Interstitial Lung Disease
Clarified Hemodynamic Definitions of WHO Group 3 Pulmonary Hypertension
The updated hemodynamic criteria for pulmonary hypertension (PH) could lead to the earlier detection and treatment of patients with World Health Organization (WHO) group 3 PH. For many patients with chronic lung disease and group 3 PH, there may be less of a need to pinpoint precise hemodynamic measurements.
“Echocardiographic technology has evolved, and echocardiographers are now able to provide more detail for inferring the presence of significant PH while effectively excluding the presence of left-sided heart disease.”
The new definition of pulmonary hypertension is a mean pulmonary arterial pressure (mPAP) of greater than 20 mm Hg at rest (ie, the threshold for an elevated mPAP was lowered from ≥25 mm Hg). Additionally, pulmonary vascular resistance of 3 or greater Wood units was included in the definition for all forms of precapillary PH (ie, in groups 1, 3, 4, and 5). Thus, emphasis was also placed on the significance of an elevated pulmonary vascular resistance in the detection of pulmonary vascular disease.
This updated definition of PH emerged from the 6th World Symposium on Pulmonary Hypertension, held in 2018 in Nice, France, where I was privileged to be the cochair of the task force on group 3 PH. Group 3 includes not only PH–interstitial lung disease (ILD) but also other lung-/hypoxia-related conditions. For patients suspected of having group 3 PH, there may be an evolving role for inferring the presence of pulmonary vascular involvement by echocardiography, without necessarily diagnosing PH by right heart catheterization. Echocardiographic technology has evolved, and echocardiographers are now able to provide more detail for inferring the presence of significant PH while effectively excluding the presence of left-sided heart disease. Therefore, clinical trials investigating novel therapies targeting the pulmonary vascular component of ILD may include patients with pulmonary vascular involvement and possible PH. If these new treatments become available, their use in clinical practice would likely mirror their use in clinical trials (eg, there may be less of a need to pinpoint whether the mPAP is 23 mm Hg vs 27 mm Hg). In one such trial, the use of inhaled ambulatory nitric oxide is being evaluated in patients with ILD suspected of having PH based on echocardiography alone, using actigraphy as the primary end point. This study involves patients wearing medical-grade activity monitors that capture activity levels at home, thereby allowing a more accurate assessment of what patients are able to accomplish outside the clinic.
With regard to definitions, another often-debated point relates to PH in connective tissue disease (CTD). CTD can result in pure pulmonary arterial hypertension (PAH) without lung disease; conversely, it may produce pure ILD without PAH. Thus, there can be some uncertainty in patients with CTD when both ILD and PH are present (ie, whether it is group 1 or group 3). In clinical trials of PAH (group 1), a forced vital capacity (FVC) of 70% or greater has been used as a cutoff for inclusion, to rule out patients with significant lung disease. However, individuals with CTD and an FVC of 70% or greater can still have significant ILD, as seen on computed tomography (CT) imaging. CT adjudication was not required in prior PAH trials; this might be an explanatory factor for the observation that patients with CTD do not respond to treatment for PAH as well as those with idiopathic PAH. In a recently completed trial evaluating inhaled treprostinil in adult patients with PH-ILD (the INCREASE study), we enrolled patients with ILD in its various forms, including CTD-ILD. To ensure that only CTD patients with group 3 PH were included, we therefore took the mirror opposite approach by only including patients with CTD with a baseline FVC of less than 70%. It should be mentioned, however, that patients with other forms of ILD who were included in this study did not have to meet this requirement of an FVC of less than 70%. Additionally, CT was used to confirm the presence of diffuse parenchymal lung disease in all patients included in this study.
ClinicalTrials.gov. A safety and efficacy study of pulsed inhaled nitric oxide in pulmonary hypertension associated with pulmonary fibrosis. Accessed June 19, 2020. https://clinicaltrials.gov/ct2/show/NCT03267108
ClinicalTrials.gov. Safety and efficacy of inhaled treprostinil in adult PH with ILD including CPFE. Accessed June 19, 2020. https://clinicaltrials.gov/ct2/show/NCT02630316
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