PH-ILD: Identification, Evaluation, and Monitoring: A Diagnostic View From Both Sides

INTRODUCTION Pulmonary hypertension (PH) has long been recognized as a complication of interstitial lung disease (ILD). It contributes significantly to morbidity and mortality and thus is of key importance in prognostication and deciding the timing of referral for lung transplant. There is increasing evidence of the complexity of its pathogenesis beyond simple fibrosis and hypoxemic vasoconstriction. The pathophysiologic overlap with pulmonary arterial hypertension (PAH) has led to trials of pulmonary vasodilatory therapy in PH-ILD. While prior trials of pulmonary vasodilatory therapy in ILD have presented mixed results, a recent trial of inhaled pulmonary vasodilator therapy in this group has shown positive effect. As a result, the early recognition of the development of PH in ILD may have a greater implication for patients than just prognostication and assessment during considerations for transplant, and may contribute to better outcomes. In this paper we review the current understanding of the pathogenesis of PH in patients with ILD and what is known about the clinical impact of PH in the context of ILD. We then review the importance of hemodynamic assessment to the diagnosis of PH in ILD. Lastly, we review different symptoms, physical exam findings and studies that raise the index of suspicion for the presence of PH in ILD and considerations for incorporating these into initial and subsequent evaluations for patients with ILD. DEFINING PH-ILD While PH can occur in many different contexts in a patient who also has ILD, the implications of labeling an individual as having PH-ILD suggests that ILD is the primary driver of the presence of PH. This can be a subtle distinction: many patients with group 1 PH (PAH), and in particular those with connective tissue disease (CTD), may have a mild form of ILD while also having PAH. Similarly, patients with sarcoidosis may have both ILD and PH while still not being considered as group 3 PH. The understanding of these distinctions is crucial for interpretation of results of clinical studies, which often use such definitions for inclusion or exclusion. Significant history exists in classification of patients with ILD into group 3 PH (PH associated with chronic lung disease) using a combination of hemodynamics and the degree of lung disease. The hemodynamic definition of PH, in the context of chronic lung disease (group 3 PH) was updated in the 6 World Symposium on Pulmonary Hypertension to include a resting mean pulmonary artery pressure of >20 mm Hg, a pulmonary artery occlusion pressure ≤15 mm Hg, and a pulmonary vascular resistance of >3 Wood units. It is important, however, to note hemodynamic definitions do not create a distinction between group 3 and group 1 PH, rather the distinction relies on defining chronic lung disease as the primary driver of precapillary PH. This is done through a combination of pulmonary function testing and imaging—evidence of significant decrement in lung volumes or evidence of significant ILD burden on imaging moves the patient from group 1 to a group 3 designation. The challenge then becomes to define “significant ILD burden”. This is particularly difficult in conditions such as CTD where PH can exist with and without the presence of ILD. If we look at most PAH trials, a lower limit of forced vital capacity (FVC) of close to 70% or total lung capacity (TLC) of 60% is used as a hard cutoff, suggesting that of the patient with higher ILD burden should be classified as group 3. Special note must be made about sarcoidosis, which leads to the development of both ILD and PH through multiple mechanisms. Currently PH due to sarcoidosis remains categorized as group 5 disease and is excluded from many studies and discussions of PH-ILD.