Abstract
Background: Combined pulmonary fibrosis and emphysema (CPFE) is a distinct entity among fibrosing lung diseases with a high risk for lung cancer and pulmonary hypertension (PH). Notably, concomitant PH was identified as a negative prognostic indicator that could help with early diagnosis to provide important information regarding prognosis. Objectives: The current study aimed to determine whether cardiopulmonary exercise testing (CPET) can be helpful in differentiating patients having CPFE with and without PH. Methods: Patients diagnosed with CPFE in 2 German cities (Hemer and Greifswald) over a period of 10 years were included herein. CPET parameters, such as peak oxygen uptake (peak VO2), functional dead space ventilation (VDf/VT), alveolar-arterial oxygen difference (AaDO2), arterial-end-tidal CO2 difference [P(a-ET)CO2] at peak exercise, and the minute ventilation-carbon dioxide production relationship (VE/VCO2 slope), were compared between patients with and without PH. Results: A total of 41 patients with CPET (22 with PH, 19 without PH) were analyzed. Right heart catheterization was performed in 15 of 41 patients without clinically relevant complications. Significant differences in peak VO2 (861 ± 190 vs. 1,397 ± 439 mL), VO2/kg body weight/min (10.8 ± 2.6 vs. 17.4 ± 5.2 mL), peak AaDO2 (72.3 ± 7.3 vs. 46.3 ± 14.2 mm Hg), VE/VCO2 slope (70.1 ± 31.5 vs. 39.6 ± 9.6), and peak P(a-ET)tCO2 (13.9 ± 3.5 vs. 8.1 ± 3.6 mm Hg) were observed between patients with and without PH (p < 0.001). Patients with PH had significantly higher VDf/VT at rest, VT1, and at peak exercise (65.6 ± 16.8% vs. 47.2 ± 11.6%; p < 0.001) than those without PH. A cutoff value of 44 for VE/VCO2 slope had a sensitivity and specificity of 94.7 and 72.7%, while a cutoff value of 11 mm Hg for P(a-ET)CO2 in combination with peak AaDO2 >60 mm Hg had a specificity and sensitivity of 95.5 and 84.2%, respectively. Combining peak AaDO2 >60 mm Hg with peak VO2/body weight/min <16.5 mL/kg/min provided a sensitivity and specificity of 100 and 95.5%, respectively. Conclusion: This study provided initial data on CPET among patients having CPFE with and without PH. CPET can help noninvasively detect PH and identify patients at risk. AaDO2 at peak exercise, VE/VCO2 slope, peak P(a-ET)CO2, and peak VO2 were parameters that had high sensitivity and, when combined, high specificity.
References
1.
Auerbach
O
, Garfinkel
L
, Hammond
EC
. Relation of smoking and age to findings in lung parenchyma: a microscopic study
. Chest
. 1974
;65
(1
):29
–35
. .2.
Wiggins
J
, Strickland
B
, Turner-Warwick
M
. Combined cryptogenic fibrosing alveolitis and emphysema: the value of high-resolution computed tomography in assessment
. Respir Med
. 1990
;84
:365
–9
.3.
Hiwatari
N
, Shimura
S
, Takishima
T
. Pulmonary emphysema followed by pulmonary fibrosis of undetermined cause
. Respiration
. 1993
;60
(6
):354
–8
. .4.
Lim
TK
. Respiratory failure from combined emphysema and pulmonary fibrosis
. Singapore Med J
. 1993
;34
(2
):169
–71
..5.
Doherty
MJ
, Pearson
MG
, O’Grady
EA
, Pellegrini
V
, Calverley
PM
. Cryptogenic fibrosing alveolitis with preserved lung volumes
. Thorax
. 1997
;52
(11
):998
–1002
. .6.
Papiris
SA
, Triantafillidou
C
, Manali
ED
, Kolilekas
L
, Baou
K
, Kagouridis
K
, et al. Combined pulmonary fibrosis and emphysema
. Expert Rev Respir Med
. 2013
;7
(1
):19
–32
. .7.
Cottin
V
, Nunes
H
, Brillet
PY
, Cordier
JF
. Groupe d’Etude et de Recherche sur les Maladies Orphelines Pulmonaires (GERM O P). Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity
. Eur Respir J
. 2005
;26
:586
–93
.8.
Kitaguchi
Y
, Fujimoto
K
, Hanaoka
M
, Kawakami
S
, Honda
T
, Kubo
K
. Clinical characteristics of combined pulmonary fibrosis and emphysema
. Respirology
. 2010
;15
(2
):265
–71
. .9.
Jacob
J
, Bartholmai
BJ
, Rajagopalan
S
, Karwoski
R
, Nair
A
, Walsh
SLF
, et al. Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema
. Respirology
. 2018
;23
(6
):593
–9
. .10.
Ryerson
CJ
, Hartman
T
, Elicker
BM
, Ley
B
, Lee
JS
, Abbritti
M
, et al. Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis
. Chest
. 2013
;144
(1
):234
–40
. .11.
Mejía
M
, Carrillo
G
, Rojas-Serrano
J
, Estrada
A
, Suárez
T
, Alonso
D
, et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension
. Chest
. 2009
;136
(1
):10
–5
. .12.
Cottin
V
, Le Pavec
J
, Prévot
G
, Mal
H
, Humbert
M
, Simonneau
G
, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome
. Eur Respir J
. 2010
;35
(1
):105
–11
. .13.
Brewis
MJ
, Church
AC
, Johnson
MK
, Peacock
AJ
. Severe pulmonary hypertension in lung disease: phenotypes and response to treatment
. Eur Respir J
. 2015
;46
(5
):1378
–89
. .14.
Wanger
J
, Clausen
JL
, Coates
A
, Pedersen
OF
, Brusasco
V
, Burgos
F
, et al. Standardisation of the measurement of lung volumes
. Eur Respir J
. 2005
;26
(3
):511
–22
. .15.
Schiller
NB
. Pulmonary artery pressure estimation by Doppler and two-dimensional echocardiography
. Cardiol Clin
. 1990
;8
(2
):277
–87
. .16.
Rosenkranz
S
, Ghofrani
HA
, Grünig
E
, Klose
H
, Olschewski
H
, Opitz
C
, et al. Pulmonary hypertension: cologne Consensus Conference 2016
. Dtsch Med Wochenschr
. 2016
;141
(24
):1778
–82
.17.
Hoeper
MM
, Bogaard
HJ
, Condliffe
R
, Frantz
R
, Khanna
D
, Kurzyna
M
, et al. Definitions and diagnosis of pulmonary hypertension
. J Am Coll Cardiol
. 2013
;62
(25 Suppl
):D42
–50
. .18.
Galiè
N
, Humbert
M
, Vachiery
JL
, Gibbs
S
, Lang
I
, Torbicki
A
, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)
. Eur Heart J
. 2016
;37
(1
):67
–119
.19.
Opitz
CF
, Blindt
R
, Blumberg
F
, Borst
MM
, Bruch
L
, Leuchte
HH
, et al. Pulmonary hypertension: hemodynamic evaluation. Updated recommendations of the Cologne Consensus Conference 2011
. Int J Cardiol
. 2011
;154
:S13
–19
.20.
Rosenkranz
S
, Behr
J
, Ewert
R
, Ghofrani
HA
, Grünig
E
, Halank
M
, et al. [Right heart catheterization in pulmonary hypertension]
. Dtsch Med Wochenschr
. 2011
;136
(50
):2601
–20
. .21.
American Thoracic Society, American College of Chest Physicians
. ATS/ACCP statement on cardiopulmonary exercise testing
. Am J Respir Crit Care Med
. 2003
; 167
(2
):211
–77
.22.
Wasserman
K
, Hansen
JE
, Sue
DY
, Whipp
BJ
, Casaburi
R
. Principles of exercise testing and interpretation
. 2nd ed. Lea & FebigerAppendix D
; 1994
. p. 454
–64
..23.
Meyer
FJ
, Borst
MM
, Buschmann
HC
, Claussen
M
, Dumitrescu
D
, Ewert
R
, et al. Belastungsuntersuchungen in der Pneumologie. Empfehlungen der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V
. Pneumologie
. 2018
;72
(10
):687
–731
.24.
Westhoff
M
, Rühle
KH
, Greiwing
A
, Schomaker
R
, Eschenbacher
H
, Siepmann
M
, et al. Ventilatorische und metabolische (Laktat-)-Schwellen. Positionspapier der Arbeitsgemeinschaft spiroergometrie
. Dtsch Med Wochenschr
. 2013
;138
(6
):275
–80
.25.
Sun
XG
, Hansen
JE
, Oudiz
RJ
, Wasserman
K
. Exercise pathophysiology in patients with primary pulmonary hypertension
. Circulation
. 2001
;104
(4
):429
–35
. .26.
van der Plas
MN
, van Kan
C
, Blumenthal
J
, Jansen
HM
, Wells
AU
, Bresser
P
. Pulmonary vascular limitation to exercise and survival in idiopathic pulmonary fibrosis
. Respirology
. 2014
;19
(2
):269
–75
. .27.
Gläser
S
, Obst
A
, Koch
B
, Henkel
B
, Grieger
A
, Felix
SB
, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. The predictive value of exercise capacity and gas exchange efficiency
. PLoS One
. 2013
;8
(6
):e65643
.28.
Laveneziana
P
, Montani
D
, Dorfmüller
P
, Girerd
B
, Sitbon
O
, Jaïs
X
, et al. Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations
. Eur Respir J
. 2014
;44
(4
):1069
–72
. .29.
Weatherald
J
, Farina
S
, Bruno
N
, Laveneziana
P
. Cardiopulmonary exercise testing in pulmonary hypertension
. Ann Am Thorac Soc
. 2017
;14
(Suppl_1
):S84
–92
. .30.
Boucly
A
, Morélot-Panzini
C
, Garcia
G
, Weatherald
J
, Jaïs
X
, Savale
L
, et al. Intensity and quality of exertional dyspnoea in patients with stable pulmonary hypertension
. Eur Respir J
. 2020
;55
(2
):1802108
. .31.
Weatherald
J
, Sattler
C
, Garcia
G
, Laveneziana
P
. Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space
. Eur Respir J
. 2018
;51
(2
):1700860
. .32.
Costa
CM
, Neder
JA
, Verrastro
CG
, Paula-Ribeiro
M
, Ramos
R
, Ferreira
EM
, et al. Uncovering the mechanisms of exertional dyspnoea in combined pulmonary fibrosis and emphysema
. Eur Respir J
. 2020
;55
(1
):1901319
. .33.
Jacob
J
, Bartholmai
BJ
, Rajagopalan
S
, Kokosi
M
, Maher
TM
, Nair
A
, et al. Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis
. Eur Respir J
. 2017
;50
(1
):1700379
. .34.
Righini
FM
, Apostolo
A
, Heck
PB
, Farina
S
, Hager
A
, Correale
M
, et al. Exercise physiology in pulmonary hypertension patients with and without congenital heart disease
. Eur J Prev Cardiol
. 2019
;26
(1
):86
–93
. .35.
Balady
GJ
, Arena
R
, Sietsema
K
, Myers
J
, Coke
L
, Fletcher
GF
, et al. Clinician’s Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association
. Circulation
. 2010
;122
(2
):191
–225
. .36.
Groepenhoff
H
, Vonk-Noordegraaf
A
, Boonstra
A
, Spreeuwenberg
MD
, Postmus
PE
, Bogaard
HJ
, et al. Exercise testing to estimate survival in pulmonary hypertension
. Med Sci Sports Exerc
. 2008
;40
(10
):1725
–32
. .37.
Groepenhoff
H
, Vonk-Noordegraaf
A
, van de Veerdonk
MC
, Boonstra
A
, Westerhof
N
, Bogaard
HJ
, et al. Prognostic relevance of changes in exercise test variables in pulmonary arterial hypertension
. PLoS One
. 2013
;8
(9
):e72013
. .38.
Wensel
R
, Francis
DP
, Meyer
FJ
, Opitz
CF
, Bruch
L
, Halank
M
, et al. Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension
. Int J Cardiol
. 2013
;167
(4
):1193
–8
. .39.
Guazzi
M
, Adams
V
, Conraads
V
, Halle
M
, Mezzani
A
, Vanhees
L
, et al. EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations
. Circulation
. 2012
;126
(18
):2261
–74
. .40.
Farina
S
, Correale
M
, Bruno
N
, Paolillo
S
, Salvioni
E
, Badagliacca
R
, et al. The role of cardiopulmonary exercise tests in pulmonary arterial hypertension
. Eur Respir Rev
. 2018
;27
(148
):170134
. .© 2021 S. Karger AG, Basel
2021
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
