Lung transplantation in children

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


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


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


PEDIATRIC LUNG TRANSPLANTATIONKaplan-Meier Survival by Age Group


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


PEDIATRIC LUNG TRANSPLANTATIONConditional Kaplan-Meier Survival by Age Group


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


PEDIATRIC LUNG TRANSPLANTATION Kaplan-Meier Survival by Era


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


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


N=773


Continuous Factors (see figures)

Recipient age

Pediatric transplant center volume


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


Recipient Age


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


Center Volume Pediatric Transplants


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


• Children aged 6 years and older can perform eNO manoeuvres using similar techniques to adults

• In younger children modified techniques are probably necessary


• 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


• 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








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 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?


• 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


(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,


Shared care

• If a child presents with unusual symptoms, eg. Anaemia, malaise, lymphadenopathy, and the cause is not obvious..


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


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

Documents

Lung transplantation in children