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doi:10.1378/chest.06-3087
(Chest. 2007; 132:998-1006)
© 2007 American College of Chest Physicians
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Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis*

Nina M. Patel, MD; David J. Lederer, MD, MS; Alain C. Borczuk, MD and Steven M. Kawut, MD, MS, FCCP

* From the Departments of Medicine (Dr. Patel) and Pathology (Dr. Borczuk), College of Physicians and Surgeons, and the Department of Medicine (Drs. Lederer and Kawut), College of Physicians and Surgeons, Joseph L. Mailman School of Public Health, Columbia University, New York, NY.

Correspondence to: Nina M. Patel, MD, Division of Pulmonary, Allergy & Critical Care, Columbia University, 622 W 168th St, PH 8 East, Room 101, New York, NY 10032; e-mail: np2199{at}columbia.edu

Abstract

Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.

Key Words: idiopathic pulmonary fibrosis • pulmonary artery pressure • pulmonary hypertension • 6-min walk test

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia, with a prevalence of 14 to 15 per 100,000 persons.12 IPF has no effective medical therapy and has been the primary indication for 19% of all lung transplant procedures performed in the United States during the past 10 years.3 The histopathologic pattern of IPF is usual interstitial pneumonia, characterized by increased collagen in the lung interstitium with fibroblastic foci interspersed by normal lung. Pathologic pulmonary vascular changes often coexist with the characteristic parenchymal findings of IPF but are less well studied. However, new evidence suggests that pulmonary hypertension (PH) may contribute substantially to morbidity and mortality in IPF.45 We will review the epidemiology, pathology, and pathophysiology of PH in IPF and present strategies to diagnose PH in this setting. The clinical implications and possible treatments for this condition will also be discussed.

Definition and Epidemiology

The Venice Clinical Classification of pulmonary hypertension considers PH in IPF under the category of "pulmonary hypertension associated with lung diseases and/or hypoxemia," differentiating this from other etiologies of PH.6 The National Institutes of Health defined pulmonary arterial hypertension (PAH) as a mean pulmonary artery pressure (mPAP) > 25 mm Hg at rest with a normal pulmonary capillary wedge pressure (PCWP) measured by right-heart catheterization.7 Whether this hemodynamic definition is suitable for the generally older population at risk for IPF is not known, although most studies of IPF have defined PH using this mPAP criterion. The absence of standardization and validation of hemodynamic measurements during exercise means that there are no generally accepted criteria for exertional PH in IPF.

The epidemiology of PH in IPF is not well described due to several factors. First, IPF is an insidious disease, so that IPF is often diagnosed late (after PH is present), making the incidence of PH in the setting of IPF difficult to study. Second, the "gold standard" used to diagnose resting PH is right-heart catheterization, an invasive and expensive test precluding longitudinal cohort studies with repeated measurements. Third, previous investigators489 have employed various methods to diagnose (and criteria to define) PH, leading to underestimates or overestimates of the occurrence of PH in this population. Last, patients referred for lung transplant have been the focus of most studies of PH in IPF because they routinely undergo right-heart catheterization. This selected cohort includes younger patients, patients without significant medical comorbidities, and patients with a greater severity of illness and level of social support, leading to findings that may not be generalizable to all individuals with IPF.

Despite these obstacles, studies have provided estimates of the frequency of PH in patients with IPF; we have supplied 95% confidence intervals (CIs) around these estimates. King et al8 studied 238 patients with IPF; 20% (95% CI, 15 to 25%) had radiographic evidence of PH (pulmonary artery enlargement on chest radiography). Nadrous et al9 performed transthoracic echocardiography (TTE) on 88 patients with IPF who were evaluated for lung transplantation. Eighty-four percent (95% CI, 76 to 92%) had PH (defined as an estimated right ventricular systolic pressure [RVSP] > 35 mm Hg). However, this estimate may be difficult to interpret, as investigators have questioned the accuracy of TTE in assessing pulmonary artery pressure in IPF (see "Diagnosis" section following).10

Few studies have invasively measured resting hemodynamics in patients with IPF. Lettieri et al4 performed a retrospective cohort study of patients with IPF who underwent right-heart catheterization during evaluation for lung transplantation at their center between 1998 and 2004. Thirty-two percent (95% CI, 21 to 42%) of the patients had PH, defined as a mPAP > 25 mm Hg. Low percentage of predicted diffusing capacity of the lung for carbon monoxide (DLCO%) [< 40%] and use of supplemental oxygen therapy were associated with a higher probability of PH, whereas percentage of predicted FVC (FVC%) and lung volumes were not. A recent update11 of this cohort (n = 118) revealed similar findings with a somewhat higher prevalence of PH (41%; 95% CI, 32 to 50%).

We reanalyzed a previously published cohort of 41 consecutive patients with IPF evaluated for lung transplantation at our center from 2000 to 2004 who underwent right-heart catheterization.12 Twenty percent (95% CI, 7 to 32%) had PH with normal PCWP (≤ 15 mm Hg). A lower DLCO% was associated with a much greater risk of having PH (odds ratio per 10-percentage-point decrease in DLCO%, 4.2; 95% CI, 1.2 to 15; p = 0.03). FVC% was not significantly associated with the presence of PH.

Two studies413 have included patients with IPF listed for lung transplantation in the United States. Twenty-five percent of patients with IPF listed with the United Network for Organ Sharing (UNOS) from 1995 to 2000 had PH.413 We found a similar estimate in a reanalysis of 376 patients listed with UNOS from 2004 to 2005 who underwent catheterization.14 Twenty-eight percent (95% CI, 24 to 33%) had PH with PCWP ≤ 15 mm Hg (median mPAP, 31 mm Hg; interquartile range, 28 to 38 mm Hg). FVC% was not associated with mPAP (Fig 1 ).


Figure 1
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  		Figure 1.. Scatter plot of FVC% vs mPAP in IPF patients listed for lung transplantation in the UNOS registry from 2004 to 2005 (n = 376) utilizing Pearson correlation coefficient (r). The regression line is shown.

 
These studies have demonstrated that PH is present at rest in approximately 20 to 40% of IPF patients who are evaluated or listed for lung transplantation. The reported point estimates and CIs for PH are somewhat variable, likely due to the previously mentioned limitations. It is also clear that abnormalities in gas transfer are associated with PH in IPF, whereas measures of ventilatory function (eg, FVC%) are not. Diffusing capacity may better gauge the reduction of pulmonary blood volume due to vascular remodeling of the small muscular pulmonary arteries and destruction of the capillary bed, two pathways that increase pulmonary vascular resistance. Alternatively, defects in gas transfer may better reflect the degree of lung fibrosis and associated ventilation/perfusion mismatch. The common finding of reduced DLCO% in patients with idiopathic PAH in the absence of parenchymal lung disease supports the former hypothesis.715 However, the link between pulmonary vascular disease and reduced diffusing capacity is not definitively established in IPF.

Pathology and Pathogenesis

Pathologic vascular findings in IPF consist of changes in the arteries, arterioles, and venules, and destruction of the capillary bed, which are traditionally attributed to hypoxia and fibrosis, respectively. Advential thickening around the pulmonary vessels occurs due to an increase of fibroblasts, myofibroblasts, and extracellular matrix deposition. Smooth-muscle cell hypertrophy and proliferation and collagen and elastin accumulation occur in the media of the small muscular pulmonary arteries, and distal pulmonary arterioles become muscularized. These changes are consistent with those seen in other hypoxia-related lung diseases. In addition, there may be extensive intimal hyperplasia, fibrosis, and reduplication of the inner elastic lamina in the small muscular pulmonary arteries in IPF; such changes are not usually observed in animal models or patients with hypoxia-related lung disease alone.161718192021 These findings are present in densely fibrotic lobules (Fig 2 , top left, A, and top right, B) as well as in less fibrotic areas (center left, C, through bottom right, F).21 In situ thrombosis has also been observed in small muscular pulmonary arteries.22 More recently, investigators21 have documented intimal proliferation and fibrosis in the pulmonary venules as well.


Figure 2
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  		Figure 2.. Pulmonary arteries from three patients with PH and IPF. Top left, A (hematoxylin-eosin, original x 25), and top right, B (original x 100): Pulmonary artery branch (with adjacent airway) is seen in an area of dense fibrosis. Top right, B: Higher magnification of this vessel shows medial thickening and significant intimal proliferation. Center left, C (original x 25), and center right, D (original x 100): A more distal pulmonary artery/arteriole with adjacent small airway in a lobule of relatively nonfibrotic lung tissue. Center right, D: Higher magnification of this vessel shows marked medial thickening. Bottom left, E (elastic von Gieson, original x 10), and bottom right, F (original x 100): A bronchiole-vascular bundle is shown in an area of relatively nonfibrotic lung. Bottom right, F: Higher magnification reveals medial thickening with elastic tissue duplication and intimal thickening.

 
Vascular regression in areas of dense fibrosis and within fibroblastic foci has been frequently observed in patients with IPF. This destruction of the pulmonary capillary bed likely contributes significantly to increased pulmonary vascular resistance.1820212324 However, numerous researchers23242526 have demonstrated increased capillary density and angiogenesis in areas of normal lung flanking regions of fibrosis. The roles of capillary regression and proliferation in contributing to PH are as of now unclear.

The cytokine milieu that characterizes IPF likely plays a significant role in the histopathologic vascular changes. Animal models of hypoxia suggest that endothelin (ET)-1, serotonin, platelet-derived growth factor, and transforming growth factor-ß affect the medial layer of large pulmonary arteries.16 Fibroblasts and/or endothelial cells in IPF release vasoactive mediators, which can lead to vascular remodeling.262728 For example, alveolar epithelium has shown increased expression of ET-1, a potent pulmonary vasoconstrictor and smooth-muscle cell mitogen, in patients with pulmonary fibrosis.29 Platelet-derived growth factor, transforming growth factor-ß, and fibroblast growth factor have been implicated in the pathogenesis of IPF as well as idiopathic PAH and hypoxia-induced PH, suggesting common mechanistic pathways.1628303132 Further studies focused on these and other candidates are necessary to understand the biological processes that initiate the vascular changes leading to PH.

Diagnosis

The symptoms of PH in patients with IPF are nonspecific. Dyspnea, pedal edema, palpitations, and/or chest discomfort are characteristic of PH but may also be attributed to the underlying parenchymal lung disease. On physical examination, patients may exhibit a loud P2 component to the second heart sound; a fixed, split S2; and a holosystolic tricuspid regurgitation murmur. Pulmonic insufficiency may lead to an early diastolic murmur. As right ventricular (RV) hypertrophy ensues, a RV heave may be palpated at the left lower sternal border, and increased right atrial pressure results in jugular venous distension. Chest radiography and CT may demonstrate RV enlargement with cardiomegaly and pulmonary artery enlargement. ECG may show signs of RV strain. Given the unproven sensitivity of these assessments, however, clinicians should maintain a low threshold to pursue further diagnostic testing for PH in the appropriate clinical setting.

Lettieri et al4 showed that DLCO% < 40% and a requirement for supplemental oxygen were specific but not sensitive for detecting PH in IPF patients undergoing evaluation for lung transplantation. Patients who met both criteria had an 87% chance of having PH by right-heart catheterization. However, patients who did not meet both criteria still had an approximately 20% chance of having PH, meaning that these criteria were insufficient to rule out PH. More recent data from Nathan et al11 also showed that pulmonary function parameters may not be sufficiently discriminating to definitively diagnose PH in a patient with IPF.

TTE is generally an excellent modality to detect PH.3334 In patients with chronic lung disease, however, TTE has a more variable performance. Arcasoy et al10 examined the use of TTE in 106 patients with diffuse parenchymal lung disease referred for lung transplantation. These investigators defined a "positive" TTE for PH as an RVSP estimate > 45 mm Hg or the presence of RV dilation, dysfunction, or hypertrophy. The estimation of RVSP on TTE was only possible in 54% of patients with an interstitial lung disease. While the RVSP estimate appeared to correlate with the pulmonary artery systolic pressure (sPAP) from right-heart catheterization, the RVSP was within 10 mm Hg of the sPAP only 37% of the time. In addition, 40% of those with elevated RVSP by TTE did not have PH by catheterization (defined as sPAP > 45 mm Hg). However, 56% of patients with normal RVSP actually had PH by catheterization. The presence of RV findings by TTE was indicative of PH by catheterization only 57% of the time; patients with normal RV morphology had PH > 25% of the time. Therefore, findings from TTE are not sufficient to confirm or rule out the presence of PH in IPF.

Given the clear limitations of TTE, a plasma biomarker that accurately predicts PH would be useful. Leuchte et al35 showed that plasma brain natriuretic peptide (BNP) levels were higher in patients with fibrotic lung disease and mPAP > 35 mm Hg than in patients with mPAP < 35 mm Hg (mean ± SD, 242 ± 66 pg/mL vs 24 ± 6 pg/mL, respectively; p < 0.001). Whether plasma BNP level can accurately discriminate between IPF patients with PH from those without PH and whether serial BNP assessments are useful in monitoring patients over time must be confirmed before routine use of BNP testing is recommended.

In summary, while measures such as resting oxygen saturation, need for supplemental oxygen, and DLCO% may be associated with PH in IPF, they are not discriminating enough to be used clinically. The accuracy and specificity of TTE are also inadequate to diagnose PH in IPF patients. Lastly, BNP may offer some promise as a screening tool for patients with suspected PH but requires further study. Therefore, right-heart catheterization remains the test of choice to diagnose resting PH in patients with IPF.

Clinical Impact and Prognosis

Ultimately, the importance of diagnosing PH in IPF is driven by the impact that pulmonary vascular changes and subsequent limitation of systemic oxygen delivery may have on functional status, quality of life, and survival, and the ability to intervene in this process with therapy. Previous studies3637 utilizing cardiopulmonary exercise testing suggest that circulatory impairment in interstitial lung disease contributes to exercise limitation to a greater extent than (and independently of) ventilatory compromise. Studies143839 have confirmed the impact of PH on exercise capacity, as assessed by the 6-min walk distance (6MWD), a reliable end point associated with a decreased quality of life and a higher risk of death in IPF. In a cohort of 34 patients with IPF, patients with PH had a significantly lower 6MWD than those without PH (144 ± 66 m vs 366 ± 82 m, respectively; p < 0.001).4 We analyzed data from our previously described cohort that included 34 patients with IPF evaluated for lung transplantation who performed a 6-min walk test and underwent right-heart catheterization.12 Patients with PH and normal PCWP (≤ 15 mm Hg) had a lower 6MWD than others after adjustment for FVC% (PH: least square mean, 210 m [SE, 50 m]; vs no PH: least square mean, 402 m [SE, 25 m]; p = 0.002). We confirmed this association in the cohort of 376 patients with IPF recently listed for lung transplantation with UNOS, which similarly demonstrated that PH was associated with a significantly lower 6MWD (Fig 3 ).14 These findings were unchanged after adjustment for age, gender, height, race, ethnicity, and FVC%.


Figure 3
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  		Figure 3.. Box-and-whisker plots of 6MWD of IPF patients listed for lung transplantation in the UNOS registry from 2004 to 2005 (n = 376). PH = mPAP > 25 mm Hg with PCWP ≤ 15 mm Hg. Whiskers are tenth to ninetieth percentile. Outliers are not shown.

 
PH also impacts adversely on survival in IPF. In one study,8 the radiographic presence of PH was associated with an increased risk of death (hazard ratio [HR], 1.96; 95% CI, 1.29 to 2.99; p = 0.0017). In another study,4 IPF patients with PH evaluated for lung transplantation had an increased mortality rate at 1 year compared to patients without PH (28.8% vs 5.5%, p = 0.002). At our center, the risk of death for IPF patients evaluated for lung transplantation increased by 50% with every 5 mm Hg increase in mPAP with or without lung transplantation (HR, 1.5; 95% CI, 1.1 to 2.1; p = 0.008).12 We found similar results in the cohort of patients listed for lung transplantation with UNOS from 2004 to 2005 with censoring of observations at transplantation.14 PH with a normal PCWP (≤ 15 mm Hg) was associated with a threefold increased risk of death (Fig 4 , Table 1 ). This was independent of age, race, FVC%, 6MWD, and other covariates.14 Despite the documented associations between PH and the risk of death, the presence of PH did not adequately discriminate between patients with high and low short-term mortality, providing sensitivity and specificity estimates of < 80% (data not shown).41214


Figure 4
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  		Figure 4.. Kaplan-Meier survival estimates of IPF patients listed for lung transplantation in the UNOS registry from 2004 to 2005 (n = 376). PH = mPAP > 25 mm Hg with PCWP ≤ 15 mm Hg.

 

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  		Table 1.. Cox Proportional Hazards Models for the Risk of Death of IPF Patients Listed for Lung Transplantation in the UNOS Registry (2004–2005, n = 376)*

 
The role of PH in outcomes for patients with IPF who undergo lung transplantation is controversial. Early case series404142 reported that preoperative hemodynamics in patients with advanced lung disease did not affect outcome. However, a study43 of 194 patients who underwent double-lung transplantation for IPF from 1995 to 2002 revealed that preoperative mPAP > 35 mm Hg was associated with increased mortality at 3 months after transplantation. These authors speculated that the increased early risk of death was due to perioperative hemodynamic instability or primary graft dysfunction. Significant PH therefore factors into the preoperative risk assessment of lung transplantation for the patient with IPF; double-lung transplantation is the preferred surgical approach in this scenario.44

These data show that PH in patients with IPF is clearly associated with reduced exercise capacity, independent of the degree of impairment in ventilation. The potential etiologies for this association include diffusion impairment, ventilation/perfusion mismatch, and increased RV afterload, all of which limit the capacity to increase oxygen delivery to meet exertional demands. PH is also strongly and independently associated with worse survival in IPF. Considering the reproducible associations between PH and mortality with adjustment for traditional metrics of restrictive lung disease (such as FVC%), it is possible that PH plays an important role in determining poor outcomes, rather than just being an epiphenomenon of underlying severe parenchymal lung disease. Further data are needed to determine if diagnosing PH improves risk stratification for the individual patient, which is as yet unproven. However, the presence and severity of PH are important to establish in an IPF patient who is a candidate for lung transplantation because this will impact on the risk of lung transplantation, the lung allocation priority score, and the preferred surgical approach.4445

Treatment

Considering the dire implications of PH in IPF, medical therapy targeting hypoxemia, vascular remodeling, and/or destruction of lung parenchyma would appear optimal treatment. As the pathology and pathophysiology of PH are attributed to local hypoxia, supplemental oxygen is the most obvious choice for prevention or treatment of PH; however, there are no data supporting the beneficial effects of oxygen on survival in this patient group. Vasoactive agents may vasodilate and remodel affected small muscular pulmonary arteries in PH. However, the suppression of physiologic vasoconstriction in low ventilation/perfusion lung units may worsen shunt and hypoxemia in IPF. Therefore, an agent that preferentially targeted the affected vessels in well-ventilated areas would seem the ideal way to improve outcomes in PH related to IPF.

There are four specific classes of targeted therapies used in other forms of PH. Calcium-channel blockade is highly effective in a very small subset of patients with idiopathic PAH, but it has no role in the treatment of the majority of patients with this and other types of PH.46 ET-1 receptor antagonists have beneficial effects in the population of patients with PAH.47484950 However, the only study51 of ET-1 receptor blockade in IPF excluded patients with PH, making the efficacy of this approach unclear.

Prostacyclin (PGI2) is an endogenous smooth-muscle vasodilator that also impairs platelet aggregation and inhibits smooth-muscle cell growth. PGI2 analogues improve exercise capacity, hemodynamics, and outcomes in patients with PAH.52 In diffuse parenchymal lung disease, however, several studies5354 have shown that IV epoprostenol decreases mPAP and increases CI but at the expense of increased pulmonary shunt flow. Because of these findings, the data currently do not support the routine use of IV epoprostenol to treat PH in IPF.

While the systemic administration of PGI2 analogues increases shunting, administering these medications via inhalation could target delivery to well-ventilated lung units and maintain (or even improve) ventilation/perfusion matching. Olschewski et al54 compared the short-term effects of IV epoprostenol and inhaled iloprost on hemodynamics and gas exchange in eight patients with diffuse parenchymal lung disease. IV epoprostenol decreased mPAP but also increased shunt fraction from 7 to 18% (p < 0.05). In contrast, inhaled iloprost led to decreases in mPAP without changes in shunt flow,54 suggesting the utility of selective pulmonary vasodilation in patients with PH in IPF. A randomized clinical trial (RCT) of inhaled iloprost for this patient group has been completed; however, results are not yet available.55

Lastly, phosphodiesterase-5 inhibitors, such as sildenafil, increase cyclic guanosine monophosphate levels in the lung and thereby promote vasodilatation and block proliferation of smooth muscle.565758 Studies5759 in animal models of hypoxic PH have demonstrated the effectiveness of sildenafil in decreasing vascular remodeling. In patients with IPF, Ghofrani et al53 showed that a single dose of sildenafil decreased mPAP and shunt flow and increased PaO2 compared to epoprostenol, which increased shunt flow. As this was only a single-dose study, the durability of the effects of sildenafil remains uncertain. More recently, Collard et al60 performed an open-label study of treatment with sildenafil for 3 months in 14 patients with PH and IPF, which showed improvements in 6MWD. While suggestive, these results warrant a RCT of sildenafil for the treatment of PH in IPF before routine use can be recommended.

In situ thrombosis has been implicated in PAH and is speculated to contribute to PH in patients with diffuse parenchymal lung disease as well.22 Long-term anticoagulation has been associated with better outcomes in a nonrandomized epidemiologic study15 of PAH. One RCT6162 in IPF suggested better outcomes with anticoagulation, although the lack of a placebo-control arm and masking limit the conclusions that can be drawn from this study.

In summary, there are several potential therapies for PH in IPF; however, convincing data regarding efficacy do not exist. Long-term RCTs are necessary to make firm conclusions. At this point, the only indicated therapy for PH in IPF remains supplemental oxygen in the setting of resting or exercise desaturation.

Conclusions

PH is present in 20 to 40% of patients with IPF who are evaluated for lung transplantation. DLCO% and other indicators of gas diffusion abnormality are predictive of PH in IPF more so than other measures of lung function. PH in IPF shares pathologic features of hypoxia-induced PH but also demonstrates marked intimal changes, which likely reflect a local and systemic cytokine effect. Right-heart catheterization should be performed when considering lung transplantation; however, other indications for the evaluation for PH remain unclear given the lack of evidence supporting patient-level prediction of outcomes and effective therapies. PH in IPF has severe consequences, including decreased exercise capacity and increased mortality before and after lung transplantation. Supplemental oxygen should be prescribed according to standard guidelines. Studies of targeted pulmonary vascular therapy with long-range follow-up and meaningful end points (eg, exercise capacity, quality of life, mortality) need to be performed before any specific therapy can be recommended for this entity.

Footnotes

Abbreviations: BNP = brain natriuretic peptide; CI = confidence interval; DLCO% = percentage of predicted diffusing capacity of the lung for carbon monoxide; ET = endothelin; FVC% = percentage of predicted FVC; HR = hazard ratio; IPF = idiopathic pulmonary fibrosis; mPAP = mean pulmonary artery pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PGI2 = prostacyclin; PH = pulmonary hypertension; RCT = randomized clinical trial; RV = right ventricular; RVSP = right ventricular systolic pressure; 6MWD = 6-min walk distance; sPAP = pulmonary artery systolic pressure; TTE = transthoracic echocardiography; UNOS = United Network for Organ Sharing

Drs. Patel and Borczuk have no potential conflicts of interest. Dr. Lederer has received research funding from Pfizer. Dr. Kawut has received research funding, consulting fees, and/or lecture fees from Cotherix, Actelion, Intermune, Pfizer, Encysive, United Therapeutics, and INO Therapeutics.

Supported in part by National Institutes of Health grant HL082895.

Received for publication December 22, 2006. Accepted for publication March 6, 2007.

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D. A. Zisman, A. S. Karlamangla, S. M. Kawut, O. A. Shlobin, R. Saggar, D. J. Ross, M. I. Schwarz, J. A. Belperio, A. Ardehali, J. P. Lynch III, et al.
Validation of a Method To Screen for Pulmonary Hypertension in Advanced Idiopathic Pulmonary Fibrosis
Chest, March 1, 2008; 133(3): 640 - 645.
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