Slow, Steady Advances: Noninvasive Diagnosis of PH in ILD Populations

No single, noninvasive, available test is capable of accurate detection and diagnosis of pulmonary hypertension (PH) in patients with interstitial lung disease (ILD), according to a comprehensive literature review published in European Respiratory Review.¹ Insufficient noninvasive screening for populations at risk for PH, especially severe PH, remain an unmet need. PH in this population—especially, of course, unidentified and untreated PH—is linked with increased morbidity and mortality.

Lung disease model | image credit: Cutie - stock.adobe.com

Applying artificial intelligence (AI) could lead to a more broadly accepted, diagnostic algorithm that would, over time, provide a more timely PH diagnosis in patients with ILD. With that, clinical outcomes could improve, write the current authors.

In their view, 2 specific models that have already been developed remain promising candidates for further investigation and clinical use.^2,3

A Long Look

The team’s literature search revealed 38 articles about noninvasive diagnostic modalities and prediction models to detect PH in patients with ILD.¹ Right now, estimated right ventricular systolic pressure (RVSP), utilizing Doppler echocardiography, remains the single most predictive factor of PH. Other indirect echocardiographic markers can increase diagnostic accuracy, they add.

Unfortunately, given many patients’ extensive lung disease, views are suboptimal, meaning RVSP can be difficult to estimate. “The majority of existing composite scores, including variables obtained from chest CT, pulmonary function tests, and cardiopulmonary exercise tests, were derived from retrospective studies, [while] lacking validation in external cohorts,” write the investigators.

Current and Future Landscape

In a best-case scenario, the PH of a patient with ILD is confirmed early on and they can begin inhaled treprostinil (Tyvaso), as per the INCREASE trial, or enroll in a clinical trial evaluating targeted vascular therapy.^4,5 However, that confirmation often occurs way too late, which isn’t surprising, stated the authors, given PH’s nonspecific medical symptoms and the limitations of conventional diagnostic modalities and available multiparametric models.¹ 

In clinical practice, to identify patients with suspected PH, Doppler transthoracic echocardiography is the standard screening tool, accompanied by pulmonary function tests, chest CT, and the 6-minute walking test (6MWT). Some noninvasive multiparametric diagnostic models and single-variable markers have been proposed, but none have been widely used in clinical spaces.The diagnostic accuracy of these models and markers is currently suboptimal, methodological limitations keep them from being widely used, and they need further investigation, note the authors.

Two particular noninvasive scores that have been developed—and are the only ones to have been validated in a second cohort—also are not generalizable due to methodological limitations. Nonetheless, the authors state, their use may help physicians detect PH earlier. The first is based on readily available functional parameters—FVC/DLCO [forced vital capacity divided by diffusion capacity for carbon monoxide], lowest oxygen saturation recorded during 6MWT, race, and 6MW distance—providing the acronym FORD. Potentially, it could be “widely used by pulmonologists to screen for the presence of even mild PH in all patients with IPF,” state the investigators.

The FORD model was shown to have moderate diagnostic accuracy to detect PH in a large cohort of patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF; area under the curve [AUC], 0.75); it had lower accuracy in the validation cohort (AUC, 0.69). One explanation is that the validation cohort included patients with severe IPF. These individuals were being evaluated for lung transplantation and most noninvasive functional parameters were already impaired.“Most markers are not PH-specific and, therefore, the diagnostic accuracy [of this model] to detect PH was limited,” the authors hypothesize.

The second is based on a stepwise approach that includes echocardiographic variables only; RVSP is the first parameter evaluated. It had better diagnostic accuracy (AUC, >0.8) in both cohorts. “However, the aim of this score was to identify the presence of severe PH among [patients with] ILD and, therefore, it is not so sensitive in detecting mild or moderate PH,” the team explains. Consequently it might be best used in facilities where echocardiography is a specialty and severe PH is suspected. 

References

1. Arvanitaki A, Diller GP, Gatzoulis MA, McCabe C, Price LC, Wort SJ. Noninvasive diagnostic modalities and prediction models for detecting pulmonary hypertension associated with interstitial lung disease: a narrative review. Eur Respir Rev.2024;33(174):240092. doi:10.1183/16000617.0092-2024 

2. Bax S, Bredy C, Kempny A, et al. A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease. ERJ Open Res. 2018;4:00124-2017. doi:10.1183/23120541.00124-2017. Published correction appears in ERJ Open Res. 2018;4(3):00124-2017-AUT.

3. Nathan SD, Chandel A, Wang Y, et al. Derivation and validation of a noninvasive prediction tool to identify pulmonary hypertension in patients with IPF: evolution of the model FORD. J Heart Lung Transplant. 2023;43(4):547-553. doi:10.1016/j.healun.2023.11.005

4. 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

5. Nathan SD, Fernandes P, Psotka M, et al. Pulmonary hypertension in interstitial lung disease: clinical trial design and endpoints: a consensus statement from the Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension. Pulm Circ. 2022;12(4):e12178. doi:10.1002/pul2.12178