State-of-the-Art Paper
Pulmonary Hypertension in Chronic Lung Diseases

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Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP ≥25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP ≥35 mm Hg or mPAP ≥25 mm Hg with low cardiac index [CI <2.0 l/min/m2]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The “severe PH group” includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care.

Key Words

combined pulmonary fibrosis and emphysema
COPD
exhausted circulatory reserve
exhausted ventilatory reserve
lung fibrosis
pulmonary hypertension in chronic lung disease

Abbreviations and Acronyms

6MWD
6-min walk distance
BNP
brain natriuretic peptide
CI
cardiac index
COPD
chronic obstructive pulmonary disease
CPFE
combined pulmonary fibrosis and emphysema
CT
computed tomography
DLCO
diffusing capacity of lung for carbon monoxide
DPLD
diffuse parenchymal lung disease
ERA
endothelin receptor antagonist
FEV1
forced expiratory volume in 1 s
FVC
forced vital capacity
IPAH
idiopathic pulmonary arterial hypertension
IPF
idiopathic pulmonary fibrosis
mPAP
mean pulmonary artery pressure
PaCo2
partial pressure of carbon dioxide in arterial blood
Pao2
partial pressure of oxygen in arterial blood
PH
pulmonary hypertension
PH-SA
pulmonary hypertension in sarcoidosis
PVR
pulmonary vascular resistance
RHC
right heart catheterization

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Dr. Seeger has received speaker fees from Pfizer and Bayer HealthCare; and consultant fees from Bayer Pharma AG. Dr. Barberà has received honoraria and consultancy fees from Actelion, Bayer, GlaxoSmithKline, and Pfizer; and his institution has received research grants from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Dr. Champion has served as a consultant to Bayer, Gilead, and Pfizer; and has received research funding from Aires Pharmaceuticals. Dr. Coghlan has received consultancy and lecture fees and honoraria from Actelion, GlaxoSmithKline, Bayer, and United Therapeutics; and equipment support from Actelion. Dr. Cottin has received speaker's fees, funding for meetings, a grant to his institution for participation in trials, and fees as an advisory board member and consultant from Actelion, GlaxoSmithKline, and Pfizer. Dr. De Marco has received honoraria and consultancy fees from Actelion and Gilead; and has received research grants from United Therapeutics and Novartis. Dr. Galiè has served on advisory boards of Eli Lilly, Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has received speaker's fees from Eli Lilly, Pfizer, Bayer-Schering, and GlaxoSmithKline; and his institution has received grants from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis. Dr. Ghio has consulted for Actelion and Pfizer. Dr. Gibbs has consulted for Gilead, Novartis, and Actelion; has served as an advisory board member with and received speaker's fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and United Therapeutics; and has received research funding from United Therapeutics. Dr. Martinez has served on advisory boards of Amgen, Boehringer Ingelheim, Carden Jennings, Forest Pharmaceuticals, GlaxoSmithKline, Ikaria, Jannsens, MedImmune, Merck, Nycomed/Takeda, Pfizer, and Vertex; has participated on steering committees or data and safety monitoring boards of Centocor, Forest, Gilead, GlaxoSmithKline, Jannsens, Nycomed/Takeda, and Stromedix; has participated in advisory teleconferences with American Institute for Research, Axon, Grey Healthcare, and Sudler and Hennessey; has served as a speaker for Bayer, Forest, GlaxoSmithKline, Nycomed and Takeda; has consulted in continuing medical education programs for Incite, Foundation for Improving Patient Care, Inova Health System, MedScape/WebMD, NACE, NCME, Peer Voice, Projects in Knowledge, St. John's Hospital, St. Mary's Hospital, University of Illinois/Chicago, University of Texas Southwestern, UpToDate, and Wayne State University; and has received royalties from Informa. Dr. Simonneau has financial relationships with Actelion, Bayer, Eli Lilly, Novartis, Pfizer, and GlaxoSmithKline; and has received consultancy and lecture fees from Actelion. Dr. Vahiery has received lecture fees from and served as an advisory board member for Actelion Pharmaceuticals, Bayer Schering Eli Lilly, GlaxoSmithKline, and Pfizer; and has received consultancy fees from Actelion Pharmaceuticals, Merck, Bayer Schering, GlaxoSmithKline, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.