How do you determine if pulmonary hypertension is disproportionate to the severity of lung disease?

This is a question we faced on a daily basis in our PH clinic. Patients with parenchymal lung disease like COPD or ILD would get an echocardiogram that showed an elevated RVSP and/or RV dilation/dysfunction and will be referred to our clinic for PH evaluation. Alternatively, the patient already underwent an RHC that confirmed the diagnosis of PH and gets a referral to us for consideration of treatment. It is expected that patients with advanced stages of parenchymal lung disease with hypoxemia will commonly have a mild degree of pre-capillary PH (group 3 PH or PH due to lung disease/hypoxemia).

There is no consensus on what degree of pre-capillary PH is considered proportional or disproportional to the degree of parenchymal lung disease/hypoxemia. It is certainly important to rule out other conditions that can concomitantly be present in patients with parenchymal lung diseases and cause precapillary PH, such as associated connective tissue disease, drugs and toxin exposure, HIV, chronic thromboembolic pulmonary disease, OSA, left heart disease with combined pre- and post-capillary PH, etc.

There are no studies testing whether PH-specific treatment of “disproportionate” PH in parenchymal lung disease is beneficial, in great part due to the difficulty in identifying these patients since they are uncommon and if they have other concomitant conditions associated with pre-capillary they will be labeled as pulmonary artery hypertension with concomitant parenchyma lung disease/hypoxemia.

At this point in time, the only medication with FDA approval to treat group 3 PH is inhaled treprostinil for patients with ILD with PVR > 3 WU, based on the INCREASE study. This study showed an improvement in the primary end-point of a 6-minute walk distance of 31.1 m at 16 weeks. In subgroup analysis of peak 6-minute walk distance, patients with PVR ≥ 4 WU appeared to have a more beneficial response with increase in distance walk of 40.8 m compared to -7.6 m for those with PVR < 4 WU.

I agree wholeheartedly with the comprehensive answer by Dr. @Dr. First Last. Patients with comorbid pulmonary vascular disease and pulmonary parenchymal or obstructive disease can exhibit both a "pulmonary vascular" predominant phenotype (sometimes identified in co-morbid PH with interstitial lung disease when the PVR is more than 5 WU), or one where the ventilatory and pulmonary parenchymal abnormalities dominate the presentation. (Humbert et al., PMID 36017548). Distinguishing between the two, to identify acceptable candidates for targeted PH therapy, can be quite challenging.

Unfortunately, particularly in the case of interstitial lung disease (but also for obstructive lung disease), the severity of PH is not particularly related to the severity of underlying lung disease: there is no good relationship between the mean PA pressure on RHC and the percentage of ILD on CT scan in idiopathic pulmonary fibrosis, or between RHC hemodynamics of PH severity (mPAP, PVR) and the degree of impairment on pulmonary function testing (FVC, DLCO) (PIccari et al., PMID 37025209). Furthermore, some degree of PH can be present in the majority of certain pulmonary diseases (Langerhans cell histiocytosis, advanced sarcoidosis), and can routinely complicate a considerable proportion of patients with diseases such as COPD with emphysema or idiopathic pulmonary fibrosis (Anderson et al., PMID 22425136).

Thus, as Dr. @Dr. First Last points out, determining therapeutic regimens for these challenging patients involves integrating the severity of PH and burden of disease on the right ventricle, assessment of comorbid conditions that could manifest with PH, and weighing the risks and benefits of targeted therapy for a given patient.

When considering therapy in patients with both PH and interstitial lung disease, I would suggest that riociguat may not be an optimal therapeutic (based on the early termination of the RISE-IIP randomized controlled trial due to increased adverse events and ILD exacerbations in the treatment group, particularly those with combined pulmonary fibrosis and emphysema, along with the lack of benefit on the primary endpoint of six-minute walk distance between treatment and placebo arms; Nathan et al., PMID 31416769), and ambrisentan may have deleterious effects on patients with underlying ILD and may need to be avoided in this patient population (based on the early termination of the ARTEMIS randomized controlled trial of IPF patients, where the treatment group showed increased hospitalizations, mortality, and a more rapid decline in lung function; Raghu et al., PMID 23648946).