IPF and Lung Transplantation

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IPF and Lung Transplantation Steven Nathan,
MD Medical Director, Lung Transplant and Advanced
Lung Disease Programs Inova Fairfax
Hospital Falls Church, VA
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Goals

• Role of transplant in IPF
• When to refer
• When to list
• When to transplant
• Who is a candidate
• What type of transplant
• Post-transplant
• What have we learnt about IPF through
  transplantation

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Raghu et al. Am J Respir Crit Care Med
2006810-816
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ADULT LUNG TRANSPLANTATION Indications
(1/1995-6/2005)
ISHLT
2006

J Heart Lung Transplant 200625880-892
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The Transplant Scale
QALY
QALY
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IPFinfluence of age
King et al. Am J Respir Crit Care Med. 2001
1641171-1181
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Erbes et al. Chest 199711151-57
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Impact of Baseline FVC and DLCO on Subsequent
Mortality
Diffusion Capacity for Carbon Monoxide
35
Forced Vital Capacity
35
30
30
25
25
20
Mortality ()
20
Mortality ()
15
15
10
10
5
5
0
0
90
8089
7079
6069
5059
4049
3039
2029
50
4049
1019
Predicted DLCO
Predicted FVC
King TE, et al. Chest. 2005127171-177.
King TE, et al. Chest. 2005127171-177.
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Desaturators
Desaturation on 6MWT Predicts Decreased Survival
in UIP (N 83)
1.0
69
0.8
0.6
35
Survival Probability
0.4
P 0.0018
0.2
0.0
0
2
1
3
4
5
Nondesaturators
Years

• Lama VN, et al. Am J Respir Crit Care Med.
  20031681084-1090.

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Mean Pulmonary Artery Pressure A Predictor of
Survival in Patients With IPF
1.0
No (mPap 25 mm Hg)
n 54
0.8
0.6
Cumulative Probability to Survival
Yes (mPap gt 25 mm Hg)
0.4
n 25
0.2
P lt 0.001
0.0
7
4
3
5
6
1
2
0
Years to Event
Lettieri CJ, et al. Chest. 2006129746-752.
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Mortality and IPF
Window of opportunity
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IPF and NSIP

• Guidelines for Referral
• Histological or radiographic evidence of UIP
  irrespective of vital capacity
• Histologic evidence of fibrotic NSIP

International Guidelines for the Selection of
Lung Transplant Candidates 2006 Update J Heart
Lung Transplant 200625745-755
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IPF and NSIP

• Guidelines for Transplantation
• Histological or radiographic evidence of UIP and
  any of the following
• DLCOlt39
• 10 decrement in FVC in 6 months
• Decrease in pulse oximetry lt88 during 6MWT
• Honeycombing on HRCT (fibrosis score gt2)
• Histological evidence of NSIP and one of the
  following
• DLCOlt35
• 10 FVC or 15 DLCO decrease in 6 months

International Guidelines for the Selection of
Lung Transplant Candidates 2006 Update J Heart
Lung Transplant 200625745-755
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Absolute Contraindications

• Malignancy lt2 years
• Except cutaneous squamous and basal cell tumors
• 5 year disease-free interval is prudent
• Untreatable advanced major organ dysfunction
• Heart, liver, kidney
• Non-curable chronic extrapulmonary infection
• Chronic active hepatitis B, hepatitis C, HIV
• Significant chest wall/spinal deformity
• Documented noncompliance or inability to follow
  through with medical therapy

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Absolute Contraindications

• Untreatable psychiatric or psychologic condition
• With the inability to cooperate or comply with
  medical therapy
• Absence of a consistent or reliable social
  support system
• Substance addiction
• Active or within last 6 months

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Relative Contraindicationsthe presence of
several relative contraindications can combine to
increase the risks of transplantation above a
safe threshold.

• Agegt65 years
• Critical or unstable clinical condition
• Severely limited functional status
• Colonization with highly resistant or highly
  virulent bacteria, fungi or mycobacteria
• BMIgt30 kg/m2
• Severe or symptomatic osteoporosis

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ADULT LUNG TRANSPLANTATION Indications for
Single Lung Transplants (Transplants January
1995 - June 2005)
Other includes Sarcoidosis 2.1 Bronchiectasi
s 0.4 Congenital Heart Disease 0.2 LAM
0.8 OB (non-ReTx) 0.7 Miscellaneous 4.8
ISHLT
2006

J Heart Lung Transplant 200625880-892
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ADULT LUNG TRANSPLANTATION Indications for
Bilateral/Double Lung Transplants (Transplants
January 1995 - June 2005)
Other includes Sarcoidosis 2.9 Bronchiectasi
s 4.8 Congenital Heart Disease 1.7 LAM
1.3 OB (non-ReTx) 1.1 Miscellaneous 0.9
ISHLT
2006

J Heart Lung Transplant 200625880-892
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ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival
By Diagnosis (Transplants January 1994 June
2004)
ISHLT
2006

J Heart Lung Transplant 200625880-892
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ADULT LUNG TRANSPLANTATION Distribution of
Procedure Type for Major Indications (1990-2004)
ISHLT
2006

J Heart Lung Transplant 200625880-892
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Idiopathic Pulmonary Fibrosis Kaplan-Meier
Survival by Procedure Type (Transplants January
1990 June 2004)
P 0.2038
ISHLT
2006

J Heart Lung Transplant 200625880-892
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Lung Allocation

• .theres a new game in town!
• What is your LAS?

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Lung Allocation Score

• Lungs formerly allocated on first come, first
  serve basis
• LAS based on lung utility
• Determined on best combination of likelihood of
  dying from primary disease vs. likelihood of
  surviving transplant x 12 months

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Standard Donor Criteria

• Agelt55 years
• ABO compatibility
• Clear CXR
• PaO2gt300 on FIO21.0, PEEP- 5 cm H2O
• Tobacco historylt20 pack years
• Absence of chest trauma
• No evidence of aspiration/sepsis
• HIV / HepB S Ag/ Hep C negative
• Sputum gram stain-absence of organisms
• Absence of purulent secretions at bronch

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Lung transplant surgery

• Single thoracotomy
• Bilateral subcostal incision
• Structures that are sacrificed
• bronchial circulation
• pulmonary nerves
• pulmonary lymphatics

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LUNG TRANSPLANTS CAUSE OF DEATH (1982-2000)
Cause of Death ()
Timing of Death
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Primary Graft Dysfunction
aka
Primary Graft Failure
Allograft dysfunction
Reperfusion edema
Donor Graft Dysfunction
Ischemia reperfusion injury
Reperfusion injury
Pulmonary reimplantation response
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Primary Graft Dysfunction

• 1) The presence within 72 hours of
  transplantation of a diffuse alveolar infiltrate
  involving the lung allograft and, in the case of
  single-lung transplant, sparing the native lung
• 2) A ratio of arterial partial pressure of
  oxygen/fraction of inspired oxygen (PaO2/FIO2) of
  lt200 persisting beyond the initial 48 hours
  postoperatively
• 3) No other secondary cause of graft dysfunction
  identified
• cardiogenic pulmonary edema
• pathologic evidence of rejection
• pneumonia
• pulmonary venous outflow obstruction
• 4) In the event of death prior to day 3, the
  patient must fulfill the above criteria at the
  time of death and must demonstrate diffuse
  alveolar damage as the predominant process on
  histologic examination of the lung

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Primary Graft Dysfunction

• 10-50 of recipients
• Risk factors
• Prolonged ischemic time, donor age, recipient
  PAH, CPB
• ARDS
• Mortality 0-50

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REJECTION
INFECTION
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Other Factors Predisposing to Infection

• Mechanical
• mucociliary clearance
• cough reflex
• lymphatic drainage
• bronchial stenosis
• bronchiolitis obliterans

• Presence of Source
• inherited
• ischemic airways
• native lung

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Immunosuppression

• Calcineurin inhibitor
• Antimetabolite
• Steroids
• Cytolytics

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FREEDOM FROM BRONCHIOLITIS OBLITERANSFor Adult
Lung Recipients (Follow-ups April 1994-June
2005)Conditional on Survival to 14 days
ISHLT
2006

J Heart Lung Transplant 200625880-892
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Gerhardt et al. Am J Respir Crit Care
Med 2003168121-5
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A randomized Trial of CSA Inhalation Solution in
Lung Transplant Recipients
NEJM 2005
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What have we learnt about IPF from lung
transplantation?

• Lung transplantation allows us to follow the
  natural history of the disease beyond the natural
  history of the patient!

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What have we learnt about IPF from lung
transplantation?

• Role of PH
• CAD
• PE
• PTx
• IDDM

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What have we learnt about IPF from lung
transplantation?

• Role of PH
• CAD
• PE
• PTx
• IDDM

49
What have we learnt about IPF from lung
transplantation?

• Role of PH
• CAD
• PE
• PTx
• IDDM

(Kiser et al. Arch Int Med 2004164551-556)
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What have we learnt about IPF from lung
transplantation?

• Role of PH
• CAD
• PE
• PTx
• IDDM

51
What have we learnt about IPF from lung
transplantation?

• Role of PH
• CAD
• PE
• PTx
• IDDM

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Frequent clinic visits
PFTs Home spirometry
Bronchoscopy
Constant Vigilance
Primary dx
Other
Native lung
Transplanted lung
Medications
Diabetes Renal insufficiency Hypertension gastroin
testinal Hyperlipidemia osteoporosis
Rejectasporin