Medically diagnosed infections and risk of
childhood leukaemia: a population-based
Jeffrey S Chang,1* Chia-Rung Tsai,1Yi-Wen Tsai2and Joseph L Wiemels3
1National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, R.O.C.,2Institute of Health and
Welfare Policy, National Yang-Ming University, Taipei, Taiwan, R.O.C. and3Department of Epidemiology and Biostatistics,
University of California, San Francisco, CA, USA
*Corresponding author. 1F No 367, Sheng-Li Road, Tainan 70456, Taiwan, R.O.C. E-mail: firstname.lastname@example.org
19 June 2012
Background Previous studies on the association between childhood infections
and childhood leukaemia have produced inconsistent results,
likely due to the recall error/bias of infection data reported by the
parents. The current study used a population-based and record-
based case–control design to evaluate the association between
childhood leukaemia and infections using the National Health
Insurance Research Database of Taiwan.
In all, 846 childhood acute lymphoblastic leukaemia (ALL) and 193
acute myeloid leukaemia (AML) patients newly diagnosed between
2000 and 2008, aged 41 and <10 years, were included. Up to four
controls (3374 for ALL and 766 for AML) individually matched to
each case on sex, birth date and time of diagnosis (reference date
for the controls) were identified. Conditional logistic regression was
performed to assess the association between childhood leukaemia
Having any infection before 1 year of age was associated with an
increased risk for both childhood ALL (odds ratio¼3.2, 95% confi-
dence interval 2.2–4.7) and AML (odds ratio¼6.0, 95% confidence
interval 2.0–17.8), with a stronger risk associated with more epi-
sodes of infections. Similar results were observed for infections
occurring 41 year before the cases’ diagnosis of childhood
Conclusions Children with leukaemia may have a dysregulated immune func-
tion present at an early age, resulting in more episodes of symp-
tomatic infections compared with healthy controls. However,
confounding by other infectious measures such as birth order and
day care attendance could not be ruled out. Finally, the results are
only relevant to the medically diagnosed infections.
Childhood leukaemia, infections, Taiwan
Leukaemia is the most common cancer among
children, accounting for approximately one-third of
all childhood cancers.1The two major histological
subtypes of childhood leukaemia are acute lympho-
blastic leukaemia (ALL) and acute myeloid leukaemia
Published by Oxford University Press on behalf of the International Epidemiological Association
? The Author 2012; all rights reserved. Advance Access publication 26 July 2012
International Journal Of Epidemiology 2012;41:1050–1059
by guest on December 28, 2015
(AML).2Approximately 10% of childhood leukaemia
cases can be explained by sex, age, race, exposure
(e.g. Down syndrome, neurofibromatosis);3,4however,
the causes of most childhood leukaemia remain
unknown. Greaves’5‘delayed infection’ hypothesis
states that microbial exposures during early childhood
are critical for the normal development of immune
function. A lack of sufficient early-life microbial chal-
lenges may result in a dysregulated immune response
to infections when encountered later in childhood,
leading to the development of leukaemia.5Kinlen’s6
‘population mixing’ hypothesis states that an elevated
increasing contact between susceptible and infected
individuals coming from different geographical popu-
lations. The ‘population mixing’ hypothesis suggests
the existence of a specific leukaemia-causing agent(s),
not; however, the common factor in both hypotheses
is the abnormal immune responses to infections,
which may lead to the development of childhood
Studies of the association between infections and
childhoodleukaemia have been
proxy measures of infections such as day care attend-
ance and birth order and with direct measures of in-
fections. In a meta-analysis of 14 studies, Urayama
et al.7reported an inverse association between day
care attendance and childhood ALL [combined odds
ratio (OR)¼0.76, 95% confidence interval (CI) 0.67–
0.87]. The association between childhood ALL and
birth order is less consistent than that for day care
attendance, with some showing an inverse associ-
ation,8–12whereas others reported either a positive
association13,14or a null association.15–19
Thirteen studies have examined the association
childhood leukaemia, mostly focusing on infections
ALL.10,12,13,15–17,20–26These studies have produced in-
consistent results on the relationship between child-
hood leukaemia and early childhood infections, with
seven reporting an inverse association,10,12,13,15,17,21,26
four reporting a null association20,23–25
Eleven10,12,13,15–17,20,21,23,25,26of the 13 studies relied
on self-report by the parents to obtain the child’s in-
fection history, which can be subject to recall error/
bias. Of the two studies that used medical records for
the child’s infection history, one reported a null asso-
ciation24and the other reported a positive associ-
population-based studies with cases and controls re-
cruited from the same source population, the partici-
pation of cases and controls was not 100%. This could
have affected the accuracy of the results if partici-
pants and non-participants had different characteris-
To avoid the potential problems associated with
recall error/bias and non-participation, the current
study used the population-based and record-based
case–control design to evaluate the association be-
tween childhood infections and childhood leukaemia
using data of 1039 childhood leukaemia cases and
4140 controls from the National Health Insurance
Research Database (NHIRD) of Taiwan.
Materials and Methods
This study was approved by the Institutional Review
Board of the National Health Research Institutes,
The data used for the current analysis came from
the NHIRD, which is a population-based database
generated for medical research using the administra-
tive and health claims data recorded by Taiwan’s
Taiwan’s NHI program is a single-payer programme
launched on 1 March 1995 and covers ?99% of the
23 million Taiwanese citizens. Health-care facilities
contracted under the NHI provide the insurees of
the NHI with inpatient care, ambulatory care, dental
care and prescription drugs. The claims data of the
NHI are routinely monitored by the Bureau of the
NHI for their accuracy and completeness.27
Two data sets of the NHIRD were used for subject
selection28: (i) Catastrophic Illness Dataset, which is
a data set containing health claims data associated
with serious illnesses, including cancer; and (ii) The
Longitudinal Health Insurance Database 2005, which
is a database containing the health claims data of 1
million enrollees randomly sampled from the 2005
NHIRD enrolment file. This 1 million-person random
sample is representative of the entire insured popula-
tion of Taiwan.
From the Catastrophic Illness Dataset, we identified
children newly diagnosed with leukaemia [ALL,
Revision, Clinical Modification (ICD-9-CM) code:
204.0 and AML, ICD-9-CM code: 205.0] between
January 1, 2000 and December 31, 2008, aged 41
year and <10 years. Patients diagnosed with malig-
nant tumours are eligible to apply for a certificate of
catastrophic illness to be exempted from all co-
payments. Because of this financial incentive, almost
everyone with cancer in Taiwan has a certificate of
catastrophic illness; thus, the identification of cancer
cases from the Catastrophic Illness Dataset should be
nearly 100%. In addition, to apply for the certificate of
catastrophic illness, one is required to have an official
INFECTION AND CHILDHOOD LEUKAEMIA
by guest on December 28, 2015
socioeconomic level in relation to childhood cancers. Int J
9Hjalgrim LL, Rostgaard K, Hjalgrim H et al. Birth weight
and risk for childhood leukemia in Denmark, Sweden,
Norway, and Iceland. J Natl Cancer Inst 2004;96:1549–56.
10Urayama KY, Ma X, Selvin S et al. Early life exposure to
infections and risk of childhood acute lymphoblastic leu-
kemia. Int J Cancer 2011;128:1632–43.
11Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J.
Association of childhood cancer with factors related to
pregnancy and birth. Int J Epidemiol 1999;28:631–39.
12van Steensel-Moll HA, Valkenburg HA, van Zanen GE.
Childhood leukemia and infectious diseases in the first
year of life: a register-based case-control study. Am J
13Jourdan-Da Silva N, Perel Y, Me ´chinaud F et al. Infectious
diseases in the first year of life, perinatal characteristics
and childhood acute leukaemia. Br J Cancer 2004;90:
14Ou SX, Han D, Severson RK et al. Birth characteristics,
maternal reproductive history, hormone use during preg-
nancy, and risk of childhood acute lymphocytic leukemia
by immunophenotype (United States). Cancer Causes
15Perrillat F, Clavel J, Auclerc MF et al. Day-care, early
common infections and childhood acute leukaemia: a
multicentre French case-control study. Br J Cancer 2002;
16Dockerty JD, Skegg DC, Elwood JM, Herbison GP,
Becroft DM, Lewis ME. Infections, vaccinations, and the
risk of childhood leukaemia. Br J Cancer 1999;80:1483–89.
17Neglia JP, Linet MS, Shu XO et al. Patterns of infection
and day care utilization and risk of childhood acute
lymphoblastic leukaemia. Br J Cancer 2000;82:234–40.
18Reynolds P, Von Behren J, Elkin EP. Birth characteristics
and leukemia in young children. Am J Epidemiol 2002;
19Rosenbaum PF, Buck GM, Brecher ML. Early child-care
and preschool experiences and the risk of childhood acute
20Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J.
Association of childhood leukaemia with factors related
to the immune system. Br J Cancer 1999;80:585–90.
21Chan LC, Lam TH, Li CK et al. Is the timing of exposure
to infection a major determinant of acute lymphoblastic
leukaemia in Hong Kong? Paediatr Perinat Epidemiol 2002;
22Roman E, Simpson J, Ansell P et al. Childhood acute
lymphoblastic leukemia and infections in the first year
of life: a report from the United Kingdom Childhood
Cancer Study. Am J Epidemiol 2007;165:496–504.
23Rosenbaum PF, Buck GM, Brecher ML. Allergy and in-
fectious disease histories and the risk of childhood acute
lymphoblastic leukaemia. Paediatr Perinat Epidemiol 2005;
24Cardwell CR, McKinney PA, Patterson CC, Murray LJ.
Infections in early life and childhood leukaemia risk: a
UK case-control study of general practitioner records. Br J
Cancer 2008;99: 1529–33.
25MacArthur AC, McBride ML, Spinelli JJ, Tamaro S,
Gallagher RP, Theriault GP. Risk of childhood leukemia
associated with vaccination, infection, and medication
Leukemia Study. Am J Epidemiol 2008;167:598–606.
26Rudant J, Orsi L, Menegaux F et al. Childhood acute leu-
kemia, early common infections, and allergy: the ESCALE
Study. Am J Epidemiol 2010;172:1015–27.
27Bureau of National Health Insurance, Department of
ID¼290 (8 June 2011, date last accessed).
28Bureau of National Health Insurance. National Health
Insurance Research Database. http://w3.nhri.org.tw/nhird//
brief_02.htm# (8 June 2011, date last accessed).
29Liu CY, Hung YT, Chuang YL et al. Incorporating devel-
opment stratification of Taiwan townships into sampling
design of large scale health interview survey. J Healthc
30Simpson J, Smith A, Ansell P, Roman E. Childhood leu-
kaemia and infectious exposure: a report from the United
Kingdom Childhood Cancer Study (UKCCS). Eur J Cancer
31Schuz J, Morgan G, Bohler E, Kaatsch P, Michaelis J.
Atopic disease and childhood acute lymphoblastic leuke-
mia. Int J Cancer 2003;105:255–60.
32Chang JS, Zhou M, Buffler PA, Chokkalingam AP,
Metayer C, Wiemels JL. Profound deficit of IL10 at
birth in children who develop childhood acute lympho-
blastic leukemia. Cancer Epidemiol Biomarkers Prev 2011;20:
33de Visser KE, Eichten A, Coussens LM. Paradoxical roles
of the immune system during cancer development. Nat
Rev Cancer 2006;6:24–37.
34Lonkar P, Dedon PC. Reactive species and DNA damage
in chronic inflammation: reconciling chemical mechan-
35Greaves M, Buffler PA. Infections in early life and risk of
childhood ALL. Br J Cancer 2009;100:863.
36McLoughlin RM, Mills KH. Influence of gastrointestinal
commensal bacteria on the immune responses that me-
diate allergy and asthma. J Allergy Clin Immunol 2011;127:
1097–107; quiz 108–09.
37Penders J, Thijs C, Vink C et al. Factors influencing the
composition of the intestinal microbiota in early infancy.
38Kwan ML, Buffler PA, Abrams B, Kiley VA. Breastfeeding
and the risk of childhood leukemia: a meta-analysis.
Public Health Rep 2004;119:521–35.
39Kaye SA, Robison LL, Smithson WA, Gunderson P,
King FL, Neglia JP. Maternal reproductive history and
birth characteristics in childhood acute lymphoblastic leu-
kemia. Cancer 1991;68:1351–55.
INFECTION AND CHILDHOOD LEUKAEMIA
by guest on December 28, 2015