PAH and Lung Transplant

FRACP Teaching 2007TJ McWilliamsRespiratory Physician

Pulmonary Hypertension

ClassificationDiagnosis and InvestigationTreatment

Pulmonary Circulation

BP 100-140/60-90Mean=70-105

LA (paw) =2-10

PA 15-30/2-8Mean=9-18

RA=2-8

RV 15-30/2-8

Diagnosis of PAH

Mean PAP ≥25 mm Hg (30mm Hg with exercise)

↑Pulmonary Vascular Resistance = >3mmHg/l/min (Woods Units) or ≥120dyne.sec.cm-5

Normal PACWP (≤15 mm Hg)

Classification of Pulmonary Hypertension*

1. PAH 2. Pulmonary Hypertension associated

with Left Heart Disease3. PH associated with Respiratory

Disease and/or Hypoxia4. PH Due to Chronic Thrombotic and/or

Embolic Disease5. Miscellaneous

* Venice 2003 – updated “Evian” Classification

Pulmonary Arterial Hypertension* Idiopathic (IPAH) Familial (FPAH) – BMPR2 mutations Associated with (APAH)

CTD Congenital Systemic to Pulmonary Shunts Portal hypertension HIV Drugs and Toxins Other

Associated with Significant Venous or Capillary Involvement PVOD PCH

PPHN

* Venice 2003 – updated “Evian” Classification

Risk Factors and Associated Conditions

Drugs Definite: Aminorex, Fenfluramine, Toxic

Rapeseed Oil Very likely: Amphetamines,

Demographic and Medical Conditions Definite: Gender Possible: Pregnancy, Systemic ↑BP

Diseases Definite: HIV Very Likely: Portal ↑BP/Liver Disease, CTD, CHD

Causes of Secondary Pulmonary Hypertension

Obesity, Kyphoscoliosis, Neuromuscular Disease

COPD, Pulmonary Fibrosis

Collagen Vascular DiseaseScleroderma (CREST), SLE

HIV, Drugs

Eisenmengers: PDA, VSD, ASD

CTEPH

Porto-pulmonaryHypertension

Pathology of PAHIntimal ThickeningIntimal ThickeningEndothelial Cell Endothelial Cell ProliferationProliferation

Medial HypertrophyMedial Hypertrophy ↑ ↑ Smooth Muscle FibersSmooth Muscle Fibers↑ ↑ CConnective Tissueonnective Tissue↑ ↑ Elastic FibersElastic Fibers

Complex Plexiform lesionsComplex Plexiform lesions::mass of disorganised vesselsmass of disorganised vesselsproliferating endothelial cells,proliferating endothelial cells, smooth muscle cells andsmooth muscle cells and myofibroblasts myofibroblasts arising from pre-existing PAarising from pre-existing PA

Diagnosing PAH Difficult to diagnose and often presents

late! (present when mean PAP = 30-40mmHg)

First symptoms may be non specific such as breathlessness, lethargy

May present with RVF: ankle oedema, weight increase, chest pain and syncope

Clinicians need to think of the diagnosis when seeing a patient with unexplained breathlessness

Diagnostic Strategy*

I. Clinical Suspicion of PH• Sx/Physical Exam/Screening/Incidental

II. Detection of PH• ECG/CXR/TTE

III. PH Clinical Class Identification• LFT/ABG/VQ Scan/HRCT/CTPA

IV. PAH Evaluation• Type (HIV, Auto Immune Screen, US Scan) • Functional Capacity (6MW , Peak VO2, NYHA)• Haemodynamics (R Heart Catheter

+Vasodilator)

*ESC Guidelines 2004 Elsevier Ltd

Right Heart Catheter HR, RAP, PAP, PWP, CO, PVR SVR, BP, ABG

and mixed venous BG Diagnostic in NYHA I and II Prognostic in NYHA III and IV

↑RAP, mPAP and ↓CO associated with the worst prognosis

Vasodilator Challenge: ↓ mPAP ≥10mmHg to reach a mPAP ≤ 40mmHg

with ↑ or stable CO 10-15% IPAH only Trial CCB

Treatment PH(NYHA III and IV) Ca Channel Blockers

PAH if vasodilator testing +ve Anticoagulation

All PH except Eisenmengers PGI Analogues

Epoprostenol IV and Iloprost nebulised Endothelin Antagonists

Bosentan Phosphodiesterase Inhibitors

Sildenafil

Prostaglandin Analogues IV Epoprostenol/Prostacycline®

2-4ng/kg/min up to 10-15ng/kg/min Side effects of hypotension, flushing,

headache, jaw pain, diarrhoea, restlessness Improved haemodynamics and functional

improvement and mortality Nebulised Iloprost/Ventavis®

Single inhalation reduces PAP by 100-20% for 1-2 hours

Short duration of action so need to use 6-12X/day

Aim for 150-300μg/day (15µ / X 6 doses))

Oral Endothelin Antagonists Bosentan (Tracleer® Actelion)

Vasodilator which antagonizes endothelin a potent vasoconstrictor in vascular endothelial cells

Improves exercise capacity haemodynamics and functional class

Dose: 62.5-125mg bd ~15% dose dependent ↑ in LFT’s Teratogenic and may reduce efficacy of OC May see some peripheral oedema

Phosphodiesterase Inhibitors Enhance endogenous NO Sildenafil (Viagara® Pfizer) selectively

acts on PDE 5 predominant in human corpora cavernosa and pulmonary vessels compared with systemic blood vessels

Dose: 25-100mg tds Side effects: headache, flushing,

dizziness, visual changes, rhinitis, headache, dyspepsia

PH associated with CTD ~2% of connective tissue diseases Occurs in:

Scleroderma and CREST* (prevalence 12%*) SLE,MCTD, Rh Arthritis, Sjogrens, DM/PM

Similar presentation to PPH, may precede symptoms of CTD

Treatment Medical May not be suitable for LT

Idiopathic Pulmonary Arterial Hypertension (IPAH) Rare disease: Incidence of 2 per million Median survival 2.8 years after diagnosis

Risk of death ≡ Haemodynamics and NYHA class Mortality: R Heart Failure 47% and Sudden

Cardiac Death 26% Risk factors

Familial (6% of cases) Drugs (fenfluramine, toxic rapeseed oil,

amphetamines) HIV Female (pregnancy)

Eisenmengers and PAH CHD that initially causes a large L→R shunt with

resultant PAH and reversal May see haemoptisis and CVA (paradoxical

emboli) Slowly progressive compared with IPAH

97% 1 year vs. 77% and 77% vs. 35% 3 year survival

Treatment Medical and then LT

CTEPHChronic Thromboembolic Pulmonary Hypertension

Caused by recurrent and/or unresolved (undiagnosed ) PE May occur despite anti-coagulation

Suspect if signs and symptoms of pulmonary hypertension and a past history of blood clots

Diagnosis: CTPA Can use prostaglandin analogue but

ultimately need Lung Transplantation

PVODPulmonary Veno-Occlusive Disease

Most devastating form of PH Median survival after dx= 84 days 71% dead in 6 months

Probably 10% of PH is in fact PVOD Histology: luminal narrowing and occlusion of

pulmonary veins Difficult to distinguish from PH

Profound hypoxia at rest CT Chest: septal thickening and ground glass

Vasodilators not used due to risk of pulmonary oedema

LUNG TRANSPLANTATION

Porto Pulmonary Hypertension

Associated with liver disease and portal hypertension (2%)

May be a contra-indication to isolated Liver Transplant

mPAP ≥ 35mmHg or PVR ≥250dynes Treatment

Vasodilators and then LiTx ?Combined Li-LTx

A Pragmatic Approach

Is this PH? Is this IPAH or is there another cause? How severe is it?

NYHA Class III or IV Is the vasodilator response +ve

?Ca channel blockers Oral treatment ? Or nebulised or IV?

Lung Transplantation

Number of LT for PH has declined in the last 10 years Now indicated for PPH, CTEPH and PVOD

who fail medical treatment Highest early and late mortality

Haemodynamic Criteria: RAP>15mmHg, CI<2l/min/m2 , PAP>55mmHg

6MW<350m, NYHA III and IV

Outcomes in LT

4% of LT (predominantly BSLT) Worse one year mortality compared

with other diagnosis RR=3.16 (SLT) RR=2.01(BSLT)

Similar long term outcomes 50% 5 year survival

Summary PH is a bad disease!

Difficult to diagnose and may present late High mortality even with treatment

Treatment options Costly Variable funding

Lung Transplantation should be reserved for selected candidates where medical treatment has failed

Update on Lung Transplantation

TJ McWilliamsRespiratory Medicine and NZ Heart and Lung Transplant UnitAuckland City Hospital

History of Lung Transplantation

First LTx performed in 1963 prisoner with Ca Lung survived 18 days ( died of renal failure)

36 LTx from 1963-1974 2 survived > 1 month

Cyclosporine developed in the 1970’s First successful HLTx in 1981 LTx is now an accepted option for

end-stage lung disease

Lung Transplant in this Millennium Survival has improved in the first 3 years but

there has been no significant change in long term mortality 50-60% 5 year survival

Chronic rejection or BOS remains the greatest limitation on long term survival

Significant problems with immunosuppression toxicity in longer term survivors

Indications

The main indications for LTx are: COPD (38%) IPF (17%) CF (17%) 1 ATD (8.6%) PPH (4%) Sarcoidosis (2.5%) Bronchiectasis (2.7%)

ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival by Era (Transplants: January 1988 – June 2003)

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10

Years

Su

rviv

al (

%)

.

1988-1994 (N=4,392)1995-1999 (N=6,726)2000-6/2003 (N=5,553)

1988-1994: 1/2-life = 3.9 Years; Conditional 1/2-life = 7.0 Years1995-1999: 1/2-life = 4.5 Years; Conditional 1/2-life = 7.0 Years

Survival comparisons by era1988-94 vs. 1995-99: p = 0.011988-94: vs. 2000-6/03: p <0.0001 1995-99 vs. 2000-6/03: p <0.0001

ISHLTJ Heart Lung Transplant 2005;24: 945-982

Recipient Criteria End stage pulmonary disease with

debilitating symptoms Age

HLTX ~ 55 years SLTx ~ 65 years (non supparative lung disease) BSLTx ~ 60 years

Disease Specific Criteria

COPD FEV1 <25%, pCO2 >7.3kPa/55mmHg ↑PAP ± Cor pulmonale

CF and Bronchiectasis FEV1 <30% rapid clinical deterioration,

malnutrition, massive haemoptisis pCO2 >6.7kPa (50mmHg) pO2 <7.3kPa

(55mmHg)

Disease Specific Criteria IPF

Rapidly progressive disease and symptomatic desaturation with exercise or at rest

FVC <70% and DLCO <50-60%

PAH Severe progressive symptoms and NYHA III-IV

despite optimal medical treatment CI <2l/min/m2, RAP >15mmHg, mean PAP

>55mmHg

Contraindications

Dysfunction of major organs other than the lung Kidneys: CrCl<50mg/ml/min Heart: consider CABGS/Angioplasty

Infection with HIV Hepatitis B antigen positive Hepatitis C (bx proven liver disease) Pulmonary Fungal Infection

Active malignancy within the last 2 years except BCC and SCC of the skin 5 years for extracapsular renal cell cancer, Ca

Breast stage 2, Ca Colon > Dukes A, Melanoma level 3

BMI <70% or >130% ideal Psychiatric disease affecting

comprehension and compliance

Relative Contraindications

Symptomatic osteoporosis Severe musculoskeletal disease

affecting the thorax kyphoscoliosis

Corticosteroid use (aim <10mg/day) Psychosocial problems

high likelihood of impacting negatively on outcome

When to Transplant

“Window of opportunity” Aim to transplant when benefit > risk

2 year survival is < 50% not so debilitated that benefit and

improvement in quality of life is limited Able to survive time on the waiting list

Ideal Donor Criteria

< 55years ABO compatible < 20 pack smoking years Clear CXR PaO2 > 300mmHg < 48 hours intubation No significant chest trauma

Updated LT Donor Acceptability Criteria* Age > 55 if ischaemia time short and otherwise ideal PaO2/FiO2 <300 ? Increased PGF CXR: consider if unilateral infiltrate G Stain +ve should not exclude a donor Can extend graft ischaemia time beyond 6 hours No adverse outcomes with donor smoking history >

20 pack years Consider Asthmatic (mild) donors, Drowning

(laryngospasm) and CO Poisoning (if otherwise ideal)

*Orens, JB et al J Heart lung Transplant 2003;22:1183-1200

Early Morbidity and Mortality

Ischemia-Reperfusion Injury (PGF) Acute Rejection Infection (Donor and Recipient

Acquired) CMV Infection

Risk Factors for Early Mortality

Pre transplant diagnosis Sarcoidosis OR=2.15, PPH OR=2.74, IPF OR=1.91

Repeat transplant OR=2.03 Tx from a ventilator or ICU OR=2.42 CMV mismatch OR=1.29

Late Morbidity and Mortality

BOS Infection Renal Impairment Malignancy Osteoporosis

Bronchiolitis Obliterans Syndrome (BOS)

Manifestation of chronic rejection Still the most significant limitation to long term

survival in LTR (Most common cause of death after 1 year)

About half of LTR have BOS by 5yrs Unexplained irreversible decline in lung

function no evidence of reversible causes fall in FEV1 and FEF25-75 compared to best post

transplant

Risk Factors for BOS

Acute Rejection high grade/recurrent

CMV Infection CMV pneumonitis/DNAaemia

HLA mismatch Lymphocytic bronchiolitis

Mechanism of Action of immunosuppressive Agents

Immunosuppression in LT Maintenance regimen typically CNI,

antiproliferative agent and corticosteroid CNI’s (Cyclosporin and Tacrolimus)

Renal impairment, ↑BP, Hirsutism (CSA) IGT (Tacrolimus)

Azathioprine and Mycophenolate Mofetil Bone marrow suppression Nausea, hepatic dysfunction

TOR Inhibitors

Everolimus and Sirolimus Not nephrotoxic but may potentiate

CNI nephrotoxicity Potent immunosuppressive agents Hyperlipidaemia

BOS Treatment

Augment Immunosuppression ATG TOR Inhibitors

Azithromycin Management of GERD

PPI Surgery

Retransplant

Other Options for End Stage Lung Disease

COPD – LVRS PAH – Medical Treatment

Summary Treatment option for end stage lung

disease without any other organ dysfunction

Improved quality of life (COPD) and length of life (CF, PAH, Bronchiectasis)

Success limited by the development of BOS and the requirement for more immunosuppression than other organ transplants

A 28 year old woman presents with SOBOE on minimal exertion which has been a problem for a year. Echo confirms pulmonary ↑BP. She had treatment for Reynaud’s disease as a student in Dunedin and has some GERD treated with Losec. RH catheter shows mPAP=64mmHg, PVR = 9,normal RAP and a negative vasodilator test. 6MW=420m

a) She has a good prognosis and should be started on calcium channel blockers because Reynaud’s is a vasoreactive disease

b) She has a poor prognosis and should be started on intravenous treatment and worked up for LT

c) She should be started on medical treatment with Bosentan or Sildenafil

d) She shouldn’t have warfarin because of a high risk of bleeding

Regarding RHC for PAH

a) It is a risky procedure and should only be considered for those who have early disease

b) A positive vasodilator test is when the mPAP falls by 10mmHg and the PVR returns to normal

c) A positive response to Iloprost means this is the best drug to use

d) RHC can help confirm the diagnosis, provide prognostic information and exclude significant L heart disease

Regarding BOS (or chronic Rejection) in LTR

a) It is diagnosed on transbronchial lung biopsies

b) It is a clinical diagnosis based on lung function

c) It is a rare complication as most LTR die of infection

d) It is easily treated by adding a TOR inhibitor such as Sirolimus or Everolimus

A 55 year retired Electrician with severe COPD presents to your general clinic. He gave up smoking 1 year ago but is now very breathless on minimal exertion with signs of early RHF. He is on Ventolin, Seretide and Spiriva. FEV1/FVC = 0.85/2.15 (20%/75%)

a) He is suitable for referral for LT but need to attend a pulmonary rehabilitation

b) He is unsuitable for LT because he may have asbestos related lung disease

c) He needs to be smoke free for 2 years before he can be referred for LT

d) He has an excellent 5 year prognosis after LT because he has CIOPD as his underlying disease