EUROPEAN RESPIRATORY JOURNAL

EDITORIAL
V. BRUSASCO AND R. PELLEGRINO

Pulmonary function interpretative strategies: from statistics to

clinical practice
Vito Brusasco1 and Riccardo Pellegrino2

1
Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy. 2Centro Medico Pneumologico Torino, Torino, Italy.

Corresponding author: Vito Brusasco ([email protected])

Shareable abstract (@ERSpublications)

The application of suitable reference equations based on a robust statistical approach is central to
pulmonary function testing, but the complexity of lung physiology makes the interpretation of
results in individual patients challenging https://bit.ly/3gUpXz5

Cite this article as: Brusasco V, Pellegrino R. Pulmonary function interpretative strategies: from
statistics to clinical practice. Eur Respir J 2022; 60: 2200317 [DOI: 10.1183/13993003.00317-2022].

Copyright ©The authors 2022. In 2005, the European Respiratory Journal published a series of American Thoracic Society (ATS)/
For reproduction rights and European Respiratory Society (ERS) consensus documents on the standardisation of pulmonary function
permissions contact
testing (PFT), which ended with an article on interpretative strategies [1]. Despite being well received by
[email protected]
the scientific community (with over 3500 citations so far), that article generated controversy in a couple of
Received: 10 Feb 2022 areas and left some questions open due to insufficient evidence available at that time. After more than
Accepted: 13 Feb 2022
10 years, the two societies felt the need to update the whole series, with the main purpose of addressing
recent technical advancements. The final document published in the current issue of the European
Respiratory Journal [2] is again on interpretative strategies. The difference between the two interpretative
documents is that the current one is focused on technical sources of uncertainty, rather than on algorithms
for lung function planning and interpretation in the clinical context.

The choice of reference equations is probably the major source of uncertainty in PFT, a problem that was
left open by the 2005 ATS/ERS committee that realised that no single set of reference values could be
recommended at that time and more work was necessary in this area. One of the greatest and most
important advancements of this new document is definitely the recommendation in favour of the reference
equations provided by the Global Lung Function Initiative (GLI). These were generated using large
datasets by a robust statistical approach taking into account mean, variability and skewness of distributions
over extended ranges of age [3–5]. This avoids uncertainties due to extrapolation beyond age for oldest
subjects, the discontinuity in the transition from adolescence to adult age and, for spirometry, ethnic
differences. Moreover, the GLI equations provide the 5th and 95th percentiles of distributions, which can
be used, as for many biological variables, to define lower and upper limits of normality. These criteria had
been already recommended by the committee of the 2005 document [1] but, unfortunately, most clinical
documents and guidelines in the respiratory field have maintained definitions of lung function
abnormalities based on age- and sex-biased thresholds. An important step forward made by the committee
of the present document is the introduction of the z-score, which is a measure of how far a measured value
is from the predicted one, expressed as standard deviations. Since z-scores can be converted to percentiles
of frequency distribution they provide an estimate of uncertainty in ruling disease in or out, particularly in
the grey area of transition between health and disease. Moreover, z-score has also been proposed for
grading the severity of abnormalities to replace the size-biased percentage of predicted [6]. Ultimately, the
advent of the z-score in respiratory medicine should help remove inconsistencies due to differences in the
definitions of the same type of lung function abnormality by different clinical committees [7, 8].

Since most PFT is undertaken to address a clinical problem, a question is whether such a statistical
approach, however robust, will help dismiss all uncertainties we may have when interpreting the results for
an individual subject. Recent studies have demonstrated that GLI-defined spirometric abnormalities and
z-score grading identify normal ageing phenotypes [9] and meaningful phenotypes of either obstructive or

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EUROPEAN RESPIRATORY JOURNAL EDITORIAL | V. BRUSASCO AND R. PELLEGRINO

restrictive disorders [10]. A general principle of decision making is that the post-test probability of disease
should be estimated considering the pre-test probability; z-score would allow this, avoiding pre-determined
thresholds. Unfortunately, information for estimating pre-test probability is often not provided by the
referring clinician and this should be encouraged by disease-related documents and guidelines.

The current ERS/ATS interpretative document [2] has certainly filled some gaps in the 2005 document [1]
by providing separate and more detailed interpretative flow charts for spirometry, lung volumes and
diffusing capacity. However, a step-by-step approach exploiting all available tests is often necessary to
interpret the PFT of individual patients, owing to the complexity of physiological factors, with possible
contrasting effects on different tests. Generally, forced expiratory volume in 1 s (FEV1) and the ratio of
FEV1 to forced vital capacity (FVC) are taken as the basic markers of lung impairment, not only for their
associations with respiratory diseases and the ease with which they can be measured, but also because they
reflect major determinants of respiratory mechanics. However, it is well known that different pathological
conditions may importantly interfere with their measurement and interpretation. Here are some examples.
As early as 1965, WOOLCOCK and READ [11] reported clinical improvement from severe asthma attack not
reflected by FEV1, which they attributed to return of total lung capacity and lung elastic recoil to
normality. In obesity, static lung volumes tend to decrease whereas FEV1/FVC tends to increase, which
may obscure the presence of airflow obstruction in patients with combined obesity and COPD [12]. In
combined pulmonary fibrosis and emphysema, the overlapping restrictive and obstructive abnormalities
may have opposing effects, by which spirometry and lung volumes may even remain within the range of
normality [13], while they have additive effects on diffusing capacity. In some purely restrictive disorders,
FVC and lung volumes may be occasionally found within normal ranges despite the presence of
significant interstitial fibrosis [14]. This may be explained by pre-morbid values within the upper limits of
normality and diffusing capacity would be required to reveal abnormal lung function.

There are also technical aspects related to manoeuvres that may influence the interpretation of spirometry
in different conditions. First, negative effort-dependence of maximal expiratory flow was documented
several years ago [15]. This phenomenon, which is due to intrathoracic gas compression, will cause FEV1
and FEV1/FVC to be higher in submaximal than maximal efforts, thus possibly masking spirometric
abnormalities. In severe emphysema this effect may account for up to 50% of the FEV1 reduction [16],
thus overrating the severity classification in comparison with COPD patients with prevailing airway
obstructive disease. Moreover, in subjects with large lung volume, gas compression may exaggerate both
bronchoconstrictor and bronchodilator responses to pharmacological agents [17], thus potentially causing
misclassification of asthma or COPD in tall subjects. Second, several studies over the past 25 years have
documented that the deep inspiration preceding the forced expiration may affect spirometric measurements
differently depending on type of disease, e.g. COPD versus asthma, and phase of disease [18]. Finally, in
very few asthma patients, serial spirometric manoeuvres show progressive bronchoconstriction [19]. This
makes the repeatability criteria inapplicable under this condition but gives a clinically useful information.
Altogether, the above examples show how the complexity of lung physiology adds uncertainty to the
interpretation of single or few indices based uniquely on statistical principles, rigorous as they may be.

Another aspect of this document that will certainly stir up discussion within our scientific community is
the role of bronchodilator testing in clinical practice. Historically, the test was born in the 1970s with the
hope of differentiating bronchial asthma from COPD. Yet since the mid-1980s, important trials have let the
purpose of the test remain unfulfilled because of a large overlap of positive responses between groups [20, 21].
In a recent study including 35 628 subjects, the authors concluded that “bronchodilator reversibility was at
least as common in participants with COPD as those with asthma. This indicates that measures of reversibility
are of limited value for distinguishing asthma from COPD in population studies” [22]. Yet to date, the test is
being used in clinical practice to support the diagnosis of COPD [7] or bronchial asthma [8]. In the present
interpretative document, it is recognised that the results of the test “are limited for clinically meaningful
thresholds across a range of diseases and age groups”, but “…there is evidence related to survival to support a
threshold-based approach”. Moreover, it is known that acute bronchodilator responses are not predictive of
responses to long-term treatment. Many colleagues would, therefore, wonder why there is still that much
emphasis on a test unable to address any clinical question and whether prediction of survival could be a good
reason for the patients to undergo this test. The conundrums with the clinical use of bronchodilator tests are
mainly the heterogeneous mechanisms of airflow obstruction, e.g. airway smooth muscle contraction versus
reduced mechanical interdependence between airways and lung parenchyma in different types and stages of
the underlying disease, the poor reproducibility, and the choice of thresholds defining positive response.

In the current document [2], an increase >10% of predicted for FEV1 and/or FVC after inhaling a
bronchodilator agent is recommended, based on population studies. As co-authors of the previous

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EUROPEAN RESPIRATORY JOURNAL EDITORIAL | V. BRUSASCO AND R. PELLEGRINO

interpretative document [1], we acknowledge that the criteria proposed at that time (>200 mL and >12%
from baseline) were imperfect, but this seems to be the case also for the new proposal. For example, in a tall
patient with predicted FEV1 of 3.00 L and baseline FEV1 of 1.20 L, a 0.25-L post-bronchodilator increase
would be said to be insignificant, even if its magnitude is like those found in the majority of clinical trials
with bronchodilators in COPD, being associated with beneficial effects on patient-related outcomes.

In conclusion, we praise the committee members for having filled some technical gaps in the interpretation
of PFT proposing robust predictive values and a rigorous statistical approach. Yet, what remains to be done
is to provide recommendations for choosing the appropriate tests to answer clinical questions in individual
patients considering the complexity of mechanisms underlying pulmonary function abnormalities and make
PFT interpretation more uniform among different disease-specific guidelines.

Conflict of interest: The authors declare no conflict of interest.

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