Pulmonary Hypertension in Patients With Interstitial Lung Diseases

REVIEW PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES

Pulmonary Hypertension in Patients With Interstitial Lung Diseases JAY H. RYU, MD; MICHAEL J. KROWKA, MD; PATRICIA A. PELLIKKA, MD; KAREN L. SWANSON, DO; AND MICHAEL D. MCGOON, MD Pulmonary hypertension (PH) in patients with interstitial lung diseases (ILDs) is not well recognized and can occur in the absence of advanced pulmonary dysfunction or hypoxemia. To address this topic, we identified relevant studies in the English language by searching the MEDLINE database (1966 to November 2006) and by individually reviewing the references of identified articles. Connective tissue disease–related ILD, sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary Langerhans cell histiocytosis are the ILDs most commonly associated with PH. Pulmonary hypertension is an underrecognized complication in patients with ILDs and can adversely affect symptoms, functional capacity, and survival. Pulmonary hypertension can arise in patients with ILDs through various mechanisms, including pulmonary vasoconstriction and vascular remodeling, vascular destruction associated with progressive parenchymal fibrosis, vascular inflammation, perivascular fibrosis, and thrombotic angiopathy. Diagnosis of PH in these patients requires a high index of suspicion because the clinical presentation tends to be nonspecific, particularly in the presence of an underlying parenchymal lung disease. Doppler echocardiography is an essential tool in the evaluation of suspected PH and allows ready recognition of cardiac causes. Right heart catheterization is needed to confirm the presence of PH, assess its severity, and guide therapy. Management of PH in patients with ILDs is guided by identification of the underlying mechanism and the clinical context. An increasing number of available pharmacologic agents in the treatment of PH allow possible treatment of PH in some patients with ILDs. Whether specific treatment of PH in these patients favorably alters functional capacity or outcome needs to be determined.

Mayo Clin Proc. 2007;82(3):342-350 COPD = chronic obstructive pulmonary disease; CTD = connective tissue disease; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; PAP = pulmonary artery pressure; PH = pulmonary hypertension; PLCH = pulmonary Langerhans cell histiocytosis

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ulmonary hypertension (PH) can occur as an isolated phenomenon or in association with various cardiac, pulmonary, and systemic disorders. Pulmonary hypertension is defined as mean pulmonary artery pressure (PAP) that exceeds 25 mm Hg at rest or 30 mm Hg with exercise.1-3 PAP may be elevated because of different mechanisms, including obstruction to blood flow with an increase in pulmonary vascular resistance, high flow state with elevated cardiac output, or increases in intravascular volume. Cor pulmonale and PH are well-known complications of advanced chronic obstructive pulmonary disease (COPD).4,5 In patients with COPD, resting PAP correlates best with resting PaO2.5,6 Pulmonary hypertension that occurs in patients with COPD is usually caused by chronic hypoxic vasoconstriction and progressive pulmonary vascular remodeling.4,5 Long-term oxygen therapy 342

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improves survival in hypoxemic patients with COPD and PH.7-10 The association of PH with interstitial lung disease (ILD) is less well recognized. However, in recent years, several reports have described PH as a potential complication of ILD.11-13 For the current review, we searched the MEDLINE database for literature published from 1966 to November 30, 2006. The Medical Subject Heading (MeSH) terms pulmonary hypertension and interstitial lung disease as well as specific ILDs including Langerhans cell histiocytosis, pulmonary fibrosis, sarcoidosis, and pneumoconiosis were used in separate searches, and studies found during each search were combined. Limits were set for human research studies in the English language. We identified additional relevant studies by manually searching bibliographies of retrieved articles. The ILDs most commonly associated with PH include connective tissue disease (CTD)–related ILD, sarcoidosis, idiopathic pulmonary fibrosis (IPF), and pulmonary Langerhans cell histiocytosis (PLCH).11-13 Pulmonary hypertension is one of the potential causes of dyspnea and exercise limitation in patients with ILDs. In some of these patients, PH has been noted to occur in the absence of resting hypoxemia or advanced pulmonary dysfunction.11-16 The presence of PH is generally associated with a worse prognosis in patients with ILDs.11-14,16-19 In this review, we summarize what is currently known regarding the prevalence, pathogenesis, diagnosis, management, and prognosis of PH in ILDs. Because PH in ILDs has not been extensively studied, many issues in this area remain unclear and are currently addressed by extrapolating from data that pertain to other forms of PH, particularly idiopathic pulmonary arterial hypertension. From the Division of Pulmonary and Critical Care Medicine (J.H.R., M.J.K., K.L.S.) and Division of Cardiovascular Diseases (P.A.P., M.D.M.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Krowka has received grant support from CoTherix, Inc. Dr McGoon is a consultant for Medtronic, Inc, a steering committee member for CoTherix, Inc, and Myogen, a data safety and monitoring committee member for United Therapeutics, and a central event committee member for Actelion; he has received grant/research support from Medtronic, Inc, CoTherix, Inc, and Myogen. Individual reprints of this article are not available. Address correspondence to Jay H. Ryu, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: ryu.jay @mayo.edu). © 2007 Mayo Foundation for Medical Education and Research

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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES

TABLE 1. Characteristics of Pulmonary Hypertension (PH) Associated With Specific Interstitial Lung Diseases (ILDs)* Disease

Prevalence of PH†

Potential mechanisms of PH

Comments

Pulmonary Langerhans cell histiocytosis

Unknown; up to 100% in advanced disease

PH can be severe and can occur in the absence of advanced parenchymal destruction; PH increases mortality

Connective tissue disease–related ILD

Unknown; 45% in scleroderma-ILD

Sarcoidosis

5.7%; up to 73.8% in advanced disease

Intrinsic proliferative pulmonary vasculopathy, vascular obstruction/destruction associated with parenchymal fibrosis, hypoxic vasoconstriction and remodeling Vasoconstriction and remodeling, vascular inflammation, in situ thrombosis, thromboembolism, diastolic dysfunction Vascular obstruction/destruction associated with parenchymal fibrosis, granulomatous vasculopathy, extrinsic compression of large pulmonary arteries by lymphadenopathy, systolic or diastolic dysfunction

Idiopathic pulmonary fibrosis

Up to 84%

Pneumoconioses

Unknown

Vascular obstruction/destruction associated with parenchymal fibrosis, hypoxic vasoconstriction and remodeling, possible intrinsic vasculopathy Vascular obstruction/destruction associated with parenchymal fibrosis, hypoxic vasoconstriction and remodeling

PH can occur alone or with ILD in patients with connective tissue diseases PH is associated with lower pulmonary function measurements and advanced radiographic changes, but PH can be seen in the absence of parenchymal fibrosis; PH increases mortality in patients awaiting lung transplantation Systolic PAP correlates inversely with DLCO measurement but not with spirometric values; PH increases mortality PH tends to correlate with the severity of parenchymal abnormalities

*DLCO = diffusing capacity of lung for carbon monoxide; PAP = pulmonary artery pressure. †Prevalence figures are primarily from retrospective case series, and some may represent overestimation.

PREVALENCE The overall prevalence of PH in ILD is not fully known and varies among the ILDs. In a prospective observational study, Leuchte et al19 reported that 31.8% of 88 consecutive patients with various ILDs undergoing right heart catheterization had significant PH (defined as mean PAP >35 mm Hg). Data are available regarding the prevalence of PH in several specific ILDs (Table 1). Perhaps the best known association is with PLCH. Pulmonary Langerhans cell histiocytosis (also known as histiocytosis X, pulmonary Langerhans granulomatosis, or eosinophilic granuloma of the lung) is characterized by the proliferation and infiltration of organs by Langerhans cells.20-22 In adults, PLCH is usually a smoking-related ILD.20-22 Pulmonary hypertension is common in patients with end-stage PLCH and tends to be more severe than that observed in other advanced lung diseases such as emphysema, lymphangioleiomyomatosis, and IPF.15,23,24 However, PH is not limited to patients with end-stage PLCH; advanced pulmonary parenchymal destruction does not appear to be a requisite for the development of PH from PLCH.15 For example, there is a lack of correlation between mean PAP (assessed by echocardiography or cardiac catheterization) and the degree of spirometric abnormalities.15,23-25 Both PH and ILD have been reported in association with all CTDs, although their respective frequencies vary.2,26-29 Elevations in PAP have been noted in 5% to 60% of patients with CTDs and are most often seen in scleroderma and CREST syndrome (limited scleroderma).2,26-29 PulmoMayo Clin Proc.

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nary hypertension can occur with or without ILD in patients with CTDs. In a study of 619 patients with scleroderma, 22.5% had evidence of ILD alone, 19.2% had isolated PH (assessed by Doppler echocardiography), and 18.1% had both ILD and PH.30 A survey of communitybased rheumatology practices found that the prevalence of PH (assessed by Doppler echocardiography) in scleroderma is 26.7%.31 Estimated systolic PAP tended to be higher in patients with scleroderma who had ILD compared with those with no ILD.32 Sarcoidosis is a multiorgan disorder of unknown cause characterized by the presence of noncaseating granulomas, most commonly involving the lungs.33,34 Pulmonary hypertension is common in patients with advanced sarcoidosis.18,35 For example, in a cohort of 363 patients with sarcoidosis on the United Network for Organ Sharing list for lung transplantation, 73.8% had PH (assessed by right heart catheterization).35 In another study, PH in patients with sarcoidosis was associated with a higher prevalence of stage 4 sarcoidosis (advanced parenchymal scarring) and lower spirometric and diffusing capacity values.36 However, PH has also been reported as an early manifestation of sarcoidosis and can be mediated by mechanisms other than parenchymal destruction or hypoxemic vasoconstriction (discussed further in the “Pathogenesis” section).16,37 Handa et al38 recently reported a prospective observational study of 212 Japanese patients with sarcoidosis who were evaluated for PH by Doppler echocardiography. Twelve patients (5.7%) had PH (defined as estimated systolic PAP ≥40 mm Hg); a weak negative correlation was found between systolic PAP and

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Exercise-induced PH was demonstrated in subjects with silicosis, more commonly with complicated silicosis vs simple silicosis.46 PATHOGENESIS

FIGURE 1. High-resolution computed tomogram of a 72-year-old female nonsmoker with idiopathic pulmonary fibrosis and pulmonary hypertension. There are reticular opacities predominantly in the peripheral lung zones, mild subpleural honeycombing, associated traction bronchiectasis, and enlarged central pulmonary arteries. Right heart catheterization revealed pulmonary artery pressure of 73/25 (mean 40) mm Hg.

percentage of predicted total lung capacity. Some patients with PH had normal values of total lung capacity and no evidence of parenchymal fibrosis. Idiopathic pulmonary fibrosis is a progressive fibrotic disorder of the lung of unknown cause that is characterized by the histopathologic pattern of usual interstitial pneumonia and associated with a high mortality rate (Figure 1).39-41 The incidence and prevalence of PH in patients with IPF is unknown. In a recent retrospective study of 88 patients who met the current diagnostic criteria for IPF40 and had undergone transthoracic Doppler echocardiography, 84% had evidence of PH.14 The mean ± SD estimated systolic PAP for these patients was 48±16 mm Hg (range, 28-116 mm Hg). Among pulmonary function parameters, systolic PAP was inversely correlated with the diffusing capacity. However, a lack of correlation between systolic PAP and the degree of spirometric abnormalities was noted in this study as well as in other investigations.14,25,42 Pneumoconioses are disorders characterized by varying degrees of fibrotic reaction in the lungs that are caused by inhaled dust such as asbestos and silica.43 Pulmonary hypertension can complicate the clinical course of patients with pneumoconioses.44-46 Additionally, PH has been seen in uranium miners with radiation-induced pulmonary fibrosis.47 A survey of Michigan hospital discharge data for the years 1990 and 1991 found PH to be associated with asbestosis, coal worker pneumoconiosis, silicosis, and unspecified pneumoconiosis.44 A hemodynamic study of subjects with asbestosis showed that an increasing severity of parenchymal opacities correlated with higher mean PAP.45 344

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The pathogenesis of PH in ILD is incompletely understood and may involve multiple diverse mechanisms, some of which are peculiar to specific forms of ILD, as discussed subsequently. In advanced lung disease, PH generally results from chronic hypoxic pulmonary vasoconstriction and vascular remodeling.4,48,49 This vascular remodeling involves all layers of the pulmonary arterial wall and includes intimal thickening and medial hypertrophy. However, PH can be seen in the absence of hypoxemia in patients with ILDs and irrespective of its severity. Other possible mechanisms include vascular obstruction or destruction associated with progressive parenchymal fibrosis, vascular inflammation, perivascular fibrosis, and thrombotic angiopathy.13,48-50 Interest in the role of pulmonary endothelial dysfunction in PH has been increasing.5,49,51-54 The pulmonary endothelial cell produces several important vasoactive mediators (eg, nitric oxide, prostacyclin, and endothelin) that modulate pulmonary vasomotor tone, vascular smooth muscle cell proliferation, and vascular remodeling.5,48,52,53 For example, endothelin 1 is an endothelium-derived vasoconstrictor that also acts as a mitogen of pulmonary vascular smooth muscle cells and induces extracellular matrix formation (profibrotic).5,48,52-58 Hypoxia increases plasma endothelin 1 levels.5,48,54 The level of circulating endothelin 1 has been reported to be elevated in patients with ILD, particularly in those with PH.55,59,60 Vascular smooth muscle dysfunction has been implicated in the pathogenesis of idiopathic pulmonary arterial hypertension. Pulmonary arterial smooth muscle cells from patients with this disorder exhibit abnormal proliferative response to growth factors such as transforming growth factor β, bone morphogenetic protein 2, and platelet-derived growth factor.61-63 Additionally, these smooth muscle cells exhibit abnormal migration and extracellular matrix formation as well as dysfunctional ion channels.61-63 Different mechanisms may contribute to the development of PH among various ILDs. For example, Fartoukh et al24 described a proliferative pulmonary vasculopathy involving muscular arteries and veins in PLCH. Progressive vascular involvement was documented in some of these patients despite relative stability of the parenchymal and bronchiolar disease.24 Pulmonary hypertension occurring in PLCH is of greater magnitude than would be anticipated on the basis of hypoxemia alone.15,24 In addition, poor correlation between the severity of PH and the degree of impair-

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ment on pulmonary function measures suggests mechanisms other than parenchymal destruction alone.15,23,24 Cardiopulmonary exercise testing has demonstrated that exercise impairment correlates with pulmonary vascular dysfunction rather than abnormalities of ventilatory function and gas exchange in patients with PLCH.64 Vascular inflammation, in situ thrombosis, and pulmonary thromboembolism (due to underlying hypercoagulable states) may contribute to the development of PH in patients with CTDs.12,26,27,65,66 Autoimmune processes, eg, antiendothelial antibodies, have been implicated in the pathogenesis of PH associated with diffuse scleroderma and CREST syndrome.27 There are likely to be differences in the pathogenesis of PH among various CTDs. In some patients with CTDs, pulmonary arterial hypertension (pulmonary arteriopathy) may coexist with ILD and not necessarily be related to parenchymal disease.67 Pulmonary hypertension due to passive elevation in the PAP caused by diastolic dysfunction may also occur in these patients.67 Although PH occurring in patients with sarcoidosis is usually related to advanced parenchymal fibrosis, a form of pulmonary vasculopathy has also been described.16,68,69 Nunes et al16 described histopathologic findings in the native lungs of 5 transplant recipients with sarcoidosis that consisted not only of granulomatous involvement of pulmonary vessels (more commonly veins than arteries) but also occlusive venopathy with intimal fibrosis and recanalization. Plexiform lesions were not present. Extrinsic compression of large pulmonary arteries by mediastinal or hilar lymphadenopathy may also play a role in the development of PH in sarcoidosis.16,70,71 Myocardial infiltration by the granulomatous process may cause diastolic dysfunction or diminished systolic function and lead to secondary PH.72 In patients with IPF and PH, it is generally thought that parenchymal fibrosis with vascular destruction is the predominant cause of PH. However, poor correlation between pulmonary function measures and the presence of PH raises the possibility of other mechanisms.14,25,42 For example, a recent study of gene expression patterns suggested the presence of an abnormal vascular phenotype in patients with IPF and PH.73 DIAGNOSIS Because exertional dyspnea is the most common symptom associated with both PH and ILD, the presence of coexisting PH could easily be overlooked in patients with ILD. Furthermore, the development of both PH and ILD is typically insidious and associated with minimal symptoms and signs in earlier stages. Advanced stages of PH are easier to recognize and are associated with symptoms of leg swelling, abdominal bloating and distention, anorexia, plethora, Mayo Clin Proc.

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and profound fatigue as right ventricular dysfunction and tricuspid valve regurgitation worsen.2,74 The diagnosis of PH relies on a high index of suspicion. Evaluation for PH should be considered in patients with ILD who complain of exertional dyspnea or fatigue, particularly if the severity of these symptoms seems to be disproportionate to the parenchymal lung disease. Symptoms of chest pain or syncope can also be manifestations of PH. Chest radiography may reveal signs suggestive of PH, including enlarged pulmonary arteries, attenuation of peripheral pulmonary vasculature, and right ventricular enlargement. These abnormalities may also be appreciated on high-resolution computed tomographic scanning that is usually needed for evaluation of the underlying parenchymal lung disease. Various radiologic criteria have been described in the diagnosis of PH. In one study, computed tomography–determined main pulmonary artery diameter of 29 mm or greater had 84% sensitivity and 75% specificity for predicting PH in patients with parenchymal lung disease.75 Assessment of pulmonary function and arterial blood oxygenation is necessary to evaluate the degree of pulmonary impairment. In our experience, a diffusing capacity measurement that is reduced disproportionately to other pulmonary function measures does not appear to be sensitive or specific in detecting associated PH in patients with ILD. For example, preexisting emphysema in a patient who subsequently develops ILD may give rise to such an abnormal pattern of pulmonary function results. Electrocardiography commonly reveals abnormalities of rightaxis deviation and right ventricular hypertrophy in patients with PH.2 Measurement of the plasma B-type natriuretic peptide level may become a useful diagnostic tool for identifying and monitoring PH in patients with ILDs.42 Subsequent diagnostic evaluation is conducted to document the presence of PH, assess its severity, and determine its potential for reversibility.2 In the initial stages of the diagnostic evaluation, the clinician should not necessarily assume a causal relationship between ILD and suspected PH. Other causes for PH must be considered, including obstructive sleep apnea, pulmonary embolism, human immunodeficiency virus infection, drugs (eg, appetite suppressants, toxic rapeseed oil, chemotherapeutic agents), thyroid disease, hepatic disease, left ventricular heart failure, and valvular heart disease.76 For example, ventilation-perfusion scintigraphy or computed tomographic chest angiography may be indicated to exclude pulmonary embolism. Overnight oximetry is useful not only in the evaluation of patients with suspected obstructive sleep apnea but also in assessing the adequacy of oxygenation during sleep for patients with other established causes of PH. Occasionally, rare pulmonary vascular disorders associated with interstitial changes on chest radiography, such as pulmonary

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TABLE 2. Management of Pulmonary Hypertension in Interstitial Lung Disease 1. 2. 3. 4. 5. 6.

Treat underlying interstitial lung disease Provide supplemental oxygen therapy when appropriate Treat heart failure Consider anticoagulant therapy Consider vasomodulator therapy Consider lung transplantation

veno-occlusive disease or pulmonary capillary hemangiomatosis, may be mistaken for ILD with PH.77,78 ECHOCARDIOGRAPHY Transthoracic Doppler echocardiography is an essential tool in the evaluation of patients with suspected PH. Doppler echocardiography can estimate the level of systolic PAP and assess the presence of associated abnormalities such as right atrial enlargement, right ventricular enlargement, right or left ventricular dysfunction, intracardiac shunt, valvular disease, and pericardial effusion.2,79 The Doppler-derived right ventricular index of myocardial performance has been related to the prognosis of patients with PH.80,81 Tricuspid regurgitation jet velocity, which is used to estimate right ventricular systolic pressure using the modified Bernoulli equation,82 has been reported to be analyzable in 39% to 86% of patients.2 Measurement is particularly challenging in patients with obstructive lung disease, who frequently have poor echocardiographic windows. Echocardiography may be imprecise in determining actual pressures compared to right heart catheterization in a portion of these patients.2,83 The sensitivity and specificity of Doppler echocardiography–estimated systolic PAP in predicting PH range from 0.79 to 1.0 and 0.6 to 0.98, respectively.2 Exertional changes in PAP can be assessed with Doppler echocardiography during supine bicycle exercise84 and can provide insight into exertional symptoms. The noninvasive nature and ready availability of Doppler echo-cardiography make this a valuable tool in serial studies to assess response to therapy. RIGHT HEART CATHETERIZATION Right heart catheterization is the diagnostic standard for measuring pulmonary hemodynamic parameters and evaluating PH.1-3 In patients with suspected PH, right heart catheterization is required to confirm the presence of PH, establish the specific diagnosis, determine the severity of PH, assess prognosis, and guide initial therapy.2,74 Vasoreactivity testing using a short-acting agent such as intravenous epoprostenol, adenosine, or inhaled nitric oxide should be considered. A positive vasodilator response is generally defined as a decrease in mean PAP of at least 10 to 40 mm Hg or lower with an increased or unchanged 346

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cardiac output.85 Caution may be needed in performing vasodilator trials in patients with parenchymal lung disease because hypoxia may worsen (discussed further in the “Vasomodulating Therapy” section).11 LUNG BIOPSY Lung biopsy may be needed to clarify the nature of the underlying ILD but is generally not required in the assessment of PH. Surgical lung biopsy in a patient with PH has a substantial risk of morbidity and mortality.2 Additionally, the histopathologic findings pertaining to the pulmonary vasculature are generally nonspecific with rare exceptions, eg, pulmonary veno-occlusive disease. With bronchoscopic lung biopsy, the presence of PH increases the risk of bleeding.86 TREATMENT Management of PH in patients with ILD is guided by the clinical context, mechanism underlying PH, severity of PH, and results of vasoreactivity testing performed during right heart catheterization. To a certain extent, PH in ILD is treatable whether one is addressing the PH itself, the underlying ILD, or both (Table 2). Some of the vasomodulating agents used in the treatment of pulmonary arterial hypertension, eg, bosentan, may have beneficial effects on the underlying parenchymal lung disease, but this issue is just beginning to be explored.87-89 Similarly, imatinib mesylate, an inhibitor of platelet-derived growth factor and transforming growth factor β, has been demonstrated to prevent or reverse pulmonary fibrosis and pulmonary arterial hypertension in animal models.90,91 Thus, an antiproliferative strategy may have relevance to both vascular and parenchymal disease in patients with ILD-associated PH. A major component of treating PH in ILD is treatment of the underlying lung disease. Optimal management of ILD, in turn, depends on accurate diagnosis that may require a surgical lung biopsy for histopathologic characterization.92 Treatment options commonly include corticosteroids and other immunosuppressive agents. For example, corticosteroid therapy can improve PH in some patients with sarcoidosis, even in the absence of parenchymal fibrosis.16,93,94 Interestingly, some patients with CTD-related pulmonary arterial hypertension have responded to combination therapy with corticosteroids and cyclophosphamide.95 Treatment of ILDs caused by exogenous agents, eg, cigarette smoking in patients with PLCH, obviously requires cessation of further inhalational exposure. Aside from the underlying ILD diagnosis, clinical context including age of the patient, comorbidities, and extrapulmonary manifestations should also be considered in making management decisions.

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Use of supplemental oxygen to maintain oxygen saturation higher than 90% is desirable in hypoxemic patients with ILD. It is not uncommon for patients with ILD to exhibit exertion-related oxygen desaturation in the absence of resting hypoxemia. Thus, oxygen saturation should be assessed with exercise and at rest. However, beneficial effects of long-term oxygen therapy for patients with ILD are not as well documented as for patients with COPD. In patients with symptomatic right heart failure, diuretics can be useful in managing volume overload, and digitalis may be indicated for selected patients. Anticoagulant therapy should be considered for patients with ILD and severe PH, similar to its use in idiopathic pulmonary arterial hypertension, but currently no data demonstrate the efficacy of anticoagulant therapy for patients with ILD-associated PH.86 Anticoagulants could be useful in the prevention of venous thromboembolism or in situ thrombosis in patients with underlying hypercoagulable states, eg, antiphospholipid antibody, previous history of thromboembolism, prolonged bed rest, or other predisposing risk factors for this complication. Recently, Kubo et al96 reported that anticoagulant therapy was associated with a reduced mortality rate after acute exacerbation of IPF. The prevalence of PH in these patients was not stated. The beneficial effects of anticoagulant therapy in these patients may have been mediated through reduction of in situ thrombosis in the pulmonary vasculature or venous thromboembolism. In situations in which PH has been sufficiently severe and protracted to result in right ventricular hypocontractility, dilatation, and ultimately clinical right ventricular heart failure, treatment of volume overload should be undertaken. The use of loop diuretics and potassium-sparing diuretics is appropriate but must be monitored carefully to avoid reducing right ventricular preload to a point at which cardiac output declines and systemic hypotension intervenes. Inotropic support of the right ventricle with digitalis has been advocated in pulmonary hypertensive conditions, although no consensus or clear outcome data are available regarding efficacy.

vasodilator testing at right heart catheterization via antiproliferative mechanisms in the pulmonary vasculature and lung parenchyma.74,85 There is an increasing availability of drugs for treating pulmonary arterial hypertension, including the nonselective endothelin A/B receptor antagonist bosentan; the prostacyclin analogues epoprostenol, treprostinil, and iloprost; and the phosphodiesterase-5 inhibitor sildenafil.56,74,85 Selective endothelin A receptor antagonists (sitaxsentan and ambrisentan) may become available in the near future. Vasomodulating therapy that targets PH in ILD has been analyzed in small clinical studies.98-102 The combined presence of ILD and PH may pose difficulties for pharmacologic treatment because systemic vasodilator therapy may be complicated by worsening hypoxemia due to increased ventilation-perfusion mismatch. Administration of intravenous prostacyclin has been associated with decreased arterial oxygen tension.99 However, inhaled nitric oxide, inhaled iloprost, and oral sildenafil therapy decreased pulmonary vascular resistance without decreasing arterial oxygen tension in patients with PH and ILD.98,100 Inhaled therapy may minimize the detrimental effect on ventilation-perfusion mismatch by exerting a vascular effect locally in better ventilated regions of the lungs; a multicenter trial using inhaled iloprost is currently in progress in patients with IPF and PH. Caution must be exercised for patients in whom PH is due to pulmonary venous disease, as has been described in some patients with PLCH24,103 and sarcoidosis,16 because vasodilation may result in acute pulmonary edema and possibly death.104-106 Assessment of the patient’s response to therapy is essential. Outcome is gauged by assessing dyspnea, exertional capacity, and quality of life as well as hemodynamic parameters measured by serial echocardiography or right heart catheterization.74,85 Treatment of PH in ILD appears to improve symptoms and may modulate the underlying parenchymal lung disease in some patients with ILDs, but its effect on survival is not yet known. Additional studies are clearly needed to further establish the safety and efficacy of vasomodulator therapy for treating PH in patients with ILD.

VASOMODULATING THERAPY Therapy for PH is directed at relief of pulmonary vasoconstriction and reduction or reversal of cellular proliferation and vascular remodeling.74,85 As in patients with idiopathic pulmonary arterial hypertension, vasomodulating agents may have the best utility in patients with favorable vasodilator testing, but this issue needs further exploration.85,97 Using vasodilator therapy for patients with ILD has associated potential risks, as discussed subsequently. However, as previously mentioned, vasomodulating therapy may also have potential benefit in patients who do not respond to

LUNG TRANSPLANTATION Lung transplantation should be considered in patients with severe or progressive impairment due to PH or ILD, particularly if pharmacologic agents fail to provide improvement. Limited experience suggests that single lung transplantation without routine use of cardiopulmonary bypass is appropriate for patients with ILD and moderate PH.107-110 For patients with severe secondary PH, the issue of single lung vs bilateral lung vs heart-lung transplantation remains unsettled.109 Living lobar lung transplantation may also be an option.107,111

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There have been conflicting reports on the effect of secondary PH on the outcome after lung transplantation.25,108,110,112,113 Overall, the presence of PH does not appear to adversely affect the survival rate of patients with ILD who undergo lung transplantation.25,108,110 However, in a study of 830 patients in the International Society for Heart and Lung Transplant registry, an increasing PAP was a risk factor for 90-day mortality after single lung transplantation in IPF.113 PROGNOSIS Pulmonary hypertension causes disability and premature death in patients with or without underlying lung disease. Prognosis in patients with ILD and PH is affected by both PH and underlying ILD. The presence of PH in patients with ILD correlates with worse prognosis.11-14,16,17,114 For example, an increasing PH correlated with worse survival in patients with IPF; those with systolic PAP greater than 50 mm Hg had a median survival of less than 1 year.14 Whether vasomodulator therapy will result in improved survival of patients with ILD and PH remains to be determined. CONCLUSION Pulmonary hypertension is an underrecognized complication in patients with ILDs and may arise through multiple mechanisms. The prevalence and clinical implications of PH in patients with ILDs require further clarification. Although some themes may be similar in the pathogenesis of PH in patients with ILDs, there are likely mechanisms peculiar to specific ILDs, and these need to be studied. The presence of PH adds to the symptoms, functional impairment, morbidity, and mortality in these patients. Preliminary studies suggest that ILD-associated PH may respond to currently available pharmacologic agents, but whether specific treatment of this complication improves functional capacity or outcome remains to be determined in clinical trials. REFERENCES 1. Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004; 126(suppl):4S-6S. 2. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl):14S-34S. 3. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(suppl):5S-12S. 4. Naeije R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2:20-22. 5. Presberg KW, Dincer HE. Pathophysiology of pulmonary hypertension due to lung disease. Curr Opin Pulm Med. 2003;9:131-138. 6. Kessler R, Faller M, Weitzenblum E, et al. “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164:219-224.

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