Pulmonary Hypertension In Interstitial Lung Disease Research Articles

Evolution of pulmonary hypertension in interstitial lung disease: a journey through past, present, and future.

Interstitial lung diseases (ILD) are a spectrum of disorders often complicated by pulmonary hypertension (PH) in its course. The pathophysiologic mechanism of WHO group 3 PH is different to other forms of PH. The advent of PH is a harbinger for adverse events like mortality and morbidity, implying that the PH component of disease expedites deteriorated clinical outcomes. In fact, WHO group 3 PH due to ILD has the worse prognosis among all groups of PH. Hence, early detection of PH by a comprehensive screening method is paramount. Given considerable overlap in clinical manifestations between ILD and PH, early detection of PH is often elusive. Despite, the treatment of PH due to ILD has been frustrating until recently. Clinical trials utilizing PAH-specific pulmonary vasodilators have been ongoing for years without desired results. Eventually, the INCREASE study (2018) demonstrated beneficial effect of inhaled Treprostinil to treat PH in ILD. In view of this pioneering development, a paradigm shift in clinical approach to this disease phenotype is happening. There is a renewed vigor to develop a well validated screening tool for early detection and management. Currently inhaled Treprostinil is the only FDA approved therapy to treat this phenotype, but emergence of a therapy has opened a plethora of research toward new drug developments. Regardless of all these recent developments, the overall outlook still remains grim in this condition. This review article dwells on the current state of knowledge of pre-capillary PH due to ILD, especially its diagnosis and management, the recent progresses, and future evolutions in this field.

Pulmonary Hypertension in the Course of Interstitial Lung Diseases-A Personalised Approach Is Needed to Identify a Dominant Cause and Provide an Effective Therapy.

The prevalence of pulmonary hypertension (PH) complicating interstitial lung diseases (ILDs) is 3.5-15% at an early stage, and up to 90% in ILD patients listed for lung transplantation. In addition, other types of PH may occur in patients with ILDs due to concomitant conditions. Therefore, any significant PH occurring in the setting of ILD requires a proper differential workup. PH increases morbidity and mortality in ILDs. The pathomechanisms underlying PH due to ILD (PH-ILD) are not fully known, and there is no straightforward correlation between the presence or severity of PH-ILD and the severity of ILD. Severe PH in mild ILD without other explanatory causes constitutes a dilemma of differentiating between PH due to ILD and pulmonary arterial hypertension coexisting with ILDs. The heterogeneity and poor prognosis of patients with ILDs coexisting with PH necessitate an individualised approach to the management of this condition. This review presents recent advances in understanding and treatment options in PH-ILD. It also addresses practical issues, such as when to suspect and how to screen for PH in ILD, what are the indications for right heart catheterisation, and how to approach an individual ILD patient to determine the dominant PH cause and apply adequate management.

Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative - Group 3 Pulmonary Hypertension.

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

Noninvasive determinants of pulmonary hypertension in interstitial lung disease.

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is associated with increased mortality and impaired exertional capacity. Right heart catheterization is the diagnostic standard for PH but is invasive and not readily available. Noninvasive physiologic evaluation may predict PH in ILD. Forty-fourpatients with PHand ILD (PH-ILD) were compared with 22 with ILDalone (non-PH ILD). Six-minwalk distance (6MWD, 223 ± 131vs. 331 ± 125 m, p = 0.02) and diffusing capacity for carbon monoxide (DLCO, 33 ± 14% vs. 55 ± 21%, p < 0.001) were lower in patients with PH-ILD. PH-ILD patients exhibited a lower gas-exchange derived pulmonary vascular capacitance (GXCAP, 251 ± 132vs. 465 ± 282 mL × mmHg, p < 0.0001) and extrapolated maximum oxygen uptake (VO2max) (56 ± 32% vs. 84 ± 37%, p = 0.003). Multivariate analysis was performed to determine predictors of VO2 max. GXCAP was the only variable that predicted extrapolated VO2 max among PH-ILD and non-PH ILD patients. Receiver operating characteristic curve analysis assessed the ability of individual noninvasive variables to distinguish between PH-ILD and non-PH ILD patients. GXCAP (area under the curve[AUC] 0.85 ± 0.04, p < 0.0001) and delta ETCO2 (AUC 0.84 ± 0.04, p < 0.0001) were the strongest predictors of PH-ILD. A CART analysis selected GXCAP, estimated right ventricular systolic pressure (eRVSP) by echocardiogram, and FVC/DLCO ratio as predictive variables for PH-ILD. With this analysis, the AUC improved to 0.94 (sensitivity of 0.86 and sensitivity of 0.93). Patients with a GXCAP ≤ 416 mL × mmHg had an 82% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and high FVC/DLCO ratio >1.7 had an 80% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and an elevated eRVSP by echocardiogram >43 mmHg had 100% probability of PH-ILD. The incorporation of GXCAP with either eRVSP or FVC/DLCO ratio distinguishes between PH-ILD and non-PH-ILD with high probability and may therefore assist in determining the need to proceed with a diagnostic right heart catheterizationand potential initiation of pulmonary arterial hypertension-directed therapy in PH-ILD patients.

DEVELOPMENT OF A RISK-ASSESSMENT TOOL FOR PREDICTION OF PULMONARY HYPERTENSION AND MORTALITY IN PATIENTS WITH INTERSTITIAL LUNG DISEASE

DEVELOPMENT OF A RISK-ASSESSMENT TOOL FOR PREDICTION OF PULMONARY HYPERTENSION AND MORTALITY IN PATIENTS WITH INTERSTITIAL LUNG DISEASE

Pulmonary hypertension in patients with interstitial lung disease: a tool for early detection.

Pulmonary hypertension (PH) complicates the treatment of interstitial lung disease (ILD) patients resulting in poor functional status and worse outcomes. Early recognition of PH in ILD is important for initiating therapy and considering lung transplantation. However, no standard exists regarding which patients to screen for PH‐ILD or the optimal method to do so. The aim of this study was to create a risk assessment tool that could reliably predict PH in ILD patients. We developed a PH‐ILD Detection tool that incorporated history, exam, 6‐min walk distance, diffusion capacity for carbon monoxide, chest imaging, and cardiac biomarkers to create an eight‐component score. This tool was analyzed retrospectively in 154 ILD patients where each patient was given a score ranging from 0 to 12. The sensitivity (SN) and specificity (SP) of the PH‐ILD Detection tool and an area‐under‐the‐curve (AUC) were calculated. In this cohort, 74 patients (48.1%) had PH‐ILD. A score of ≥6 on the PH‐ILD Detection tool was associated with a diagnosis of PH‐ILD (SN: 86.5%; SP: 86.3%; area‐under‐the‐curve: 0.920, p < 0.001). The PH‐ILD Detection tool provides high SN and SP for detecting PH in ILD patients. With confirmation in larger cohorts, this tool could improve the diagnosis of PH in ILD and may suggest further testing with right heart catheterization and earlier intervention with inhaled treprostinil and/or lung transplant evaluation.

Pulmoner Tutulumu Olan Sistemik Skleroz Hastalarında Hematolojik Parametrelerin Rolü

Aim: Systemic sclerosis (SSc) is an autoimmune disease characterized by generalized micro and macroangiopathy. Mortality in SSc is primarily due to pulmonary complications. This study was aimed to reveal the relationship between parenchymal and vascular involvements of the pulmonary system and hematological parameters in patients with SSc. &#x0D; Material and Method: Participants were divided into three groups: both interstitial lung disease (ILD) and pulmonary hypertension (PH), those with only ILD and those with neither ILD nor PH. Laboratory data were compared between these groups. &#x0D; Results: ILD was found to be associated with high red cell distribution width (RDW) and erythrocyte sedimentation rate, independent of PH. The platelet (PLT) count was significantly lower, and the RDW to PLT ratio (RPR) level was significantly higher in those with ILD and PH coexistence compared to those with only ILD.&#x0D; Conclusion: RPR can be used as screening parameters for PH in ILD associated with SSc.

Clinical assessment for pulmonary hypertension in interstitial lung disease.

Pulmonary hypertension (PH) is an important complication of interstitial lung disease (ILD), as its development confers a poor prognosis. There are no specific recommendations for methods of assessment for PH in ILD populations. To determine current assessment practices for PH in an Australian ILD centre. In the Austin Health ILD database, 162 consecutive patients with idiopathic pulmonary fibrosis or connective tissue disease-associated ILD were identified and retrospectively evaluated for methods of PH assessment with transthoracic echocardiography (TTE), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and right heart catheterisation (RHC) in relation to patient demographic and physiological parameters. The median follow-up was 30 (14.4-56.4) months. At baseline, vital capacity was 80.0 ± 18.4% predicted, and diffusing capacity for carbon monoxide was 59.6 ± 15.2% predicted. Evaluation for PH was performed in 147 (90.7%) patients, among whom 105 (64.8%) had TTE performed at least once. At the initial TTE, 33.7% patients had high probability of PH, defined as RVSP >40 mmHg + RAp and/or right ventricular dysfunction. At the time of the most recent TTE, these criteria were met in 45 (52.3%) patients. Elevated serum NT-proBNP levels during the first year were observed in 47 (38.8%) patients. Only 14 (8.6%) patients had RHC. Our institutional PH assessment practice in ILD demonstrates a substantial prevalence of probable PH at baseline. As new therapies emerge for the treatment of PH in ILD, well-defined screening practices are important in this population for early identification and optimal management.

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

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

Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide.

Patients with pulmonary hypertension (PH) due to chronic lung disease (Group 3 PH) have poor long-term outcomes. However, predictors of survival in Group 3 PH are not well described. We performed a cohort study of Group 3 PH patients (n = 143; mean age 65 ± 12 years, 52% female) evaluated at the University of Minnesota. The Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. The clinical characteristics and survival were compared in patients categorized by PH severity based on the World Health Organization (WHO) classification and lung disease etiology. After a median follow-up of 1.4 years, there were 69 (48%) deaths. The 1-, 3-, and 5-year survival rates were 79%, 48%, and 31%. Age, coronary artery disease, atrial fibrillation, Charlson comorbidity index, serum N-terminal pro‒brain natriuretic peptide (NT-proBNP), creatinine, diffusion capacity of carbon monoxide (DLCO), total lung capacity, left ventricular ejection fraction, right atrial and right ventricular enlargement on echocardiography, cardiac index, and pulmonary vascular resistance (PVR) were univariate predictors of survival. On multivariable analysis, DLCO was the only predictor of mortality (adjusted hazard ratio [HR] for every 10% decrease in predicted value: 1.31 [95% confidence interval 1.12 to 1.47]; p = 0.003). The 1-/5-year survival by tertiles of DLCO was 84%/56%, 82%/44%, and 63%/14% (p = 0.01), respectively. On receiver-operating characteristic curve analysis, DLCO <32% of predicted had the highest sensitivity and specificity for predicting survival. The 1- and 5-year survival in patients with a DLCO ≥32% predicted was 84% and 60% vs 68% and 13% in patients with a DLCO <32% predicted (adjusted HR: 2.5 [95% confidence interval 1.3 to 5.0]; p = 0.007). Lung volumes and DLCO were not related, but higher PVR was strongly associated with reduced DLCO. There was increased mortality in interstitial lung disease‒PH as compared with chronic obstructive pulmonary disease‒PH, but PH severity based on the WHO classification did not alter survival. Low DLCO is a predictor of mortality and should be used to risk-stratify Group 3 PH patients.

Pulmonary hypertension associated with chronic lung diseases.

In 2015, the international guidelines for diagnosis and treatment of pulmonary hypertension (PH) were updated. Group 3 of the current classification includes PH associated with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), other pulmonary diseases with restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, and developmental lung diseases [1]. PH associated with COPD and ILD is common but difficult to manage, as no long-term randomised controlled trial (RCT) has been conducted with specific pulmonary arterial hypertension (PAH) drugs in PH associated with COPD, and the one recent RCT in PH associated with ILD had to be stopped early due to a possible increased risk of death and side effects in the treatment group. Specific treatment may thus be harmful and may worsen gas exchange as a result of possible recruitment of less oxygenised areas, i.e. by increasing ventilation-perfusion mismatch. Management of PH patients with chronic lung diseases requires careful evaluation and understanding of pathophysiological mechanisms. Interestingly, mediators in PAH and in fibrotic lung disease show some overlaps. Several drugs effective in PAH have been evaluated for anti-fibrotic treatment in ILD, but until today without consistent success. While new drugs with anti-fibrotic effects are now accessible, a specific evidence-based treatment for PH in ILD or COPD with or without emphysema is not yet available.

Pulmonary hypertension in chronic interstitial lung diseases

Pulmonary hypertension (PH) is a common complication of interstitial lung diseases (ILDs), particularly in idiopathic pulmonary fibrosis and ILD associated with connective tissue disease. However, other lung diseases, such as combined pulmonary fibrosis and emphysema syndrome, pulmonary Langerhans cell histiocytosis, and lymphangioleiomyomatosis, may also include PH in their clinical manifestations. In all of these diseases, PH is associated with reduced exercise capacity and poor prognosis. The degree of PH in ILDs is typically mild-to-moderate. However, some of these patients may develop a disproportionate increase in PH that cannot be justified solely by hypoxia and parenchymal injury: this condition has been termed "out-of-proportion" PH. The pathogenesis of PH in these diseases is various, incompletely understood and may be multifactorial. The clinical suspicion (i.e. increased dyspnoea, low diffusion capacity) and echocardiographic assessment are the first steps towards proper diagnosis of PH; however, right heart catheterisation remains the current gold standard for diagnosis of PH. At present, no specific therapies have been approved for the treatment of PH in patients with ILDs.

Distinguishing Pulmonary Hypertension in Interstitial Lung Disease by Ventilation and Perfusion Defects Measured by Cardiopulmonary Exercise Testing

Background: Pulmonary hypertension (PH) is common in interstitial lung disease (ILD). Since cardiopulmonary exercise testing (CPET) is useful in understanding the pathophysiology of respiratory disorders and can distinguish between ventilation and perfusion (V/Q) defects, it may have a role in the detection of PH in ILD. We evaluated whether CPET can detect PH through analysis of V/Q defects in ILD. Objectives: We aimed to use CPET to determine if there are changes in the ventilation and the activity pattern of mixed-expired carbon dioxide pressure (PE<smlcap>CO</smlcap>₂) and end-tidal carbon dioxide pressure (Pet<smlcap>CO</smlcap>₂) in ILD patients with and without PH. Methods: A retrospective chart review was done of all patients who received lung transplants at the Columbia University Medical Center between 2000 and 2011 with the diagnosis of ILD. CPETs were performed during the 2 years prior to transplantation; right heart catheterizations and pulmonary function tests were performed within 4 months of CPET. Results: The ILD patients with PH demonstrated significantly lower Pet<smlcap>CO</smlcap>₂ and PE<smlcap>CO</smlcap>₂ during certain levels of exercise with a distinctive activity pattern for PE<smlcap>CO</smlcap>₂/Pet<smlcap>CO</smlcap>₂. Conclusions: Evaluation of V/Q defects through the PE<smlcap>CO</smlcap>₂ and Pet<smlcap>CO</smlcap>₂ patterns on CPET in ILD patients can distinguish between patients with and without PH.

Diagnostic and prognostic role of biomarkers for pulmonary hypertension in interstitial lung disease

Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the relation of NT-proBNP, fibrin D-dimer, troponin-T, uric acid and exhaled nitric oxide (NO) to the presence of PH and mortality in ILD. In a previously described cohort of 212 ILD patients of whom 29 had PH, levels of the above mentioned biomarkers were analyzed as routine tests. A value of NT-proBNP below 95ng/l had a negative predictive value for PH of 99% (95% CI: 94-100). Values of troponin-T were higher in patients with PH (median (inter quartile range)=9 (9-20) vs. 9(9-10)ng/l), and the odds ratio (OR) for PH was increased in patients with abnormal levels of uric acid (OR (95% CI)=3.1(1.1-8.8)). NT-proBNP and troponin-T values above the 50(th) percentile, and uric acid and fibrin D-dimer values above the 90th percentile were each associated with increased mortality. A value of NT-proBNP below 95ng/l may be used as a rule-out test for PH in ILD, while an abnormal value of uric acid is a risk factor for PH. NT-proBNP, troponin-T, uric acid and fibrin D-dimer have prognostic value in ILD patients, while exhaled levels of NO do not seem to predict PH or mortality.

154 Exercise Testing: Influence of Pulmonary Hypertension in Patients with Interstitial Lung Disease Awaiting Lung Transplantation

Pulmonary hypertension (PH), a complication in patients with interstitial lung disease (ILD), has a prevalence of 30-40% and is a predictor of mortality. Early diagnosis of PH in ILD before clinical signs of right heart failure develop is needed. Since physical stress often allows for the detection of abnormalities not seen at rest, cardiopulmonary exercise testing (CPET) may offer a way to non-invasively test for PH. We investigated the impact of PH on exercise capacity and the correlation between mean pulmonary artery pressure (mPAP), CPET and pulmonary function test (PFT) parameters in patients with ILD awaiting lung transplantation (LTx).

Severe Pulmonary Hypertension in Idiopathic Nonspecific Interstitial Pneumonia

Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), particularly in idiopathic pulmonary fibrosis (IPF) and ILD associated with connective tissue disease, where the underlying pathology is often a nonspecific interstitial pneumonia (NSIP) pattern. The degree of PH in ILD is typically mild to moderate and radiographic changes of ILD are usually prominent. We describe four patients with idiopathic NSIP and severe PH (mPAP > 40 mmHg). The average mean pulmonary artery pressure was 51±7 mmHg and pulmonary vascular resistance was 13±4 Wood's units. Pulmonary function was characterized by mild restriction (total lung capacity 63–94% predicted) and profound reductions in DLCO (19–53% predicted). Computed tomographic imaging revealed minimal to moderate interstitial thickening without honeycombing. In two of the cases, an initial clinical diagnosis of idiopathic pulmonary arterial hypertension was made. Both were treated with intravenous epoprostenol, which was associated with worsening of hypoxemia. All four patients died or underwent lung transplant within 4 years of PH diagnonsis. Lung pathology in all four demonstrated fibrotic NSIP with medial thickening of the small and medium pulmonary arteries, and proliferative intimal lesions that stained negative for endothelial markers (CD31 and CD34) and positive for smooth muscle actin. There were no plexiform lesions. Severe pulmonary hypertension can therefore occur in idiopathic NSIP, even in the absence of advanced radiographic changes. Clinicians should suspect underlying ILD as the basis for PH when DLCO is severely reduced or gas exchange deteriorates with pulmonary vasodilator therapy.

Idiopathic pulmonary fibrosis‐related pulmonary hypertension; an exercising diagnosis?

Idiopathic pulmonary fibrosis‐related pulmonary hypertension; an exercising diagnosis?

The use of sildenafil to treat pulmonary hypertension associated with interstitial lung disease

Limited data suggest a benefit following sildenafil treatment in patients with pulmonary hypertension (PH) and interstitial lung disease (ILD). The role of sildenafil in the management of PH in ILD is not clear. We report our experience of ILD patients with PH after 6-month sildenafil therapy. We reviewed 15 patients (mean age 55 ± 15 years; 8 men) with ILD (mean FVC 52.6 ± 15.4%) and PH (mean right ventricular systolic pressure 73.8 ± 17.8 mm Hg). Median brain natriuretic peptide: 37 (5-452) pmol/L; mean 6MWD: 156 ± 101 m. Following 6-month treatment with sildenafil, brain natriuretic peptide levels were lower (n = 12, P = 0.03), 6MWD was higher (n = 6, P < 0.05), but no change in right ventricular systolic pressure (n = 11) was demonstrated. Our observations suggest that sildenafil may be useful in the management of PH in ILD. Controlled trials are warranted before therapeutic recommendations can be made.

Interstitielle Lungenerkrankungen und pulmonale Hypertonie

The prevalence of pulmonary hypertension in interstitial lung disease (ILD) is high (30-40%). However, diagnosis of pulmonary hypertension in ILD is often delayed. Pulmonary hypertension can occur in the absence of advanced pulmonary dysfunction or severe hypoxia and is associated with a worse prognosis. A number of pathogenic mechanisms such as oxidative stress, cytokines, and the endothelin system have been implicated in remodeling of both the lung parenchyma and the vessels. In addition, hypoxic vasoconstriction, vascular destruction and progressive fibrosis play an important role. Since clinical signs are often non-specific echocardiography, radiology and laboratory parameters such as NT-proBNP may be helpful. However, the definitive diagnosis of pulmonary hypertension is still confirmed by right heart catheterization. Treatment options of pulmonary hypertension in ILD are limited to the treatment of the underlying diseases. Newer vasodilating drugs may improve the prognosis but have first to be evaluated in clinical trials. Lung or lung and heart transplantation is the therapeutic option in end stage disease.

Pulmonary hypertension in interstitial lung disease

In the lungs, parenchymal and vascular remodelling share pathomechanisms that may explain the relatively high prevalence (30-40%) of pulmonary hypertension (PH) in interstitial lung disease (ILD) patients. Notably, PH significantly contributes to exercise limitation and dismal prognosis of ILD patients. The absence of specific clinical symptoms commonly leads to delayed diagnosis. Besides clinical judgment and out-of-proportion reduction in diffusing capacity, severe hypoxaemia or exercise oxygen desaturation, echocardiography and biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-hormone BNP are potentially helpful tools in identifying PH. However, right heart catheterisation is still necessary to confirm the diagnosis. Management of PH in ILD comprises treatment of the underlying disease process and long-term oxygen therapy. Affected patients should be listed for lung transplantation without delay, when appropriate. However, due to age and comorbidities only a minority of ILD patients will be eligible for lung transplantation. In the absence of satisfactory therapies for many ILDs, and considering the clinical burden of PH in affected patients, specific vasomodulatory therapies presently approved for PAH may be promising options for ILD patients. Consequently, there is an urgent need for adequately designed clinical trials to assess the effectiveness of specific PH therapy in the context of ILDs.