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. 2022 Feb 15;162(1):145–155. doi: 10.1016/j.chest.2022.02.012

Screening Strategies for Pulmonary Hypertension in Patients With Interstitial Lung Disease

A Multidisciplinary Delphi Study

Franck F Rahaghi a, Nicholas A Kolaitis b, Ayodeji Adegunsoye c, Joao A de Andrade d, Kevin R Flaherty e, Lisa H Lancaster f, Joyce S Lee g, Deborah J Levine h, Ioana R Preston i, Zeenat Safdar j, Rajan Saggar k, Sandeep Sahay l, Mary Beth Scholand m, Oksana A Shlobin n, David A Zisman o, Steven D Nathan p,∗
PMCID: PMC9993339  PMID: 35176276

Abstract

Background

Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD) and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates, but there are currently no standardized screening approaches. Trials have identified therapies that are effective in this setting, providing another rationale to routinely screen patients with ILD for PH.

Research Question

What screening strategies for identifying PH in patients with ILD are supported by expert consensus?

Study Design and Methods

The study convened a panel of 16 pulmonologists with expertise in PH and ILD, and used a modified Delphi consensus process with three surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to survey 1 and contained statements about PH screening that panelists rated from −5 (strongly disagree) to 5 (strongly agree).

Results

Panelists reached consensus on several triggers for suspicion of PH including the following: symptoms, clinical signs, findings on chest CT scan or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-min walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH.

Interpretation

Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for pulmonary hypertension-interstitial lung disease and can be used to assess the risk of PH. Because standardized approaches are lacking, this consensus statement is intended to aid physicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

Key Words: echocardiography, idiopathic pulmonary fibrosis, interstitial lung disease, pulmonary hypertension, right heart catheterization, screening

Abbreviations: 6MWD, 6-min walk distance; BNP, brain natriuretic peptide; Dlco, diffusing capacity of the lung for carbon monoxide; FDA, Food and Drug Administration; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; NT-proBNP, N-terminal pro-brain natriuretic peptide; PFT, pulmonary function test; PH, pulmonary hypertension; RHC, right heart catheterization; RVSP, right ventricular systolic pressure

Graphical Abstract

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Take-home Points.

Study Question: What screening strategies for identifying pulmonary hypertension (PH) in patients with interstitial lung disease (ILD) are supported by expert consensus?

Results: Panelists reached consensus on several triggers for suspicion of PH based on certain signs, symptoms, and other findings in usual tests performed in the care of patients’ with ILD (eg, pulmonary function tests, CT scans).

Interpretation: Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. This consensus statement may help physicians to identify PH in patients with ILD.

Pulmonary vascular involvement by numerous etiologies can result in pulmonary hypertension (PH), which is defined by a mean pulmonary artery pressure of > 20 mm Hg.1 The interstitial lung diseases (ILDs) are a broad, heterogenous group of conditions with > 200 etiologies, which are always accompanied by variable amounts of inflammation and/or fibrosis. PH is a common complication of ILD and is classified as group 3 in the World Symposium on Pulmonary Hypertension classification.1 PH associated with ILD is associated with worse outcomes, including an approximately threefold increased risk of mortality, a heightened propensity for acute exacerbations, impaired quality of life, decreased exercise capability, and increased need for supplemental oxygen.2, 3, 4, 5, 6, 7, 8, 9, 10

The reported prevalence of PH in ILD varies based on the underlying population studied, the disease severity, and the method used for diagnosing PH. This has resulted in a wide range of reported prevalence rates, anywhere from 3% to 86% in different studies.11,12 In idiopathic pulmonary fibrosis (IPF), for example, the reported prevalence of PH ranges from 8% to 15% at diagnosis, 29% to 46% at evaluation for lung transplant, and 86% at the time of lung transplant.9,12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Although echocardiography is an excellent noninvasive screening tool for PH, it has limited accuracy in estimating the right ventricular systolic pressure in the setting of ILD and is typically used for assessing the risk of PH rather than for diagnosis.21,22 Definitive diagnosis of PH requires right heart catheterization (RHC) to measure hemodynamics. In addition to confirming the diagnosis, RHC differentiates between precapillary and postcapillary PH while providing other prognostic hemodynamic factors (eg, right atrial pressure, cardiac index).1

Historically, evaluation of PH in patients with ILD was performed primarily as part of the assessment for lung transplantation listing and to evaluate the patient’s prognosis.23 In the absence of an effective therapy for pulmonary hypertension-interstitial lung disease (PH-ILD), the costs and risks of screening and confirmatory RHC have been thought to outweigh the potential benefits, except in the context of lung transplant evaluations.24 Consensus recommendations from the sixth World Symposium on Pulmonary Hypertension suggested individualized care by expert PH centers for patients with severe PH and lung disease, with acknowledgment that agents approved for the treatment of pulmonary arterial hypertension (group 1 PH) were sometimes used off-label to treat selected patients.25 There is no standard approach to assessing patients’ risk of PH. Based on these factors, variations in practice patterns mean that patients with ILD may not routinely be screened for PH and strategies for PH risk assessment may vary across different practices.

Two randomized trials in PH associated with ILD reported positive outcomes: a phase II trial of inhaled nitric oxide, and a phase III trial of inhaled treprostinil. The latter led to US Food and Drug Administration (FDA) approval of inhaled treprostinil for PH associated with ILD. With the advent of effective therapy for PH associated with ILD, the paradigm has shifted, making assessment of PH important for more than transplant evaluation and prognostication. Rather, diagnosis of PH in patients with ILD may lead to improved functional capacity through targeted therapy.

Because there is currently no generally accepted standard approach for PH screening in patients with ILD, the results and the availability of a specific therapy for PH-ILD raise questions of when and how to screen for PH in this population. We therefore conducted a modified Delphi study to identify current practices used by experts in the field to screen for PH in patients with ILD.

Study Design and Methods

Panel Selection

This modified Delphi study was conceived by members of a PH-ILD working group convened by the study sponsor (United Therapeutics Corp). The working group consisted of recognized experts in ILD and/or ILD-associated PH. Members of the working group constituted most of the Delphi panel. The working group members each nominated one or two colleagues as additional panelists, based on the colleague’s experience treating patients with PH-ILD and their clinical and research interest in PH-ILD. The candidates were reviewed, and the nominated experts were invited based on the number of nominations and diversity. The nominees were invited to participate by an independent project organizer and were also invited to further participate as coauthors. Coauthors were required to complete at least two of three Delphi surveys, including the final survey; and to contribute to, review, and approve the manuscript, thereby meeting International Committee of Medical Journal Editors criteria for authorship. The sponsor reviewed the article at each draft and made minor editorial comments.

The Delphi panel consisted of 16 panelists, all of whom are pulmonologists who practice in the United States. The panel had a median of 15 to 19 years’ experience treating patients with ILD (range, 7-30 years), and had treated a median of 1,000 to 1,999 patients (range, 150-15,000) in their careers. Their practice settings include ILD centers (12 panelists), PH centers (eight panelists), general pulmonology practice (one panelist), and other settings (two panelists) (some panelists practice in multiple settings).

Modified Delphi Methodology

The Delphi methodology describes a structured method for group decision-making in situations where evidence is lacking. This version was developed by Delbecq et al26 in 1975 and is now widely used in medical settings including pulmonology.27, 28, 29, 30, 31, 32, 33, 34, 35 This study’s modified Delphi method used three rounds of surveys, all moderated by three coauthors (F. F. R., N. A. K., and S. D. N.). Each survey was developed by the moderators. Surveys were elicited by electronic means. Panelists were asked to respond independently.

The initial survey consisted of open-ended questions intended to elicit panelist’s views on screening for PH in ILD. Question topics included the following: patients likely to benefit from early diagnosis and treatment of PH, routine test and imaging results that might suggest the need to screen for PH (CT scan, oxygen saturation, brain natriuretic peptide [BNP] or N-terminal proBNP [NT-proBNP], diffusing capacity of the lung for carbon monoxide [Dlco]), other pulmonary function tests (PFTs), physical signs and symptoms that might raise suspicion for PH, the role of comorbidities, and the participants’ overall approach to screening.

Survey 2 consisted of statements related to screening for PH in ILD. The moderators derived the statements by combining panelists’ responses to survey 1, while eliminating outlier responses and editing the responses for clarity and consistent language. Panelists were asked to rate their agreement with each statement on a Likert scale ranging from −5 (strongly disagree) to 5 (strongly agree). The statements were grouped into topics, and panelists were invited to expand on their responses with an open-response question for each topic.

Survey 3 contained the same statements as survey 2, along with each panelist’s own answer to survey 2 and the mean and SD of all panelists’ responses. This allowed panelists to reevaluate their answers in light of the group’s average responses and was intended to build consensus.

The study began in July 2020 with distribution of survey 1 and concluded in March 2021 with collection of all responses to survey 3. Surveys were aggregated by Parexel under the direction of the moderators. Only descriptive statistics were used.

Consensus was predefined as a Likert scale mean score ≥ 2.5 with an SD in the scores not crossing 0. These criteria have been used in previous Delphi studies; however, there are no generally accepted criteria for defining consensus in Delphi studies.27, 28, 29, 30,33, 34, 35 The Likert scale criteria we used have been used in several other studies in pulmonology and other specialties.31,32,36, 37, 38

Because no patient contact or patient information was used in this study, institutional review board approval was not required.

Results

At the conclusion of survey 3, panelists reached consensus on 80 of 135 items (59%). The full questionnaire and scores are presented in e-Table 1.

Patients With ILD Who Are Likely to Benefit From Early Diagnosis and Screening for PH

Panelists reached consensus that, if an FDA-approved therapy for PH in patients with ILD became available, earlier evaluations for PH than are done in current practice are likely to benefit patients, with a mean consensus score ± SD of 4.56 ± 0.70. Early diagnosis and treatment for PH-ILD would be beneficial for a wide array of ILDs (Fig 1). Early diagnosis and treatment would also be beneficial for patients with progressive ILD, patients who require supplemental oxygen, and patients with symptoms or signs disproportionate to the severity of their ILD, especially when changes in symptoms are not explained by progression of ILD (Fig 1).

Figure 1.

Figure 1

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Delphi consensus scores for ILD types and disease characteristics that could benefit from earlier diagnosis and treatment of pulmonary hypertension if a Food and Drug Administration-approved treatment is available. Items that reached consensus. Vertical rectangles indicate the mean consensus score for each item. Horizontal error bars depict the SD. Consensus was defined as a mean score ≥ 2.5 with an SD that does not cross 0. FDA = United States Food and Drug Administration; ILD = interstitial lung disease; PH = pulmonary hypertension.

Triggers for Suspicion of PH

In the initial Delphi survey, panelists suggested 19 signs and symptoms as possible triggers for suspicion of PH in patients with ILD. In survey 3, panelists reached consensus on nine of these signs and symptoms: syncope, jugular venous distension, peripheral edema, ascites, altered heart sounds (especially loud P2 or S2), hepatomegaly, history of pulmonary embolism, dizziness, and palpitations (Fig 2). Development or worsening of these symptoms should prompt further evaluation. No consensus was reached for the signs and symptoms of weight gain, dyspnea on exertion, shortness of breath, cough, chest pain, arrhythmias, abnormal arterial blood gases, fatigue, signs of left heart failure, hemoptysis, Raynaud’s disease, or increased heart rate response to exercise (e-Fig 1).

Figure 2.

Figure 2

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Delphi consensus scores for signs and symptoms in the patient history that are possible triggers for pulmonary hypertension screening in patients with interstitial lung disease. Items that reached consensus. Vertical rectangles indicate the mean consensus score for each item. Horizontal error bars depict the SD. Consensus was defined as a mean score ≥ 2.5 with an SD that does not cross 0.

Panelists reached consensus that several standard tests and procedures are triggers for suspicion of PH, including abnormalities on chest CT scan, poor oxygen saturation, elevated BNP or NT-proBNP, PFTs, and a reduced 6-min walk distance (6MWD) (Fig 3). CT scan-related triggers that reached consensus included right ventricular enlargement, several measures related to pulmonary artery enlargement (eg, pulmonary artery/aorta ratio > 1), and flattening of the interventricular septum. Worsening or disproportionate oxygen desaturation is a trigger, but no specific oxygen saturation threshold reached consensus. Panelists arrived at a consensus that an elevated BNP or NT-proBNP is a trigger for suspicion, at BNP levels > 200 pg/mL or NT-proBNP > 395 pg/mL (cutoff based on a study of patients with systemic sclerosis with or without pulmonary arterial hypertension).39 The PFT-related triggers that reached consensus were Dlco % predicted < 40%, rapid decline in Dlco (≥ 15%), and Dlco disproportionate to lung volumes (FVC/Dlco ratio > 1.6), but no consensus was reached on the use of FVC or total lung capacity or any thresholds for these parameters. A worsening 6MWD despite stable PFTs also reached consensus as a trigger for suspicion. No consensus was reached on specific 6MWD thresholds or other exercise tests (e-Figs 2, 3).

Figure 3.

Figure 3

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Delphi consensus scores for tests and procedure results that are possible triggers for pulmonary hypertension screening in patients with ILD. Items that reached consensus. Vertical rectangles indicate the mean consensus score for each item. Horizontal error bars depict the SD. Consensus was defined as a mean score ≥ 2.5 with an SD that does not cross 0. 6MWD = 6-min walk distance; BNP = brain-type natriuretic peptide; Dlco = diffusing capacity of the lung for carbon monoxide; ILD = interstitial lung disease; NT-proBNP = N-terminal pro-brain natriuretic peptide; PFT = pulmonary function test; Scl-ILD = scleroderma-associated ILD.

Approach to Screening and Confirmation When PH Is Suspected

The panelists reached consensus that when PH is suspected, echocardiography and BNP or NT-proBNP are useful as subsequent screening tests. In addition to these two tests, panelists reached consensus that CT scan of the chest, PFTs, and 6MWD are useful to evaluate ILD stability or progression when symptoms are disproportionate to the severity of the underlying ILD (Fig 4).

Figure 4.

Figure 4

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Delphi consensus scores for initial screening tests and tools to evaluate symptoms. Items that reached consensus. Vertical rectangles indicate the mean consensus score for each item. Horizontal error bars depict the SD. Consensus was defined as a mean score ≥ 2.5 with an SD that does not cross 0. 6MWD = 6-min walk distance; BNP = brain-type natriuretic peptide; Dlco = diffusing capacity of the lung for carbon monoxide; ILD = interstitial lung disease; NT-proBNP = N-terminal pro-brain natriuretic peptide; PFT = pulmonary function test.

There was no consensus for initial screening with RHC, ECG, CT angiogram, V·/Q· scan, or cardiac MRI scan (e-Table 1). Settings in which use of RHC to confirm a diagnosis of PH reached consensus include the following: potential lung transplant candidates, echocardiography findings suggestive of PH (in particular, elevated right ventricular systolic pressure [RVSP], right ventricular abnormalities including dilation or enlargement, and a low tricuspid annular plane systolic excursion), high clinical suspicion of PH (eg, based on the signs and symptoms described in Fig 1), and autoimmune ILD. A low threshold for RHC was considered appropriate to confirm a PH diagnosis, particularly with suggestive clinical or echocardiography findings (Fig 5).

Figure 5.

Figure 5

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Delphi consensus scores for triggers for RHC. Items that reached consensus. Vertical rectangles indicate the mean consensus score for each item. Horizontal error bars depict the SD. Consensus was defined as a mean score ≥ 2.5 with an SD that does not cross 0. ∗In patients for whom RHC can be performed safely. ECHO = echocardiogram; ILD = interstitial lung disease; PH = pulmonary hypertension; RHC = right heart catheterization; RV = right ventricular; RVSP = right ventricular systolic pressure; TAPSE = tricuspid annular plane systolic excursion.

Discussion

This modified Delphi study convened a panel of experts in ILD and PH to gain information on their practices regarding screening for and diagnosing PH in patients with ILD now that a therapy for PH in this setting has been approved. Panelists came to a consensus to perform early screening for PH, with a low threshold of suspicion. Early screening to identify patients with PH-ILD may benefit patients by prompting early treatment and transplant referral in this high-risk population. However, at this writing, the long-term impact of the available medical therapies for PH-ILD is not known. Patients who develop PH-ILD should still be referred for lung transplantation because medical therapy may provide only transient improvement.

Routine clinical evaluations and tests assessed for suspicion of PH included signs and symptoms suggestive of PH, CT imaging suggestive of pulmonary artery or right ventricular enlargement, desaturation or changes in oxygen supplementation, PFT results (particularly Dlco and the FVC/Dlco ratio), decreases in the 6MWD, and abnormal BNP or NT-proBNP levels. If suspicious findings are present, screening echocardiography and a BNP or NT-proBNP test should be considered, possibly along with other tests based on clinical judgment and the patient’s specific situation. Confirmatory RHC is necessary if any combination of findings raises suspicion of PH. Figure 6 summarizes a consensus approach to screening and diagnosis of PH in patients with ILD.

Figure 6.

Figure 6

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Consensus approach to screening for PH in patients with ILD. ∗ Individual laboratories may have different thresholds. 6MWT = 6-min walk test; BNP = brain-type natriuretic peptide; Dlco = diffusing capacity of the lung for carbon monoxide; ILD = interstitial lung disease; NT-proBNP = N-terminal pro-brain natriuretic peptide; PA = pulmonary artery; PH = pulmonary hypertension; RHC = right heart catheterization; RV = right ventricular.

Until recently, the primary benefit of assessing patients with ILD for PH was an improved estimate of the patient’s prognosis. There was no evidence for treating PH associated with ILD. On the contrary, several trials found no benefit from the PH therapies evaluated.24 The BPHIT study (Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia) showed no benefit in the primary and many of the secondary end points.39,40 The RISE-IIP (Riociguat in Patients with Symptomatic Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias) study demonstrated a harmful signal in patients with PH because of idiopathic interstitial pneumonias who received riociguat.25 The ARTEMIS-IPF trial (Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF) found that ambrisentan was ineffective and possibly increased the risk of disease progression and hospitalization regardless of the presence of PH.41

The STEP-IPF (Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis) trial found no benefit for 6MWD from sildenafil in patients with advanced IPF.42 Although RHC confirmation of PH was not available for these patients, a subgroup analysis of patients with right ventricular dysfunction on echocardiography demonstrated significant improvements in 6-min walk test and health-related quality of life for sildenafil vs placebo.43

Recently, two studies have found promising results in treating PH associated with ILD. A phase II randomized, placebo-controlled study of inhaled nitric oxide in 41 patients with fibrotic ILD who were at risk of PH by echocardiography found that inhaled nitric oxide was associated with maintenance of physical activity as measured by actigraphy compared with placebo patients who had serial declines in activity.44 This modality of therapy is now being tested in a phase III clinical trial (A Study to Assess Pulsed Inhaled Nitric Oxide in Subjects With Pulmonary Fibrosis at Risk for Pulmonary Hypertension: REBUILD).45 The phase III randomized, placebo-controlled INCREASE trial demonstrated that inhaled treprostinil improved 6MWD, reduced NT-proBNP, and slowed rates of clinical worsening in patients with PH caused by ILD, in comparison with placebo.46 The results of this study led to FDA approval of inhaled treprostinil for PH associated with ILD. The approval of an effective therapy for PH-ILD lowers the bar for making a diagnosis, and our study provides an outline for which patients should be screened.

Several earlier studies have evaluated approaches to screening or prediction of PH in patients with various subtypes of ILD.24 Zisman et al47 validated an equation using FVC/Dlco (percent predicted) and oxygen saturation on room air to estimate the mean pulmonary artery pressure in patients with IPF. Alkukhun et al48 found that impaired right ventricular function and an elevated pulmonary artery/aorta ratio predict PH in IPF, but have a limited ability to discriminate between patients with and without PH. Sonti et al49 reported that RVSP measured by echocardiography, the FVC/Dlco ratio, and the pulmonary artery/aorta ratio predict PH more reliably than RVSP alone. Despite multiple studies assessing noninvasive screening techniques for PH in patients with ILD, there is no substitute for the criterion standard RHC.

We have taken a somewhat different, ILD-focused, approach to PH risk assessment and screening in that many of the screening techniques found useful in our surveys are already part of routine care in patients with ILD. Specifically, PFTs, chest CT scan, oxygen saturation, oximetry with ambulation, and perhaps 6MWD are routinely obtained at the time of diagnosis, during serial follow-up, and as part of the assessment for lung transplant. Because many of these patients are older and other causes for their shortness of breath are frequently sought, it is not uncommon for these patients to have one or more echocardiograms during the course of their disease management. Although these tests are not intended for PH screening in routine ILD practice, we have tried to highlight that these test results can provide useful information on risk stratification for underlying PH, and can be used in concert to identify patients who should be referred for RHC. It is our hope and goal that this report will increase awareness and spotlight these existing tests that can serve to prompt further investigation that might ultimately culminate in the performance of an RHC. Clinical judgment will of course need to be exercised by physicians on a case-by-case basis in terms of obtaining further testing.

This study has several limitations. There is potential for bias in the selection of panelists and the development of the Delphi surveys. All our Delphi participants practice in the United States, mostly in specialty PH and/or ILD centers. Although the practice patterns reported here may not be reflective of other settings, we regard this as a strength because all the participants had expertise in PH, ILD, or both. By considering ILD as a whole, we may have reduced emphasis on specific ILD subtypes for which increased suspicion of PH is more appropriate. We also might not have highlighted all available screening options; for example, regarding the 6MWD, we focused on distance and oxygen desaturation, but there are other parameters within this study that might further increase the suspicion for underlying PH (eg, Borg Dyspnea Scale, heart rate recovery).50 Similarly, our survey did not list all noninvasive parameters but only included NT-proBNP/BNP given that this biomarker is most routinely used in the care of patients with ILD and has the most literature supporting its significance. As in all Delphi studies, this study’s conclusions are based on expert opinion rather than clinical evidence. Our survey and recommendations included patients with ILD related to connective tissue disorders. Arguably, screening for PH is generally recommended for these patients already. However, screening recommendations in connective tissue disorders are mostly geared toward patients with scleroderma, and we therefore think that our guidance reinforces the need for screening in not only patients with scleroderma, but in all patients with ILD related to connective tissue disorders.51 Finally, the survey did not include every echocardiographic parameter that could be used in assessing for PH, and a comprehensive review of echocardiographic results is warranted in risk stratifying patients for underlying PH.

A notable strength of this paper is that it helps fills a void highlighted by the recent approval of an agent to treat PH-ILD. Specifically, the consensus of seasoned physicians in the field may aid physicians at a time when definitive guidance is lacking and may further serve as a useful starting point for studies to better define screening parameters for this high-risk population. To our knowledge, this is the first time the question of screening for PH in patients with ILD has been considered by a large panel of experts in the field. In addition, the panel took an ILD-specific approach that focused primarily on tests routinely obtained in the management of ILD, with a focus on how these tests can be used to risk stratify for PH complicating ILD.

Interpretation

The development and availability of novel therapies specifically for PH in ILD, and rapid gains in scientific knowledge of the condition, have brought attention to the unmet need for guidelines on screening for PH in this setting. Our study highlights parameters that are important for screening for PH in patients with ILD. We further contextualize these through our methodical three-phase Delphi process and Likert weighting, which may provide a foundation and impetus for further guideline development. We hope this work will encourage further research to identify appropriate screening parameters and thresholds, and to develop and validate a strategy for screening (eg, a screening algorithm and/or a scoring system that more accurately quantifies the risk of PH in ILD).

Acknowledgments

Author contributions: All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. S. D. N., N. A. K., and F. F. R. made substantial contributions to the conception and design of the work. All authors contributed to the acquisition of the study data and participated in at least two surveys including the final survey. All authors contributed to the interpretation of the data, and to drafting and revising of the manuscript. All authors have read and approved the manuscript.

Funding/support: This study was funded by an independent grant provided by United Therapeutics Corp.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: F. F. R. has received writing support for the present manuscript from United Therapeutics; grants or contracts from Bayer, Janssen PH, and Acceleron; consulting fees from United Therapeutics, Janssen PH, Bayer, and Acceleron; and payments or honoraria from United Therapeutics, Janssen PH, and Bayer. N. A. K. has received consulting fees from United Therapeutics (outside the scope of this article) and advisory board fees from Bayer. A. A. has received consulting fees from Boehringer Ingelheim and Genentech, and payment or honoraria for serving on a speakers bureau for Boehringer Ingelheim. J. A. has received payments for lectures, manuscript writing, or educational events from Boehringer Ingelheim and Genentech, and for serving on a data and safety monitoring board (DSMB) for the NIH/NHLBI (Pulmonary Trials Consortium). K. R. F. has received consulting fees from Bellerophon, Respivant, Blade Therapeutics, Shionogi, DevPro, AstraZeneca, Pure Health, Horizon, FibroGen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, and PureTech; and chairs the steering committee for the Pulmonary Fibrosis Foundation patient registry. L. L. has received grants or contracts from Genentech, Boehringer Ingelheim, Respivant, Biogen, Celgene, Galapagos, Galactic, Novartis, Bristol Myers Squibb, and Bellerophon as a principal investigator for research through Vanderbilt University; has received consulting fees from AstraZeneca, Galapagos, and United Therapeutics; has served on speakers bureaus for Boehringer Ingelheim and Genentech; has participated on a DSMB for Senhwa; and is a member of the Pulmonary Fibrosis Foundation Registry Steering Committee and the CHEST Diffuse Ling Disease Committee. J. S. L. has received an NIH/NHLBI grant outside the submitted work; has received a grant from Boehringer Ingelheim (outside the submitted work); has received consulting fees from Galapagos, Boehringer Ingelheim, United Therapeutics, and Eleven P15, outside the submitted work; has participated on a DSMB for the TETON trial (United Therapeutics) and the DSMB for Avalyn; and is a senior medical advisor for the Pulmonary Fibrosis Foundation. I. R. P. has received medical writing support from Parexel in support for this article; has received grants from Acceleron, Actelion, PhaseBio, Tenax, and United Therapeutics; has received payments or honoraria from MedOnTheGo, Medscape, and Integrity CME; has received payment for expert testimony from Bayer; has participated on DSMBs for Acceleron, Actelion, Altavant, Respira, Pfizer, and United Therapeutics; and has a leadership role in the ISHLT. Z. S. has received medical writing support from United Therapeutics for other manuscripts; has received support for travel or meetings; has received consulting fees; and is on the advisory board from United Therapeutics, Johnson & Johnson, Bayer, Genentech, Boehringer Ingelheim, and United Therapeutics. S. S. has received an ACCP CHEST ILD research grant (2020); has received consulting fees from Bayer, J&J, United Therapeutics, and Acceleron; has received payments or honoraria from J&J, United Therapeutics, and Bayer; has received a patent submitted for J&J as an inventor (secondary titration of Uptravi); has participated on the DSMB for a clinical trial sponsored by the NIH and Biogen of dimethyl fumarate in scleroderma; has participated in advisory boards for United Therapeutics, Bayer, Liquidia, and Acceleron; and is a member in the PVD network and ACCP CHEST. M. B. S. received medical writing support from United Therapeutics for the present manuscript; has received consulting fees from United Therapeutics and Veracyte; has received payments or honoraria from United Therapeutics, Genentech, Boehringer Ingelheim, and Veracyte; has received support for travel or meetings form United Therapeutics; and has participated on a DSMB or advisory board for Veracyte, United Therapeutics, and Polarean. O. S. has received payment or honoraria from United Therapeutics, Bayer, and Johnson & Johnson; and has participated on DSMBs or advisory boards for United Therapeutics, Bayer, Johnson & Johnson, and Altavant. S. D. N. has received support for the present manuscript from United Therapeutics; has received consulting fees from United Therapeutics, Bellerophon, Merck, Bayer, Roche, and Boehringer Ingelheim; and has received payment for expert testimony from Roche. None declared (D. L., R. S., D. A. Z.).

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: Editorial and logistic assistance was provided by Parexel International Corp. Medical writing support was provided by Edward K. Baldwin, PhD. Both were funded by an independent grant from United Therapeutics Corp.

Additional information: The e-Figures and e-Table are available online under “Supplementary Data.”

Supplementary Data

e-Online Data
mmc1.docx (136.2KB, docx)

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