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, idio-
pathic pulmonary fibrosis, and pulmonary Langerhans cell histiocy-
tosis 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 vasoconstric-
tion 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 sus-
pected 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 func-
tional 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 pulmo-
nary fibrosis; PAP = pulmonary artery pressure; PH = pulmonary hyper-
tension; PLCH = pulmonary Langerhans cell histiocytosis
P ulmonary hypertension (PH) can occur as an isolated
phenomenon or in association with various cardiac,
pulmonary, and systemic disorders. Pulmonary hyperten-
sion is defined as mean pulmonary artery pressure (PAP)
that exceeds 25 mm Hg at rest or 30 mm Hg with exer-
cise.1-3 PAP may be elevated because of different mecha-
nisms, including obstruction to blood flow with an in-
crease in pulmonary vascular resistance, high flow state
with elevated cardiac output, or increases in intravascular
volume. Cor pulmonale and PH are well-known compli-
cations of advanced chronic obstructive pulmonary dis-
ease (COPD).4,5 In patients with COPD, resting PAP cor-
relates best with resting PaO2.5,6 Pulmonary hypertension
that occurs in patients with COPD is usually caused by
chronic hypoxic vasoconstriction and progressive pulmo-
nary vascular remodeling.4,5 Long-term oxygen therapy
342 Mayo Clin Proc. • March 2007;82(3):342-350
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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 complica-
tion 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 histiocy-
tosis, 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 bibliog-
raphies 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 hy-
pertension 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, man-
agement, 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 ex-
trapolating 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
• www.mayoclinicproceedings.com
 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 Unknown; up to 100% Intrinsic proliferative pulmonary vasculopathy, PH can be severe and can occur in the absence
cell histiocytosis in advanced disease vascular obstruction/destruction associated of advanced parenchymal destruction; PH
with parenchymal fibrosis, hypoxic increases mortality
vasoconstriction and remodeling
Connective tissue Unknown; 45% in Vasoconstriction and remodeling, vascular PH can occur alone or with ILD in patients
disease–related ILD scleroderma-ILD inflammation, in situ thrombosis, with connective tissue diseases
thromboembolism, diastolic dysfunction
Sarcoidosis 5.7%; up to 73.8% in Vascular obstruction/destruction associated PH is associated with lower pulmonary
advanced disease with parenchymal fibrosis, granulomatous function measurements and advanced
vasculopathy, extrinsic compression of large radiographic changes, but PH can be seen
pulmonary arteries by lymphadenopathy, in the absence of parenchymal fibrosis; PH
systolic or diastolic dysfunction increases mortality in patients awaiting lung
transplantation
Idiopathic pulmonary Up to 84% Vascular obstruction/destruction associated Systolic PAP correlates inversely with DLCO
fibrosis with parenchymal fibrosis, hypoxic measurement but not with spirometric values;
vasoconstriction and remodeling, possible PH increases mortality
intrinsic vasculopathy
Pneumoconioses Unknown Vascular obstruction/destruction associated PH tends to correlate with the severity of
with parenchymal fibrosis, hypoxic parenchymal abnormalities
vasoconstriction and remodeling
*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 nary hypertension can occur with or without ILD in pa-

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 cath-
eterization 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 his-
tiocytosis (also known as histiocytosis X, pulmonary
Langerhans granulomatosis, or eosinophilic granuloma of
the lung) is characterized by the proliferation and infiltra-
tion of organs by Langerhans cells.20-22 In adults, PLCH is
usually a smoking-related ILD.20-22 Pulmonary hyperten-
sion 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, lymphangioleiomyoma-
tosis, 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 devel-
opment of PH from PLCH.15 For example, there is a lack of
correlation between mean PAP (assessed by echocardiog-
raphy or cardiac catheterization) and the degree of spiro-
metric 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 pa-
tients with CTDs and are most often seen in scleroderma
and CREST syndrome (limited scleroderma).2,26-29 Pulmo-
tients with CTDs. In a study of 619 patients with sclero-
derma, 22.5% had evidence of ILD alone, 19.2% had iso-
lated PH (assessed by Doppler echocardiography), and
18.1% had both ILD and PH.30 A survey of community-
based rheumatology practices found that the prevalence of
PH (assessed by Doppler echocardiography) in sclero-
derma 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 hyper-
tension 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 trans-
plantation, 73.8% had PH (assessed by right heart catheter-
ization).35 In another study, PH in patients with sarcoidosis
was associated with a higher prevalence of stage 4 sarcoido-
sis (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 destruc-
tion 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 (de-
fined as estimated systolic PAP ≥40 mm Hg); a weak
negative correlation was found between systolic PAP and

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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
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 pneumo-
nia 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 under-
gone 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. How-
ever, 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 hy-
pertension can complicate the clinical course of patients
with pneumoconioses.44-46 Additionally, PH has been seen
in uranium miners with radiation-induced pulmonary fibro-
sis.47 A survey of Michigan hospital discharge data for the
years 1990 and 1991 found PH to be associated with asbes-
tosis, coal worker pneumoconiosis, silicosis, and unspeci-
fied pneumoconiosis.44 A hemodynamic study of subjects
with asbestosis showed that an increasing severity of pa-
renchymal opacities correlated with higher mean PAP.45
344 Mayo Clin Proc. • March 2007;82(3):342-350
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Exercise-induced PH was demonstrated in subjects with
silicosis, more commonly with complicated silicosis vs
simple silicosis.46
PATHOGENESIS
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 re-
sults from chronic hypoxic pulmonary vasoconstriction
and vascular remodeling.4,48,49 This vascular remodeling
involves all layers of the pulmonary arterial wall and in-
cludes intimal thickening and medial hypertrophy. How-
ever, 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 de-
struction associated with progressive parenchymal fibrosis,
vascular inflammation, perivascular fibrosis, and throm-
botic angiopathy.13,48-50
Interest in the role of pulmonary endothelial dysfunction
in PH has been increasing.5,49,51-54 The pulmonary endothe-
lial cell produces several important vasoactive mediators
(eg, nitric oxide, prostacyclin, and endothelin) that modu-
late pulmonary vasomotor tone, vascular smooth muscle
cell proliferation, and vascular remodeling.5,48,52,53 For ex-
ample, endothelin 1 is an endothelium-derived vasocon-
strictor that also acts as a mitogen of pulmonary vascular
smooth muscle cells and induces extracellular matrix for-
mation (profibrotic).5,48,52-58 Hypoxia increases plasma
endothelin 1 levels.5,48,54 The level of circulating endo-
thelin 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 impli-
cated 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-de-
rived 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 develop-
ment of PH among various ILDs. For example, Fartoukh et
al24 described a proliferative pulmonary vasculopathy in-
volving 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 corre-
lation 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 Cardiopul-
monary exercise testing has demonstrated that exercise
impairment correlates with pulmonary vascular dysfunc-
tion rather than abnormalities of ventilatory function and
gas exchange in patients with PLCH.64
Vascular inflammation, in situ thrombosis, and pulmo-
nary thromboembolism (due to underlying hypercoagu-
lable 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 (pul-
monary arteriopathy) may coexist with ILD and not neces-
sarily be related to parenchymal disease.67 Pulmonary hy-
pertension 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 na-
tive lungs of 5 transplant recipients with sarcoidosis that
consisted not only of granulomatous involvement of pul-
monary vessels (more commonly veins than arteries) but
also occlusive venopathy with intimal fibrosis and recan-
alization. Plexiform lesions were not present. Extrinsic
compression of large pulmonary arteries by mediastinal or
hilar lymphadenopathy may also play a role in the develop-
ment 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 pre-
dominant 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 ex-
ample, 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 coexist-
ing PH could easily be overlooked in patients with ILD.
Furthermore, the development of both PH and ILD is typi-
cally 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 swell-
ing, abdominal bloating and distention, anorexia, plethora,
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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
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, par-
ticularly if the severity of these symptoms seems to be
disproportionate to the parenchymal lung disease. Symp-
toms 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 pe-
ripheral pulmonary vasculature, and right ventricular en-
largement. These abnormalities may also be appreciated on
high-resolution computed tomographic scanning that is
usually needed for evaluation of the underlying parenchy-
mal 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% specific-
ity 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 ca-
pacity 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. Electro-
cardiography commonly reveals abnormalities of right-
axis 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 docu-
ment 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 im-
munodeficiency virus infection, drugs (eg, appetite suppres-
sants, 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. Over-
night oximetry is useful not only in the evaluation of pa-
tients 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 intersti-
tial changes on chest radiography, such as pulmonary
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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
TABLE 2. Management of Pulmonary Hypertension in
Interstitial Lung Disease
1. Treat underlying interstitial lung disease
2. Provide supplemental oxygen therapy when appropriate
3. Treat heart failure
4. Consider anticoagulant therapy
5. Consider vasomodulator therapy
6. Consider lung transplantation
veno-occlusive disease or pulmonary capillary hemangio-
matosis, 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. Dop-
pler echocardiography can estimate the level of systolic
PAP and assess the presence of associated abnormalities
such as right atrial enlargement, right ventricular enlarge-
ment, right or left ventricular dysfunction, intracardiac
shunt, valvular disease, and pericardial effusion.2,79 The
Doppler-derived right ventricular index of myocardial per-
formance 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 win-
dows. 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 ex-
ercise84 and can provide insight into exertional symptoms.
The noninvasive nature and ready availability of Doppler
echo-cardiography make this a valuable tool in serial stud-
ies 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 Vaso-
reactivity testing using a short-acting agent such as intrave-
nous 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 Mayo Clin Proc. • March 2007;82(3):342-350
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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 assess-
ment 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 broncho-
scopic 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 under-
lying ILD, or both (Table 2). Some of the vasomodulating
agents used in the treatment of pulmonary arterial hyper-
tension, 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 trans-
forming growth factor β, has been demonstrated to prevent
or reverse pulmonary fibrosis and pulmonary arterial hy-
pertension in animal models.90,91 Thus, an antiproliferative
strategy may have relevance to both vascular and paren-
chymal 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 re-
quire a surgical lung biopsy for histopathologic character-
ization.92 Treatment options commonly include corticoster-
oids and other immunosuppressive agents. For example,
corticosteroid therapy can improve PH in some patients
with sarcoidosis, even in the absence of parenchymal fibro-
sis.16,93,94 Interestingly, some patients with CTD-related
pulmonary arterial hypertension have responded to combi-
nation therapy with corticosteroids and cyclophospha-
mide.95 Treatment of ILDs caused by exogenous agents, eg,
cigarette smoking in patients with PLCH, obviously re-
quires cessation of further inhalational exposure. Aside
from the underlying ILD diagnosis, clinical context includ-
ing age of the patient, comorbidities, and extrapulmonary
manifestations should also be considered in making man-
agement decisions.
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Use of supplemental oxygen to maintain oxygen satura-
tion 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 pa-
tients with ILD-associated PH.86 Anticoagulants could be
useful in the prevention of venous thromboembolism or in
situ thrombosis in patients with underlying hypercoagu-
lable states, eg, antiphospholipid antibody, previous his-
tory of thromboembolism, prolonged bed rest, or other
predisposing risk factors for this complication. Recently,
Kubo et al96 reported that anticoagulant therapy was associ-
ated 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 hypocontractil-
ity, dilatation, and ultimately clinical right ventricular heart
failure, treatment of volume overload should be under-
taken. 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 inter-
venes. 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.
VASOMODULATING THERAPY
Therapy for PH is directed at relief of pulmonary vasocon-
striction 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 vasodi-
lator testing, but this issue needs further exploration.85,97
Using vasodilator therapy for patients with ILD has associ-
ated potential risks, as discussed subsequently. However,
as previously mentioned, vasomodulating therapy may also
have potential benefit in patients who do not respond to
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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
vasodilator testing at right heart catheterization via antipro-
liferative mechanisms in the pulmonary vasculature and
lung parenchyma.74,85
There is an increasing availability of drugs for treating
pulmonary arterial hypertension, including the nonselec-
tive endothelin A/B receptor antagonist bosentan; the pros-
tacyclin analogues epoprostenol, treprostinil, and iloprost;
and the phosphodiesterase-5 inhibitor sildenafil.56,74,85 Se-
lective 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 pharma-
cologic treatment because systemic vasodilator therapy
may be complicated by worsening hypoxemia due to in-
creased ventilation-perfusion mismatch. Administration of
intravenous prostacyclin has been associated with de-
creased arterial oxygen tension.99 However, inhaled nitric
oxide, inhaled iloprost, and oral sildenafil therapy de-
creased 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 ef-
fect 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 re-
sult in acute pulmonary edema and possibly death.104-106
Assessment of the patient’s response to therapy is essen-
tial. Outcome is gauged by assessing dyspnea, exertional
capacity, and quality of life as well as hemodynamic param-
eters measured by serial echocardiography or right heart
catheterization.74,85 Treatment of PH in ILD appears to im-
prove symptoms and may modulate the underlying paren-
chymal 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.
LUNG TRANSPLANTATION
Lung transplantation should be considered in patients with
severe or progressive impairment due to PH or ILD, par-
ticularly if pharmacologic agents fail to provide improve-
ment. Limited experience suggests that single lung trans-
plantation 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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PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
There have been conflicting reports on the effect of
secondary PH on the outcome after lung transplanta-
tion.25,108,110,112,113 Overall, the presence of PH does not ap-
pear 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 trans-
plantation 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 ex-
ample, 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 complica-
tion in patients with ILDs and may arise through multiple
mechanisms. The prevalence and clinical implications of
PH in patients with ILDs require further clarification. Al-
though 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 impair-
ment, morbidity, and mortality in these patients. Prelimi-
nary 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 hyper-
tension: 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.
348 Mayo Clin Proc. • March 2007;82(3):342-350
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
7. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal
oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial.
Ann Intern Med. 1980;93:391-398.
8. Report of the Medical Research Council Working Party. Long term
domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating
chronic bronchitis and emphysema. Lancet. 1981;1:681-686.
9. Ashutosh K, Mead G, Dunsky M. Early effects of oxygen admin-
istration and prognosis in chronic obstructive pulmonary disease and cor
pulmonale. Am Rev Respir Dis. 1983;127:399-404.
10. Timms RM, Khaja FU, Williams GW. Hemodynamic response to
oxygen therapy in chronic obstructive pulmonary disease. Ann Intern Med.
1985;102:29-36.
11. Maloney JP. Advances in the treatment of secondary pulmonary
hypertension. Curr Opin Pulm Med. 2003;9:139-143.
12. Shapiro S. Management of pulmonary hypertension resulting from
interstitial lung disease. Curr Opin Pulm Med. 2003;9:426-430.
13. Strange C, Highland KB. Pulmonary hypertension in interstitial lung
disease. Curr Opin Pulm Med. 2005;11:452-455.
14. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in
patients with idiopathic pulmonary fibrosis. Chest. 2005;128:2393-2399.
15. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and
clinical characteristics of pulmonary hypertension complicating pulmonary
Langerhans cell histiocytosis. Mayo Clin Proc. 2004;79:1269-1275.
16. Nunes H, Humbert M, Capron F, et al. Pulmonary hypertension
associated with sarcoidosis: mechanisms, haemodynamics and prognosis.
Thorax. 2006;61:68-74.
17. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM.
Predicting survival in idiopathic pulmonary fibrosis: scoring system and
survival model. Am J Respir Crit Care Med. 2001;164:1171-1181.
18. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with
sarcoidosis awaiting lung transplantation. Chest. 2002;122:233-238.
19. Leuchte HH, Baumgartner RA, Nounou ME, et al. Brain natriuretic
peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit
Care Med. 2006;173:744-750.
20. Vassallo R, Ryu JH. Pulmonary Langerhans’ cell histiocytosis. Clin
Chest Med. 2004;25:561-571.
21. Sundar KM, Gosselin MV, Chung HL, Cahill BC. Pulmonary
Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology,
and clinical evolution of disease. Chest. 2003;123:1673-1683.
22. Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell
granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases. Am J
Surg Pathol. 1993;17:971-986.
23. Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary
histiocytosis X is associated with severe pulmonary hypertension [letter].
Chest. 1997;111:1142-1144.
24. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hyper-
tension in histiocytosis X. Am J Respir Crit Care Med. 2000;161:216-223.
25. Harari S, Simonneau G, De Juli E, et al. Prognostic value of pulmonary
hypertension in patients with chronic interstitial lung disease referred for lung
or heart-lung transplantation. J Heart Lung Transplant. 1997;16:460-463.
26. Hoeper MM. Pulmonary hypertension in collagen vascular disease. Eur
Respir J. 2002;19:571-576.
27. Fagan KA, Badesch DB. Pulmonary hypertension associated with
connective tissue disease. Prog Cardiovasc Dis. 2002;45:225-234.
28. Rayner CF, Grubnic S. Pulmonary manifestations of systemic
autoimmune disease. Best Pract Res Clin Rheumatol. 2004;18:381-410.
29. Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary
hypertension in limited and diffuse scleroderma. Chest. 1996;110:1515-
1519.
30. Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with
combined pulmonary hypertension and interstitial lung disease. J Rheumatol.
2003;30:2398-2405.
31. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C.
The prevalence of undiagnosed pulmonary arterial hypertension in subjects
with connective tissue disease at the secondary health care level of community-
based rheumatologists (the UNCOVER study). Arthritis Rheum. 2005;52:2125-
2132.
32. Hesselstrand R, Ekman R, Eskilsson J, et al. Screening for pulmonary
hypertension in systemic sclerosis: the longitudinal development of tricuspid
gradient in 227 consecutive patients, 1992-2001. Rheumatology (Oxford).
2005;44:366-371.
33. Cox CE, Davis-Allen A, Judson MA. Sarcoidosis. Med Clin North Am.
2005;89:817-828.
• www.mayoclinicproceedings.com

34. Statement on sarcoidosis: this joint statement of the American Thoracic
Society (ATS), the European Respiratory Society (ERS) and the World
Association of Sarcoidosis and Other Granulomatous Disorders (WASOG)
was adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med. 1999;160:736-755.
35. Shorr AF, Helman DL, Davies DB, Nathan SD. Pulmonary hyperten-
sion in advanced sarcoidosis: epidemiology and clinical characteristics. Eur
Respir J. 2005;25:783-788.
36. Sulica R, Teirstein AS, Kakarla S, Nemani N, Behnegar A, Padilla ML.
Distinctive clinical, radiographic, and functional characteristics of patients
with sarcoidosis-related pulmonary hypertension. Chest. 2005;128:1483-1489.
37. Rizzato G, Pezzano A, Sala G, et al. Right heart impairment in sarcoi-
dosis: haemodynamic and echocardiographic study. Eur J Respir Dis. 1983;64:
121-128.
38. Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and
its clinical relevance in patients with sarcoidosis. Chest. 2006;129:1246-1252.
39. Ryu JH, Colby TV, Hartman TE. Idiopathic pulmonary fibrosis: current
concepts. Mayo Clin Proc. 1998;73:1085-1101.
40. Idiopathic pulmonary fibrosis: diagnosis and treatment: international
consensus statement: this joint statement of the American Thoracic Society
(ATS) and the European Respiratory Society (ERS) was adopted by the ATS
Board of Directors, July 1999 and by the ERS Executive Committee, October
1999. Am J Respir Crit Care Med. 2000;161:646-664.
41. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J
Med. 2001;345:517-525.
42. Leuchte HH, Neurohr C, Baumgartner R, et al. Brain natriuretic peptide
and exercise capacity in lung fibrosis and pulmonary hypertension. Am J
Respir Crit Care Med. 2004;170:360-365.
43. Glazer CS, Newman LS. Occupational interstitial lung disease. Clin
Chest Med. 2004;25:467-478.
44. Rosenman KD, Zhu Z. Pneumoconiosis and associated medical
conditions. Am J Ind Med. 1995;27:107-113.
45. Tomasini M, Chiappino G. Hemodynamics of pulmonary circulation in
asbestosis: study of 16 cases. Am J Ind Med. 1981;2:167-174.
46. Scano G, Garcia-Herreros P, Stendardi D, Degre S, De Coster A,
Sergysels R. Cardiopulmonary adaptation to exercise in coal miners. Arch
Environ Health. 1980;35:360-366.
47. Archer VE, Renzetti AD, Doggett RS, Jarvis JQ, Colby TV. Chronic
diffuse interstitial fibrosis of the lung in uranium miners. J Occup Environ
Med. 1998;40:460-474.
48. Hopkins N, McLoughlin P. The structural basis of pulmonary hyper-
tension in chronic lung disease: remodelling, rarefaction or angiogenesis? J
Anat. 2002;201:335-348.
49. Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM,
Voelkel NF. The pathobiology of pulmonary hypertension: endothelium. Clin
Chest Med. 2001;22:405-418.
50. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of
vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(suppl):
25S-32S.
51. Cella G, Bellotto F, Tona F, et al. Plasma markers of endothelial
dysfunction in pulmonary hypertension. Chest. 2001;120:1226-1230.
52. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in
pulmonary hypertension. Circulation. 2004;109:159-165.
53. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular
pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;
43(suppl):13S-24S.
54. Galie N, Manes A, Branzi A. The endothelin system in pulmonary
arterial hypertension. Cardiovasc Res. 2004;61:227-237.
55. MacLean MR. Endothelin-1 and serotonin: mediators of primary and
secondary pulmonary hypertension? J Lab Clin Med. 1999;134:105-114.
56. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin
receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol.
2004;43(suppl):62S-67S.
57. Kirchengast M, Luz M. Endothelin receptor antagonists: clinical
realities and future directions. J Cardiovasc Pharmacol. 2005;45:182-191.
58. Braun-Moscovici Y, Nahir AM, Balbir-Gurman A. Endothelin and
pulmonary arterial hypertension. Semin Arthritis Rheum. 2004;34:442-453.
59. Trakada G, Nikolaou E, Pouli A, Tsiamita M, Spiropoulos K. Endo-
thelin-1 levels in interstitial lung disease patients during sleep. Sleep Breath.
2003;7:111-118.
60. Yamakami T, Taguchi O, Gabazza EC, et al. Arterial endothelin-1 level
in pulmonary emphysema and interstitial lung disease: relation with pulmonary
hypertension during exercise. Eur Respir J. 1997;10:2055-2060.
Mayo Clin Proc. • March 2007;82(3):342-350
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
61. Rabinovitch M. The mouse through the looking glass: a new door into
the pathophysiology of pulmonary hypertension. Circ Res. 2004;94:1001-
1004.
62. Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin
Invest. 2005;115:2691-2694.
63. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension.
Circulation. 2006;114:1417-1431.
64. Crausman RS, Jennings CA, Tuder RM, Ackerson LM, Irvin CG, King
TE Jr. Pulmonary histiocytosis X: pulmonary function and exercise patho-
physiology. Am J Respir Crit Care Med. 1996;153:426-435.
65. Yousem SA. The pulmonary pathologic manifestations of the CREST
syndrome. Hum Pathol. 1990;21:467-474.
66. Tuder RM, Lee SD, Cool CC. Histopathology of pulmonary hyper-
tension. Chest. 1998;114(suppl):1S-6S.
67. Galie N, Manes A, Farahani KV, et al. Pulmonary arterial hypertension
associated to connective tissue diseases. Lupus. 2005;14:713-717.
68. Judd PA, Finnegan P, Curran RC. Pulmonary sarcoidosis: a clinico-
pathological study. J Pathol. 1975;115:191-198.
69. Smith LJ, Lawrence JB, Katzenstein AA. Vascular sarcoidosis: a rare
cause of pulmonary hypertension. Am J Med Sci. 1983;285:38-44.
70. Damuth TE, Bower JS, Cho K, Dantzker DR. Major pulmonary artery
stenosis causing pulmonary hypertension in sarcoidosis. Chest. 1980;78:888-
891.
71. Hennebicque AS, Nunes H, Brillet PY, Moulahi H, Valeyre D, Brauner
MW. CT findings in severe thoracic sarcoidosis. Eur Radiol. 2005;15:23-
30.
72. Bargout R, Kelly RF. Sarcoid heart disease: clinical course and
treatment. Int J Cardiol. 2004;97:173-182.
73. Gagermeier J, Dauber J, Yousem S, Gibson K, Kaminski N. Abnormal
vascular phenotypes in patients with idiopathic pulmonary fibrosis and
secondary pulmonary hypertension. Chest. 2005;128(suppl):601S.
74. Rubin LJ, Badesch DB. Evaluation and management of the patient with
pulmonary arterial hypertension. Ann Intern Med. 2005;143:282-292.
75. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential
assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;
43(suppl):40S-47S.
76. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J
Respir Crit Care Med. 2000;162:1964-1973.
77. Almagro P, Julia J, Sanjaume M, et al. Pulmonary capillary hemangio-
matosis associated with primary pulmonary hypertension: report of 2 new
cases and review of 35 cases from the literature. Medicine (Baltimore). 2002;
81:417-424.
78. Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW,
Medical College of Wisconsin Lung Transplant Group. Utility of CT scan
evaluation for predicting pulmonary hypertension in patients with
parenchymal lung disease. Chest. 1998;113:1250-1256.
79. Bossone E, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hyper-
tension: the key role of echocardiography. Chest. 2005;127:1836-1843.
80. Tei C, Dujardin KS, Hodge DO, et al. Doppler echocardiographic index
for assessment of global right ventricular function. J Am Soc Echocardiogr.
1996;9:838-847.
81. Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB.
Value of a Doppler-derived index combining systolic and diastolic time
intervals in predicting outcome in primary pulmonary hypertension. Am J
Cardiol. 1998;81:1157-1161.
82. Currie PJ, Seward JB, Chan KL, et al. Continuous wave Doppler
determination of right ventricular pressure: a simultaneous Doppler-cathe-
terization study in 127 patients. J Am Coll Cardiol. 1985;6:750-756.
83. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic
assessment of pulmonary hypertension in patients with advanced lung disease.
Am J Respir Crit Care Med. 2003;167:735-740.
84. Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery
pressure response in asymptomatic carriers of primary pulmonary hyper-
tension gene. Circulation. 2000;102:1145-1150.
85. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for
pulmonary arterial hypertension: ACCP evidence-based clinical practice
guidelines. Chest. 2004;126(suppl):35S-62S.
86. Wahidi MM, Rocha AT, Hollingsworth JW, Govert JA, Feller-Kopman
D, Ernst A. Contraindications and safety of transbronchial lung biopsy via
flexible bronchoscopy: a survey of pulmonologists and review of the literature.
Respiration. 2005;72:285-295.
87. Vassallo R, Thomas CF. Advances in the treatment of rheumatic
interstitial lung disease. Curr Opin Rheumatol. 2004;16:186-191.
• www.mayoclinicproceedings.com 349
PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASES
88. Brown KK, Raghu G. Medical treatment for pulmonary fibrosis: current
trends, concepts, and prospects. Clin Chest Med. 2004;25:759-772.
89. Hocher B, Schwarz A, Fagan KA, et al. Pulmonary fibrosis and chronic
lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol.
2000;23:19-26.
90. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental
pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811-
2821.
91. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the
profibrogenic activity of TGF-β and prevents bleomycin-mediated lung
fibrosis. J Clin Invest. 2004;114:1308-1316.
92. Ryu JH, Olson EJ, Midthun DE, Swensen SJ. Diagnostic approach to
the patient with diffuse lung disease. Mayo Clin Proc. 2002;77:1221-1227.
93. Rodman DM, Lindenfeld J. Successful treatment of sarcoidosis-
associated pulmonary hypertension with corticosteroids. Chest. 1990;97:500-
502.
94. Gluskowski J, Hawrylkiewicz I, Zych D, Zielinski J. Effects of
corticosteroid treatment on pulmonary haemodynamics in patients with
sarcoidosis. Eur Respir J. 1990;3:403-407.
95. Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immuno-
suppressive therapy in connective tissue diseases-associated pulmonary
arterial hypertension. Chest. 2006;130:182-189.
96. Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for
idiopathic pulmonary fibrosis. Chest. 2005;128:1475-1482.
97. Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with
prostacyclin in primary and secondary pulmonary hypertension. Chest.
1989;96:784-789.
98. Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin
and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J
Respir Crit Care Med. 1999;160:600-607.
99. Strange C, Bolster M, Mazur J, Taylor M, Gossage JR, Silver R.
Hemodynamic effects of epoprostenol in patients with systemic sclerosis and
pulmonary hypertension. Chest. 2000;118:1077-1082.
100. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of
lung fibrosis and pulmonary hypertension: a randomised controlled trial.
Lancet. 2002;360:895-900.
101. Yung GL, Kriett JM, Jamieson SW, et al. Outpatient inhaled nitric oxide
in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation.
J Heart Lung Transplant. 2001;20:1224-1227.
350 Mayo Clin Proc. • March 2007;82(3):342-350
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
102. Fisher KA, Serlin DM, Wilson KC, Walter RE, Berman JS, Farber HW.
Sarcoidosis-associated pulmonary hypertension: outcome with long-term
epoprostenol treatment. Chest. 2006;130:1481-1488.
103. Hamada K, Teramoto S, Narita N, Yamada E, Teramoto K, Kobzik L.
Pulmonary veno-occlusive disease in pulmonary Langerhans’ cell granuloma-
tosis. Eur Respir J. 2000;15:421-423.
104. Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary
capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann
Intern Med. 1988;109:106-109.
105. Dufour B, Maitre S, Humbert M, Capron F, Simonneau G, Musset D.
High-resolution CT of the chest in four patients with pulmonary capillary
hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol.
1998;171:1321-1324.
106. Palmer SM, Robinson LJ, Wang A, Gossage JR, Bashore T, Tapson VF.
Massive pulmonary edema and death after prostacyclin infusion in a patient
with pulmonary veno-occlusive disease. Chest. 1998;113:237-240.
107. Alalawi R, Whelan T, Bajwa RS, Hodges TN. Lung transplantation and
interstitial lung disease. Curr Opin Pulm Med. 2005;11:461-466.
108. Huerd SS, Hodges TN, Grover FL, et al. Secondary pulmonary
hypertension does not adversely affect outcome after single lung trans-
plantation. J Thorac Cardiovasc Surg. 2000;119:458-465.
109. Conte JV, Borja MJ, Patel CB, Yang SC, Jhaveri RM, Orens JB. Lung
transplantation for primary and secondary pulmonary hypertension. Ann
Thorac Surg. 2001;72:1673-1679.
110. Fitton TP, Kosowski TR, Barreiro CJ, et al. Impact of secondary pul-
monary hypertension on lung transplant outcome. J Heart Lung Transplant.
2005;24:1254-1259.
111. Lu BS, Bhorade SM. Lung transplantation for interstitial lung disease.
Clin Chest Med. 2004;25:773-782.
112. Bando K, Keenan RJ, Paradis IL, et al. Impact of pulmonary
hypertension on outcome after single-lung transplantation. Ann Thorac Surg.
1994;58:1336-1342.
113. Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative
pulmonary artery pressure on early survival after lung transplantation
for idiopathic pulmonary fibrosis. J Heart Lung Transplant. 2005;24:1269-
1274.
114. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of
pulmonary arterial hypertension: ACCP evidence-based clinical practice
guidelines. Chest. 2004;126(suppl):78S-92S.
• www.mayoclinicproceedings.com