes the characteristics of several of the most important studies. These studies have identified issues in many key areas, which are discussed in turn.

Physiological mechanisms associated with bronchodilator responsiveness

Whatever their mode of action, inhaled bronchodilators produce rapid relaxation of airway smooth muscle and improve the expiratory flow rate. In COPD, in which increased peripheral airways resistance and a variable loss of lung elastic recoil exists, expiratory flow limitation (a disorder in which the expiratory flow rate cannot be increased or falls despite increasing effort) often occurs during tidal breathing.47, 48 Flow limitation develops earlier during a forced expiratory manoeuvre in

Methodological challenges with spirometry data

The measurement of spirometry involves patient cooperation, is effort dependent, and has a known within-day reproducibility in COPD.64 The 200 mL threshold incorporated as part of the reversibility definition is designed to take into account the variation in spirometric measurement and to ensure that any change reported has not happened because of chance variation in the test itself.15, 65 Nonetheless, some positive tests can arise by chance, especially when the baseline FEV1 value is low. This

Clinical and research lessons for the future

Several decades of intensive study of reversibility testing in COPD has highlighted some important truths about COPD and our general approach to interpretation of spirometry data in clinical settings. First, the apparent simplicity of classification of a patient as either reversible or not on the basis of one test has proven to be an illusion. Without an understanding of the between and within test variability in FEV1, this apparently straightforward test of lung function can easily be

Conclusion

Bronchodilator reversibility in patients with COPD is a normally distributed continuous variable and the application of specific criteria defining significant and insignificant reversibility is arbitrary. Careful study has revealed that bronchodilator reversibility varies between tests, often as a function of baseline FEV1—ie, for an individual on a specific testing day, a decreased baseline FEV1 is associated with an increased chance of significant reversibility. This finding is independent of

Search strategy and selection criteria

This Review combines the research of the authors over many years with a search of Medline and Embase for articles published in English from Jan 1, 2003, to Oct 30, 2012, using the search terms “bronchodilator reversibility”, “chronic obstructive pulmonary disease” OR “chronic bronchitis” OR “emphysema”, and “reversibility testing”. Relevant references published before the search period were also included and references from relevant articles were also searched. Review articles and book chapters

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