Pulmonary Hypertension due t o L u n g D i s e a s e an d / o r H y p o x i a Steven D. Nathan, MDa,*, Paul M. Hassoun, MDb KEYWORDS  Obstructive lung disease  Interstitial lung disease  Pulmonary hypertension  Sarcoidosis  Prognosis  Respiratory function tests  Echocardiography

KEY POINTS  Pulmonary hypertension frequently complicates the course of patients with diffuse parenchymal lung disease.  The presence of pulmonary hypertension does not always correlate with the severity of the underlying parenchymal lung disease, attesting to other factors likely playing a role in the pathogenesis.  The presence of pulmonary hypertension is invariably associated with reduced functional status, greater supplemental oxygen needs, and increased mortality.  There are many unknowns and areas ripe for further research including in whom and how best to screen for pulmonary hypertension and the role, if any, for vasoactive therapies.

Pulmonary hypertension (PH) may complicate the course of many forms of diffuse parenchymal lung disease.1,2 There is a growing appreciation for this interceding complication and its association with functional impairment, greater oxygen needs, quality of life, and prognosis. PH due to lung disease, most commonly interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD), as well as hypoxia are classified within the World Health Organization (WHO) group 3.3 Other forms of diffuse parenchymal lung disease such as sarcoidosis, lymphangioleiomyomatosis, and pulmonary Langerhans cell histiocytosis are more complex in their etiology and are currently classified as WHO group 5 with other miscellaneous disorders. The severity of PH in the context of lung disease tends to be mild to

moderate, but there are cases where it may be severe. There is an interplay of many factors in the pathogenesis of WHO group 3 PH, which is evidently more complex than the simple concept of loss of lung units and pulmonary vascular bed. Some of the multifactorial contributors are common to many forms of parenchymal lung disease and others are unique to the specific disease entities. The focus of this article is to describe the prevalence and impact of PH in diffuse parenchymal lung disease (DPLD) and the role of hypoxia. The pathogenesis is discussed, highlighting commonalities and disease-specific nuances as well as areas for future research into the pathogenesis. The hemodynamic impact and whether the currently held definition of PH is appropriate in the context of lung disease are discussed as well as the concept of disproportionate PH. The

Disclosures: S.D. Nathan has been a consultant and is on the speakers’ bureau for Actelion, Gilead Sciences and United Therapeutics. He has also received research funding from these companies. P.M. Hassoun serves on advisory boards for Merck, Gilead, and Novartis and has received research funding from Actelion/United Therapeutics for the REVEAL Registry, and from the NIH/NHLBI (P01HL84946 and R01 HL114910). a Advanced Lung Disease and Transplant Program, Department of Medicine, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA; b Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 East Monument Street, Baltimore, MD 21287, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 695–705 http://dx.doi.org/10.1016/j.ccm.2013.08.004 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

chestmed.theclinics.com

INTRODUCTION

696

Nathan & Hassoun groundswell of interest in group 3 and 5 PH stems largely from the availability and effectiveness of vasoactive agents in modulating the course of disease in patients with group 1 PH. The data, or paucity thereof, supporting the use of these agents in PH due to lung disease are discussed, as well as the caveats and potential pitfalls to instituting such therapies in the absence of the necessary prospective trials. Whether PH is an adaptive or maladaptive phenomenon remains unknown. It is possible that there is a spectrum where initially PH might be an adaptive phenomenon, but with time may transform to a maladaptive one. Whether and when such a transition occurs is integral to the concept of disproportionate or severe PH, as is identifying the patient phenotype best suited for enrollment in future clinical trials of vasoactive therapies.

EPIDEMIOLOGY AND PREVALENCE OF PH The prevalence of PH in the various forms of DPLD spans a wide spectrum. In COPD, there have been prevalence rates reported between 5% and 90%.2,4–12 In idiopathic pulmonary fibrosis (IPF), there is a similarly wide reported range of 10% to 86%.13–20 These wide ranges attest to the issue of when the presence of PH is addressed. It makes intuitive sense that the earlier in the disease course it is sought, the lower the prevalence, whereas a late look results in a higher prevalence. What is clear and common to all the different parenchymal lung disorders, is that the presence of PH does portend a worse outcome. Although the accepted hemodynamic definition of a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg has been used to delineate PH, there is also evidence to suggest that mPAP cutoffs as low as 17 mm Hg do discern groups with differing prognoses.19 Whether lower pressure increases should be used to define an abnormal pulmonary vascular response in parenchymal lung disease is an issue that warrants further study and debate. Whether it is the mPAP itself that should define an aberrant vasculopathic response also merits further discussion. An interesting and noteworthy observation is the excellent prognostic discrimination provided by echocardiographic (echo) estimates of the right ventricular systolic pressure (RVSP), specifically in IPF.14,21 Although it is well recognized that echo-derived estimates tend to be inexact, especially in patients with advanced lung disease, this does raise the notion that it is perhaps the pulmonary artery (PA) systolic pressure that is most important.22,23 The pressure generated during systolic excursion is influenced by the available cross-sectional area, afterload,

and capacitance of the pulmonary circulation, which then raises the notion that the PA systolic pressure might reflect the severity of the associated parenchymal disease. Therefore, whether it is the PH itself that determines outcomes or the increased pressures that are a surrogate for the parenchymal aspects of the disease remains uncertain. One may speculate that both might be true; specifically that PH is the passenger to the parenchymal process, with evolution over time becoming the driver of outcomes, especially when right ventricular decompensation ensues. There are certain risk factors that are common to all the parenchymal lung disorders. As a general rule, the more severe the disease, the greater the risk of intervening PH. In parallel with this, hypoxia is a risk factor, but it remains unclear if the hypoxemia is causing the PH or vice versa. Whichever occurred first might be immaterial because it seems likely that they are interdependent and perpetuate each other in an inexorable feedback loop mechanism.

IDIOPATHIC PULMONARY FIBROSIS In IPF, it seems that complicating PH is a relatively common occurrence, even in patients with early or mild disease.16,24 Most of the studies evaluating the presence of PH have been in patients with more advanced disease, specifically patients who are being evaluated as potential lung transplant candidates. On the upper end of the prevalence spectrum, an 86% prevalence estimate was documented in a study of patients who received right heart catheterizations (RHC) at the time of their lung transplant.18 An approximate 10% prevalence was found in a prospective cohort of patients with mild or early disease, who had a mean disease duration of less than 1 year and a mean value of forced vital capacity (FVC) of 70% of predicted.16 In addition, approximately 5% of enrolled patients in this study had hemodynamic evidence of group II PH with increased pulmonary capillary wedge pressures (PCWP). This attests to the potential multifactorial cause of PH, especially when dealing with diseases such as IPF and COPD, which tend to afflict the elderly in whom systolic and heart failure with preserved ejection fraction (HF-pEF) are common. PH in IPF is generally associated with more advanced age, a greater need for supplemental oxygen therapy, reduced exercise tolerance, worse lung function, and a longer duration of disease. The hemodynamic severity of PH tends to be mild with w50% of patients having mPAPs of 30 mm Hg or less.13 Nonetheless, severe PH can occur and an mPAP greater than 40 mm Hg has been described in

Pulmonary Hypertension due to Lung Disease 2% to 9% of patients with IPF listed for lung transplantation.13,15 The evolution of PH in the setting of IPF tends to be progressive with some cases demonstrating an accelerated trajectory. This progressive course has been evaluated in 1 study in which serial RHCs were evaluated from the time of workup for lung transplantation and at the time of actual transplant.18 In some of these patients the second RHC did demonstrate PA pressures that were almost systemic in severity. IPF can occur in combination with comorbidities that can contribute to the underlying PH. Common comorbidities that seem to have an increased prevalence in IPF and may contribute to PH include congestive heart failure, obstructive sleep apnea (OSA), and COPD. Combined pulmonary fibrosis and emphysema (CPFE) has been described as a distinct IPF phenotype, with evidence of emphysematous changes noted in approximately one-third of patients with IPF.25 In cases of CPFE, the prevalence of PH tends to be high at w50%. Clues to the presence of coexistent emphysema are well-preserved lung volumes with a markedly reduced single-breath diffusing capacity for carbon monoxide (DLCO) and marked hypoxemia. The lung volumes tend to be well preserved due to the opposing restrictive and obstructive mechanical forces, and the DLCO is markedly reduced due to destruction of the pulmonary vascular bed by both disease processes.

COPD The prevalence of PH in COPD has been reported at between 5% and 90%.2,4–12 These estimates are difficult to compare because the methodology and cutoff points to define PH have differed, as have the patient populations studied. These have spanned the spectrum from primary care–based community cohorts to patients being considered for surgical intervention in the form of either lung volume reduction surgery (LVRS) or lung transplantation. PH is generally associated with a lower forced expiratory volume in the first second of expiration (FEV1) and more severe hypoxemia. There seems to be an association between age and the likelihood of PH in COPD, but whether this is attributable to age alone or an increased propensity for other comorbidities remains uncertain.26 Gender might also have a role to play with 1 study reporting that PH is more common in women exposed to smoke from biomass fuels.27 Similar to IPF, PH associated with COPD tends to be mostly mild in its severity. However, there does seem to be a distinct clinical COPD phenotype with moderate to severe PH, usually seen in

the context of moderate airflow obstruction. A clue to the presence of PH in this patient population is a markedly reduced DLCO in conjunction with severe hypoxemia and exercise desaturation. In 1 study of patients with COPD referred for LVRS or transplant, 7.4% had a modest decrement in FEV1 (mean 48% of predicted) in association with significant PH (mean mPAP of 39.8 mm Hg).2

SARCOIDOSIS PH is an increasingly recognized complication of sarcoidosis with a reported prevalence of between 1% and 74%.28–33 PH is most commonly detected in patients with stage IV fibrocystic disease, but can also occur in the context of relatively normal lung function and preserved parenchymal architecture. The presence of PH should be considered in any patient with recalcitrant dyspnea and in those with disease and symptoms severe enough to warrant consideration for lung transplantation. It is in these latter patients that the higher end of the prevalence range has been defined (w74%).32 A distinguishing epidemiologic feature of the PH complicating sarcoidosis is the distribution in the mPAPs, which is interesting to contrast with that of patients with COPD and IPF. Whereas the latter 2 groups of patients tend to have a Gaussian distribution, the histogram distribution of the mPAP in sarcoidosis tends to demonstrate a tail of patients with more severe PH. Fig. 1 shows the difference in distribution among these 3 patient groups (COPD, IPF, and sarcoidosis) from the Inova Fairfax Advanced Lung Disease Program.

NONSPECIFIC INTERSTITIAL PNEUMONITIS There is a paucity of literature on PH complicating nonspecific interstitial pneumonia (NSIP). It is the second most common of the idiopathic interstitial pneumonias and although it does portend a better prognosis than IPF, there is a subgroup of patients who develop advanced disease and succumb from this condition. There are data to suggest that the course of NSIP parallels that of IPF once the DLCO breaches 35% of the predicted threshold.34 It is possible that this marks the subgroup of patients who have developed PH, which one can speculate is then the driver of outcomes in both groups.

LYMPHANGIOLEIOMYOMATOSIS Lymphangioleiomyomatosis (LAM) is a rare disease that is classified as group 5 PH. It occurs almost exclusively in women of reproductive age and is characterized by abnormal smooth muscle proliferation affecting the thoracic lymphatics,

697

698

Nathan & Hassoun

Fig. 1. Distribution of mPAPs of patients with IPF, COPD, and sarcoidosis referred to a large tertiary care center (Advanced Lung Disease Program, Inova Fairfax Hospital) and who underwent right heart catheterization. The prevalence and distribution of pressures depicted does not reflect that of the general population with these diseases, because there is likely bias introduced by referral patterns as well as patient selection for catheterization.

bronchioles, and vasculature. PH is rare in this population, but an increase in RVSP with lowlevel exercise may be seen fairly commonly, which attests to some degree of pulmonary vascular involvement.35–37

PULMONARY LANGERHANS CELL HISTIOCYTOSIS Pulmonary Langerhans cell histiocytosis (PLCH) is another rare ILD related to tobacco use, which may regress spontaneously with smoking cessation. However, irreversible airflow obstruction may ensue and 20% to 30% of cases do progress to chronic respiratory insufficiency.38–41 PH, which may be severe, is frequently seen in these advanced cases with a reported prevalence as high as 92% to 100%.38–41 Purported mechanisms involved in the pathogenesis of PH include chronic hypoxia, abnormal pulmonary parenchymal mechanics, vascular remodeling, and the abnormal production of inflammatory cytokines and growth factors. Similar to other parenchymal lung diseases, pulmonary pressures do not correlate with spirometry and PH may also occur in the absence of significant parenchymal disease.38

PH COMPLICATING SLEEP APNEA The reported prevalence of PH in OSA has varied from 17% to 40% depending on the method of diagnosis (RHC vs echocardiography) and the pulmonary arterial pressure cutoff used to define PH.42–44 PH in OSA is usually mild to moderate, can be multifactorial, and related to precapillary or postcapillary causes.43–46 The presence of comorbid conditions including cardiopulmonary diseases is associated with an increased likelihood of PH in these patients.46,47 Among cardiovascular diseases, diastolic dysfunction is often associated with OSA.48 In a study of 83 patients in whom RHC

was available within 6 months of OSA diagnosis, 70% of patients had PH including 31% with pulmonary capillary wedge pressures greater than 15 mm Hg.49 PH correlated with female gender, nocturnal desaturation, FEV1 less than 70% and a body mass index greater than 26 kg/m2. The pathophysiologic mechanisms involved in the development of vascular disease, and by inference PH, in OSA have included endothelial dysfunction related to intermittent hypoxia leading to oxidative stress, systemic inflammation, increased sympathetic activity, as well as intrathoracic pressure swings causing direct vascular damage.50–56 A comprehensive review of these complex mechanisms and their putative actions can be found elsewhere.57 As for other diseases of the lung causing PH, effective treatment of PH related to OSA relies essentially on proper diagnosis of the underlying disease (ie, polysomnogram), continuous positive airway pressure (CPAP) titration when indicated, and other appropriate treatment (nutritional counseling and weight loss, or tracheostomy and bariatric surgery in extreme cases), to prevent nocturnal apneas and oxygen desaturation. When PH is suspected, a screening echocardiogram is warranted followed by RHC if suspicion is high (eg, increased RVSP >40 mm Hg in particular in the presence of a dilated right ventricle). However, if the echocardiographic changes are mild, it is reasonable to institute treatment of OSA first and then obtain a repeat echocardiogram after 6 months of adequate therapy. Adherence to CPAP therapy has been shown to improve hemodynamics in patients with OSA.58,59

OVERLAP SYNDROMES It is not uncommon that patients may have more than 1 cause of their PH that may be within the

Pulmonary Hypertension due to Lung Disease same WHO PH grouping (eg, OSA and COPD) or from different WHO groups in the case of parenchymal lung disease with associated cardiac abnormalities, such as HF-pEF. HF-pEF may be found in as many as 15% to 17% of patients with parenchymal lung disease.6,24,33 Similarly, patients with connective tissue disease (CTD) complicated by PH are usually classified in group 1 (pulmonary arterial hypertension [PAH]). However, certain CTDs such as scleroderma can be complicated by ILD, which, when moderate or severe, can also be complicated by PH.60 In the latter case, patients may be categorized as having group 3 PH. In up to 25% of these patients, the mPAP can be greater than 35 mm Hg and is believed to be out of proportion to ILD and likely related to intrinsic vascular disease in addition to the alveolar disruption.3,61,62 Several studies have now suggested that the combination of PH and ILD in these patients with scleroderma significantly worsens their prognosis as suggested by a median survival of less than 2 years compared with 4 years in patients with sclerodermaassociated PAH.62–64 PAH-specific therapies did not seem to have a beneficial effect on WHO functional class, 6-minute walk distances, hemodynamic measures, or survival in 1 cohort of patients with combined PH and ILD studied retrospectively in the context of the scleroderma spectrum of disease.64

PATHOGENESIS OF PH IN LUNG DISEASE/ HYPOXIA Increased pulmonary vascular load characteristic of PH results from remodeling of the pulmonary vasculature involving, to various degrees, all layers of the vasculature (intima, media, and adventitia). Pulmonary vascular remodeling in chronic hypoxia and lung parenchymal diseases is believed to be multifactorial in its cause. Contributory factors include endothelial dysfunction, excessive vasoconstriction, proliferation of various cells (including endothelial, smooth muscle cells, and fibroblasts) and thrombosis, all of which contribute to narrowing of the vasculature.65 Whereas plexiform lesions (resulting from uncontrolled proliferation of endothelial cells and fibroblasts at the branching sites of medium size arteries) are characteristic of PAH, medial hypertrophy of small muscular arteries and neomuscularization of more distal arterioles are often the hallmark of hypoxic lung diseases (and animal models of PH induced by chronic hypoxia), with lesser degrees of intimal and adventitial remodeling. In addition, influx of inflammatory cells (eg, macrophages, dendritic cells, and B and T lymphocytes) has been

increasingly recognized.66 In the case of chronic pulmonary parenchymal diseases, excessive fibrosis (eg, in ILD) and loss of parenchymal tissue (eg, COPD) contribute to disruption and loss of small vessels of the pulmonary vascular bed. Imbalances between ventilation and perfusion (V/Q) matching, characteristic of chronic parenchymal lung diseases, cause precapillary pulmonary vasoconstriction through mechanisms that remain poorly understood but include changes in nitric oxide balance, release of vasoconstrictors, and metabolic alterations (potassium and calcium flux in smooth muscle cells).67,68 At high altitude with chronic continuous hypoxia (Monge disease), and in some diseases characterized by chronic intermittent hypoxia (such as sleep apnea syndrome), release of catecholamines and changes in acid-base status may, in addition, cause pulmonary venoconstriction, further exacerbating the increase in pulmonary vascular pressure.69 Thromboembolic lesions can further impede pulmonary vascular flow, and frequently may complicate chronic lung diseases such as COPD, sarcoidosis, and IPF.70–74 In COPD, pulmonary vascular remodeling correlates with the degree and severity of inflammatory cell infiltrates in small airways and is characterized, in smokers, by inflammatory cells infiltrating the adventitia of muscular PAs, largely constituted by activated T lymphocytes with a predominance of the CD81 T-cell subset.75 Several growth factors, including vascular endothelial growth factor and transforming growth factor b (TGF-b), and occasionally their receptors (eg, TGF-b RII) have increased expression in remodeled pulmonary arteries of smokers with mild-to-moderate COPD, suggesting that these mediators may play a role in the pulmonary vascular remodeling of COPD.76–78

SCREENING FOR PH IN PATIENTS WITH PARENCHYMAL LUNG DISEASES Screening for parenchymal lung disease should be routine in the evaluation of patients referred for PH. A thorough history should inquire about symptoms suggestive of COPD, ILD, and sleep apnea. Baseline tests should include pulmonary function tests (spirometry, lung volumes, and DLCO), resting, exercise, and nocturnal oxygen saturation, a plain chest film, a high-resolution chest computerized tomogram (CT) scan, a ventilation-perfusion scan, appropriate serologies to rule out CTD, and a polysomnogram when indicated. Lung volume measurements do not tend to correlate with underlying PH.2,24 However, a low DLCO (