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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
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