Pulmonary Hypertension With ILD: Diagnostic and Treatment Challenges

Interstitial lung disease, CT scan
Although pulmonary hypertension as a result of interstitial lung disease is linked to significant morbidity and mortality, there is no consensus regarding screening or management of the disease.

Although pulmonary hypertension as a result of interstitial lung disease (PH-ILD) is commonly encountered in clinical practice and linked to significant morbidity and mortality, there is no consensus regarding screening or management of the disease. A recent review published in CHEST details the challenges involved in the diagnosis and treatment of PH-ILD.1

“We have the tools we need to make a diagnosis of PH in ILD. However, it is often difficult to determine what contributes more to patients’ symptomatology — underlying ILD or superimposed PH,” according to coauthor Oksana A. Shlobin, MD, FCCP, medical director of the Pulmonary Hypertension Program and director of education for the Advanced Lung Disease and Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia, and associate professor of clinical medicine at both Georgetown University School of Medicine in Washington, DC, and Virginia Commonwealth University in Richmond.

Screening and Diagnosis

Although a recent study2 showed that physical examination cannot predict PH-ILD, a range of common test results may indicate a greater likelihood of PH-ILD. For example, the results of an  retrospective cohort study indicated that a severely reduced single breath diffusing capacity of the lung for carbon monoxide (DLCO; <30% predicted) was linked to a 2-fold increase in PH risk in patients with idiopathic pulmonary fibrosis (IPF).3

Reduced DLCO was also the only pulmonary function test (PFT) variable that predicted mortality in a multivariate analysis of data from patients with group 3 PH, with 1-year and 5-year survival rates of 68% and 13%, respectively, in those with DLCO <32% compared with 84% and 60% in patients with DLCO ≥32%. These findings highlight the prognostic utility of DLCO in cases of established PH-ILD.4

Reagarding the 6-minute walk test (6MWT), studies have demonstrated that reduced heart rate recovery predicted PH in patients with IPF, and a substantially lower distance walked and greater desaturation was shown to predict mortality more accurately than spirometry.1

In research using thoracic CT scan imaging, a pulmonary artery to aorta (PA/A) ratio >0.9 was found to predict an mean pulmonary arterial pressure (mPAP) >20 (area under the curve [AUC],0.75; 95% CI, 0.65-0.84) and increased mortality in patients with IPF, and an right ventricular (RV) to left ventricular (LV) ratio >1 was associated with increased pulmonary vascular resistance and greater mortality in patients with ILD.1

Traditional transthoracic echocardiography (TTE) is the most commonly used tool in PH-ILD diagnosis, historically based on “calculation of the right ventricular systolic pressure (RVSP) after measurement of the tricuspid regurgitant jet.” However, this “may be difficult to visualize in many patients with ILD and may over- or underestimate the RVSP when compared to diagnostic [right heart catheterization].”1

Recent studies results suggest that several other methods to assess RV function may have greater diagnostic accuracy in PH-ILD and may also have a role in predicting poor outcomes in these patients. These include right ventricular outflow tract (RVOT) diameter, tricuspid annular plane systolic excursion (TAPSE), and fractional area of change (FAC).1

While right heart catheterization (RHC) remains the only conclusive technique for diagnosis and risk stratification in PH-ILD, it should be reserved for select cases. “RHC is required in any ILD patient undergoing transplant evaluation and should be considered for patients with symptoms out of proportion to their fibrotic lung disease or with suspected PH-ILD who are being considered for pulmonary vasodilator therapy,” the review authors advised.1 “Exercise testing during RHC can be useful in unmasking Group 2 pulmonary hypertension and may provide additional prognostic information.”

In screening for PH in patients with ILD, the review authors recommended a thorough review of PFT, imaging, and data from exercise testing, as well as TTE performed annually or upon a change in symptoms, since the increasing incidence of PH  has been observed with the progression of fibrotic lung disease.5

Treatment of PH-ILD

Roham Zamanian, MD, pulmonologist, critical care specialist, and associate professor of pulmonary and critical care medicine at Stanford University Medical Center in California notes the challenge of choosing treatment strategies in the absence of approved therapies for PH-ILD.

Based on various trial results demonstrating lack of efficacy and adverse effects, endothelin receptor antagonists (ERAs) and the soluble guanylate stimulator riociguat are not recommended for PH-ILD treatment.

Given their successful use in PAH, there has been substantial interest in the potential role of pulmonary vasodilators in the treatment of PH-ILD. “Until recently, however, most of the larger trials investigating FDA-approved Group 1 PAH medications for this patient population were disappointing, although a number of smaller trials suggested that there may be therapeutic benefit,” Dr Shlobin explained.

Limited data indicate that the phoshodiesterase (PDE)-5 inhibitor sildenafil could provide some benefit in PH-ILD. In the STEP-IPF trial6 (ClinicalTrials.gov Identifier: NCT00517933) of patients with advanced IPF, sildenafil demonstrated improvements in multiple secondary end points (but not the primary end point based on 6MWT) such as arterial oxygen saturation, DLCO, and quality of life, along with a trend toward decreased mortality at 24 weeks compared to placebo (P =.07). “It should be noted that sildenafil is unlikely to provide a meaningful increase in life expectancy and should be used primarily as a bridge to lung transplant or in an effort to improve functional status and quality of life in patients who are not transplant candidates.”1

Observations from several case series support favorable effects of prostanoids in severe PH-ILD, including improvements in functional class, 6MWT, hemodynamics, and RV function on TTE in patients receiving inhaled or intravenous treprostinil, without adversely affecting oxygenation.

More recently, preliminary findings from the INCREASE trial (ClinicalTrials.gov Identifier: NCT02630316) and other research “have reinvigorated medical and pharma communities,” according to Dr Shlobin. Inhaled treprostinil led to a 21-meter increase in the 6MWT distance of patients with PH-ILD (primary end point), as well as improvements in numerous secondary end points including reductions in N-terminal pro B natriuretic peptide and time to clinical worsening.7

“The results of these studies are in line with our clinical experience, with inhaled or IV treprostinil being well tolerated and beneficial in patients with severe PH-ILD with a high PVR [pulmonary vascular resistance] and RV dysfunction,” as stated in the review.1 “It should be emphasized that use of pulmonary vasodilator therapy in ILD patients should only be undertaken by experienced PH centers.”

Dr Zamanian summarized the key components of treatment for this population as follows: full workup of patients including PFT and CT imaging; referral to ILD centers to clarify if underlying disease can be treated first; determination of severity of PH and consideration of therapy optimization; early referral to lung transplantation.

The review authors described their current approach to the management of patients with suspected PH-ILD, beginning with general principles such as optimal treatment of the fibrotic lung disease, regular evaluation of exertional desaturation, prescription of supplementary oxygen as warranted, and screening and treatment of sleep-disordered breathing and nocturnal hypoxemia if present. Additionally, referral to pulmonary rehabilitation and evaluation for lung transplantation are recommended in appropriate cases.1

“As with any type of PH, the treatment plan begins with a thorough diagnostic evaluation,” including serologic testing for causes of WHO [World Health Organization] Group 1 PAH, imaging to assess for chronic thromboembolic disease (Group 4 PH), and RHC for all patients, with strong consideration of “provocative maneuvers such as exercise testing or volume challenge to possibly identify WHO Group 2 PH,” they wrote.1

A thorough review of clinical data is warranted if RHC reveals hemodynamics indicating precapillary PH (pulmonary artery occlusion pressure  ≤15 mm Hg, mPAP >20 mm Hg, and PVR >3 Wood Units). “The distinction between Group 1 PAH and Group 3 PH is rather arbitrary and requires consideration of the hemodynamics in the context of the burden of their fibrotic lung disease,” as stated in the paper. The presence of Group 1 PAH risk factors — for instance, an underlying connective tissue disorder (CTD) — may further obscure the clinical picture. “CTD-ILD not only carries the consideration of ILD as a cause of PH, but it is known that CTD can cause PAH separately,” Dr Zamanian explained.

For both patients with Group 1 PAH with concurrent mild ILD and patients with Group 3 PH with mild interstitial involvement and significantly affected hemodynamics (mPAP ≥35 mm Hg or CI <2.0 L/min), the authors employ a similar treatment approach. This typically includes PDE-5 inhibitors (tadalafil or sildenafil) and/or prostanoids (inhaled/ IV/SQ treprostinil), with “full disclosure to the patient that there is limited data on treatment of PH in the presence of ILD” and close monitoring for potential improvement, worsening, or side effects.1

Future research efforts in this area should include “more well-conducted trials with properly diagnosed patient populations and well-thought-out clinical end points,” said Dr Shlobin.


1. King CS, Shlobin OA. The trouble with group 3 pulmonary hypertension in interstitial lung disease: dilemmas in diagnosis and the conundrum of treatment. [published online May 6, 2020]. CHEST. doi:10.1016/j.chest.2020.04.046

2. Braganza M, Shaw J, Solverson K, et al. A prospective evaluation of the diagnostic accuracy of the physical examination for pulmonary hypertension. CHEST. 2019;155(5):982-990.

3. Nathan SD, Shlobin OA, Ahmad S, Urbanek S, Barnett SD. Pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fibrosis. CHEST. 2007;131(3):657-663.

4. Rose L, Prins KW, Archer SL, et al. Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusuion capacity of the lungs for carbon monoxide. J Heart Lung Transplant. 2019;38(2):145-155.

5. Nathan SD, Shlobin OA, Ahmad S, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration. 2008; 76(3):288-294.

6. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620-628.

7. United Therapeutics announces INCREASE study of Tyvaso® meets primary and all secondary endpoints. News release. United Therapeutics. February 24, 2020. Accessed July 10, 2020. https://ir.unither.com/news/press-releases/press-release-details/2020/United-Therapeutics-Announces-INCREASE-Study-Of-Tyvaso-Meets-Primary-And-All-Secondary-Endpoints/default.aspx