Chest
Volume 158, Issue 4, October 2020, Pages 1651-1664
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Pulmonary and Cardiovascular: CHEST Reviews
The Trouble With Group 3 Pulmonary Hypertension in Interstitial Lung Disease: Dilemmas in Diagnosis and the Conundrum of Treatment

https://doi.org/10.1016/j.chest.2020.04.046Get rights and content

Pulmonary hypertension (PH) due to interstitial lung disease (ILD; PH-ILD) can complicate a multitude of ILDs, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and nonspecific interstitial pneumonia. Development of PH-ILD is associated with increased need for supplemental oxygen, reduced mobility, and decreased survival. A high index of suspicion is required to make the diagnosis, given the substantial overlap in symptoms with those of ILD without PH. Severely reduced diffusing capacity or 6-min walk test distance, prominent exertional desaturation, and impaired heart rate recovery after exercise are all suggestive of the development of PH-ILD. Traditional transthoracic echocardiography is the most commonly used screening test for PH-ILD, but it lacks sensitivity and specificity. Newer echocardiographic tools involving 3-dimensional assessment of the right ventricle may have a role in both prognosis and the monitoring of patients with PH-ILD. Right-sided heart catheterization remains the gold standard for confirming a diagnosis of PH-ILD. Although there is little debate about the use of supplemental oxygen and diuretic therapy in the treatment of PH-ILD, treatment with pulmonary vasodilator therapy remains controversial. Although several studies have been terminated prematurely for harm, the recently completed INCREASE trial of inhaled treprostinil appears to validate the concept of treating PH-ILD with pulmonary vasodilators and, we hope, will serve as a foundation from which future studies can be developed.

Section snippets

How Is PH-ILD Defined, and How Often Does It Occur?

The 6th WSPH recently updated the definition of group 3 PH to a resting mean pulmonary artery pressure (mPAP) > 20 mm Hg, with an accompanying pulmonary vascular resistance (PVR) ≥ 3 Wood units and a pulmonary artery occlusion pressure (PAOP) ≤ 15 mm Hg at right-sided heart catheterization (RHC) in the setting of chronic lung disease (Table 1).5 Severe group 3 PH is defined as an mPAP ≥ 35 mm Hg or mPAP ≥ 25 mm Hg with a cardiac index of < 2.0 L/min/m2 and PAOP ≤ 15 mm Hg.5 The distinction

What Are the Effects of PH-ILD?

The development of PH-ILD is associated with substantial morbidity in the form of increased need for supplemental oxygen, increased symptoms of dyspnea, and reduced mobility. The effect has been examined in two ways: (1) comparison with ILD without PH and (2) comparison with other PH causes. Lettieri and colleagues9 found patients with PH-IPF had a lower mean 6-min walk test (6MWT) distance (143.5 m ± 65.5 vs 365.9 m ± 81.8; P < .001) and lower oxygen desaturation nadir (80.1% ± 3.7

What Causes PH-ILD to Occur?

The pathogenesis of PH-ILD is incompletely understood, but it appears a number of factors are at play. Hypoxic pulmonary vasoconstriction (HPVC) may occur in response to alveolar hypoxemia, pulmonary arterial hypoxemia, hypercapnia, or acidemia. Although HPVC is typically reversible with supplemental oxygen, repeated or sustained episodes may result in pulmonary vascular remodeling and PAH.22 In addition, chronic hypoxia appears to interfere with the ability of endothelial nitric oxide synthase

Who Should Be Evaluated for PH-ILD, and How Should It Be Diagnosed?

No standard exists regarding which patients to screen for PH-ILD or the optimal method of doing so. The diagnosis can be difficult to make as there is significant overlap of symptoms between fibrotic lung disease and PH.27 The physical examination also lacks the sensitivity to predict PH-ILD accurately. A recent study showed no individual physical examination finding could accurately predict PH.28 The combination of jugular venous distension, peripheral edema, and a parasternal heave was

What Is the Rationale Behind Treatment of PH-ILD?

Given the morbidity and mortality associated with PH-ILD and current absence of available treatments, as well as the large armamentarium of pulmonary vasodilators that have been successfully used in PAH, it is not surprising that there has been great interest in the treatment of PH-ILD with pulmonary vasodilator therapy. Arguments both for and against treatment have been made. One potentially negative effect of pulmonary vasodilator therapy is worsening hypoxemia due to uncoupling of the

What Have the Studies on PH-ILD Performed So Far Shown?

Multiple clinical trials of pulmonary vasodilator therapy in ILD have been performed, mostly with disappointing results. Although a mounting number of studies have been performed in PH-ILD, there remain major deficiencies in the available literature. The biggest flaw is that most trials enrolled patients with PH diagnosed on the basis of diffusion capacity and/or TTE criteria rather than hemodynamically. Moreover, no trial has focused specifically on severe PH-ILD. Such a trial is difficult to

The End of Endothelin Receptor Antagonists?

Six randomized controlled trials (RCTs) have examined the role of endothelin receptor antagonists (ERAs) in IPF. Four of these trials aimed to evaluate the effects of ERAs on functional status and parenchymal disease progression in patients with ILD rather than in those with PH-ILD. RCTs of bosentan and macitentan both failed to demonstrate improvements in slowing disease progression and did not appear to have salutary effects on functional status.49, 50, 51 The Randomized, Placebo-Controlled

Say NO to Drugs: The RISE and Fall of Riociguat

A pilot trial of the soluble guanylate stimulator riociguat in PH-ILD generated enthusiasm after demonstrating improvements in hemodynamics with few safety events.55 This study served as the impetus for the Safety of Riociguat in Patients With Symptomatic Pulmonary Hypertension (PH) Associated With Idiopathic Interstitial Pneumonias (IIP) (RISE-IIP) study, a phase IIb study of riociguat in patients with idiopathic interstitial pneumonias with RHC-confirmed PH.56 The study was terminated early

Phosphodiesterase 5 Inhibitors: Sildenafil Saga

The results of the clinical trials and registry data examining the role of sildenafil in PH-ILD are the most promising to date. The COMPERA registry enrolled incident patients with PH-ILD who had pulmonary vasodilator therapy initiated. The majority (88%) of the 151 patients followed up were treated with phosphodiesterase 5 inhibitors. The treated group demonstrated a median improvement in 6MWT distance of 24.5 m and nearly one-quarter improved functional class.11 Moreover, patients whose 6MWT

Prostanoids to the Rescue?

Until recently, data on the safety and efficacy of prostanoids in PH-ILD were limited to several small series. Olschewski and colleagues45 studied the effects of both IV and inhaled prostanoids in eight patients with PH-ILD. They found IV therapy decreased systemic BP and arterial oxygen saturation, but inhaled therapy was well tolerated. Ghofrani and colleagues44 conducted a small RCT comparing IV epoprostenol (n = 8) and oral sildenafil (n = 8); they found epoprostenol worsened oxygenation

Should PH-ILD Be Treated? If So, How?

There is no universally agreed on approach to the treatment of PH-ILD. Patients with PH-ILD have a poor prognosis and should be evaluated and listed for LTx when appropriate. However, we emphasize that use of pulmonary vasodilator therapy in patients with ILD should be undertaken only by experienced PH centers. We hope that clinical trials focused on severe group 3 PH will emerge, and, whenever available, we strongly advocate for populating these studies to enrich the existing body of

What Is the Future of PH-ILD?

The INCREASE trial is a major step forward in the treatment of PH-ILD. We hope its results will stimulate further research in the area. A randomized, double-blind, placebo-controlled clinical study to assess the safety and efficacy of pulsed, inhaled nitric oxide (iNO) in subjects with pulmonary hypertension associated with pulmonary fiborsis on long term oxygen therapy (PULSE), a clinical trial of inhaled nitric oxide in PH-ILD, has demonstrated favorable patient-reported outcomes and

Conclusions

PH-ILD is an incompletely understood clinical entity, which complicates the clinical course of many patients with ILD. It is recognized to be associated with significant morbidity and mortality. Effective therapeutic strategies are currently lacking; however, clinical trials to address this gap in the medical literature are currently underway.

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: C. S. K. is a speaker for Boehringer Ingelheim; Genentech, Inc; and Johnson & Johnson and has done consulting for Boehringer Ingelheim, Johnson & Johnson, and United Therapeutics, as well as for the France Foundation. O. A. S. has done consulting and is a speaker for Bayer AG, Johnson & Johnson, and United Therapeutics.

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