1. Infectious proxies and childhood leukaemia UKCCS Update www.UKCCS.org.uk

2. www.ukccs.org

3. Study population  Children (≤ 15 years) registered for primary care with a General Practitioner (GP) Cases - ascertained from multiple sources:-  Treating/referring hospitals  Cross-checks with cancer registries Controls – selected from primary care population registers and individually matched to cases on:-  date of birth  sex  region of residence

4. UKCCS

7. Measures of exposure to infection Most direct Least direct SerologySocio-demographicproxies Clinical records

10. GP consultations in the first year of life (controls N= 1031, 2-5 years old) non-infectious diagnosis/symptoms non-infectious diagnosis/symptoms N(%) N(%) infectious diagnosis/symptoms N(%) N(%) 3.0 (2.8 – 3.2) 3.9 (3.7– 4.1) mean (95%CI) 860 (83.4) 919 (89.1) 1+ 171 (16.6) 112 (10.9) 0

11. GP consultations in the first year: mean (95% CI) ages 2-5 years 3.3(2.9-3.6)3.0(2.8-3.2)Non-infection 4.5(4.2-4.9)3.9(3.7-4.1)InfectionALLN=425ControlsN=1031Diagnosis/symptoms

12. At least one infectious diagnoses in the first month (neonatal) Controls(%)Cases(%) OR(95% CI) Any18.123.81.4(1.1-1.9) Conjunctivitis7.28.21.1(0.7-1.7) URTI5.15.21.1(0.6-1.8) Fungal3.15.71.9(1.1-3.2) Gastrointestinal1.21.41.4(0.5-3.7)

13. Neonatal infections & age at ALL diagnosis Number Mean(95% CI) 324 45.2(43.8-46.6) 78 45.8(42.8-48.7) 23 37.7(32.5-42.8) Neonatal infections Age at diagnosis (months)

14. ALL (2-5 yrs) and infection< 1 yr Compared to controls case children had: -  More episodes of infectious illness  Excess apparent from birth  No obvious specificity Within the case series: -  Children with more infections tended to be diagnosed earlier

15. Measures of exposure to infection Most direct Least direct SerologySocio-demographicproxies Clinical records Maternal illness reports

18. Infectious diagnosis first year: UKCCS controls > 15mths old Number Mean (95% CI) Infectious diagnosis 12882.9(2.8-3.0) - Birth order 15612.9(2.7-3.0) 2+7232.9(2.8-3.0) - Regular social contact outside the home no6062.9(2.7-3.0) yes6822.9(2.8-3.1) - Deprivation at birth low/med10932.8(2.7-2.9) high1923.3(3.0-3.6)

19. Infectious diagnosis first year: UKCCS cases > 15mths old Number Mean (95% CI) Infectious diagnosis 7033.2(3.1-3.3) - Birth order 13012.7(2.5-2.9) 2+3993.6(3.4-3.7) - Regular social contact outside the home no3873.1(2.9-3.3) yes3163.3(3.1-3.5) - Deprivation at birth low/med5653.0(2.9-3.2) high1363.8(3.5-4.1)

20. Infectious diagnosis first year: UKCCS ALL controls & cases >15 mths Odds ratio (95% CI) - Birth order 10.9(0.6-1.4) 2+1.6(1.1-1.2) - Regular social contact outside the home no1.0(0.7-1.4) yes1.7(1.1-2.5) - Deprivation at birth low/med1.1(0.9-1.3) high2.7(1.2-6.0)

21. ALL and prior infectious illness  From birth onwards, children who develop ALL have more infectious illness episodes than those who do not  The difference appears most marked in those exposed to infectious challenge from other children

22. Infections first year: maternal report of infection with GP visit >15 months Odds ratio (95% CI) - Birth order 10.7(0.5-1.0) 2+0.8(0.6-1.0) - Regular social contact outside the home no0.9(0.7-1.2) yes0.6(0.5-0.9) - Deprivation at birth low/med0.7(0.6-0.9) high0.8(0.5-1.4)

23. Infection (any) in the first year: UKCCS controls Mother’sreport GP infection record YesNo Total (%) yes758118876(68) no297115412(32) 1055(82)233(18)1288(100)

24. Infection (any) in the first year: UKCCS controls Mother’sreport GP infection record YesNo Total (%) yes758118876(68) no297115412(32) 1055(82)233(18)1288(100)

25. Ear infection in the first year: UKCCS controls Mother’sreport Otitis media GP record YesNo Total (%) yes84146230(18) no1549041058(82) 238(19)1050(81)1288(100)

26. Ear infection in the first year: UKCCS controls Mother’sreport Otitis media GP record YesNo Total (%) yes84146230(18) no1549041058(82) 238(19)1050(81)1288(100)

27. Ear infection in the first year: UKCCS cases Mother’sreport Otitis media GP record YesNo Total (%) yes6177138(17) no102571673(83) 163(20)648(80)811(100)

28. Age 3 days conjunctivitis 9 months URTI, ?otitis media 12 months Cold 13 months Cough 15 months Cough 16 months Conjunctivitis 19 months Chesty cough 2 years 7 months Pharyngitis 2 years 8 months Chesty, wheeze Infections recorded in GP notes, birth to diagnosis – control

29. Age 3 days conjunctivitis 9 months URTI, ?otitis media 12 months Cold 13 months Cough 15 months Cough 16 months Conjunctivitis 19 months Chesty cough 2 years 7 months Pharyngitis 2 years 8 months Chesty, wheeze Infections recalled by mother, birth to diagnosis – control

30. Age 2 weeks Severe oral thrush 3 weeks URTI, oral thrush, thrush nappy rash 6 weeks Severe oral thrush 7 weeks Conjunctivitis 8 weeks Conjunctivitis persists 7 months Cold 9 months Otitis media 10 months Viral infection 11 months Conjunctivitis 15 months Ringworm 16 months Diarrhoea 18 months Viral encephalitis  hospitalised 19 months Cough 20 months Nasal congestion, ?chronic tonsillitis 21 months Smelly nasal discharge, ?sinusitis 2 years URTI, conjunctivitis, otitis media 2 years 1 month Otitis media 2 years 6 months Otitis media 2 years 8 months Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk  ALL Oral thrush Infections recorded in GP notes, birth to diagnosis

31. Age 2 weeks Severe oral thrush* 3 weeks URTI, oral thrush, thrush nappy rash 6 weeks Severe oral thrush 7 weeks Conjunctivitis 8 weeks Conjunctivitis persists 7 months Cold 9 months Otitis media 10 months Viral infection Cold 11 months Conjunctivitis 15 months Ringworm 16 months Diarrhoea 18 months Viral encephalitis  hospitalised 19 months Cough 20 months Nasal congestion, ?chronic tonsillitis 21 months Smelly nasal discharge, ?sinusitis 2 years URTI, conjunctivitis, otitis media 2 years 1 month Otitis media 2 years 6 months Otitis media 2 years 8 months Unwell for 10 days, yellow tinge, blue lips, loose motions, leg pains, won’t walk  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

34. UKCCS: primary care record current analysis  Eczema in controls (typically diagnosed in the first two-years of life) in press  Eczema and infection in leukaemia cases and controls in progress  Combined analysis of obstetric and primary care data in progress

35. UKCCS: primary care record current analysis  As expected, compared to children of birth order two or more, those of birth order one were at increased risk of eczema (p<0.018)  But, as has been shown by others, children diagnosed with eczema before the age of two had more prior clinically diagnosed infections recorded than children without eczema - RR = 1.26 (1.18 - 1.36)  The difference was apparent from birth and throughout the first two years of life Eczema in controls in press

38. Childhood cancer and deprivation: interviewed cases (3835) and first choice controls (7621) BirthDiagnosis Affluent11.01.0 21.05(0.93-1.19)1.10(0.98-1.24) 31.00(0.88-1.13)1.06(0.93-1.19) 41.09(0.96-1.23)1.15(1.01-1.29) Deprived51.12(0.99-1.27)1.22(1.07-1.38)

39. Childhood cancer and deprivation: all cases (4430) and first choice controls (7663) BirthDiagnosis Affluent11.01.0 21.04(0.92-1.18)1.08(0.96-1.21) 30.99(0.87-1.12)0.99(0.88-1.12) 41.03(0.91-1.17)1.04(0.92-1.17) Deprived50.95(0.84-1.07)0.98(0.87-1.10)

41. Published UKCCS findings for infection/immunity based on interview data alone are broadly consistent with those of other case control studies

45. www.ukccs.org