What are the Determining Factors in Disease Continuing from Childhood to Adulthood?

Andrew Bush MD FRCP FRCPCH

Imperial School of Medicine &Royal Brompton Hospital

Email: a.bush@rbht.nhs.uk

Importance of Early Life Events Aspects of Lung Growth

Important Diseases Wheezing Syndromes Cystic Fibrosis Chronic Lung Disease of Prematurity

Summary and Conclusions

Beam me down Scotty

An adult view of childhood events

Normal Lung Development

1. The bronchial tree is developed by 16/40 And even beyond to bronchioles

2. Alveoli largely develop after birth But only for a very short time

3. Preacinar vessels follow airway development, intra-acinar those of alveoli

Acinus = 3 generations respiratory bronchioles (no cartilage), alveolar ducts & sacs

Postnatal Alveolar Development Alveolar numbers at birth:

variously n = 0 - 5 X 106

Completion of alveolarizationvariously age 2 - 20 years

Probable rapid phase in first 6 months, slow phase ending by two years

Importance of Early Life Events Aspects of Lung Growth

Important Diseases Wheezing Syndromes Cystic Fibrosis Chronic Lung Disease of

Prematurity

Summary and Conclusions

Infant Wheezing Phenotypes

Transient wheeze Non-atopic (viral

induced) wheeze Atopic wheeze

Stein RT et al Thorax 1997;52:946-52

Martinez FDPediatrics 2002;109:362-7

???

The Tucson Study

Evolution of lung function in Infant Wheezing Phenotypes

Transient Wheezers (VAW, VIW)

Have abnormal lung function soon after birth

Have abnormal lung function before the 1st wheezing episode

Do not have AHR Do not have eosinophilic

inflammation Do not respond to prophylactic

inhaled steroids

Virus Associated Wheeze and BAL Cytology

Clin Exp Allergy 1997; 27: 1027-1035

•Blind non-FOB BAL•Children anaesthetised for routine surgery

•No evidence of airway eosinophilia in VAW

Further evolution of Lung Function

Dunedin Multidisciplinary Health Study

Sears, NEJM 2003

60

70

80

90

100

7 10 14 21 28 35 42

age at review (years)

FE

V1/

FV

C

c

mwb

wb

a

sa

Lung function Changes over time:ICS therapy rarely used!

VAW – Lifelong Problem? FU of 1964 cohort

177 subjects, age 45-50 years

Adjust for age, height, gender, smoking, socio-economic status

Chest 2003; 124: 18-24

0

0.5

1

1.5

2

2.5

3

Contr VAW

FEV1

P<0.05

Asth

P=NS

VAW – Lifelong Problem? Rate of decline of

FEV1 over 2 years

Conclusion VAW decline faster

than normal, having attained normal lung function in adult life

Chest 2003; 124: 18-24

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Contr VAW

^FEV1

P<0.05

Asth

P=NS

LCCF Studies Five London CF centres

RBH, GOSH, Kings, Lewisham, Royal London

Infant and Preschool Lung Function Tests, Institute of Child Health

Prof J Stocks, Drs Per Gustafsson, Ranganathan, Aurora, Ljungberg

47 CF infants, 187 controls

Raised volume forced expiratory manoeuvres

-50050100150-300

0

300

600

900

F=0

Volume (mL)

Flo

w (

mL

.s-1)

Raised volume F-V curve

Partial F-V curve

V’maxFRC

Full and partial flow-volume curves

FEV0.4 vs length in healthy infants and infants with CF: repeated measures

FE

V 0.4

(mL )

Length (cm)

Healthy

CF

LCCF Infant Studies: Conclusions

Airway obstruction at diagnosis even in those with no apparent respiratory illness

No ‘catch-up’ growth over next 6 months despite treatment

Lancet 2001; 358: 1964-5; BlueJ 2002; 166: 1350-7; BlueJ (in press)

BlueJ 2004; 169: 1209-16

Adult Physicians

50 yr old man, 40 packyear history.

Diagnosis?

HRCT in adolescent survivor of preterm birth

PFTs in “resolving” CLD

Patients 33 preterms, 24-31/40, BW 589-1891 gms

Methods Studied at 43 weeks post-conception, then three monthly for one year; Vmax.FRC, mean SaO2 and SaO2 variability

Arch Dis Child 1997; 76: F113-F117

Change in Lung Function in the First Year of Life

There is no evidenceof catch up growth

154 subjects seen in mid-childhood

95 subjects ‘found’

80 suitable for study10 living abroad5 cerebral palsy

59 not located

8 DNA12 refused

60 recruited into the index study group

60 attended for visit 1 55 attended for visit 2

250 survivors in mid-childhood

317 entered into study

67 died

Lung Function in LBW aet 7 Yrs

Patients 130 children BW < 2 kg; 120 unselected schoolchildren

Methods All neonatal data saved; Flow volume loops (FEV0.75 not FEV1)

Statistical analysis Four groups: no illness, oxygen only, IPPV, oxygen dependant

Arch Dis Child 1989; 64: 1284-93

Lung Function age 7-9 years: effect of birth weightArch Dis Child 1989; 64: 1284-93

Lung Function in LBW aet 7 Yrs

Conclusions 1. Children with chronic lung disease had

impaired lung function age 7-9 years

2. Low birth weight, maternal smoking and male sex had an adverse effect in the more mildly affected children

Arch Dis Child 1989; 64: 1284-93

Lung function at age 20-22 years

Birthweight in Index Study Group SGA Subjects

200018001600140012001000800600

zME

F 25

75

2

1

0

-1

-2

-3

-4

-5

Birth Weight in SGA, not AGA babies determinesLung function in adulthood, r2 = 0.44, p<0.001

Exercise stage

RecoveryFinal exerciseRest

Mea

n a

nd

95

% C

I Q

eff z

sco

res

.5

0.0

-.5

-1.0

-1.5

AGA

SGA

Control

Exercise data at age 20-22 yearrs

Importance of Early Life Events Aspects of Lung Growth

Important Diseases Wheezing Syndromes Cystic Fibrosis Chronic Lung Disease of Prematurity

Summary and Conclusions

Overall Conclusions Intrauterine Factors are Vital

Especially SGA, smoking, maternal atopy, maternal hypertension

The first three years of life are Pivotal Offers a window for intervention

We need to find ethical ways of researching these difficult questions