Clinical bottom line
Inhaled treprostinil is an emerging therapeutic option for pulmonary hypertension (PH) associated with interstitial lung disease (ILD-PH), showing promise in improving exercise capacity and pulmonary hemodynamics with a generally manageable safety profile. Current evidence suggests inhaled treprostinil may offer clinical benefit particularly in patients with ILD-PH who have limited treatment options, including those awaiting lung transplantation. However, the magnitude of benefit, optimal dosing strategies, and long-term outcomes remain areas requiring further validation. Clinicians should consider inhaled treprostinil as a putative adjunct in carefully selected ILD-PH patients, balancing potential symptomatic improvement against tolerability and the underlying ILD severity.
What the evidence shows
ILD-associated pulmonary hypertension represents a complex clinical challenge with limited approved therapies. Inhaled treprostinil, a prostacyclin analogue delivered via inhalation, has been investigated for its pulmonary vasodilatory effects with the goal of improving right ventricular function and exercise tolerance without systemic hypotension.
The INCREASE trial and subsequent real-world studies have demonstrated that inhaled treprostinil can improve 6-minute walk distance (6MWD) and reduce pulmonary vascular resistance in ILD-PH patients (Cottin et al., 2023). Nagaoka et al. (2025) reported that inhaled treprostinil improved exercise capacity and oxygenation parameters in a cohort of ILD-PH patients, with acceptable safety. Genecand et al. (2024) explored dose-response relationships, suggesting higher doses may confer greater functional benefit, though with increased adverse events, highlighting the need for individualized dosing.
Bandyopadhyay et al. (2026) reviewed current realities and future possibilities, emphasizing inhaled treprostinil’s role as a targeted therapy that may alter the natural history of ILD-PH. Yuen et al. (2025) specifically evaluated inhaled treprostinil in lung transplant candidates, noting improved hemodynamics and functional status that could optimize transplant candidacy.
Dagher et al. (2025) contrasted inhaled treprostinil with other prostacyclin pathway agents like selexipag in connective tissue disease-associated PH with ILD, underscoring inhaled treprostinil’s favorable pulmonary selectivity and tolerability. Earlier work by Faria-Urbina et al. (2017) laid foundational evidence for inhaled prostacyclin analogues in lung disease-associated PH, supporting the rationale for ongoing clinical use and investigation.
Caveats and uncertainty
Despite encouraging data, several uncertainties temper enthusiasm for widespread adoption. Most studies have relatively small sample sizes and short follow-up durations, limiting definitive conclusions on long-term efficacy and safety. The heterogeneity of ILD subtypes and PH severity complicates extrapolation of results to all patients.
The optimal dosing regimen remains unclear. While higher doses may improve outcomes, they also increase the risk of cough, headache, and other prostacyclin-related adverse effects (Genecand et al., 2024). The impact on survival and hospitalization rates is not yet well established.
Potential interactions with antifibrotic therapies and other PH agents require further study. Moreover, inhaled treprostinil’s role relative to systemic prostanoids or oral agents in ILD-PH treatment algorithms is not fully defined (Bandyopadhyay et al., 2026).
Finally, patient selection criteria need refinement to identify those most likely to benefit without worsening ventilation-perfusion mismatch or hypoxemia.
How this may change practice
Inhaled treprostinil offers a promising adjunctive therapy for ILD-PH, particularly for patients with moderate to severe disease who are symptomatic despite standard care. Its inhaled route may reduce systemic side effects compared to parenteral prostanoids, making it more tolerable for ambulatory patients.
Clinicians should consider inhaled treprostinil in ILD-PH patients who have preserved lung volumes but significant pulmonary vascular disease, and in lung transplant candidates to optimize hemodynamics pre-transplant (Yuen et al., 2025). Dose titration should be cautious, balancing efficacy and adverse effects.
This therapy may also encourage earlier PH screening in ILD patients to identify candidates before advanced right heart failure develops. Multidisciplinary collaboration between pulmonologists and PH specialists is essential to integrate inhaled treprostinil into personalized treatment plans.
Ongoing and future studies will clarify its long-term impact on morbidity and mortality, potentially establishing inhaled treprostinil as a foundational treatment in ILD-PH management.