WHAT IS ALREADY KNOWN ON THIS TOPIC

Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP) only (>20 mm Hg), while precapillary PH is defined by a combination of elevated MPAP and pulmonary vascular resistance (PVR). In patients with interstitial lung disease (ILD), PH is reported to be a fatal complication, but the clinical significance of non-severe PH in patients with various types of ILD has not been fully elucidated.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYIntroduction

Interstitial lung disease (ILD) comprises a wide range of lung diseases associated with fibrotic destruction of the lung parenchyma and has various causes, clinical manifestations and variable outcomes.1 Pulmonary hypertension (PH) is an important complication that negatively affects exercise tolerance, quality of life and mortality in patients with ILD, even when it is non-severe.2–5

The previous consensus definition of PH was a mean pulmonary arterial pressure (MPAP) of ≥25 mm Hg. The characteristics of precapillary PH were categorised using pulmonary artery wedge pressure (PAWP) of <15 mm Hg and pulmonary vascular resistance (PVR) of ≥3 Wood units (WU).6 Recently, the 2022 ESC/ERS guidelines proposed a new definition of PH as MPAP>20 mm Hg at rest, and the cut-off value of PVR in precapillary PH was changed from 3 to 2 WU for the early detection of pulmonary vascular disease.7

MPAP of >20 mm Hg even at initial evaluation was reported to increase the mortality rate especially in patients with idiopathic pulmonary fibrosis (IPF).3 To detect the early stage of PH in patients with IPF, we have established a screening tool that uses a combination of non-invasive examinations.8 However, the clinical significance of MPAP and PVR in patients with various types of ILD has not been fully elucidated.

The purpose of this study is to evaluate the clinical significance of MPAP and PVR values for mortality in patients newly diagnosed with ILD.

MethodsSubjects

We retrospectively analysed consecutive patients with ILD who underwent right heart catheterisation (RHC) in the initial evaluation of ILD between April 2007 and April 2018 at Tosei General Hospital. We excluded patients who had received any treatment for ILD and/or PH, including long-term oxygen therapy, at the initial evaluation. Because the diagnostic criteria for IPF and IIPs had been amended, in January 2020 we re-diagnosed all eligible patients by multidisciplinary discussion including a review of the medical history, based on the 2018 idiopathic pulmonary fibrosis guidelines,9 the 2013 idiopathic interstitial pneumonia statement10 or other corresponding disease guidelines.

Measurements

Clinical data including patient characteristics, laboratory examination, pulmonary function test and RHC at the initial evaluation were obtained from medical records. All patients underwent spirometry (CHESTAC-55 V; Chest, Tokyo, Japan) according to American Thoracic Society/European Respiratory Society recommendations.11 RHC was performed percutaneously from the femoral or antecubital vein at rest using a Swan-Ganz catheter. The zero level of the pressure transducer was adjusted at the midthoracic line in supine patients. MPAP was measured in the main pulmonary artery and PAWP in the wedge position, both at the end-expiratory phase. Cardiac output was measured using the thermodilution method. The duration from initial evaluation to last attendance or death was recorded until October 2019.

Definitions

To evaluate the impact of MPAP and PVR values on mortality in patients with ILD, we classified patients into six groups based on the 2022 the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) guidelines for PH and their MPAP and PVR values.7 MPAP was categorised into three groups: 20 mm Hg or less, 20<MPAP<25 mm Hg and 25 mm Hg or more, respectively. PVR was categorised into two groups: less than or equal to 2 WU and higher than 2 WU. Finally, the combination of MPAP and PVR groups resulted in six groups. According to the latest guidelines for PH,7 PH was haemodynamically defined as MPAP>20 mm Hg and precapillary PH as MPAP>20 mm Hg, PAWP≤15 mm Hg and PVR>2 WU.

Statistical analysis

Continuous variables were described as median (IQR), and categorical variables were described as frequency (%). The difference among groups was analysed using the Mann-Whitney U test, χ2 test or Fisher’s exact test, as appropriate. The Kaplan-Meier method was applied to show unadjusted survival curves. Univariate and multivariate Cox proportional hazard analyses were used to evaluate the relationships between MPAP, PVR and mortality rate, presented in terms of estimated HRs with corresponding 95% CIs, adjusted for the quadruple severity by the ILD–Gender, Age and Physiology (ILD-GAP) Index12 unless otherwise stated. Cases for which the ILD-GAP Index could not be obtained were excluded. The HR was assumed to be constant over time for the analysis. Time-dependent receiver operating characteristic analysis was conducted to compare the predictive performance of MPAP and PVR values. To exclude the potential effect of PAWP to elevate the MPAP and the adverse effect of IPF diagnosis to mortality, a sensitivity analysis was performed in patients with PAWP≤15 mm Hg and in non-IPF patients. We evaluated the Harrell’s concordance index for mortality using PVR values varying by 0.1 points increments.13 P values of less than 0.05 were considered to be statistically significant. Statistical analyses were performed using IBM SPSS Statistics V.24 (IBM Corporation, Armonk, New York, USA) and R statistical software (The R Project for Statistical Computing, www.r-project.org/).

Results

A total of 854 consecutive patients with ILD who underwent RHC at initial evaluation were analysed. In total, 167 patients (19.6%) had MPAP>20 mm Hg; 118 patients showed PVR>2 WU; and 61 had 20<MPAP<25 mm Hg with PVR>2 WU, whereas 57 had MPAP≥25 mm Hg with PVR>2 WU (table 1). Only 6 patients had PAWP>15 mm Hg among the 118 patients with MPAP>20 mm Hg and PVR>2 WU. Of the 687 patients with MPAP≤20 mm Hg, 180 (26.2%) showed PVR>2 WU without PAWP>15 mm Hg (table 1). Patients with PVR>2 WU had lower forced vital capacity (FVC) (72.5% vs 87.6%, p<0.0001), lower carbon monoxide transfer factor (51.4% vs 69.0%, p<0.0001), a higher proportion with a low cardiac index (C.I.<2.2 L/min/m2) (5.7% vs 1.4%, p=0.0009) and a higher proportion of IPF (54.4% vs 43.7%, p=0.0032). There was no significant difference in the proportion of more than 2 cardiac comorbidities and that of PAWP>15 mm Hg between patients with PVR>2 WU and those with PVR≤2 WU (online supplemental table 1). When classified by the cut-offs of PVR 2 and 5 WU, patients with a higher ILD-GAP Index were more likely to have PVR>5 WU, 2<PVR≤5 WU and PVR≤2 WU, in that order (χ2 test, p<0.0001) (online supplemental table 2). The proportion of patients with precapillary PH (MPAP>20 mm Hg, PAWP<15 mm Hg and PVR>2 WU) was 14.6% in IPF, 7.7% in non-IPF idiopathic interstitial pneumonias and 18.7% in connective tissue disease associated ILD (online supplemental table 3). The list of diagnoses in patients with ILD is shown in online supplemental table 4.

Table 1

Baseline characteristics based on haemodynamic definition of pulmonary hypertension (PH)

In total, 326 patients (38.2%) died during the observation period, with the main cause of death being respiratory causes: chronic respiratory failure (46.9%) and acute exacerbation (AE) of ILD (23.6%). There were no significant differences in respiratory causes of death between the patients with PVR>2 WU and those with PVR≤2 WU. In total, 22 patients (6.7% of all deaths) died from cardiovascular events (online supplemental table 5). Baseline characteristics based on the previous haemodynamic definition of PH6 are shown in online supplemental table 6.

Kaplan-Meier analysis demonstrated that patients with PH showed higher mortality than those without PH (figure 1A). The median time to death in the total cohort was 7.6 years. Stratified by MPAP and PVR categories, patients with PVR>2 WU had higher mortality rate than those with PVR≤2 WU, regardless of MPAP values (figure 1B). HRs with 95% CIs for mortality classified by the cut-offs of MPAP 20 and 25 mm Hg and PVR 2 WU are shown in online supplemental table 7. Comparison of Kaplan-Meier survival curves categorised by precapillary PH definition and cut-offs of MPAP 20 and 25 mm Hg and PVR 3 WU are shown in online supplemental figures 1 and 2. In univariate Cox proportional hazard analyses, higher MPAP and higher PVR were associated with high mortality rates, whereas PAWP was not (online supplemental table 8). In Cox proportional hazard models with adjustment for the ILD-GAP Index, when either PVR or MPAP was included, PVR>2 WU and MPAP>20 mm Hg were associated with a worse mortality rate (HR 1.61, 95% CI 1.28 to 2.02, p<0.0001; HR 1.30, 95% CI 1.00 to 1.68, p=0.0492, respectively). Moreover, PVR but not MPAP was associated with a higher mortality rate when continuous or categorised values of both PVR and MPAP were included (continuous values: PVR: HR 1.37, 95% CI 1.23 to 1.52, p<0.0001, MPAP: HR 0.98, 95% CI 0.96 to 1.01, p=0.1671; categorised values: PVR>2 WU: HR 1.53, 95% CI 1.20 to 1.95, p=0.0005, 20<MPAP<25 mm Hg: HR 0.96, 95% CI 0.70 to 1.33, p=0.8226, MPAP≥25 mm Hg: HR 1.46, 95% CI 0.99 to 2.15, p=0.0538, respectively) (table 2). Compared with PVR≤2 WU, 2<PVR≤5 WU and PVR>5 WU were associated with a worse mortality rate (HR 1.53, 95% CI 1.21 to 1.93, p<0.0004; HR 4.03, 95% CI 2.30 to 7.05, p<0.0001, respectively) (online supplemental table 9). In sensitivity analyses, PVR>2 WU also showed an increased risk of mortality in patients with PAWP≤15 mm Hg and/or non-IPF patients (online supplemental table 10). Even in patients with IPF and connective tissue disease-related ILD, PVR>2 WU was associated with a high mortality rate regardless of MPAP values (online supplemental figure 3).

Figure 1

(A) Kaplan-Meier curves for survival classified by the pulmonary haemodynamic definition of pulmonary hypertension (PH). The figure shows survival curves of all patients according to the pulmonary haemodynamic definition of PH. (B) Kaplan-Meier curves for survival classified by the cut-offs of MPAP 20 and 25 mm Hg and PVR 2 WU. The figure shows survival curves of all patients according to the cut-offs of MPAP 20 and 25 mm Hg and PVR 2 WU. Tick marks represent censored patients. Regardless of MPAP values, patients with PVR>2 WU had a higher mortality rate (median survival time, 48.0 vs 102.7 months; log-rank, p<0.0001). HRs with 95% CIs for mortality are shown in online supplemental table 7. MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; WU, Wood units.

Table 2

Comparison of Cox proportional hazard models of mortality with adjustment for the ILD-GAP Index

Compared with MPAP, PVR showed better prognostic ability for the mortality rate every year (figure 2). Time-dependent AUCs, sensitivity and specificity for 1-year, 5-year and 10-year prognoses are presented in online supplemental table 11 and online supplemental figure 4. We determined the optimal cut-off value for PVR to be 2.2, as this maximised Harrell’s concordance index in the Cox hazard analysis for mortality (online supplemental table 12 and online supplemental figure 5).

Figure 2

Comparison of the time-dependent area under the receiver operating characteristic curves (AUC) for mortality. The time-dependent AUC for MPAP and PVR. The horizontal axis shows the years after the initial evaluation and the vertical axis shows the estimated AUC for mortality at the time of interest. Red and blue solid lines indicate the estimated AUCs for the PVR and MPAP. Red and blue dashed lines indicate the regression lines. Shaded areas represent the 95% CI. PVR had higher predictive performance than MPAP. MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance.

Discussion

We conducted a retrospective analysis of 854 consecutive ILD patients with RHC at initial evaluation and revealed that approximately 20% and 35% of patients had MPAP>20 mm Hg and PVR>2 WU, respectively. The proportions of PVR>2 WU in patients with MPAP≤20 mm Hg, 20<MPAP<25 mm Hg and ≥25 mm Hg were 26.2%, 60.4% and 86.4%, respectively. In Cox proportional hazards analyses, not MPAP but PVR was associated with a higher mortality rate. To our knowledge, this is the first study to demonstrate that PVR>2 WU is associated with a higher mortality rate in patients with newly diagnosed ILD, even in those with MPAP≤20 mm Hg. These findings suggest that we need to be aware of the value of PVR from the time of ILD diagnosis and the simultaneous interpretation of PVR and MPAP are important in patients with ILD.

We showed that PVR of >2 WU was associated with a high mortality rate in patients with newly diagnosed ILD. Although the 2022 ESC/ERS guidelines state that PVR>5 WU is a predictor of poor prognosis in patients with lung disease,7 this is based on data from patients with advanced ILD14–18 and the impact of PVR on mortality in newly diagnosed patients with ILD is not known. The fact that the optimal cut-off value for PVR predicting mortality in our study was 2.2 WU suggests that PVR>2 WU is important even in ILD, just as in other diseases.7 This result is consistent with reports that the upper limit of normal PVR and the lowest prognostically relevant PVR threshold are >2 WU.19–22

The clinical significance of PVR and PAWP in patients with ILD is still poorly understood. Although PVR>3 WU with PAWP>15 mm Hg was reported to be associated with a reduced exercise capacity and with high mortality in PH associated with left heart disease,23 24 we previously reported that in PH patients with ILD there was no significant difference in mortality between patients with PAWP≤15 mm Hg and those with PAWP>15 mm Hg when adjusted for PVR and the ILD-GAP score.25 In the present study, only 6 of 19 patients (0.7% of the total cohort) with PAWP>15 mm Hg had PVR>2 WU, making it difficult to evaluate the effect of PAWP in PVR>2 WU.

The mechanism for the greater prognostic significance of PVR than of MPAP in ILD is unclear. PVR, which is calculated using MPAP, cardiac output and PAWP, is a better marker of pulmonary vascular disease than MPAP.26 The major mechanism of pulmonary vascular disease in patients with ILD has been attributed to fibrotic destruction of the lung parenchyma and hypoxic pulmonary vasoconstriction, leading to obliteration of the vascular bed.27 28 Furthermore, recent studies suggest that the pathogenesis lies in the complicated interaction of epithelial cells, fibroblasts and vascular cells, with a focus on endothelial apoptosis and growth factor-induced remodelling of the pulmonary artery wall.29 Indeed, the group with PVR>2 WU in our study showed lower partial pressure of arterial oxygen and FVC, which may affect the elevation of PVR.

When classified by PVR>2 WU, the proportion of causes of death was similar between the two groups. Previous studies demonstrated that cardiovascular events are the main cause of death in PAH, especially right heart failure due to right ventricular dysfunction.30–33 However, only a few studies on patients with PH-ILD have been reported. In our study, deaths due to cardiovascular events occurred in only 22 patients (6.7% of all deaths). Respiratory causes of death were the most common, at 230 (70.5%). Of them, 77 (23.6%) were AE of ILD. AE is fatal and thus the most significant event in patients with ILD. Some previous studies have reported that an elevation of MPAP (>25 mm Hg or 20<MPAP<25 mm Hg) was associated with increased risk of AE in patients with ILD.34 35 However, in our study, the proportion of death due to AE was similar regardless of the PVR value. Further studies are needed to reveal the relationship between AE and PVR.

There are several limitations to this study. First, it was a retrospective study in a single centre, so further multicentre prospective studies will be needed. Next, left heart catheterisation was not performed in this study, so we could not evaluate cardiac impairment which might have affected pulmonary haemodynamics. Third, the number of patients with MPAP≥25 mm Hg was small. Therefore, the statistical examination of mortality was limited and our results have to be considered with caution. Fourth, we may have overestimated the effect of PVR in patients with severe status because we assessed patients who did not receive long-term oxygen therapy, which may affect haemodynamic status. Fifth, we could not routinely evaluate the right heart size and function using echocardiography. Nevertheless, we believe our findings are important because this is the first study to show that PVR>2 WU at the time of ILD diagnosis is associated with a higher mortality rate.

We conclude that PVR>2 WU is associated with higher mortality rate in patients with ILD, regardless of MPAP values. These findings suggest that the simultaneous interpretation of PVR and MPAP is important in patients with ILD.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

This study involves human participants and was approved by Tosei General Hospital institutional review board (IRB No. 920). The Japanese Clinical Trials Act allows opt-out consent for observational research using existing data, a consent method we used in this study. Participants gave informed consent to participate in the study before taking part.