Infectious proxies and childhood leukaemia

Infectious proxies and Infectious proxies and childhood leukaemiachildhood leukaemia

UKCCS Update UKCCS Update

www.UKCCS.org.uk

http://www.ukccs.org.uk/

www.ukccs.org

Study populationStudy population Children (≤ 15 years) Children (≤ 15 years)

registered for primary registered for primary care with a General care with a General Practitioner (GP)Practitioner (GP)

CasesCases - ascertained from - ascertained from multiple sources:-multiple sources:-

Treating/referring Treating/referring hospitalshospitals

Cross-checks with Cross-checks with cancer registriescancer registries

ControlsControls – selected from – selected from primary care primary care population registers population registers and individually and individually matched to cases on:- matched to cases on:-

date of birth date of birth sex sex region of residence region of residence

UU

KK

CC

CC

SS

Measures of exposure to infectionMeasures of exposure to infection

Most directMost direct

Least directLeast direct

SerologSerologyy

Socio-Socio-demographicdemographicproxiesproxies

Clinical recordsClinical records

GP consultations in the first year of lifeGP consultations in the first year of life(controls N= 1031, 2-5 years old)(controls N= 1031, 2-5 years old)

non-infectious non-infectious diagnosis/symptomsdiagnosis/symptoms

N(%)N(%)

infectious infectious diagnosis/symptomsdiagnosis/symptoms

N(%)N(%)

3.0 (2.8 – 3.2)3.0 (2.8 – 3.2)3.9 (3.7– 4.1)3.9 (3.7– 4.1)mean mean (95%CI)(95%CI)

860 (83.4)860 (83.4)919 (89.1)919 (89.1)1+1+

171 (16.6)171 (16.6)112 (10.9)112 (10.9)00

GP consultations in the first GP consultations in the first year: mean (95% CI) ages 2-5 year: mean (95% CI) ages 2-5

yearsyears

3.3(2.9-3.6)3.3(2.9-3.6)3.0(2.8-3.2)3.0(2.8-3.2)Non-infectionNon-infection

4.5(4.2-4.9)4.5(4.2-4.9)3.9(3.7-4.1)3.9(3.7-4.1)InfectionInfection

ALLALL

N=425N=425ControlsControls

N=1031N=1031DiagnosiDiagnosis/s/

symptosymptomsms

At least one infectious At least one infectious diagnoses in the first month diagnoses in the first month

(neonatal) (neonatal)

ControlsControls

(%)(%)CasesCases

(%)(%)OR(95% OR(95% CI)CI)

AnyAny 18.118.1 23.823.8 1.4(1.1-1.4(1.1-1.9)1.9)

ConjunctivitisConjunctivitis 7.27.2 8.28.2 1.1(0.7-1.1(0.7-1.7)1.7)

URTIURTI 5.15.1 5.25.2 1.1(0.6-1.1(0.6-1.8)1.8)

Fungal Fungal 3.13.1 5.75.7 1.9(1.1-1.9(1.1-3.2)3.2)

GastrointestiGastrointestinalnal

1.21.2 1.41.4 1.4(0.5-1.4(0.5-3.7)3.7)

20

30

40

50

60

70

none one > one

Neonatal infections & age at ALL diagnosis Neonatal infections & age at ALL diagnosis

Number Mean(95% CI)

32445.2(43.8-46.6)

78 45.8(42.8-48.7)

2337.7(32.5-42.8)

Neonatalinfections

Age at diagnosis(months)

ALL (2-5 yrs) and infection< 1 ALL (2-5 yrs) and infection< 1 yryr

Compared to controls case children Compared to controls case children had: -had: -

More episodes of infectious illness More episodes of infectious illness Excess apparent from birthExcess apparent from birthNo obvious specificityNo obvious specificity

Within the case series: -Within the case series: - Children with more infections Children with more infections

tended to be diagnosed earliertended to be diagnosed earlier

Measures of exposure to infectionMeasures of exposure to infection

Most directMost direct

Least directLeast direct

SerologSerologyy

Socio-Socio-demographicdemographicproxiesproxies

Clinical recordsClinical records

Maternal Maternal illness illness reportsreports

Infectious diagnosis first year: Infectious diagnosis first year: UKCCS UKCCS controlscontrols >> 15mths old 15mths old

NumbNumberer

Mean (95% Mean (95% CI)CI)

Infectious diagnosisInfectious diagnosis 1288 1288 2.9(2.8-3.0)2.9(2.8-3.0)

- Birth order- Birth order 11 561561 2.9(2.7-3.0)2.9(2.7-3.0)

2+2+ 723723 2.9(2.8-3.0)2.9(2.8-3.0)

- Regular social contact outside the - Regular social contact outside the homehome

nono 606606 2.9(2.7-3.0)2.9(2.7-3.0)

yesyes 682682 2.9(2.8-3.1)2.9(2.8-3.1)

- Deprivation at birth- Deprivation at birth low/low/medmed

10931093 2.8(2.7-2.9)2.8(2.7-2.9)

highhigh 192192 3.3(3.0-3.6)3.3(3.0-3.6)

Infectious diagnosis first year: Infectious diagnosis first year: UKCCS UKCCS casescases >> 15mths old 15mths old

NumbNumberer

Mean (95% CI)Mean (95% CI)

Infectious diagnosisInfectious diagnosis 703 703 3.2(3.1-3.3)3.2(3.1-3.3)

- Birth order- Birth order 11 301301 2.7(2.5-2.9)2.7(2.5-2.9)

2+2+ 399399 3.6(3.4-3.7)3.6(3.4-3.7)


nono 387387 3.1(2.9-3.3)3.1(2.9-3.3)

yesyes 316316 3.3(3.1-3.5)3.3(3.1-3.5)


565565 3.0(2.9-3.2)3.0(2.9-3.2)

highhigh 136136 3.8(3.5-4.1)3.8(3.5-4.1)

Infectious diagnosis first year: Infectious diagnosis first year: UKCCS ALL UKCCS ALL controls & casescontrols & cases >>15 15

mthsmths Odds ratio (95% CI)Odds ratio (95% CI)

- Birth order- Birth order 11 0.9(0.6-1.4)0.9(0.6-1.4)

2+2+ 1.6(1.1-1.2)1.6(1.1-1.2)


nono 1.0(0.7-1.4)1.0(0.7-1.4)

yesyes 1.7(1.1-2.5)1.7(1.1-2.5)


1.1(0.9-1.3)1.1(0.9-1.3)

highhigh 2.7(1.2-6.0)2.7(1.2-6.0)

ALL and prior infectious ALL and prior infectious illness illness

From birth onwards, children who develop From birth onwards, children who develop ALL have more infectious illness episodes ALL have more infectious illness episodes than those who do notthan those who do not

The difference appears most marked in The difference appears most marked in those exposed to infectious challenge those exposed to infectious challenge from other childrenfrom other children

Infections first year: Infections first year: maternalmaternal reportreport of of

infection with GP visit infection with GP visit >>15 months15 months

Odds ratio (95% CI)Odds ratio (95% CI)

- Birth order- Birth order 11 0.7(0.5-1.0)0.7(0.5-1.0)

2+2+ 0.8(0.6-1.0)0.8(0.6-1.0)


nono 0.9(0.7-1.2)0.9(0.7-1.2)

yesyes 0.6(0.5-0.9)0.6(0.5-0.9)


0.7(0.6-0.9)0.7(0.6-0.9)

highhigh 0.8(0.5-1.4)0.8(0.5-1.4)

Infection (any) in the first year: Infection (any) in the first year:

UKCCS UKCCS controlscontrols

Mother’s Mother’s

report report GP infection recordGP infection record

YesYes No No Total (%)Total (%)

yesyes 758758 118118 876(68)876(68)

nono 297297 115115 412(32)412(32)

Total (%)Total (%) 1055(82)1055(82) 233(18)233(18) 1288(1001288(100))

Infection (any) in the first year: Infection (any) in the first year:

UKCCS UKCCS controlscontrols


report report GP infection recordGP infection record


yesyes 758758 118118 876(68)876(68)

nono 297297 115115 412(32)412(32)

Total (%)Total (%) 1055(82)1055(82) 233(18)233(18) 1288(1001288(100))

Ear infection in the first year: Ear infection in the first year: UKCCS UKCCS controlscontrols


report report Otitis media GP recordOtitis media GP record


yesyes 8484 146146 230(18)230(18)

nono 154154 904904 1058(82)1058(82)

Total (%)Total (%) 238(19)238(19) 1050(811050(81))

1288(1001288(100))

Ear infection in the first year: Ear infection in the first year: UKCCS UKCCS controlscontrols




yesyes 8484 146146 230(18)230(18)

nono 154154 904904 1058(82)1058(82)

Total (%)Total (%) 238(19)238(19) 1050(811050(81))

1288(1001288(100))

Ear infection in the first year: Ear infection in the first year: UKCCS UKCCS casescases




yesyes 6161 7777 138(17)138(17)

nono 102102 571571 673(83)673(83)

Total (%)Total (%) 163(20)163(20) 648(80)648(80) 811(100)811(100)

AgeAge

3 days3 days conjunctivitisconjunctivitis

9 months9 months URTI, ?otitis mediaURTI, ?otitis media

12 months12 months ColdCold

13 months13 months CoughCough


16 months16 months ConjunctivitisConjunctivitis

19 months19 months Chesty coughChesty cough

2 years 7 2 years 7 monthsmonths

PharyngitisPharyngitis


Chesty, wheezeChesty, wheeze

Infections recorded in GP notes, birth to diagnosis – control

AgeAge

3 days3 days conjunctivitisconjunctivitis

9 months9 months URTI, ?URTI, ?otitis mediaotitis media





19 months19 months Chesty coughChesty cough


PharyngitisPharyngitis


Chesty, wheezeChesty, wheeze

Infections recalled by mother, birth to diagnosis – control

AgeAge

2 weeks2 weeks Severe oral thrushSevere oral thrush

3 weeks3 weeks URTI, oral thrush, thrush nappy rashURTI, oral thrush, thrush nappy rash


7 weeks7 weeks ConjunctivitisConjunctivitis

8 weeks8 weeks Conjunctivitis persistsConjunctivitis persists


9 months9 months Otitis mediaOtitis media

10 months10 months Viral infectionViral infection


15 months15 months RingwormRingworm

16 months16 months DiarrhoeaDiarrhoea

18 months18 months Viral encephalitis Viral encephalitis hospitalised hospitalised


20 months20 months Nasal congestion, ?chronic tonsillitisNasal congestion, ?chronic tonsillitis

21 months21 months Smelly nasal discharge, ?sinusitisSmelly nasal discharge, ?sinusitis

2 years2 years URTI, conjunctivitis, otitis mediaURTI, conjunctivitis, otitis media

2 years 1 2 years 1 monthmonth

Otitis mediaOtitis media




Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk ALL ALL

Oral thrush

Infections recorded in GP notes, birth to diagnosis

AgeAge

2 weeks2 weeks SevereSevere oral thrush* oral thrush*

3 weeks3 weeks URTI, oral thrush, thrush nappy rashURTI, oral thrush, thrush nappy rash


7 weeks7 weeks Conjunctivitis Conjunctivitis

8 weeks8 weeks Conjunctivitis persistsConjunctivitis persists


9 months9 months Otitis mediaOtitis media

10 months10 months Viral infection Viral infection ColdCold


15 months15 months RingwormRingworm

16 months16 months DiarrhoeaDiarrhoea

18 months18 months Viral encephalitis Viral encephalitis hospitalised hospitalised


20 months20 months Nasal congestion, ?chronic tonsillitisNasal congestion, ?chronic tonsillitis

21 months21 months Smelly nasal discharge, ?sinusitisSmelly nasal discharge, ?sinusitis

2 years2 years URTI, conjunctivitis, URTI, conjunctivitis, otitis mediaotitis media

2 years 1 2 years 1 monthmonth





Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk ALL ALL

Infections recalled by mother, birth to diagnosis

*mother’s recall: one mouth infection that lasted 5 days

Mother also recalled:-

Otitis media x1, <3 months

Otitis media x1, 3-5 months

Chest infection x1, 2 years 7 months

UKCCS: UKCCS: primary care recordprimary care record current analysiscurrent analysis

Eczema in controls (typically diagnosed Eczema in controls (typically diagnosed in the first two-years of life) in the first two-years of life) in pressin press

Eczema and infection in leukaemia Eczema and infection in leukaemia cases and controls cases and controls in progressin progress

Combined analysis of obstetric and Combined analysis of obstetric and primary care data primary care data in progressin progress

UKCCS: UKCCS: primary care recordprimary care record current analysiscurrent analysis

As expectedAs expected, compared to children of birth order two , compared to children of birth order two or more, those of birth order one were at increased or more, those of birth order one were at increased risk of eczema (p<0.018) risk of eczema (p<0.018)

But, as has been shown by others, But, as has been shown by others, children children diagnosed with eczema before the age of two had diagnosed with eczema before the age of two had more prior clinically diagnosed infections recorded more prior clinically diagnosed infections recorded than children without eczema - RR = 1.26 (1.18 -than children without eczema - RR = 1.26 (1.18 -1.36) 1.36)

The difference was apparent from birth and The difference was apparent from birth and throughout the first two years of life throughout the first two years of life

Eczema in controls Eczema in controls in pressin press

Childhood cancer and deprivation: Childhood cancer and deprivation: interviewed cases (3835) and first choice interviewed cases (3835) and first choice

controls (7621)controls (7621) BirthBirth DiagnosisDiagnosis

AffluentAffluent 11 1.01.0 1.01.0

22 1.05(0.93-1.05(0.93-1.19)1.19)

1.10(0.98-1.10(0.98-1.24)1.24)

33 1.00(0.88-1.00(0.88-1.13)1.13)

1.06(0.93-1.06(0.93-1.19)1.19)

44 1.09(0.96-1.09(0.96-1.23)1.23)

1.15(1.01-1.15(1.01-1.29)1.29)

DeprivedDeprived 55 1.12(0.99-1.12(0.99-1.27)1.27)

1.22(1.07-1.22(1.07-1.38)1.38)

Childhood cancer and deprivation: all Childhood cancer and deprivation: all cases (4430) and first choice controls cases (4430) and first choice controls

(7663)(7663) BirthBirth DiagnosisDiagnosis

AffluentAffluent 11 1.01.0 1.01.0

22 1.04(0.92-1.04(0.92-1.18)1.18)

1.08(0.96-1.08(0.96-1.21)1.21)

33 0.99(0.87-0.99(0.87-1.12)1.12)

0.99(0.88-0.99(0.88-1.12)1.12)

44 1.03(0.91-1.03(0.91-1.17)1.17)

1.04(0.92-1.04(0.92-1.17)1.17)

DeprivedDeprived 55 0.95(0.84-0.95(0.84-1.07)1.07)

0.98(0.87-0.98(0.87-1.10)1.10)

Published UKCCS findings for Published UKCCS findings for infection/immunity based on interview infection/immunity based on interview data alone are broadly consistent with data alone are broadly consistent with

those of other case control studiesthose of other case control studies

www.ukccs.org

Documents

Infectious proxies and childhood leukaemia