Problem with spirometry

Historically spirometry, has been used to monitor changes in global lung function over time in health and disease and in clinical trials. This is because spirometry reflects airway calibre and spirometers are inexpensive and portable. However, spirometry has limitations as the technique is highly dependent on breathing technique, requires subject cooperation, and is effort dependant (Faria et al, 2010; Kubota et al, 2009).

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Spirometry is performed under conditions unreflective of normal tidal breathing.

The technique requires a forced manoeuvre that can induce bronchoconstriction (Orehek et al, 1981) and can result in dynamic compression of the airways (Elshout et al, 1990). Respiratory breathing manoeuvres of deep inspiration and forced expiration have both been shown to result in alterations to airway tone (Burns and Gibson, 2002;

Faria et al, 2010; Malmberg et al, 1993; Neild et al, 1989; Orehek et al, 1981).

Spirometry alone may not detect abnormalities in respiratory function early in the manifestation of lung disease. Spirometry does not always detect the changes in respiratory mechanics due to smoking (Coe et al, 1989). It may take several subsequent tests over time before an abnormality is detected since the day to day biological variation can be large.

In patients with COPD, pathological changes leading to COPD are usually progressive, starting many years before a lung function abnormality can be detected with spirometry or radiology imaging (Baughman et al, 2012) and, the FEV1 does not capture the complexity of COPD (Agusti et al, 2010). Additionally, FEV1 correlates poorly with patient centred outcomes such as dyspnoea, exercise capacity, and quality of life (Jones, 2001; Mahler and Harver, 1992). Indeed, in patients with COPD, dyspnoea has been demonstrated to decline while FEV1 remained stable over two years (Halpin, 2009).

182 5.1.3 Beyond spirometry

Longitudinal studies looking at measurements of complete respiratory function and airway inflammatory changes over time are scarce in comparison to studies using spirometry. This is surprising since many patients with asthma and COPD (as well as other respiratory conditions) have previously performed (and continue to perform) more extensive respiratory function tests once or more annually over several years at specialist lung function departments. This includes lung volumes measured by body plethysmography (or helium dilution) and single (or rebreathing transfer factor tests).

Together with spirometry these form the more ‘routine’ lung function tests.

In Chapter 4, I reported on advanced (specialist), lung function tests of exhaled nitric oxide, multiple-breath nitrogen washout and impulse oscillometry as physiological techniques that may be complementary to the established conventional lung function approaches. These tests also allow the assessment of ‘large’ and also ‘small’ airway calibre and the Chapter described a cross-sectional investigation of patients with asthma and COPD to see how respiratory function and inflammation differed across groups. In particular the presence of small airways dysfunction was noted using the advanced tests, that conventional spirometry was unable to detect. One-off physiological results obtained for individual patients are usually used to guide therapy and assess lung health, but if longitudinal data are collected from patients prospectively this would yield valuable information on the variation in respiratory function in patients stratified by disease and severity and also inform on treatment effects over time.

183 5.1.4 Aims of study

In this Chapter a longitudinal study was performed looking at routine and advanced respiratory function measurements in patients with asthma and COPD, importantly including tests of small airways function. The aim was to assess the natural history of the disease and variability with respect to the large, but also small airways function, which may go under-recognised in patients with asthma and COPD using conventional lung function tests.

5.1.5 Hypothesis

The hypothesis was that during the stable clinical state, specialized tests of small and large airway function and inflammation demonstrate a better signal of change of these compartments and variability over time, than measurements obtained from routine conventional lung function tests.

5.2 METHODS

5.2.1 Subjects and study design

This was a longitudinal study that enrolled the same patients and healthy subjects from the cross sectional study (section 2.3, Chapter 2 Methods). The parameters of respiratory function and inflammation have been described in the previous Chapter (4.2.2, Chapter 4) and patients were diagnosed with asthma and COPD and their severity classified according to criteria as previously discussed (section 2.3, Chapter 2 Methods ). Respiratory tests were undertaken every 8 months for a total

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of 3 study visits. This time period was chosen to allow sufficient recruitment of subjects over the 30 month study period such that each subject could attend all 3 visits.

Patients with lung disease continued their medications as normal during the study to reflect real-life practice. All asthmatic and COPD patients were in a stable condition (≥ 4 weeks) at study visits, all tests were tolerated with no patients requiring rescue medication (β2-agonists) and there were no adverse events during study visits. A 5-item Asthma Control Test^TM (ACT) (QualityMetric Incorporated, 2002) questionnaire was provided to measure asthma control in the asthmatic patients at each visit.

5.2.2 Statistical analysis

A repeated measures ANOVA was used to determine if results for each respiratory function parameter were different between the three study visits time points.

The differences were considered statistically significant at a p value <0.01. The intraclass correlation coefficient (ICC) and coefficient of variation (CoV) was calculated for each respiratory function parameter to determine between visit variability.

Parameters that were not normally distributed could not be analysed using the repeated measures ANOVA and are not included here (CalvNO [manual], AXEX, and AX).

Statistical analysis was performed using SPSS statistical package (SPSS version 22 for Windows; SPSS Inc. Chicago, IL)

185 5.3 RESULTS