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PNEUMOTRIESTE 2011
Pulmonary hypertension and diffuse parenchymal diseases:
therapeutic options
Carlo Albera
Università di Torino
Facoltà di Medicina e Chirurgia San Luigi Gonzaga
Dipartimento di Scienze Cliniche e Biologiche
Ambulatorio Interstiziopatie Polmonari / Malattie Rare
Pulmonary hypertension and diffuse parenchymal diseases:
therapeutic options
To date no approved drugs
Thank you for your attention
Clinical Classification of Pulmonary Hypertension
(Dana Point 2008)
1. Pulmonary Arterial Hypertension
1.1 Idiopatic
1.2 Heritable
1.2.1 BMPR2
1.2.2 ALK1, endoglin (+ / - hereditary haemorrhaigc
teleangectasia)
1.2.3 Unknown
1.3 Drugs and toxins induced
1.4 Associated with (APAH)
1.4.1 Connective Tissue Diseases
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.4.6 Chronic haemolityc anaemia
1.5 Persistent PH of the newborn
1’. PVOD and/or Pulm capill Haemang.
2. PH due to left heart disease
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular diseases
3. PH due to lung dis/hypoxiaemia
3.1 COPD
3.2 ILD
3.3 Other pulmonary diseases with mixed
restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormabilities
4. Chronic thromboembolic PH
5. PH with unclear and/or multifact mechs
5.1 Haematological dis: myieloproliferative,
splenectomy
5.2 Systemic diseases: sarcoidosis, pulmonary
Langerhans cell histiocytosis,
lymphangioleiomyomatosis
5.3 Metabolic dis: glycogen storage disease.
Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing
mediastinitis, CRF on dialysis
Diffuse Parenchymal Lung Disease
DPLD of known
cause or
association
Idiopathic
interstitial
pneumonias
Idiopathic
pulmonary
fibrosis
Granulomatous
Other forms of IP
e.g. LAM, PLCH,
eosinophilic pneumonia,
etc.
IP other than
idiopathic
pulmonary fibrosis
Desquamative interstitial
pneumonia
Acute interstitial
pneumonia
Non-specific interstitial
pneumonia
Respiratory bronchiolitis
interstitial lung disease
Cryptogenic
organising pneumonia
Lymphocytic
interstitial pneumonia
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonia
AJRCCM 2002; 165: 277-304
Pulmonary hypertension and
ILDs
What from guidelines ?
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Treatment of selected complications and comorbid
conditions
There is an increasing awareness of complications and
comorbid conditions frequently associated with IPF.
These include acute exacerbation of IPF, pulmonary
hypertension, gastroesophageal reflux disease, obesity,
emphysema, and obstructive sleep apnea.
It is unknown if treating these comorbidities influences
clinical outcomes.
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Question:
Should pulmonary hypertension be treated in patients with IPF ? (1)
Recommendation:
Pulmonary hypertension should not be treated in the majority of
patients with IPF, but treatment may be a reasonable choice in a
minority (weak recommendation, very low-quality evidence).
Values:
This recommendation places a high value on cost and the potential
for drug-related morbidity, and a low value on very low-quality
data suggesting a possible benefit in selected patients.
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Question:
Should pulmonary hypertension be treated in patients with IPF ? (2)
Remarks:
In patients with moderate to severe pulmonary hypertension
documented by right heart catheterization (i.e., mPAP ≥ 35 mm
Hg), in line with the interpretation of a weak recommendation, a
trial of vasomodulatory therapy may be indicated.
The committee recognizes the need for clinical trials of
vasomodulatory therapies in this patient population.
(Vote: 8 for use, 14 against use, 1 abstention, 8 absent.)
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Monitoring for Complications and Comorbidities:
Comorbidities including pulmonary hypertension,
pulmonary embolism, lung cancer, and coronary artery
disease are known to occur in IPF.
While the development of these comorbidities may
influence survival, the role of routine screening to
identify such complications in patients with IPF is
unknown. (???)
Thus, a recommendation for routine screening cannot be
made
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Monitoring for Complications and Comorbidities:
pulmonary hypertension (1)
In patients demonstrating progressive disease, the
identification of PH may impact consideration for lung
transplantation in eligible patients, and evaluation is
indicated.
Echocardiography is inaccurate in estimating pulmonary
hemodynamics in patients with fibrotic lung disease and
should not be relied upon to assess the presence and
severity of pulmonary hypertension.
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
Monitoring for Complications and Comorbidities:
pulmonary hypertension (2)
BNP levels have been shown to correlate with the
presence of moderate to severe PH, but have not been
validated as a screening tool
At the present time, right heart catheterization is
required to confirm the presence of PH.
ATS/ERS/JRS/ALAT EBM GUIDELINES Am J Respir Crit Care Med 183, 788–824, 2011
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
In COPD the presence of PH is associated with
shorter survival and frequent episodes of exacerbation.
In interstitial lung diseases PH is a poor prognostic
factor and PAP is the most important predictor of
mortality.
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Diagnosis
echocardiography is the best screening tool for the
assessment of PH.
its diagnostic value in advanced respiratory diseases is
lower than in PAH
Echocardiographic estimation of PAPs l ILDs may be
inaccurate.
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Diagnosis
The specificity of systolic PAP in detecting PH is low
The negative predictive value is acceptable.
Indications for echocardiography for the screening of
PH in COPD and ILDs are:
(i) exclusion of significant PH
(ii) evaluation of concomitant left heart disease;
(iii)selection of patients for RHC
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Diagnosis
A definite diagnosis of PH relies on measurements at RHC.
The indication for RHC in advanced lung disease are:
(i)proper diagnosis of PH incandidates for surgical treatments
(transplantation, lung volume reduction);
(ii)suspected ‘out of proportion’ PH potentially amenable to be
enrolled in RCT with specific PAH drug therapy;
(iii) frequent episodes of RV failure;
(iv) inconclusive echocardiographic study in cases with a high
level of suspicion
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Therapy
Currently there is no specific therapy for PH associated with
COPD or interstitial lung diseases.
Long-term O2 administration has been shown partially toreduce
the progression of PH in COPD.
Nevertheless, with this treatment PAP rarely returns to normal
values and the structural abnormalities of pulmonary vessels
remain unaltered.
In interstitial lung diseases, the role of long-term O2 therapy in
PH progression is less clear.
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Therapy
Treatment with conventional vasodilators is not recommended
because they may impair gas exchange due to:
•the inhibition of hypoxic pulmonary vasoconstriction
•lack of efficacy after long-term use.
Published experience with specific PAH drug therapy is scarce
and consists of the assessment of acute effects and
uncontrolled studies in small series.
European Heart Journal (2009) 30, 2493–2537
PH due to lung diseases and/or hypoxaemia (group 3)
Therapy
The treatment of choice for patients with COPD or interstitial lung
diseases and associated PH who are hypoxaemic is long-term O2
therapy.
Patients with ‘out of proportion’ PH due to lung diseases (dyspnoea
insufficiently explained by lung mechanical disturbances and mPAP
>40-45mmHg at rest) should be referred to expert centres and
enrolled in clinical trials targeting PAH-specific drug therapy.
The use of targeted PAH therapy in patients with COPD or interstitial
lung diseases and mean PAP <40 mmHg is currently discouraged
because there are no systematic data regarding its safety or efficacy.
European Heart Journal (2009) 30, 2493–2537
Recommendations for PH due to lung diseases
Statement
Class (a)
Level (b)
TTE is recommended as screening tool for the assessement of PH
due to lung diseases
I
C
RHC is recommended for a definite diagnosis of PH due to lung
diseases
I
C
The optimal treatment of the underlying lung disease including long- I
term O2 therapy in patients with chronic hypoxaemia is
recommended in patients with PH due to lung diseases
C
Patients with ‘out of proportion’ PH due to lung diseases should be
enrolled in RCTs targeting PAH-specific drugs
IIa
C
The use of PAH-specific drug therapy is not recommended in
patients with PH due to lung diseases
III
C
a) Class of recommendation.
b) Level of evidence.
European Heart Journal (2009) 30, 2493–2537
Take home message from guidelines
Actually there are no EBM-supported therapeutic options
for the treatment of PH associated to ILDs
The therapy of ILDs is probably the best way to prevent/delay
the development of associated PH
Effective antifibrotic drug(s) may offer in the next future some
new chances
The treatment of ILDs-associated PH represent a still unmet
medical need
ILDs- associated PH if “Out proportion” may be considered and
managed in a different way
Some additional data on ILDs and PH
Report 2010 Registro Malattie Rare Regione Piemonte/Val d’Aosta
www.malattierarepiemonte.it
PATOLOGIA
N° Casi totali
N° Centri
39
8
San Luigi
Molinette
6 altri Centri
16
15
8
Sarcoidosi
cronica
ed
extrapolmonare
242
16
San Luigi
Molinette
14 altri centri
133
27
82
IPF
210
10
San Luigi
Molinette
8 altri centri
142
42
26
iPAH
Centro e N° Casi
Dana Point Group III
Dana Point Group V
Nathan SD Int J Clin Pract.20081742-1241
Diffuse Parenchymal Lung Disease
Idiopathic
interstitial
pneumonias
Idiopathic
pulmonary
fibrosis
Granulomatous
SARCOIDOSIS
Other forms of IP
e.g. LAM, PLCH,
eosinophilic pneumonia,
etc.
IP other than
idiopathic
pulmonary fibrosis
Non-specific interstitial
pneumonia
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonia
AJRCCM 2002; 165: 277-304
Pulmonary Hypertension and
Sarcoidosis
Dana Point group 5
5. PH with unclear and/or multifact mechs
5.1 Haematological dis: myieloproliferative, splenectomy
5.2 Systemic diseases: sarcoidosis, pulmonary
Langerhans cell histiocytosis,
lymphangioleiomyomatosis
5.3 Metabolic dis: glycogen storage disease. Gaucher
disease, thyroid disorders
5.4Others: tumoral obstruction, fibrosing mediastinitis,
CRF on dialysis
 Prospective, observational study
 246 consecutive sarcoidosis patients
 PH defined as estimated sPAP > 40 mm Hg
 212 patients evaluated for sPAP
 12 patients (5.7%) had PH.
 Decreased lung volume increases the risk of PH
developing in patients with sarcoidosis.
Handa,T et al. CHEST 2006; 129:1246–1252
Arthritis Research & Therapy 2007, 9(Suppl 2):S8
Endothelin-1 levels in BAL fluid
Endothelin-1 / albumin levels in
bronchoalveolar lavage fluid (BAL) fluid
in sarcoid patients and healthy controls.
Arthritis Research & Therapy 2007, 9(Suppl 2):S8
Suspected if:
•unexplained dyspnoea in sarcoidosis
•worsening dyspnoea in steroid-refractory sarcoidosis
Pathogenetic mechanism of PH in sarcoidosis appears
to be multifactorial:
•direct compression of the pulmonary arteries
•fibrotic destruction of the lung vasculature
•hypoxia and a pulmonary vasculopathy
•vasculitis
•veno-occlusive PH (ECHO vs RHC !!!)
Arthritis Research & Therapy 2007, 9(Suppl 2):S8
Pulmonary Hypertension and
Idiopathic Pulmonary Fibrosis (IPF)
Dana Point group 3
3.PH due to lung dis/hypoxemia
3.1 COPD
3.2 ILD
3.3 Other pulmonary diseases with mixed
restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormabilities
Pulmonary Hypertension in IPF
•Pathogenesis
•Prevalence, detection, diagnosis
•Course and significance
•Therapy
Pulmonary Hypertension in IPF
•Pathogenesis
•Prevalence, detection, diagnosis
•Course and significance
•Therapy
Pathogenesis of PAH
IPF- associated PH
Hypoxia
Local milieu (cytokines,chemokines, growth factors,etc) → fibrosis
Genetic predisposition
Risk factors and
Loss
of
capillary
and/or
angiogenesis,
in situconditions
thrombosis
(mutations BMPR-2, ALK-1,
associated
5HT polymorphism, NOS)
(e.g. HIV, anorexigens)
PULMONARY VASCULAR INJURY
Matrix, platelets,
inflammatory cells
Endothelial
cells
Smooth muscle
cells
Vasoconstriction – proliferation
inflammation – thrombosis
Pulmonary vascular disease
Clinical syndrome of PAH
BMPR-2: bone morphogenetic protein
receptor type 2; ALK-1: activin receptorlike kinase 1; 5HT: 5-hydroxytryptamine
or seratonin; NOS: nitric oxide synthase
1. Adapted from Gaine S JAMA 2000; 284: 3160–3168
(n 376)
(n 376)
bronchiole-vascular
bundle in
in aanlobule
area
medial +medial
intimalthickening
thickening +elastic tissue
Pulmonary
artery/arteriole
marked
PH
in
IPF
shares
pathologic
features
of
hypoxia-induced
Pulmonary
artery
branch inlung
an area
of
Medial thickening and significant intimal
ofrelatively
relatively
nonfibrotic
tissue
duplication
of
nonfibrotic
lung tissue.
dense
fibrosis.
proliferation.
.
PH
but
also demonstrates marked
intimal changes, which
likely reflect a local and systemic cytokine effect.
Patel N et al CHEST 2007; 132:998–1006
Pulmonary Hypertension in IPF
•Pathogenesis
•Prevalence, detection, diagnosis
•Course and significance
•Therapy
Author, year
# Pts
Disease
Diagn PH
Cut off
PH Prevalence
Hassan
2005
Retrosp
’94-’96
88
UIP
ATS/biopsy
(first visit)
TTE
PAPs > 35
mmHg
84 %
Gagermeier
2005
Retrosp
117
UIP
biopsy
TTE
RVsP > 30
mmHg
40 %
17%(# 20) > 45 mmHg
Lettieri
2006
Retrosp
’98-’04
79
UIP
ATS+biopsy
RHC
PAPm> 25
mmHg
31 %
29% vs 6%
1y mortality
Nathan
2007
Retrosp
‘97-’05
118
UIP
73% SLB
RHC
PAPm> 25
mmHg
40.7 %
Swanson
2008
Prospec
‘04-’05
92
UIP
ATS+biopsy
TTE
RVsP > 40
mmHg
53 %
31% (# 27) > 50 mmHg
Median surv 0.7 y
Vs
Median surv 4 y
40 / 53 underwent RHC
In 75% RHC confirmed ECHO
12% nn ; 13% Venous PH
Diagnosis of P(A)H: a four-stage process
1. Suspicion of
pulmonary
hypertension
2. Detection of
pulmonary
hypertension
• Symptoms and
physical examination
• Electrocardiogram
• Screening procedures
• Chest radiograph
• Incidental findings
• Transthoracic Doppler
echocardiography
3. Pulmonary
hypertension
class
identification
• Pulmonary function tests
and arterial blood gases
• Ventilation/perfusion
lung scan
• High-resolution CT
• Spiral CT
Nt-pro BNP
• Pulmonary angiography
Angio-RMN
Galiè N et al Eur Heart J 2004; 25: 2243–2278
4. Pulmonary
arterial
hypertension
evaluation
• Type (blood tests and
immunology, HIV test,
abdominal ultrasound)
• Exercise capacity (6MWD,
peak oxygen consumption)
• Haemodynamics (RHC)
Pulmonary Hypertension in IPF
•Pathogenesis
•Prevalence, detection, diagnosis
•Course and significance
•Therapy
PAH associata a sclerodermia: curve di
sopravvivenza
% di sopravvivenza
100
Nessun coinvolgimento degli
organi interni (es. cuore)
(n = 138)
80
60
Coinvolgimento polmonare
(senza PAH) n = 73)
40
20
0
PAH associata a sclerodermia (n = 17)
0
2
Koh et al. Br J Rheumatol 1996;35:989-993
4
6
8
10
Anni dalla diagnosi di PAH
12
5-year survival rates of patients with IPF
grouped by mPAP
mPAP <17 mm Hg
mPAP ≥ 17 mm Hg
Hamada K et al CHEST 2007; 131:650–656
Comparison of the survival curves between the patients with sPAP
≥40 mmHg and those with sPAP < 40 mmHg.
Song JW et al Respiratory Medicine (2009) 103, 180 186
Comparison of the survival curves of subjects
stratified to their sPAP and BNP levels.
Group 1:
sPAP < 40 mmHg and BNP ratio < 1.
Group 2:
sPAP ≥40 mmHg or BNP ratio ≥ 1.
Group 3:
sPAP ≥ 40 mmHg and BNP ratio ≥ 1
Song JW et al Respiratory Medicine (2009) 103, 180 186
Reanalysis of 376 patients listed for lung
transplantation in the UNOS registry from 2004 to
2005 who underwent catheterization.
28% had PH with PCWP ≤ 15 mm Hg (median mPAP,
31 mm Hg)
CHEST 2007; 132:998–1006
PH is present in 20%
to
40%
of
patients
with
IPF
(n 376)
who are evaluated for lung transplantation.
DlCO% and other indicators of gas diffusion
abnormality are predictive of PH in IPF more than other
measures of lung function.
Patel N et al CHEST 2007; 132:998–1006
110 IPF patients wer evaluated.
The prevalence of emphysema in the IPF cohort was 28%
Pulmonary arterial hypertension (PAH) was evaluated with TTE
and defined by an eSPAP > 45 mmHg
All IPF patients with emphysema showed PAH
IPF with emphysema was highly associated with severe PAH
(eSPAP: 82.3 ± 20.2 mmHg versus 56.7± 15.3 mmHg, p < 0.0001).
Chest; Prepublished online February 18, 2009;
Rossato Silva D et al J Bras Pneumol. 2008;34(10):779-786
eSPAP (mmHg) 56.7 ― 15.3
eSPAP (mmHg) 82.3 ―20.2
Chest; Prepublished online February 18, 2009;
“Out of proportion” PH in IPF
Advanced PH in the presence of underlying lung disease
of less severity raises the possibility of a primary
vasculopathy
that
is
at
least
partly
independent from the underlying parenchymal
process. (Girgis, Clin Chest Med, 2007)
Based on analogy to primary pulmonary hypertension, more
specific interventions aiming at the restoration of
endothelial vasoconstrictor-dilator imbalance could be
undertaken.
Randomized controlled trials of oral therapy endothelin
receptor blockers and phosphodiesterase 5 inhibitors are
being considered. (Naeije, Proc Am Thorac Soc, 2005)
Pulmonary Hypertension in IPF
•Pathogenesis
•Prevalence, detection,diagnosis
•Course and significance
•Therapy
Treatment of ph in the context of ILD : A still unmet need
The primary treatment approach is directed to control the
underlying ILD Do we have any active drug for IPF ?
Treatment recommendations for patients with PH have
only been established for PAH patients, which refers to Group
I patients of the Dana Point classification
No clear evidence of that the same approach may be useful in
all cases of ILD-associatedOff
PH label drugs:careful and limited use !!
ECHO
and
to be
included
inILD
the isdiagnostic
workout
Screening
for
PHRHC
in each
patient
with
mandatory
and follow-up in IPF ?
RCS are needed
RCS : in progress; study design: end-points !!
CHEST 2006; 130:182–189
Immunosuppressive Therapy in
Connective Tissue Diseases-Associated PAH
 No patients with SSC associated PAH did respond
 PAH associated with SLE or MCTD might respond to
a treatment combining glucocorticosteroids and
cyclophosphamide.
CHEST 2006; 130:182–189
57
Work in progress
ARTEMIS-PH - Study of Ambrisentan in Subjects With
Pulmonary Hypertension Associated With Idiopathic
Pulmonary Fibrosis (Phase III)
This study will compare the efficacy and safety of
ambrisentan to placebo in subjects with pulmonary
hypertension associated with idiopathic pulmonary
fibrosis.
Double Blind, Randomized Trial of Bosentan for Sarcoidosis
Associated Pulmonary Hypertension (BOSAPAH) (Phase II-III)
Patients with advanced sarcoidosis often develop pulmonary
hypertension.
The purpose of this study is to determine if bosentan
(Tracleer) will help sarcoidosis associated pulmonary
hypertension.
Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary
Fibrosis And Treatment With Sildenafil (Phase IV)
•Pulmonary Arterial Hypertension (PAH) in the setting of Idiopathic
Pulmonary Fibrosis(IPF)is a risk factor for morbidity and mortality in the
peri-lung transplant(LT) setting.
•Currently there is no significant data to support the use of pulmonary
vasodilators for PAH in the setting of interstitial lung disease such as IPF.
•The majority of IPF patients have PAH either at rest or during exercise.
•The study hypothesis is that sildenafil may improve morbidity and mortality
in the peri-LT setting in both IPF cohorts with either resting or exercise
PAH.
A controlled trial of sildenafil in advanced IPF
80 patients enrolled in the study.
Primary outcome :
•proportion of patients with an increase in the 6-minute walk distance
of 20% or more.
Key secondary outcomes:
•changes in oxygenation
•degree of dyspnea
•quality of life
The difference in the primary outcome was not significant
Zisman DA, et al N Engl J Med. 2010 12;363(7):620-8.
There were small but significant differences in key secondary
endpoints:
arterial oxygenation
DlCO
degree of dyspnea
quality of life
favoring the sildenafil group.
Serious adverse events were similar in the two study groups.
This study did not show a benefit for sildenafil for the primary
outcome.
The presence of some positive secondary outcomes creates
clinical equipoise for further research.
Zisman DA, et al N Engl J Med. 2010 12;363(7):620-8.
Treprostinil Therapy For Patients With Interstitial Lung Disease
And Severe Pulmonary Arterial Hypertension (Phase III)
Using Either Intravenous (IV) or Subcutaneous (SQ)
Treprostinil to Treat Pulmonary Hypertension Related to
Underlying Interstitial Lung Disease
The hypothesis is that IV or SQ Treprostinil can improve 6
minute walk distance, hemodynamics and quality of life in
patients with interstitial lung disease and severe secondary
pulmonary arterial hypertension.
Summary and conclusions (1)
Prognostic significance of PH in IPF could be considerd as a
background to introduce PH evaulation in diagnosis /follow-up of
patients with IPF
Both screening and diagnosing for PH patients with IPF should be
included among procedures used to manage selected ILDs in daily
practice
Many measures of ILDs outcome (DLCO, PAO2, 6 min wt, QOL) usually
employed to evaluate disease porgression (parenchimal) in IPF patients
are influenced not only by parenchimal changes, but also by both the
presence and the level of associated PH
The treatment of PH in IPF is mainly the treatment of parenchimal
disease in order to prevent PH development
Summary and conclusions (2)
When PH develops lesson learned from previous experiences in
treating PAH must be taken in account (in PAH associated with PSS
no drug approved for patients with PAH associated to UIP-like
parenchymal disease)
Treatment of PH associated to ILDs is a still unmet need and
even in presence of negative results of RC trials further studies
are recruiting patients
Early detection, diagnosis of PH in IPF probably will play a not
negligible role in our daily practice for the clinical management of
patients with UIP