The long-standing conceptual separation between pulmonary hypertension (PH) and interstitial lung disease (ILD) is rapidly dissolving.1 What was once viewed as a coincidental overlap is now increasingly understood as a unified, pathobiologically interconnected syndrome—and one that demands a reassessment of diagnostic strategies, therapeutic models, and care delivery.
For clinicians, this shift represents more than semantic evolution. It reflects a fundamental transformation in how to detect, interpret, and treat disease at the intersection of parenchymal fibrosis and pulmonary vascular remodeling.1
“The field has undergone a fundamental transformation over the past few years, moving from a landscape of limited options to one in which PH is now recognized as a treatable complication of fibrotic lung disease,” said Tejaswini Kulkarni, MD, MPH, FCCP, Director of the Interstitial Lung Disease Program and Associate Medical Director of the Lung Health Center at The University of Alabama at Birmingham.
A common and consequential overlap
PH is a frequent and clinically significant sequela of ILD. The development of PH in this population is associated with marked reductions in exercise capacity, increased hospitalization risk, and substantially worse survival outcomes compared with ILD alone.1,2
Studies have suggested that the prevalence of PH rises with disease severity, with reports suggesting it may occur in up to 86% of patients with end-stage idiopathic pulmonary fibrosis.1 Despite this, diagnosis remains challenging, as symptoms such as dyspnea, fatigue, and reduced exercise tolerance overlap with those of ILD itself.
This diagnostic ambiguity often leads to delayed recognition.
“One of the biggest challenges is identifying which patients actually have PH, particularly given that definitive diagnosis still depends on invasive right heart catheterization,” Dr. Kulkarni said.
Moreover, the severity of pulmonary vascular disease does not consistently correlate with the extent of fibrotic lung involvement.1
“We do not rely on echo for the diagnosis of PH, especially in group 3 disease, where echocardiographic estimates may mislead,” said Todd M. Bull, MD, Director of the Center for Lungs and Breathing and the Pulmonary Vascular Disease Center at the University of Colorado Anschutz. “When suspicion is high and treatment is contemplated, invasive hemodynamic assessment remains essential.”
This disconnect reinforces the need to move beyond a simplistic advanced ILD framework and instead recognize PH-ILD as a distinct entity.1
Disease of dual pathobiology
At its core, PH-ILD reflects the convergence of two interrelated but partially independent processes: pulmonary fibrosis and vascular remodeling.1 Chronic hypoxia, endothelial dysfunction, and inflammatory signaling contribute to progressive remodeling of small pulmonary arteries, increasing pulmonary vascular resistance and ultimately imposing strain on the right ventricle. At the same time, fibrotic pathways—driven by cytokines, growth factors, and extracellular matrix deposition—continue to reshape the lung parenchyma.
Profibrotic and vasoconstrictive mediators act in both domains, reinforcing what is increasingly recognized as a dual-pathway disease.1 This challenges the notion that PH is merely a late manifestation of ILD. Rather, it positions PH-ILD as a distinct cardiopulmonary syndrome requiring targeted evaluation and management.
From silos to synergy
Historically, ILD and PH have been treated within parallel clinical silos—pulmonologists focusing on antifibrotic therapies and PH specialists targeting vascular dysfunction. That model is rapidly becoming obsolete.
For optimal care, Dr. Kulkarni said, it is important to bring together the ILD specialist, the PH expert, and, as the disease advances, lung transplant teams, so they can all work together.
Dr. Bull said this collaboration reflects a broader shift in care delivery and is essential to effective care. “It involves partnering PH specialists with other providers integral to the care of the patient to provide the best evidence-based care,” he said.
Importantly, the push toward multidisciplinary care is not driven solely by pathophysiology; it is also shaped by patient priorities.
“In all ILD trials, we have physiologic outcomes. I’m making their lung function test look better, but that may not matter to the patient,” said Corey Kershaw, MD, FCCP, Chair of CHEST’s Diffuse Lung Disease and Lung Transplant Network and Clinical Services Chief of the Pulmonary and Critical Care Medicine at UT Southwestern Medical Center.
He recalled a patient who asked, “What about the fact that I can’t play golf anymore? Is that test going to help me play golf?” That encounter changed Dr. Kershaw’s care priorities.
“We need to think about comorbidity management and things that matter for the patient,” he said. “It’s so far beyond difficulty breathing. We need to have partners to help manage the things that matter the most to the patient.”
The impact of treprostinil
Few developments have reshaped PH-ILD management as dramatically as the emergence of inhaled treprostinil.3 Historically, therapeutic progress in this space was limited and there were significant concerns that pulmonary vasodilators might worsen ventilation-perfusion mismatch.
“For years, we didn’t have anything,” Dr. Kulkarni said. “Our treatment options for the past decade focused on antifibrotic therapies. But as the disease progressed and patients developed PH, therapeutic options were limited and lung transplantation remained the only curative strategy. It is now recognized as a treatable complication of fibrotic lung disease, particularly for patients who are not eligible for lung transplant.”
The INCREASE trial demonstrated that inhaled treprostinil improves exercise capacity and reduces clinical worsening in PH-ILD—marking the first successful randomized trial in this population.3 Dr. Bull described this milestone as “a huge step forward.”
An expanding therapeutic pipeline
While inhaled treprostinil has become foundational, it is increasingly clear that it represents only the beginning of a wider therapeutic evolution. Emerging agents are targeting shared mechanisms across vascular and fibrotic pathways, reflecting a shift toward integrated disease modification.
One example is CS014, an investigational oral histone deacetylase (HDAC) inhibitor.4 By influencing gene expression pathways linked to tissue scarring, blood vessel abnormalities, and abnormal clotting, it aims to address multiple drivers of PH-ILD simultaneously. Dosing and participant visits in a phase 1 pharmacokinetic-bridging study have been completed, with top-line results anticipated later this year.5
Other approaches include mechanistic target of rapamycin (mTOR) inhibition with inhaled sirolimus (LAM-001). Data from a small phase 2a open-label study suggest improvements across multiple clinically relevant end points, including a 67.4-meter increase in 6-minute walk distance and a 33.9% reduction in pulmonary vascular resistance at 24 weeks in patients with PH-ILD.6 LAM-001 targets the mTOR pathway, implicated in both pulmonary vascular remodeling and fibrotic processes, further reinforcing the convergence of vascular and fibrotic biology.
The broader pipeline includes inhaled soluble guanylate cyclase activators, tyrosine kinase inhibitors such as seralutinib, and novel prostacyclin formulations.1 While many remain investigational, the diversity of mechanisms reflects a shift toward combination and pathway-targeted therapies.
At the same time, drug delivery is evolving. Current inhaled therapies can be burdensome, often requiring multiple daily doses. Although improvement in symptoms or exercise capacity is clinically meaningful for patients, treatment regimens requiring administration four times a day may present adherence challenges, Dr. Kulkarni said.
The PH-ILD experience has also highlighted an important cautionary lesson: Treatments that are effective in patients with pulmonary arterial hypertension cannot be assumed to translate to PH-ILD.7 Endothelin receptor antagonists and riociguat have failed to demonstrate benefit. Similarly, phosphodiesterase-5 inhibitors have shown inconsistent results.
Dr. Bull advised caution, noting that he generally does not recommend them because of a lack of evidence of efficacy and the potential for harm, particularly related to ventilation-perfusion mismatch.
The path forward
Despite meaningful progress, several critical challenges remain. One unresolved issue is the clinical significance of mild or “borderline” PH in ILD. As hemodynamic definitions evolve, determining when treatment is warranted remains uncertain.
Early detection is another unmet need. Drs. Kulkarni, Bull, and Kershaw all agreed that improved screening strategies to identify patients before advanced hemodynamic compromise develops are needed.
“One of the biggest challenges is identifying these patients sooner so we can start them on treatment sooner,” Dr. Kulkarni said.
The PHINDER study aims to address this need by investigating a standardized evidence-based clinic screening algorithm for early identification of PH in patients who have ILD.8
Disease surrogates are another area of ongoing interest and research. This is perhaps where machine learning applied to larger physiologic data sets, such as PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) will be fruitful, Dr. Bull said.9
As the evidence evolves, capturing data on tolerability as well as measures such as time to clinical worsening will be important to better reflect the patient experience, Dr. Kershaw said.
For clinicians, the shift in this space demands a broader perspective that integrates vascular and parenchymal disease, emphasizes early detection, and prioritizes multidisciplinary care.
“We have gone from no specific treatments to an FDA-approved medication and multiple ongoing trials,” Dr. Bull said. “It is an exciting time in PH-ILD research.”
This article was originally published in the Fall 2026 issue of CHEST Physician.
References
1. Raghu G, Sahay S, Price LC, et al. Pulmonary hypertension associated with interstitial lung disease: state-of-the-art review. Eur Respir J. 2026;67(3):2502651. doi:10.1183/13993003.02651-2025
2. Olsson KM, Hoeper MM, Pausch C, et al. Pulmonary vascular resistance predicts mortality in patients with pulmonary hypertension associated with interstitial lung disease: results from the COMPERA registry. Eur Respir J. 2021;58(2):2101483. doi:10.1183/13993003.01483-2021
3. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325-334. doi:10.1056/NEJMoa2008470
4. Nathan SD, Smith P, Deng C. Phase 3 trials of inhaled treprostinil for idiopathic pulmonary fibrosis. N Engl J Med. 2026;395:115-126. doi:10.1056/NEJMoa2501488
5. Press release. Cereno Scientific broadens development focus for CS014 to pulmonary hypertension associated with interstitial lung disease. Cereno Scientific. Published February 4, 2026.
6. Press release. Quince Therapeutics announces clinically meaningful improvements across functional, hemodynamic and biomarker measures in phase 2 study in PAH and PH-ILD. Published May 18, 2026.
7. Yogeswaran A, Hassoun PM, Saleh K, et al. Hemodynamics and phosphodiesterase-5 inhibitor treatment associated with survival in pulmonary hypertension in interstitial lung disease: a PVRI GoDeep Meta-Registry analysis. Am J Respir Crit Care Med. 2025;211(10):1855-1866. doi:10.1164/rccm.202412-2371OC
8. Kulkarni T, Zisman DA, Shlobin OA, et al. Study design and rationale for the PHINDER study: pulmonary hypertension screening in patients with interstitial lung disease for earlier detection. Pulm Ther. 2025;11(3):491-501. doi:10.1007/s41030-025-00307-0
9. Tang WHW, Wilcox JD, Jacob MS, et al. Comprehensive diagnostic evaluation of cardiovascular physiology in patients with pulmonary vascular disease: insights from the PVDOMICS program. Circ Heart Fail. 2020;13(3):e006363. doi:10.1161/CIRCHEARTFAILURE.119.006363
