Lung transplantation in children
Paul Aurora
Respiratory and Cardiothoracic Transplant Units
Great Ormond Street Hospital for Children
Portex Respiratory Unit, Institute of Child Health
London, UK
AGE DISTRIBUTION OF PEDIATRIC LUNG RECIPIENTS
By Year of Transplant
1 3 4 6
20
48 51 48
8274
87 89
68 6863
7175 78
87 8795
102
43
0
10
20
30
40
50
60
70
80
90
100
110
12-17 Years
1-11 Years
<1 Year
Num
ber
of T
rans
plan
ts
2010ISHLTAurora, JHLT, 2010
NUMBER OF PEDIATRIC LUNG TRANSPLANTSBY CENTER VOLUME
0
10
20
30
40
50
60
70
80
90
100
110
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Transplant Year
20+ transplants
10-19 transplants
5-9 transplants
1-4 transplants
Nu
mb
er
of
Tra
ns
pla
nts
2010ISHLTAurora, JHLT, 2010
DIAGNOSIS IN PEDIATRIC LUNG RECIPIENTSBY YEAR OF TRANSPLANT
Age: 12-17 Years
0
25
50
75
100
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
% o
f T
ran
spla
nts
IPAH Cystic Fibrosis
2010ISHLTAurora, JHLT, 2010
This is a small field
• International pediatric lung transplant collaboration formed in 2004
• Number of multicentre descriptive reports published, most important being CMV care1, fungal infections2,3, and outcomes of mild rejection4
• Recent/ongoing studies re effect of transplantation on QoL, and impact of post-transplatation viral infections
1 Danziger-Isakov, Transplantation 2009, 2 Danziger-Isakov, JHLT 2008, 3 Liu, JHLT 2009, 4 Benden, Ped Transpl, 2010
LUNG TRANSPLANTATIONKaplan-Meier Survival by Age Group
(Transplants: January 1990 - June 2008)
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Years
Su
rviv
al (
%)
Adult (N=27,851)
Pediatric (N=1,174)
HALF-LIFE Adult = 5.2 Years; Pediatric = 4.6 Years
P = 0.9423
2010ISHLTAurora, JHLT, 2010
PEDIATRIC LUNG TRANSPLANTATIONKaplan-Meier Survival by Age Group
(Transplants: January 1990 - June 2008)
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
Su
rviv
al (
%)
<1 Year (N=84)
1-11 Years (N=334)
12-17 Years (N=756)
<1 year vs. 1-11 years: p = 0.3124<1 year vs. 12-17 years: p = 0.83871-11 years vs. 12-17 years: p = 0.0395
HALF-LIFE<1 Year: 6.4 Years1-11 Years: 6.0 Years12-17 Years: 4.3 Years
N at risk = 10N at risk = 17
N at risk = 20
2010ISHLTAurora, JHLT, 2010
PEDIATRIC LUNG TRANSPLANTATIONConditional Kaplan-Meier Survival by Age Group
(Transplants: January 1990 - June 2008)
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
Su
rviv
al (
%)
<1 Year (N=50)
1-11 Years (N=231)
12-17 Years (N=524)
<1 year vs. 1-11 year: p = 0.6485<1 year vs. 12-17 years: p = 0.13861-11 years vs. 12-17 years: p =0.0696
N at risk = 10
N at risk = 17
N at risk = 20
CONDITIONAL HALF-LIFE<1 Year: 8.8 Years1-11 Years: 8.7 Years12-17 Years: 6.1 Years
2010ISHLTAurora, JHLT, 2010
PEDIATRIC LUNG TRANSPLANTATION Kaplan-Meier Survival by Era
(Transplants: January 1988 - June 2008)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years
Su
rviv
al
(%)
1988-1994 (N=208)
1995-2001 (N=457)
2002-6/2008 (N=519)
HALF-LIFEUnconditional 1988-1994: 2.8 Years; 1995-2001: 4.3 Years; 2002-6/2008: 5.3Conditional 1988-1994: 7.1 Years; 1995-2001: 6.9 Years; 2002-6/2008: na
1988-1994 vs. 1995-2001: p = 0.08491988-1994 vs. 2002-6/2008: p < 0.00011995-2001 vs. 2002-6/2008: p = 0.0261
N at risk = 13
N at risk = 15
N at risk = 11
2010ISHLTAurora, JHLT, 2010
N=773
VARIABLE N Relative
Risk P-value
95% Confidence Interval
On ventilator 120 3.73 <0.0001 2.5 5.57
Year of transplant: 1991-1998 vs. 1999-6/2008 319 2.18 <0.0001 1.59 3.01
Double Lung transplant 746 0.40 0.0045 0.21 0.75
PEDIATRIC LUNG TRANSPLANT RECIPIENTS (1/1991-6/2008) Risk Factors For 1 Year Mortality/Graft Failure
2010ISHLTAurora, JHLT, 2010
N=773
PEDIATRIC LUNG TRANSPLANT RECIPIENTS (1/1991-6/2008) Risk Factors For 1 Year Mortality/Graft Failure
Continuous Factors (see figures)
Recipient age
Pediatric transplant center volume
2010ISHLTAurora, JHLT, 2010
0
0.5
1
1.5
2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Recipient Age
Re
lati
ve
Ris
k o
f 1
Ye
ar
Mo
rta
lity
p = 0.0394
PEDIATRIC LUNG TRANSPLANT RECIPIENTS (1/1991-6/2008) Risk Factors For 1 Year Mortality/Graft Failure
Recipient Age
2010ISHLTAurora, JHLT, 2010
0
0.5
1
1.5
2
2.5
3
0 5 10 15 20
Center Volume (cases per year)
Re
lati
ve
Ris
k o
f 1
Ye
ar
Mo
rta
lity
P = 0.0095
PEDIATRIC LUNG TRANSPLANT RECIPIENTS (1/1991-6/2008) Risk Factors For 1 Year Mortality/Graft Failure
Center Volume Pediatric Transplants
2010ISHLTAurora, JHLT, 2010
Indications for listing
• Children are only listed for transplant if:
– Predicted life expectancy without transplant is two years or less
– No contraindications
– Poor quality of life
– Full informed consent
Post transplant monitoringPaediatric aspects
Pulmonary complications
• Complications with graft are the main impediment to good long-term outcome, i.e.– Rejection– Infection– Bronchiolitis Obliterans Syndrome (BOS)
• BOS has multifactorial origin, but repeated rejection and infection are probable causes
• Early detection and treatment are essential
Graft monitoring, 1: Symptoms
• Rejection and lower respiratory infection can present with mild, non-specific symptoms– Dyspnoea– Reduced exercise tolerance– Cough– Low grade fever– Malaise
• The child and family must be educated as to the importance of these symptoms
Graft monitoring, 2: Lung function
• Most children over 4 years age can perform spirometry, following training
• Outcome measures (and quality control criteria) may need to be modified, e.g. report FEV0.75 rather than FEV1
• Monitor in clinic, but also at home
• Drop of greater than 10% should cause concern
WHICH ANIMATION…?...CANDLES?
…FLYING TOASTER?
…BALLOON?
Only for initial training or PEF
Too complex for the very young
Ideal for preschoolers
Graft monitoring, 2: Lung function
• Children aged 6 years and older can perform eNO manoeuvres using similar techniques to adults
• In younger children modified techniques are probably necessary
Graft monitoring, 2: Lung function
• Data from Estenne and colleagues suggest that gas mixing studies allow earlier detection of graft dysfunction than spirometry
• Although the single breath washout test is not possible in young children, a modified version of multiple-breath washout can be performed instead
Graft monitoring, 2: Lung function
• Lung function testing in infants is usually performed during (sedated) sleep
• Variety of techniques available, which mirror tests performed in adults
Forced expiratory maneuvers adapted for use in infants
Graft monitoring, 3: Transbronchial biopsy
• As for adults, is essential for distinguishing between rejection and infection
• Difficult to perform successfully with small bronchoscopes, but newer generation scopes may be better
• Use of X-ray screening is essential, and general anaesthesia via laryngeal mask airway is helpful
Transbronchial biopsy
Ext diam. 4.9mm 3.6mm 2.8mm
Int diam. 2.0mm 1.2mm 1.2mm
Age 4 yrs + 1 yr + from birth
Transbronchial biopsy
Ext diam. 4.9mm 3.6mm 2.8mm
Int diam. 2.0mm 1.2mm 1.2mm
Age 4 yrs + 1 yr + from birth
Ext diam. 4.9mm 4.0mm 2.8mm
Int diam. 2.0mm 2.0mm 1.2mm
Age 4 yrs + 1 yr + from birth
Graft monitoring, 3: Transbronchial biopsy
• Biopsies should be performed in sick children, where diagnosis is uncertain
• Use of routine biopsy in well children is controversial
• Most paediatric centres perform biopsies regularly in first year
Graft monitoring, 4: Radiology
• Plain radiographs performed regularly post-transplant, but don’t distinguish between rejection and infection
• Either process may be present with normal radiograph
Graft monitoring, 4: Radiology
• New generation of multislice scanners allow rapid acquisition of HRCT data
• Speed of scanner means that sedation is not necessary even in very young children
• Protocols MUST be adjusted to minimise radiation exposure
• What is the role?
Post transplant OB, inspiratory film
Post transplant OB, expiratory film
Post-transplant infections
• Primary viral infections more common in paediatric recipients as many will not have previous exposure
• Measles and varicella can be fatal post transplant
• Essential to immunise pre-transplant, and to advise family regarding precautions
Post-transplant infections
• Post transplant lymphoproliferative disease is much more common in children
• Presents clinically with lymphadenopathy, anaemia, low grade pyrexia, malaise…
• Possible to monitor quantitative EBV count by PCR, but is this of any help?
Post-transplant infections
• Also be aware of – CMV infection – respiratory viruses – PCP – fungi – Low grade bacterial infection
– As for adults
Non allogeneic causes of BOS
• Recent interest in role of gastrooesophageal reflux, bacterial infections
• Approach should be same as for adult subjects
Side-effects of immunosuppression
• Maintenance therapy usually triple:– ciclosporin or tacrolimus – azathioprine or MMF– corticosteroids
• As well as immunosuppression itself, all agents have specific side effects
• Common to adult patients, but still v important
Side-effects of immunosuppression
• Ciclosporin and tacrolimus are nephrotoxic, this is partly dose related and reversible, but there is also irreversible progressive component
• Marrow suppression with aza/MMF
• Diabetes mellitus, particularly in children with CF on tacrolimus
Other CF complications
• Bone density is abnormal in many children, particularly those with CF
• Also need to be aware of non-respiratory complications of CF
Growth failure
• Many children referred for transplant already have growth failure
• This is worsened by corticosteroids
• Reduce dose as much as possible
• Growth hormone is controversial
Do the lungs grow?
• Yes, provided the child remains healthy – Forced expiratory flows increase as expected,
suggesting that airways grow– Do alveoli multiply, or do they distend?
Psychosocial issues
• Many children are socially and physically immature prior to transplant
• Behavioural difficulties post transplant are common
• Greatest concern is non-adherence to therapy, particularly amongst adolescents
How is this delivered?
Child
Medical staff Nursing staffPharmacist Psychologist
Local paediatrician
Community team
Other medicaland surgicalteams
Non invasive Monitoringi.e. cardiac and respiratoryphysiology
Invasive Monitoringi.e. catheter studiesand bronchoscopy
Local pharmacist
Anaesthesia
Surgical staff
Child
Medical staff Nursing staffPharmacist Psychologist
School
GP Community nurses
Wider family and friends
Local paediatrician
What should the local paediatrician do?
Shared care
• Lung transplantation in children is uncommon
• Large centres produce better outcomes
• Only a small number of transplant centres are needed, and many patients will live a long way from the transplant centre
• Shared care with the local paediatrician or paediatric pulmonologist is essential
Shared care
• The local team will see the child regularly in clinic
• On each occasion– Spirometry– Full Blood Count– Renal function / blood biochemistry– Immunosuppressant blood levels
must be performed
Shared care
• Any concerns?
Phone the transplant centre
Shared care
• If a child presents unwell, with respiratory symptoms
– Remember that it is very difficult to distinguish rejection from infection
– Prompt treatment is essential
– Biopsy may be necessary
Shared care
• So, if a child presents unwell, with respiratory symptoms
Phone the transplant centre
(Unless, you have been running shared care for some time, you know the child well, and it is clear that the child does not have rejection)
Shared care
• If a child presents with gastroenteritis
– Check tacrolimus level and renal function– Ensure well hydrated– Then,
Phone the transplant centre
Shared care
• If a child presents with unusual symptoms, eg. Anaemia, malaise, lymphadenopathy, and the cause is not obvious..
Phone the transplant centre
Transplantation in infants
• Transplant programme at GOS started in 1988
• Lower age limit for lung transplantation has always been 4 years (height 100cm)
Background
• Reason for limit:1. Poor outcomes, why bother?2. Will some of these recipients be ventilated
prior to transplant?3. Will they have a longer post op ICU/hospital
course?4. Donor shortage5. Technical difficulties of surgery6. Difficult bronchoscopic biopsies7. Difficult lung function testing
CHOP experience
• Ro et al (CHOP) 1999• 48 children listed in 4 years – 19 were under 1
year• Diagnoses were:
– CHD with secondary PH (4)– PPH (3)– BPD (2)– Congenital pulmonary vein stenosis (7)– Alveolar proteinosis (2)– Chronic pneumonitis of infancy (1)
CHOP experience
• All 19 were ventilated prior to transplant• 5 were on ECMO• 10 died before transplant (inc all 5 on ECMO) with
median time from listing to death of 35 days• 9 were transplanted with median wait of 35 days• Median LoS post Tx was 56 days, vs 24 for
children• Rates of infection and rejection similar• Survival to discharge worse in infants• 1 year survival identical to older children (67%)
St Louis experience
• Lisanne et al, 2006• 37 infants transplanted between 1993 and 2005• 13 with SPB deficiency, 13 with other
parenchymal lung disease, 11 with pulmonary hypertension. First two groups ventilated prior to transplant, last wasn’t.
• 5-year post transplant survival was 50% for all 3 groups, but attrition on list was high (20% in infants with parenchymal lung disease, 50% in PH), even with median wait less than 2 months
• Long term function in survivors is acceptable
Is rejection less common?
• Ibrahim et al, St Louis, 2002• 100 lung recipients, of whom 26 were infants• Maintenance immunosupression similar for both
groups (CyA, aza, pred)• Much lower rate of early rejection, late rejection,
and recurrent rejection in infants • Similar results in cardiac recipients• Overall survival similar
Will they be ventilated pre-op?
• In many (most) cases, yes
• Infants have great capacity to grow new lung tissue, even after a difficult start, and we will be reluctant to list infants unless they clearly have end-stage disease
Will they have longer LoS?
• According to US data, yes
• St Louis report median LoS 35 days
• CHOP report median LoS 56 days
Donor shortage
• Data from UKT, April 2003 til April 2006 (3 years)
under 80 cm 19 offers
80-100 cm 25 offers
100-120cm 41 offers
where H offered but not L 49 offers
Surgery
• Early outcomes after infant cardiac transplantation and after lung transplantation in older subjects are now excellent
• No longer considered an issue in our centre
Transbronchial biopsy
Lung function testing
Summary
• Lung transplantation in infants is feasible, and satisfactory results can be obtained
• Many of the projected problems can/have been overcome
• There is probably an unmet demand for this service
• There are probably unused donors at present
• There are cost implications
So, should we change our policy?
Everything changes