Prof. Leo Kinlen

An infective basis in childhood Leukaemia: the evidence of epidemiology

INFECTION-LINKED CANCERS

Primary liver cancer Hepatitis B virus

Primary liver cancer Hepatitis C virus

Burkitt’s lymphoma Epstein-Barr virus

Cervix cancer Human Papillomavirus types 16, 18

Penis cancer Human Papillomavirus types 16, 18

Adult T-cell leukaemia Human T-cell leukaemia virus

Kaposi’s sarcoma Human herpes virus 8

Nasopharynx cancer Epstein-Barr virus

Stomach cancer Helicobacter pylori

Hodgkin’s disease Epstein-Barr virus

Post-transplant lymphoma Epstein-Barr virus

Oro-pharynx cancer Human Papillomavirus type 16

Bladder cancer Schistosoma haematobium

Cholangiocarcinoma Opisthorcis viverrini

Squamous cell skin cancer in EV* Human Papillomavirus types 5 & 8

* Epidermodysplasia verruciformis

The Infective Hypothesis

• Childhood leukaemia is a rare response to a common, but unidentified, infection.

• When appreciable numbers of susceptible and infected individuals first mix, a localised (frequently sub-clinical) epidemic of the underlying infection is promoted.

• This epidemic leads to an excess of cases of the uncommon complication, childhood leukaemia.

POLIOMYELITIS MORTALITY (MALES 20-64) BY SOCIAL CLASS 1950-53

Social Class Observed Deaths Relative Risk

V 29 1.00

IV 58 1.50

III 300 2.15

II 132 4.08

I 59 7.02

Rural-Urban Population Mixing

• Susceptible individuals are more prevalent in rural areas (less opportunity for exposure).

• When rural populations mix with urban populations on a large scale, the excess risk of childhood leukaemia might be detected.

• Variety of ways in which this mixing can occur, but the basic infective hypothesis remains the same.

LEUKAEMIA 0-14 YEARS. RURAL EVACUEE AREAS

Mixing Ratio Evacuees:local children

Population Observed No. Relative Risk 95% CI

< 0.2 : 1 580,927 61 1.00

- 0.4 : 1 583,426 78 1.27 (0.91 , 1.80)

> 0.4 : 1 585,855 90 1.47 (1.07 , 2.06)

Trend p <0.05

LEUKAEMIA AT 0-4 YEARS: O/E (O) BY DENSITY OF OIL WORKERS IN RURAL SCOTLAND

OIL WORKER DENSITY

PRE-MIXING (1974 - 78)

POST-MIXING(1979 – 83)

Low 1.09 (19) 0.70 (11)

Medium 1.10 (19) 0.93 (15)

High 1.05 (17) 1.87 (31)**

CHILDHOOD LEUKAEMIA IN EARLY GROWTH PERIOD (1946-65) OF NEW TOWNS: O/E RATIOS

Age Rural Overspill

0-4 years 2.75*** (20) 0.95 (22)

5-14 years 0.64 (3) 0.91 (22)

0-14 years 1.92** (23) 0.93 (44)

**p<0.01, ***p<0.001

LEUKAEMIA IN COHORTS OF ORKNEY AND SHETLAND CHILDREN

Age-groupWartime

O/E Ratio (Obs)Post-war

O/E Ratio (Obs)

0-4 yrs 5.13** (4) 1.28 (2)

5-14 yrs 2.96* (5) 0.64 (1)

Total 3.64** (9) 1.06 (3)

*p<0.05 **p<0.01

EXTREME RURAL POPULATION MIXING AND CHILDHOOD LEUKAEMIA (0-14 YEARS): UK STUDIES

Type of Area Observed Expected O/E ratio P-valueRural New Towns 23 14.59 1.58 *

High Rural ‘Oil’ Areas 28 31.43 1.53 **

Rural ‘Military’ Areas 71 43.29 1.65 **

Growth Local Authority Areas 81 54.74 1.40 **

‘High Rural Evacuee’ Areas 90 60.99 1.47 *

Constructions Projects 130 94.89 1.37 ***

Wartime Orkney and Shetland 9 2.47 3.81 *

Growth Rural Census Tracts 58 40.56 1.43 *

TOTAL 490 342.96 1.43 ***

Childhood Leukaemia (0-14 yrs) in the High Category of Similar Degrees of Urban and Rural Population Mixing

URBAN RURAL

Study O/E ratio Obs No O/E ratio Observed

New Towns 0.93 44 1.58* 23

Military Areas 1.12 226 1.64** 71

‘North Sea Oil’ Areas 0.96 53 1.53** 48

Evacuee Areas 0.92 80 1.47* 90

Total 1.06 226 1.59*** 142

RURAL POPULATION MIXING (RPM) AND C.L. (0-14 YRS): EXTREME CATEGORY IN STUDIES OUTSIDE UK

Country Study Type Observed Expected O/E Ratio CL/ALL 1st Author, Yr

France Growth Communes (M)

8 6.7 1.19 CL Laplanche 1994

N.Z. New forestry (M)

14 16.6 0.84 CL Dockerty 1996

Hong Kong (New Terr.)

Rural New Towns

9 0.2 40.1*** ALL Alexander 1997

Canada (Ontario)

Growth Census Subdivisions

85 67.6 1.26* ALL Koushik 2001

France La MancheDept-La Hague

6 1.7 3.53* ALL Boutou 2002

U.S. Growth Rural Counties

9 2.1 4.30** ALL Wartenberg 2004

TOTAL 131 94.9 1.38***

CASE-CONTROL STUDY OF LEUKAEMIA AT 0-4 YRS BY PATERNAL OCCUPATIONAL CONTACT

Occupation Levels Cases Controls OR 95%CI trend

Most rural

Medium and low 114 504 1.00

High 71 266 1.18 0.85, 1.64

Very high 11 14 3.47 1.54, 7.85 p=0.02

Intermediate rural

Medium and low 293 1152 1.00

High 121 537 0.89 0.70, 1.12

Very high 19 43 1.74 1.00, 3.03 p=0.79

Most urban

Medium and low 204 787 1.00

High 120 532 0.87 0.68, 1.12

Very high 17 45 1.46 0.82, 2.60 p=0.86

RISKS OF A.L.L. (0-14 yrs) BY BIRTH ORDER

Birth order Number of cases Adj. Odds Ratio 95% C.I.

1 1255 1.00

2 1029 0.92 0.82-1.04

3 404 0.84 0.71-0.99

4 158 0.72 0.56-0.93

5 53 0.72 0.48-1.06

>6 43 0.52 0.34-0.80

p for trend <0.001 (Dockerty et al. 2001)

CASE-CONTROL STUDIES OF EARLY DAY CARE

Start of early child care Number Exposed

Expected Odds Ratio

Reference

>3 months at ages 0-1 yrs 4 14.3 0.28 Petridou et al 1993

Not defined, but duration was greater among 255 cases than 760 controls Rosenbaum et al 2000

<6 months of age 165 181.3 0.91 Neglia et al 2000

<2 yrs of age 35 71.4 0.49 Infante-Rivard et al 2000

Not defined 92 124.3 0.74 Ma et al 2002

<6 months of age 24 48 0.50 Perrillat et al 2002

<3 months of age 61 101.6 0.60 Jourdan-DaSilva 2004

Not defined, but 97 cases and 303 controls showed no difference Dockerty et al 1999

CHILDHOOD LEUKAEMIA IN THE HIGH EXPOSURE CATEGORY OF RURAL POPULATION MIXING IN DIFFERENT STUDIES

TYPE OF AREA 2-6 yrs Rem. 0-14 yrs

Obs (Exp) Obs (Exp)Rural New Towns 17 (7.49) 6 (7.10)

Rural ‘Military’ Areas 30 (27.62) 41 (15.69)

High Rural ‘Oil’ Areas 23 (17.49) 25 (13.94)

Commuting-Increase Areas 43 (29.08) 36 (22.12)

‘High Rural Evacuee’ Areas 53 (31.15) 37 (36.65)

Construction sites 60 (47.66) 70 (47.14)

Growth Local Authority Areas 32 (28.73) 49 (29.01)

Wartime Orkney and Shetland 3 (1.14) 6 (1.59)

TOTAL 265 (190.25) 266 (173.35)

Over all O/E ratios 1.39*** 1.53***

*p<0.05, **p<0.01, ***p<0.001

RECENTLY IDENTIFIED INFECTIVE AGENTS

Disease Infective Agent

Peptic ulcer Helicobacter Pylori

Whipple disease Tropheryma Whippelii

Creutzfeld-Jakob disease Prion-protein

Guillain-Barre syndrome Campylobacter jejuni

Lyme disease Borrelia burgdorferi

Welcome to the

International Scientific Conference

for

Childhood Leukaemia

incidencecausal mechanisms

prevention