Il sospetto di Ipertensione polmonare secondaria a malattia

polmonare (ILD)

F. MeloniUniversità di Pavia

Fondazione IRCCS Policlinico San MatteoSC Malattie Apparato Respiratorio

PH in ILD: Why, When, and How to look for and treat

Aims:

• Define and assess the occurrence of PH in ILD• Define Pathogenesis and pathophysiology• Define when and how to suspect the presence

of PH and screen for it• Analyse Clinical findings and outcomes• Treatment???

Classification

• PH due to ILD mostly in Group III Dana Point Classification

• Exceptions:– Sarcoidosis– PLCH

Miscellaneous group V

Due to multiple potential ethiologic mechanisms

Diagnosis of PH in ILD

Mean PAP > /= 25 mmHg while PCWP </= 15 mmHg• RHC gold standard for diagnosis – Expensive – Invasive

• Echocardiography – Low accuracy in IPF

• Clinico/radiological variables (suspicion)

Diagnosis commonly missed

Epidemiology

Common complication in ILD (cor pulmonale expected sequela of advanced ILD) prevalence not completely defined timingdiagnostic approach

PLCH 72.5-100% (no correlation of onset with disease severity)

IPF Echo (sPAP) 84%RHC (pts awaiting Tx) 31.6%UNOS data (pts listed) 45% PH

Pulmonary Hypertension and PulmonaryFunction Testing in Idiopathic

Pulmonary FibrosisSteven D. Nathan, (CHEST 2007; 131:657–663)

Over 8 Yr period 347 ILD pts examined118 had RHC and PFT (diagnosis IPF 87 pts by surg

biopsy)48 pts (40.7%) PH (mean PAP >/=25 at rest)12 of those (25%) had PCWPs >15 (of them 2 TPG<10)• Serial RHC :38.6% (17/44) of pts had PH at baseline.at

baseline ----77,8% after roughly 1 yr and---- 86.4% at Tx

Epidemiology

• SSc related ILD – 12% of patients with co-existent ILD (registry cohort)– 19.2% isolated PH, 18.2 % co-existence

(echocardiography based study)– 20% of all pts with PH have a co-existence with ILD

(RHC study)

Connective Tissue Disease–associated PulmonaryArterial Hypertension in the Modern Treatment EraRobin Condliffe et al , Am J Respir Crit Care Med Vol 179. pp 151–157, 2009

Epidemiology

• Sarcoidosis– Prospective Echo study on general Sarco cohort: 5.7% (RVSP

>40 mmHg)– Sarco awaiting Lung Tx 74% PH documented RHC

• Associated to a ↑ mortality on waiting list

• LAM• 7% PH prevalence in 95 patients with LAM, by (sPAP)

>35 mmHg on echocardiography.• PH( RHC : mean PAP >25 mmHg), present in 9 of 20

patients (45%) listed for Tx

Pathophysiology

• Group III and group V could share etiological mechanisms and pathophysiologic pathways

• Different pathways may have different weight in various forms of ILD or even in the same clinical picture (i.e. IPF patients)

PATHOLOGIC ARTERIOPATHY

Cytokine Milieu

Vascular remodeling

Regional hypoxemic

vasoconstriction

Destruction of vascular

bed

Comorbidities

Veno-occlusive disease

In situ thrombosis

Direct vascular

involvement

Hystological changes in IPF-PH

Low-power view of a surgical lung biopsy from a patient with typical interstitial pneumonia-like features

Vessel showing moderate medial hypertrophywithin an area of relatively normal lung

Subpleural fibrosis with vessels showing varying degrees of vasculopathic changes

Vascular ablation within an area of extensive fibrosis.

Comorbidities

• Several co-morbidities may have a significant impact on PH pathogenesis

– ↑Thrombotic Risk ( factor VIII, APS → PTE)– Coexistence of Emphysema (CFPE)– Sleep disordered breathing – Dyastolic dysfunction (↑ PCWP)

Arterial muscle cell

Cytokine “soupe” (vascular)

Fibroblast

Endothelial cell

Epithelial cellTGF-beta

↑PDGF

↓VEGF

APOPTOSIS

Hypoxia ET-1

Vasoconstriction

ProliferationExtracellular matrix formation

+

+

Hypertrophy

TGF-beta

Screening, Suspicion and Diagnosis

• Is it worthwhile to screen ILD patients for PH?• Which clinical features raise the suspicion of

ILD associated PH?• Which is the best screening method?• How the diagnosis should be made?

Screening: when?

• There are NO guidelines on when to sceen ILD patients for PH

– Therefore the decision is taken on an individual basis , according to physician experience.

– However, due to the clear implication of PH on survival screening is PRUDENT AND ADVISABLE

Suspicion

• Physical examination (elevated jugular venous pressure, parasternal heave,pronounced second pulmonic heart sound, murmur of tricuspid regurgitation…) is frequently negative

• Serum biomarkers : BNP and pro-BNP are accurate predictors

BNP

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: either sPAP > 40 mmHg or BNP ratio > or =1. Group 3: sPAP >40 mmHgand BNP ratio >1 (p-value < 0.001 [group 1 vs. 2, p < 0.001;group 2 vs. 3, pZ0.009]).

Jin Woo Song, Respiratory Medicine (2009) 103, 180

Suspicion : 6MWT• ILD-PH patients have shorter 6MWT. • ILD-PH patients are more likely to desaturate below

88%.• Borg dyspnoea score is significantly higher in mild PH

compared to the non-PH group. • Corrected for age, gender, BMI, lung function

parameters and the presence of IPF, the difference in 6MWT between patients without and with PH was 58 ± 22 m, p = 0.01

The presence of PH reduced 6MWT independently of lung function and the presence of IPF

6MWT

A: Dotplot of 6MWT in patients with no, mild and severe PH. B: Model estimated by multiple linear regression showing 6MWT distance for men who did not have IPF with average age (61 years), BMI (27), lungfunction (TLC Z 69, FVC Z 71 and FEV1 Z 67) as a function of diffusion capacity and no, mild or severe PH. *p < 0.05 vs no PH.

Respiratory Medicine (2012) 106, 875e882

Heart Rate recovery post 6MWT

Kaplan–Meier survival curve for entire cohort stratified HRR1 min. Solid line:subjects with normal HRR1. Dashed line: abnormal HRR1.

Swigris et al, Respirology (2011) 16, 439–445

A failure of heart rate toreduce by at least 14 beats/min after the firstminute of recovery following 6MWT : independent predictor of mortality and of PH

48% of pts with abnormal HRR had PH while only 18% of those with normal HRR

Suspicion: does lung function correlate with PH?

CHEST 2007; 131:657–663

Correlation of mPAP with:

FVC (%) DLCO (%) FVC/DLCO ratio

Suspicion: does lung function correlate with PH?

ROCs of FVC% (A), Dlco% (B), and FVC%/Dlco% ratio (C).

CHEST 2007; 131:657–663

Baseline KCO (diffusing capacity of carbonmonoxide/alveolar volume)and 6-month decline in KCO

reflect PH

Corte T et al, Respirology (2012) 17, 674–680

ALL Kco<50%

Decline in Kco Either Kco<50% or decline in Kco

Screening: how?

• Echocardiography: the most common tool for screening

• In pts with advanced lung diseases estimates may be inaccurate– Study on 347 LTx candidates : • ECHO estimated RSVP in 44% pts only• Among them 52% had estimated RVSP in >10 mmHg ≠

from pressure measured directly by RHC• Among them 48% incorrectly estimated to have PH

– Echo can aid but should not be solely relied upon for definitive diagnosis

Diagnosis

• Definitive diagnosis by RHC (important to assess PCWP!)

• Aid in diagnosis by CT (TE, Emphysema)

Clinical implications (Outcome)PH in ILD affects : – Morbidity– MORTALITY• SSC + ILD and PH affects significantly mortality

irrespective of the presence of fibrosis

D Mukerjee, Ann Rheum Dis 2003;62:1088–1093

Clinical implications (Outcome)

IPF• Mortality is significantly higher with PH

Chest 2005;128;2393-2399 Hassan F. Nadrous, and coll.

1 yr mortality in a RHC study of IPF patients :• 5.5% without PH• 28% with PH

1 U increase in PVR associated to a 22% higher risk of death HR in Pts with PH 10.4(Minai OA , 2009, ISHLT meeting Paris)

Clinical implications (Outcome)

• Another study included 79 patients PAH (RHC) was present in 31.6% of patients

CHEST 2006; 129:746–752

Survey on belief and practice patterns

Electronic survey to member of the American College Chest Physiscian (n°453)

Minai OA et al, Resp Med 2010 May;104(5):741-8.

Survey on belief and practice patterns

Survey on belief and practice patterns

Survey on belief and practice patterns

Workflow

• 1) Suspect• 2) Screen• 3) Diagnosis• 4) Rule out other co-morbidities (sleep

disorders, emphysema, CHF, acute or chronic TE)

• 5) Treat…?

Treatment: HOW?

• Treat hypoxia (increase of oxidative stress…)• Diuretics• Steroids/immunosuppressants?!• Anticoagulants (no evidence , case by case, on the basis of

weighted risk/benefit)

…. And pulmonary vasodilators? NO EVIDENCE BASED GUIDELINE!Caveat: Worsen ventilation /perfusion ratioPresence of PVOD (IPF, Sarco, PLCH)

Study Type of disease

Type of study Pts Therapy Outcome

Preston,2001 sarc Prosp/observ 8 iNO, EPO,CaCh BL ↓PVRmPAP,↑6MWT (short term)

Fisher, 2006 Sarc Case series 8 EPO ↓NYHA class

Barnett, 2009 Sarc Case series 22 EPO ,iILO, Bosentan, Sildenafil

↑ 6MWT ↓NYHA class

Milman, 2008 Sarc Retrosp 24 Sildenafil ↓PVR ,mPAP, ↑CO

Sharma, 2005 SarcSSc, CTEP

Case series 6 Bosentan ↓NYHA class↑ 6MWT

Minai, 2008 IPF,CTD,sarc Case series 19 EPO,Bosentan ↓NYHA class↑ 6MWT (short term)

Krowka , 2007 IPF Rando/plac Contr 51 iILO → 6MWT NYHA class

Collard , 2007 IPF Open /prosp 14 Sildenafil !! 57% ↓ 6MWT

Ghofrani, 2002 Fibrosing ILD Rando/controld 16 Sildenafil,iNO, EPO

Sild RHC and gas exch

STEP-IPF IPF (no RHC and no PH assmt

Prosp /random/plac contr

170 Sildenafil ↑O2, dyspnea and QoL

ACTIVE IPF –PH (Echo) D blind/rando - iILO →

BUILD1-BUILD3 IPF (no assm PH) Dblind/plac contr - Bosentan → but suggestion subgroup might benefit

ARTEMIS –PH IPF-PH (RHC!) Dblind/plac contr - Ambrisentan HALTED

Conclusion

• PH is very common in ILD patients • ILD related PH may be caused by different

mechanisms• PH significantly affects outcome of ILD• Suspicion of PH can raise on the basis of 6MWT,BNP,

DLco /Kco (not FVC)• Echo first line screen (do not rely solely upon it for

diagnosis→ RHC)• Treatment? Urgent need for EVIDENCE

thanks