The authors declare that they have no competing interests.
Authors’ contributions
JP, DIB and CD2 designed the cohort design and analysis plan. Analyses were performed by CD2. All authors (JP, LP, CP, RB, HN, CD2 and DIB) contributed to recruitment, data collection, discussion of results and final approval of the submitted manuscript.
The single-breath carbon monoxide diffusing capacity (DL
CO) is the product of two measurements during breath holding at full inflation: the rate constant for carbon monoxide uptake from alveolar gas (K
CO [minute
−1]) and the “accessible” alveolar volume (V
A). Consequently, the same DL
CO may result from various combinations of K
CO and V
A values. Changes in each of K
CO and V
A may reflect different injury sites and mechanisms. In theory, the decrease in DL
CO may result from a fall in V
A (mainly due to restrictive and/or obstructive defects) and/or a fall in K
CO (due to alveolar/capillary damage or a microvascular disease). Few studies have focused on the significance of DL
CO in diffuse parenchymal lung diseases (DPLD) [
1–
5], highlighting the prognostic value of its component K
CO. No study to our knowledge has sought to assess the validity of the above mentioned theory in the context of DPLD. Our primary objective in the present study was to assess in a large cohort of distinct types of DPLD the potential variability of both V
A and K
CO for fixed values of DL
CO. A secondary objective was to determine whether a low V
A value in this context might reflect a distal airway obstruction in addition to a potential restrictive defect. To this end, we designed a retrospective, cross-sectional study of three distinct types of DPLD: idiopathic pulmonary fibrosis (IPF, the prototype for fibrotic pulmonary diseases predominantly affecting the lower lobes), stage IV sarcoidosis (predominantly affecting the upper lobes) and connective tissue disease-associated interstitial lung diseases (CTD-ILDs, which are usually characterized by diffuse, inflammatory lesions rather than fibrotic damage).
Methods
Each of three university hospitals in France provided pulmonary function test (PFT) datasets from around 80 DPLD patients (75, 80 and 87 patients, respectively). Pulmonary function tests had been performed according to international recommendations and had used similar quality criteria [
6–
8]. Only raw PFT data were provided and % predicted values were subsequently calculated by a single investigator (CD2) for the whole population according to Stanojevic for spirometry [
9] and other international recommendations for DL
CO and static lung volumes respectively [
10,
11]. The PFTs (spirometry, body plethysmography and single-breath carbon monoxide transfer) using routine techniques had been performed for clinical purposes. We got approval from the Institutional Review Board of the French learned society for respiratory medicine – Société de Pneumologie de Langue française, which judged our study as fully observational and which therefore did not require any informed consent.
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Two-hundred and forty-two patients with complete datasets were retrospectively assigned to IPF (n = 85), sarcoidosis (n = 73) or CTD-ILD (n = 84) groups. Patients with IPF and CTD-ILD exhibited lower values of DL
CO than those with sarcoidosis (43 ± 18 % predicted (11-89 %), 44 ± 15 (12-88 %), and 56 ± 18 % (19-115 %), in IPF, CTD-ILD and sarcoidosis, respectively, p < 0.0001). Then, three PFT datasets (one per group) were matched for DL
CO % predicted (agreement 5 %, by a single investigator (CD2)) to allow comparisons of the groups at similar levels of DL
CO. Consequently, 77 patients were excluded from the analysis due to matching selection (for instance IPF and CTD-ILD subjects with very low DL
CO % predicted values and sarcoidosis subjects with high DL
CO values). Results were expressed as means ± SD. Continuous variables were compared using the Student’s
t-test or the analysis of variance (ANOVA, see Table) as appropriate. The chi-squared test was used for the comparison of qualitative variables (smoking history). Statistical significance was defined by a
p value <0.05. All analyses were performed using the Statview 4 package (SAS institute, Grenoble, France).
Results
One hundred and sixty-five PFT datasets (55 per group) were analysed (Table
1). The three study groups had similar mean values for K
CO and V
A as well as for DL
CO (the matching criterion). However, on an individual patient basis, a similar DL
CO could be obtained from various combinations of K
CO and V
A (Fig.
1). This figure clearly shows that K
CO can vary from decreased (diffuse loss of units) to normal or barely increased (discrete loss of units) values. We show here that for a similar DL
CO value of 50 % predicted, for instance, K
CO varied from 60 to 95 % predicted and V
A from 55 to 85 % predicted.
Table 1
Demographic and functional characteristics of the study participants
Relationships between DL
CO on one hand and V
A (left panel) and K
CO (right panel) on the other. Circles represent sarcoidosis (closed: with airflow limitation, n = 17; open: without airflow limitation).
a Dotted lines describe “reduced expansion” (upper bold line) and “loss of units” effects, calculated according to Hughes and Pride [
4]. Patients with DPLD lied in the discrete to diffuse loss of alveolar unit areas.
b The dotted line is the identity line for the DL
CO-K
CO plot; patients along this line have normal V
A and the reduced DL
CO is related to a decrease in K
CO due to microvascular pathology
×
In addition, 17 patients exhibited an airflow limitation (FEV
1/FVC < lower limit of normal). They all belonged to the sarcoidosis group (Table
1). The reduction in alveolar volume (measured using a dilution technique) relative to total lung volume (TLC, measured using body plethysmography), expressed as V
A/TLC, was correlated with parameters of central airway obstruction (FEV
1/FVC: r
2 = 0.10, p < 0.001) and even more strongly with distal airway obstruction (RV/TLC: r
2 = 0.25, p < 0.001). Since the V
A/TLC value of the population as a whole may seem lower than expected (Table
1) even in patients without significant airflow limitation (n = 148, FEV
1/FVC = 0.82 ± 0.06), we further evaluated whether some patients exhibited a small airways obstructive syndrome defined by a normal FEV
1/FVC ratio and a greater reduction of both FEV
1 and FVC than TLC (FVC % predicted/TLC % predicted < 0.80). We found 20 such subjects, described in Table
2. Similarly to proximal airflow limitation, small airways obstructive syndrome was predominantly present in sarcoidosis.
Table 2
Small airway obstructive syndrome (SAOS) in patients without proximal airflow limitation (FEV1/FVC > lower limit of normal)
Our present study confirms that an abnormally low DL
CO can result from very different combinations of the primary measurements K
CO and V
A. This was the case for all three types of DPLD. Furthermore, the assessment of V
A/TLC [
12], the latter being obtained from body plethysmography, may suggest both central or peripheral airway obstruction and this was observed particularly in sarcoidosis thereby providing additional clues to the pathogenic features of this condition. We recently described diseases associated with a small airway obstructive syndrome (a non-specific pattern frequently observed in pulmonary function testing units [
13]). It is noteworthy that in that study, sarcoidosis and interstitial pneumonia were two of the conditions associated with this pattern. In the present work, we extend our previous data showing that a DPLD can exhibit a mixed pattern associating both a restrictive syndrome and a small airways obstructive syndrome.
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Conclusions
In conclusion, we confirmed that the components of DL
CO (K
CO and V
A) may largely vary in DPLD while DL
CO appears constant. The magnitudes of K
CO and V
A values might indicate distinct disease mechanisms and thereby bear a relative prognostic value in addition to giving clues to pathogenesis of these diseases. For these reasons, clinicians should take into account not only DL
CO but also V
A and K
CO when seeking to assess DPLD, in order to provide a more informed and better care to these patients.
Acknowledgements
The authors thank Mr David FRASER (Biotech Communication) for his writing assistance.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JP, DIB and CD2 designed the cohort design and analysis plan. Analyses were performed by CD2. All authors (JP, LP, CP, RB, HN, CD2 and DIB) contributed to recruitment, data collection, discussion of results and final approval of the submitted manuscript.
