PAH%20and%20Lung%20Transplant

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PAH and Lung Transplant

• FRACP Teaching 2007
• TJ McWilliams
• Respiratory Physician

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Pulmonary Hypertension

• Classification
• Diagnosis and Investigation
• Treatment

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Pulmonary Circulation
BP 100-140/60-90 Mean70-105
PA 15-30/2-8 Mean9-18
LA (paw) 2-10
RA2-8
RV 15-30/2-8
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Diagnosis of PAH

• ?Mean PAP 25 mm Hg (30mm Hg with exercise)
• ?Pulmonary Vascular Resistance gt3mmHg/l/min
  (Woods Units) or 120dyne.sec.cm-5
• Normal PACWP (15 mm Hg)

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Classification of Pulmonary Hypertension

1. PAH
2. Pulmonary Hypertension associated with Left Heart
   Disease
3. PH associated with Respiratory Disease and/or
   Hypoxia
4. PH Due to Chronic Thrombotic and/or Embolic
   Disease
5. Miscellaneous

Venice 2003 updated Evian Classification
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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
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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

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Causes of Secondary Pulmonary Hypertension
Obesity, Kyphoscoliosis, Neuromuscular Disease
Eisenmengers PDA, VSD, ASD
COPD, Pulmonary Fibrosis
CTEPH
Collagen Vascular Disease Scleroderma (CREST),
SLE HIV, Drugs
Porto-pulmonary Hypertension
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Pathology of PAH
Intimal Thickening Endothelial Cell Proliferation

• Complex Plexiform lesions
• mass of disorganised vessels
• proliferating endothelial cells,
• smooth muscle cells and
• myofibroblasts
• arising from pre-existing PA

Medial Hypertrophy ? Smooth Muscle Fibers ?
Connective Tissue ? Elastic Fibers
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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

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Diagnostic Strategy

• Clinical Suspicion of PH
• Sx/Physical Exam/Screening/Incidental
• Detection of PH
• ECG/CXR/TTE
• PH Clinical Class Identification
• LFT/ABG/VQ Scan/HRCT/CTPA
• 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
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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

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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

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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))

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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 LFTs
• Teratogenic and may reduce efficacy of OC
• May see some peripheral oedema

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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

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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

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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)

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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

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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

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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

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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

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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?

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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 RAPgt15mmHg, CIlt2l/min/m2 ,
  PAPgt55mmHg
• 6MWlt350m, NYHA III and IV

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Outcomes in LT

• 4 of LT (predominantly BSLT)
• Worse one year mortality compared with other
  diagnosis
• RR3.16 (SLT) RR2.01(BSLT)
• Similar long term outcomes
• 50 5 year survival

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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

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Update on Lung Transplantation

• TJ McWilliams
• Respiratory Medicine and NZ Heart and Lung
  Transplant Unit
• Auckland City Hospital

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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 gt 1 month
• Cyclosporine developed in the 1970s
• First successful HLTx in 1981
• LTx is now an accepted option for end-stage lung
  disease

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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

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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)

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ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival
by Era (Transplants January 1988 June 2003)
Survival comparisons by era 1988-94 vs. 1995-99
p 0.01 1988-94 vs. 2000-6/03 p lt0.0001
1995-99 vs. 2000-6/03 p lt0.0001
ISHLT
J Heart Lung Transplant 200524 945-982
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Recipient Criteria

• End stage pulmonary disease with debilitating
  symptoms
• Age
• HLTX 55 years
• SLTx 65 years (non supparative lung disease)
• BSLTx 60 years

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Disease Specific Criteria

• COPD
• FEV1 lt25, pCO2 gt7.3kPa/55mmHg
• ?PAP Cor pulmonale
• CF and Bronchiectasis
• FEV1 lt30 rapid clinical deterioration,
  malnutrition, massive haemoptisis
• pCO2 gt6.7kPa (50mmHg) pO2 lt7.3kPa (55mmHg)

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Disease Specific Criteria

• IPF
• Rapidly progressive disease and symptomatic
  desaturation with exercise or at rest
• FVC lt70 and DLCO lt50-60
• PAH
• Severe progressive symptoms and NYHA III-IV
  despite optimal medical treatment
• CI lt2l/min/m2, RAP gt15mmHg, mean PAP gt55mmHg

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Contraindications

• Dysfunction of major organs other than the lung
• Kidneys CrCllt50mg/ml/min
• Heart consider CABGS/Angioplasty
• Infection with HIV
• Hepatitis B antigen positive
• Hepatitis C (bx proven liver disease)
• Pulmonary Fungal Infection

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• 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 gt Dukes A, Melanoma ?
  level 3
• BMI lt70 or gt130 ideal
• Psychiatric disease affecting comprehension and
  compliance

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Relative Contraindications

• Symptomatic osteoporosis
• Severe musculoskeletal disease affecting the
  thorax
• kyphoscoliosis
• Corticosteroid use (aim lt10mg/day)
• Psychosocial problems
• high likelihood of impacting negatively on outcome

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When to Transplant

• Window of opportunity
• Aim to transplant when benefit gt risk
• 2 year survival is lt 50
• not so debilitated that benefit and improvement
  in quality of life is limited
• Able to survive time on the waiting list

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Ideal Donor Criteria

• lt 55years
• ABO compatible
• lt 20 pack smoking years
• Clear CXR
• PaO2 gt 300mmHg
• lt 48 hours intubation
• No significant chest trauma

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Updated LT Donor Acceptability Criteria

• Age gt 55 if ischaemia time short and otherwise
  ideal
• PaO2/FiO2 lt300 ? 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 gt
  20 pack years
• Consider Asthmatic (mild) donors, Drowning
  (laryngospasm) and CO Poisoning (if otherwise
  ideal)

Orens, JB et al J Heart lung Transplant
2003221183-1200
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Early Morbidity and Mortality

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

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Risk Factors for Early Mortality

• Pre transplant diagnosis
• Sarcoidosis OR2.15, PPH OR2.74,
• IPF OR1.91
• Repeat transplant OR2.03
• Tx from a ventilator or ICU OR2.42
• CMV mismatch OR1.29

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Late Morbidity and Mortality

• BOS
• Infection
• Renal Impairment
• Malignancy
• Osteoporosis

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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

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Risk Factors for BOS

• Acute Rejection
• high grade/recurrent
• CMV Infection
• CMV pneumonitis/DNAaemia
• HLA mismatch
• Lymphocytic bronchiolitis

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Mechanism of Action of immunosuppressive Agents
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Immunosuppression in LT

• Maintenance regimen typically CNI,
  antiproliferative agent and corticosteroid
• CNIs (Cyclosporin and Tacrolimus)
• Renal impairment, ?BP,
• Hirsutism (CSA)
• IGT (Tacrolimus)
• Azathioprine and Mycophenolate Mofetil
• Bone marrow suppression
• Nausea, hepatic dysfunction

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TOR Inhibitors

• Everolimus and Sirolimus
• Not nephrotoxic but may potentiate CNI
  nephrotoxicity
• Potent immunosuppressive agents
• Hyperlipidaemia

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BOS Treatment

• Augment Immunosuppression
• ATG
• TOR Inhibitors
• Azithromycin
• Management of GERD
• PPI
• Surgery
• Retransplant

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Other Options for End Stage Lung Disease

• COPD LVRS
• PAH Medical Treatment

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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

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• 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 Reynauds disease as a student in
  Dunedin and has some GERD treated with Losec. RH
  catheter shows mPAP64mmHg, PVR 9,normal RAP
  and a negative vasodilator test. 6MW420m

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• She has a good prognosis and should be started on
  calcium channel blockers because Reynauds is a
  vasoreactive disease
• She has a poor prognosis and should be started on
  intravenous treatment and worked up for LT
• She should be started on medical treatment with
  Bosentan or Sildenafil
• She shouldnt have warfarin because of a high
  risk of bleeding

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Regarding RHC for PAH

1. It is a risky procedure and should only be
   considered for those who have early disease
2. A positive vasodilator test is when the mPAP
   falls by 10mmHg and the PVR returns to normal
3. A positive response to Iloprost means this is the
   best drug to use
4. RHC can help confirm the diagnosis, provide
   prognostic information and exclude significant L
   heart disease

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Regarding BOS (or chronic Rejection) in LTR

• It is diagnosed on transbronchial lung biopsies
• It is a clinical diagnosis based on lung function
• It is a rare complication as most LTR die of
  infection
• It is easily treated by adding a TOR inhibitor
  such as Sirolimus or Everolimus

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• 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)

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• He is suitable for referral for LT but need to
  attend a pulmonary rehabilitation
• He is unsuitable for LT because he may have
  asbestos related lung disease
• He needs to be smoke free for 2 years before he
  can be referred for LT
• He has an excellent 5 year prognosis after LT
  because he has CIOPD as his underlying disease