American Journal of Epidemiology Vol. 189, No.

10
© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of DOI: 10.1093/aje/kwaa062
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Advance Access publication:
April 23, 2020

Original Contribution

History of Early Childhood Infections and Acute Lymphoblastic Leukemia Risk

Among Children in a US Integrated Health-Care System

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Libby M. Morimoto∗, Marilyn L. Kwan, Kamala Deosaransingh, Julie R. Munneke, Alice Y. Kang,
Charles Quesenberry, Jr., Scott Kogan, Adam J. de Smith, Catherine Metayer, and
Joseph L. Wiemels
∗ Correspondence to Dr. Libby M. Morimoto, School of Public Health, University of California, Berkeley, 1995 University Avenue,
Suite 460, Berkeley, CA 94704 (e-mail: libbym@berkeley.edu).

Initially submitted November 12, 2019; accepted for publication April 14, 2020.

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute
lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life
infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote
risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated
health-care system in the United States. Cases of ALL (n = 435) diagnosed between 1994–2014 among children
aged 0–14 years, along with matched controls (n = 2,170), were identified at Kaiser Permanente Northern
California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections
during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life
was not associated with ALL risk (odds ratio (OR) = 0.85, 95% confidence interval (CI): 0.60, 1.21). However,
infections with at least 1 medication prescribed (i.e., more “severe” infections) were inversely associated with risk
(OR = 0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded
to include medication-prescribed infections throughout the subjects’ lifetime (OR = 0.52, 95% CI: 0.32, 0.85).

childhood ALL; childhood leukemia; early-life infections; medical record

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CI, confidence interval; KPNC, Kaiser
Permanente Northern California; OR, odds ratio; VDW, Virtual Data Warehouse.

A rich and consistent literature has shown that patterns of and vaccinations (8, 9). Studies of population mixing within
infection influence childhood acute lymphoblastic leukemia new towns provide evidence that specific infections might
(ALL) risk. Greaves proposed a “delayed infection” hypoth- influence risk (10); however, no specific postnatal infection
esis that leukemia follows a 2-hit model, in which the first has yet been identified that precipitates ALL.
hit occurs in utero, producing a preleukemic clone, and a While surrogate measures of postnatal infectious expo-
second hit occurs postnatally (1, 2). Exposure to infectious sures have consistently been associated with ALL risk, the
agents might influence the occurrence of that second hit lack of a specific infection or leukemic agent has made it
during early childhood. It is surmised that early exposure to difficult to directly measure the association of exposure to
a variety of infections “educates” and modulates the immune infectious agents and subsequent responses. Most studies
system, thereby lessening any leukemogenic-stimulating, have used history of infections as a measure of exposure,
aberrantly strong reactions to infections or other environ- with generally mixed results (3, 11). However, in an exam-
mental factors that might lead to damaging mutations. This ination of the United Kingdom Childhood Cancer Study
idea is strongly supported by several studies of reduced risk (UKCCS), the number of physician-diagnosed infections
of ALL and exposure to childhood contacts, and other surro- during the first year of life was higher among case children
gate measures of early immune stimulation such as daycare (odds ratio (OR) = 1.4, 95% confidence interval (CI): 1.1,
attendance (3–5), larger family size/higher birth order (6, 7), 1.9; P < 0.05) relative to controls (12); a subsequent UKCCS

1076 Am J Epidemiol. 2020;189(10):1076–1085

 Early Childhood Infections and ALL Risk 1077

analysis found that this increased risk was specific to devel- if the child had Down syndrome (n = 35), had a prior history
oping ALL after 2 years of age (13). Similar results were of cancer (n = 4), or was not continuously enrolled in the
observed in a population-based analysis of national health KPNC health plan for at least 1 year after birth (n = 10).
records in Taiwan. When compared with controls, Taiwanese Five control subjects for each case were randomly sampled
children who developed leukemia were more likely to have with replacement from the membership data set, individually
had infections diagnosed by a physician in their first year of matched by age at diagnosis (within 365 days), calendar
life (OR = 3.18, 95% CI: 2.17, 4.66) and in any period before year of cancer diagnosis, sex, race, Hispanic ethnicity, and
diagnosis (censored 1 year prior to diagnosis, OR = 3.90, age at KPNC enrollment, using the incidence-density sam-
95% CI: 2.61, 5.81) with a dose-response relationship (14). pling technique to obtain a set of controls representative
These results from unbiased population clinical records are of the underlying pool of eligible cohort members (20).
provocative and raise the question of whether physician- Web Figure 1 (available at https://academic.oup.com/aje)
diagnosed infections early in life are not a measure of expo- describes the relationships between ALL, infections, and

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sure to infectious agents, but rather, a reflection of a stronger potential confounders/mediators. All subjects had to have at
immune response to common pathogens due to differences least 1 year of continuous KPNC enrollment to be included
in innate immunity at birth. This hypothesis is suggested in the study. The final matched cohort had 579 cases and
by differences in serum immune factors in neonatal samples 2,891 controls. After excluding 2 cases (for previous use of
(15–17). anticancer medications) and their matched controls, the final
Infection history ascertained from medical record abstrac- analytical cohort consisted of 575 cases and 2,870 controls.
tion and administrative databases can be superior to self- This study was approved by the KPNC and University of
report because it is less susceptible to recall bias. There- California, Berkeley, institutional review boards.
fore, in the present analysis, we asked whether medically
diagnosed infections were related to ALL risk in an inte- Data collection
grated and multiethnic health-care system in the United
States. Infection history from medical records of childhood Data on infection history and associated medications dis-
ALL cases (and matched nonleukemia controls) from Kaiser pensed were obtained from the KPNC Virtual Data Ware-
Permanente Northern California (KPNC) were examined in house (VDW). The VDW is a data source for research
relation to ALL status and compared with results for acute maintained by the KPNC Division of Research and other
myeloid leukemia (AML), which is not known to have an health-care systems (21). It consists of content areas and
infection-related etiology. data elements from KPNC electronic databases that have
been harmonized to facilitate research use. The VDW data
warehouse includes files on membership enrollment, utiliza-
METHODS tion of health services and pharmacy, verifiable in situ and
Study population invasive cancer data, laboratory results, vital signs, mortality
information, census, member demographics, and provider
Childhood leukemia cases and matched controls were se- information.
lected from the KPNC member population. KPNC is one Diagnoses for common infections for each subject were
of the largest integrated health-care systems in the United obtained from the VDW diagnosis file using International
States, with 4.3 million members covering the greater San Classification of Diseases, Ninth Revision (ICD-9), diag-
Francisco–Oakland Bay Area and Sacramento Area and nosis codes. The following 18 infection categories were
including over 6,000 physicians, 21 hospitals, and 233 out- identified and included: intestinal infectious diseases, other
patient clinics covering a 14-county region in Northern Cali- bacterial diseases, septicemia, bacterial infections, menin-
fornia. The KPNC Cancer Registry, which reports to the Bay gitis, viral diseases, other diseases due to viruses, fungal
Area and State of California’s Surveillance, Epidemiology, infections, other infectious and parasitic diseases, conjunc-
and End Results Program Cancer Registries, has information tivitis, otitis media, hearing loss, acute respiratory infections,
on tumor characteristics such as American Joint Committee pneumonia and influenza, unspecified bronchitis, infections
on Cancer stage, morphology, and grade (18). Data are col- of skin and subcutaneous tissue, other inflammatory condi-
lected, coded, and then added to the KPNC Cancer Registry tions of skin and subcutaneous tissue, and perinatal infec-
approximately 4–6 months after diagnosis. Details on inva- tions. Categories composed of allergies and asthma were
sive and in-situ cancers diagnosed in the KPNC population excluded. Web Table 1 shows the groupings of specific ICD-
are available from 1947 through the present. Eligible cases 9 diagnosis codes per category. Diagnoses resulting from all
were those diagnosed with childhood leukemia at ages 0– types of patient encounters (inpatient, outpatient, telephone
14 years from 1994–2014 (beginning the year that tumor, encounters, and other visit types) were included. Medica-
node, and metastasis staging defined by American Joint tions commonly used to treat the infections described above
Committee on Cancer criteria were required to be collected were obtained for each subject from the VDW pharmacy file;
in National Cancer Institute’s Surveillance, Epidemiology, these included systemic antibiotics, topical/external antibi-
and End Results Program registries, as well as KPNC Cancer otics, nonsteroidal antiiflammatory drugs, steroidal respi-
Registries) (19). They were identified from the KPNC Can- ratory drugs, and nonsteroidal respiratory drugs. Finally,
cer Registry using International Classification of Diseases study covariates including age at cancer diagnosis or refer-
for Oncology, 3rd Edition, morphology codes (9811, 9812, ence date, date of birth, sex, and race/ethnicity were obtained
9814, 9813, 9815, 9816, 9817, 9818). Cases were excluded from the VDW demographic file.

Am J Epidemiol. 2020;189(10):1076–1085
1078 Morimoto et al.

Table 1. Characteristics of Leukemia Cases and Controls, Kaiser Permanente Northern California, 1994–2014

Total (n = 3,445) Cases (n = 575) Controls (n = 2,870)

Characteristic
No. % No. % No. %

Age at diagnosis, years

<1 132 3.83 22 3.83 110 3.83
1–3 1,146 33.27 191 33.22 955 33.28
4–6 867 25.17 145 25.22 722 25.16
7–9 516 14.98 86 14.96 430 14.98

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10–12 510 14.80 85 14.78 425 14.81
13–14 274 7.95 46 8.00 228 7.94
Race
Asian/Pacific Islander 545 15.82 91 15.83 454 15.82
Black 300 8.71 50 8.70 250 8.71
Multiracial 14 0.41 3 0.52 11 0.38
Native American/Alaska Native 293 8.51 49 8.52 244 8.50
White 2,293 66.56 382 66.43 1911 66.59
Hispanic
Yes 1,052 30.54 176 30.61 876 30.52
No 2,393 69.46 399 69.39 1994 69.48
Diagnosis year
1994–1997 678 19.68 113 19.65 565 19.69
1998–2001 612 17.76 102 17.74 510 17.77
2002–2005 648 18.81 108 18.78 540 18.82
2006–2009 752 21.83 126 21.91 626 21.81
2010–2014 755 21.92 126 21.91 629 21.92
Sex
Male 1859 53.96 310 53.91 1,549 53.97
Female 1,586 46.04 265 46.09 1,321 46.03
Leukemia subtype
Acute lymphoblastic leukemia 2,605 75.62 435 75.65 2,170 75.61
Acute myeloid leukemia 401 11.64 67 11.65 334 11.64
Other/not otherwise specified 439 12.74 73 12.70 366 12.75

Statistical analysis tious exposures as well as an increased risk of ALL, we cre-

ated a classification system for infection severity based upon
Odds ratios and 95% confidence intervals were estimated whether medications were prescribed. By linking the KPNC
using conditional logistic regression. History of infection pharmacy and infection diagnosis data, we inferred infection
(excluding asthma and allergies) was assessed in relation severity based upon whether medications were dispensed on
to leukemia risk, parameterized as any infection (yes/no) the same day and up to 2 days following infection diagnosis
and number of infections diagnosed. Number of medica- date. Infections “requiring” 0 medications were classified as
tions dispensed (including all drug classes described above “mild” and infections requiring at least 1 medication were
but excluding formulations specific for asthma and aller- classified as “medication-prescribed.” For severity analy-
gies) was also evaluated in relation to risk, independent of ses, multiple medications and multiple infections dispensed/
infection status. Individual infections or medications pre- diagnosed on the same day were collapsed into a single
scribed on the same date were considered independent and medication/diagnosis instance, because it was not possible,
counted separately in analyses. Because the premise behind without chart review, to determine which medications were
this investigation was that children with an “uneducated” prescribed for which infection, and counting them separately
immune system might have a more severe response to infec- might result in double (or more) counting.

Am J Epidemiol. 2020;189(10):1076–1085
 Early Childhood Infections and ALL Risk 1079

We evaluated infections occurring 1) in the first year of during the first year of life and in the subjects’ lifetime were
life, and 2) during the child’s lifetime. For all analyses, not statistically significantly related to AML risk (Tables 2
infections diagnosed within 6 months of leukemia diagno- and 3). There was a suggestion of a U-shaped relationship
sis date/reference date were excluded because they might between medication-prescribed infections and AML, with
represent prodromes of the leukemia. Infections diagnosed both 1 medication-prescribed infection (OR = 4.51, 95%
only during a telephone visit (as opposed to an in-person CI: 0.95, 21.44) and 3 or more medication-prescribed infec-
encounter in the clinic, emergency room, or hospital admis- tions (OR = 4.62, 95% CI: 0.71, 30.18) associated with a
sion) were excluded. We also conducted analyses stratified greater than 4-fold increased risk of AML, and 2 medication-
by child’s Hispanic ethnicity status, limited to cases diag- prescribed infections associated with a 1.4-fold increased
nosed between ages 2 and 5 years (“common” ALL). In an risk (OR = 1.37, 95% CI: 0.11, 16.66), during the first
attempt to isolate infections most likely to be of bacterial year of life. Similar trends were observed when infections
origin, we conducted analyses limited to medication use over the subjects’ lifetime were evaluated. However, given

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defined as systemic antibiotics only. the extremely small numbers of AML cases and matched
controls in each exposure stratum, all point estimates were
imprecise, with wide confidence intervals.
RESULTS
In stratified analyses, there was no evidence that the rela-
In our cohort of 575 leukemia cases and 2,870 matched tionships between infections, medications, and ALL risk
controls, there were 435 ALL cases and 2,170 matched were modified by Hispanic ethnicity for exposures occurring
controls, 67 AML cases and 334 matched controls, and 74 in the first year or during their lifetime (Web Tables 2
leukemia cases with unknown subtype and 366 matched and 3). Similarly, no significant associations were observed
controls. Years of diagnosis ranged from 1994 to 2014. when analyses were limited to cases diagnosed between
There were 33,831 unique infection diagnoses and 17,992 ages 2 and 5 years (“common” ALL) (Web Table 4). When
unique prescriptions dispensed. Because of matching, cases medications were limited to only systemic antibiotics during
and controls were similar with respect to age, race, ethnicity, first year of life (Web Table 5), results were similar to the
calendar year of diagnosis, age at enrollment, and sex. A main associations (e.g., suggestion of inverse association
total of 34% of the cases and controls were non-White (16% with increasing numbers of infections, particularly those
Asian/Pacific Islander, 9% Black, 8.5% Native Ameri- requiring medications) but attenuated.
can/Alaskan); 31% were Hispanic (Table 1).
Neither a history of any infection during the first year of DISCUSSION
life (OR = 0.85, 95% CI: 0.60, 1.21) nor increasing numbers
of infections diagnosed during the first year of life (5 or more In this ethnically diverse cohort from an integrated health-
vs. none OR = 0.72, 95% CI: 0.46, 1.12) were significantly care system, increasing number of infections, especially
associated with risk of ALL overall (Table 2), although there infections requiring medication, was inversely associated
was a suggestion of an inverse association with increasing with risk of childhood ALL. This relationship was ob-
numbers of infections (P value for trend = 0.10). When served for both infections occurring during the first year
infections were classified by “severity,” this inverse associa- of life and those occurring through the child’s lifetime (up
tion appeared to be stronger for infections requiring med- to 6 months prior to diagnosis). Conversely, the increasing
ication, with 3 or more severe infections associated with number of medication-prescribed infections was associated
a 58% decrease in ALL risk (OR = 0.42, 95% CI: 0.20, with increased risk of AML, although results were imprecise
0.88). Again, the P value for trend fell short of statistical due to small sample sizes.
significance, possibly due to the small number of infections Several assessments of infections ascertained from medi-
within each cell. When the exposure window was expanded cal record abstraction or administrative databases and risk
to include infections occurring throughout the subjects’ life- of ALL have been conducted, with studies in the United
time (up to diagnosis/reference date minus 6 months), the Kingdom (12) and Taiwan (14) reporting positive asso-
observed association remained (for 3 or more medication- ciations with increasing numbers of early-life infections,
prescribed infections vs. none, OR = 0.52, 95% CI: 0.32, studies in Denmark, Scotland, New Zealand, and France
0.85) and the P value for trend was significant (P < 0.003) reporting inverse associations (22–25), and studies in the
(Table 3). For these “lifetime” analyses, sensitivity analy- United Kingdom and Denmark reporting no association (26,
ses were conducted, excluding children with discontinuous 27). While the present study does little to clarify the direction
enrollment (i.e., who were not continuously enrolled in of this association, it does underscore the significant het-
KPNC from birth to diagnosis). Because results were similar erogeneity across studies that makes comparisons between
to analyses including all subjects, but with wider confi- them problematic. In our present analysis, we attempted
dence intervals, only results with all subjects are presented. to distinguish weak from strong responses to infections to
Independent of infections, neither numbers of medications help assess infections that might be healthy modulators of
dispensed during the first year of life (OR = 0.79, 95% CI: immune development (weak) from those that can be dam-
0.44, 1.40) nor through the subjects’ lifetime (OR = 0.72, aging by causing extensive inflammation, reactive metabo-
95% CI: 0.50, 1.03) were associated with ALL risk. lites, and cytokine-induced cell growth (strong). Therefore,
Similar to ALL, any infections, increasing number of we hypothesized that we would find evidence of differ-
infections, and increasing number of medications prescribed ential associations by severity. Instead, our data provide

Am J Epidemiol. 2020;189(10):1076–1085
 Table 2. History of Childhood Infections, Associated Prescriptions (All Medications) During the First Year of Life, and Risk of Childhood Leukemia, Kaiser Permanente Northern California,
1994–2014
1080

Acute Lymphoblastic Leukemia Acute Myeloid Leukemia

Infection and Medication Cases Controls Cases Controls

History (n = 435) (n = 2,170)a (n = 67) (n = 334)a
ORb 95% CI P Value ORb 95% CI P Value
Morimoto et al.

No. % No. % No. % No. %

Any infection diagnosedc

No 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
Yes 154 35.4 800 36.9 0.85 0.60, 1.21 0.36 21 31.3 96 28.7 1.37 0.53, 3.51 0.52
No. of infections diagnosedc
0 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
1 35 8.0 156 7.2 0.99 0.62, 1.58 0.97 5 7.5 32 9.6 0.94 0.27, 3.27 0.93
2–4 67 15.4 335 15.4 0.87 0.58, 1.30 0.49 12 17.9 37 11.1 1.94 0.69, 5.46 0.21
≥5 52 12.0 309 14.2 0.72 0.46, 1.12 0.14 4 6.0 27 8.1 0.87 0.21, 3.68 0.85
P for trend 0.10 0.73
No. of medications prescribed
for infections
0 318 73.1 1,576 72.6 1.00 Referent 50 74.6 266 79.6 1.00 Referent
1–2 64 14.7 308 14.2 1.00 0.69, 1.46 0.98 10 14.9 39 11.7 1.79 0.65, 4.89 0.26
3–5 35 8.0 176 8.1 0.95 0.60, 1.52 0.84 5 7.5 19 5.7 1.92 0.53, 6.93 0.32
≥6 18 4.1 110 5.1 0.79 0.44, 1.40 0.42 2 3.0 10 3.0 1.43 0.25, 8.13 0.68
P for trend 0.17 0.42
Frequency of mild infections (no
medications prescribed)
0d 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
1 54 12.4 242 11.2 0.99 0.65, 1.51 0.96 8 11.9 41 12.3 1.24 0.40, 3.82 0.71
2 30 6.9 183 8.4 0.70 0.42, 1.16 0.17 4 6.0 19 5.7 1.28 0.31, 5.34 0.73
≥3 53 12.2 284 13.1 0.84 0.54, 1.29 0.42 5 7.5 26 7.8 1.10 0.29, 4.16 0.88
P for trend 0.43 0.68
Frequency of medication-prescribed
infections (≥1 medications
prescribed)
0d 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
1 43 9.9 214 9.9 0.86 0.52, 1.42 0.56 8 11.9 20 6.0 3.50 0.88, 13.88 0.07
2 27 6.2 103 4.7 1.13 0.62, 2.04 0.69 1 1.5 10 3.0 0.99 0.09, 10.56 0.99
≥3 20 4.6 170 7.8 0.46 0.24, 0.87 0.02 5 7.5 16 4.8 3.40 0.63, 18.21 0.15
P for trend 0.06 0.26

Table continues

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 Table 2. Continued

Acute Lymphoblastic Leukemia Acute Myeloid Leukemia

Infection and Medication Cases Controls Cases Controls

History (n = 435) (n = 2,170)a (n = 67) (n = 334)a
ORb 95% CI P Value ORb 95% CI P Value
No. % No. % No. % No. %

Am J Epidemiol. 2020;189(10):1076–1085
Frequency of mild infections, adjusted
for medication-prescribed
infections
0d 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
1 54 12.4 242 11.2 1.04 0.68, 1.59 0.86 8 11.9 41 12.3 1.15 0.36, 3.64 0.81
2 30 6.9 183 8.4 0.75 0.45, 1.25 0.27 4 6.0 19 5.7 1.22 0.29, 5.14 0.79
3 53 12.2 284 13.1 0.93 0.59, 1.47 0.75 5 7.5 26 7.8 0.94 0.22, 3.96 0.93
P for trend 0.76 0.34
Frequency of medication-prescribed
infections, adjusted for mild
infections
0d 281 64.6 1,370 63.1 1.00 Referent 46 68.7 238 71.3 1.00 Referent
1 43 9.9 214 9.9 0.82 0.47, 1.41 0.47 8 11.9 20 6.0 4.51 0.95, 21.44 0.06
2 27 6.2 103 4.7 1.05 0.54, 2.04 0.88 1 1.5 10 3.0 1.37 0.11, 16.66 0.80
3 20 4.6 170 7.8 0.42 0.20, 0.88 0.02 5 7.5 16 4.8 4.62 0.71, 30.18 0.11
P for trend 0.08 0.15

Abbreviations: CI, confidence interval; OR, odds ratio

a Controls matched 5:1 to case on sex, race, Hispanic ethnicity, age at KPNC enrollment, calendar year of leukemia diagnosis.
b From conditional logistic regression.
c From International Classification of Diseases, Ninth Revision, diagnosis codes.
d Reference group = no infections; does not add to 100% because not all infection and medication groupings shown.
Early Childhood Infections and ALL Risk
1081

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 Table 3. History of Childhood Infections, Associated Prescriptions (All Medications) During Lifetime, and Risk of Childhood Leukemia, Kaiser Permanente Northern California, 1994–2014
1082

Acute Lymphoblastic Leukemia Acute Myeloid Leukemia

Infection and Medication Cases Controls Cases Controls

History (n = 435) (n = 2,170)a (n = 67) (n = 334)a
ORb 95% CI P Value ORb 95% CI P Value
No. % No. % No. % No. %
Morimoto et al.

Any infection diagnosedc

No 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
Yes 299 68.7 1,522 70.1 0.88 0.64, 1.22 0.44 45 67.2 200 59.9 1.94 0.84, 4.5 0.12
No. of infections diagnosedc
0 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
1 40 9.2 203 9.4 0.90 0.59, 1.38 0.64 11 16.4 32 9.6 2.71 1.02, 7.23 0.05
2–4 83 19.1 417 19.2 0.89 0.61, 1.29 0.54 12 17.9 65 19.5 1.47 0.54, 3.96 0.45
≥5 176 40.5 902 41.6 0.86 0.59, 1.24 0.41 22 32.8 103 30.8 1.74 0.64, 4.75 0.28
P for trend 0.14 0.72
No. of medications prescribed
for infections
0 176 40.5 836 38.5 1.00 Referent 29 43.3 165 49.4 1.00 Referent
1–2 77 17.7 389 17.9 0.89 0.63, 1.24 0.48 13 19.4 56 16.8 1.57 0.66, 3.69 0.31
3–5 76 17.5 326 15.0 1.01 0.70, 1.44 0.97 5 7.5 37 11.1 1.03 0.32, 3.36 0.96
≥6 106 24.4 620 28.6 0.72 0.50, 1.03 0.07 20 29.9 76 22.8 2.11 0.81, 5.45 0.13
P for trend 0.03 0.57
Frequency of mild infections (no
medications prescribed)
0d 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
1 65 14.9 342 15.8 0.84 0.57, 1.23 0.37 15 22.4 42 12.6 3.12 1.24, 7.85 0.02
2 53 12.2 215 9.9 1.09 0.71, 1.67 0.68 8 11.9 39 11.7 1.70 0.57, 5.06 0.34
≥3 162 37.2 843 38.8 0.83 0.57, 1.21 0.32 19 28.4 103 30.8 1.38 0.52, 3.65 0.52
P for trend 0.93 0.42
Frequency of medication-prescribed
infections (≥1 medications
prescribed)
0d 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
1 59 13.6 309 14.2 0.76 0.49, 1.18 0.23 11 16.4 41 12.3 2.60 0.74, 9.14 0.14
2 58 13.3 198 9.1 1.19 0.74, 1.91 0.48 4 6.0 24 7.2 1.80 0.37, 8.68 0.47
≥3 103 23.7 640 29.5 0.59 0.37, 0.93 0.02 17 25.4 71 21.3 2.81 0.72, 10.96 0.14
P for trend 0.01 0.39

Table continues

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 Table 3. Continued

Acute Lymphoblastic Leukemia Acute Myeloid Leukemia

Infection and Medication Cases Controls Cases Controls

History (n = 435) (n = 2,170)a (n = 67) (n = 334)a
ORb 95% CI P Value ORb 95% CI P Value
No. % No. % No. % No. %

Am J Epidemiol. 2020;189(10):1076–1085
Frequency of mild infections, adjusted
for medication-prescribed
infections
0d 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
1 65 14.9 342 15.8 0.88 0.60, 1.30 0.52 15 22.4 42 12.6 3.03 1.2, 7.65 0.02
2 53 12.2 215 9.9 1.16 0.76, 1.78 0.49 8 11.9 39 11.7 1.60 0.53, 4.82 0.40
≥3 162 37.2 843 38.8 0.97 0.66, 1.45 0.90 19 28.4 103 30.8 1.18 0.42, 3.31 0.75
P for trend 0.12 0.13
Frequency of medication-prescribed
infections, adjusted for mild
infections
0d 136 31.3 648 29.9 1.00 Referent 22 32.8 134 40.1 1.00 Referent
1 59 13.6 309 14.2 0.73 0.47, 1.14 0.17 11 16.4 41 12.3 2.87 0.81, 10.21 0.10
2 58 13.3 198 9.1 1.13 0.70, 1.82 0.63 4 6.0 24 7.2 2.02 0.41, 9.83 0.39
≥3 103 23.7 640 29.5 0.52 0.32, 0.85 0.01 17 25.4 71 21.3 3.48 0.85, 14.27 0.08
P for trend 0.003 0.10

Abbreviations: CI, confidence interval; OR, odds ratio

a Controls matched 5:1 to case on sex, race, Hispanic ethnicity, age at KPNC enrollment, calendar year of leukemia diagnosis.
b From conditional logistic regression.
c From International Classification of Diseases, Ninth Revision, diagnosis codes.
d Reference group = no infections; does not add to 100% because not all infection and medication groupings shown.
Early Childhood Infections and ALL Risk
1083

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1084 Morimoto et al.

moderate support for infections in general modulating risk As discussed above, our findings are concordant with
downwards, with no effect modulation by severity. These significant prior data indicating that infants’ daycare atten-
observations support the original Greaves’ hypothesis. dance, larger family size/higher birth order, and vaccinations
Differences in health-care utilization practices in different (all of which elicit immune responses) are associated with
countries could explain some of the heterogeneity across decreased risk of ALL. In light of the large proportion of
studies. Whether and when an individual seeks medical childhood leukemia that is ALL, our findings should reas-
attention for illness might vary by national, cultural, and sure families that early infections leading to a physician visit
economic health-care utilization practices. Parents might be do not place children at increased risk of leukemia. In addi-
more likely to take their child to the doctor in countries tion, given that studies to date have not elucidated the mech-
with public or universal health care than those without (28). anisms through which exposure to infections or response to
Among the studies using medical record or administrative infections influence childhood leukemia risk, further investi-
databases to ascertain or confirm infection history, only the gations in this area should include ancillary and contributory

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present study was conducted in a country without some form information to help clarify responder status of the child in
of public health care. While KPNC is an integrated health- addition to the infections themselves. Examination of addi-
care delivery system, in which all primary to tertiary clinical tional variables of interest might permit the identification of
care is provided to subscribers, the consumer frequently characteristics of infectious agents and of hosts that alone or
assumes a copayment at the point of service (which varies in combination are indicative of protection or susceptibility.
by insurance plan). Even within a single health-care system, Such additional information might include immune pro-
predictors of utilization are complex and can include patient files of mothers and their children, detection of subclinical
and system-level factors such as distance from medical congenital infections (e.g., cytomegalovirus), assessment of
facility, available transportation, education, health literacy, microbiomes of mothers and infants, and identification of
and acculturation—factors that we could not account for in prenatally acquired preleukemic genetic lesions. Ultimately,
this analysis. Finally, the lack of a consistent association it is hoped that these studies will lead to interventions that
among studies might indicate that history of infection is not reverse the incidence trends of ALL, which have increased
a valid indicator of exposure to infectious agents and/or an in the past 50 years (30, 31).
individuals’ response to immune system stimulation in some
study settings.
Our population for this study was not large but did indicate
a different relationship of infection to leukemia risk for ACKNOWLEDGMENTS
AML versus ALL. Medication-prescribed infections were
nonsignificantly related to AML incidence, with consis- Author affiliations: Division of Epidemiology and
tently high risk ratios for infections occurring during the Biostatistics, School of Public Health, University of
first year and lifetime. AML is not a disease thought to have California, Berkeley, Berkeley, California (Libby M.
risk reduction from exposure to infectious stimuli; in fact, Morimoto, Alice Y. Kang, Catherine Metayer); Division of
the only study showing a relationship with infections indi- Research, Kaiser Permanente Northern California,
cates strong (OR of approximately 6) risk from physician- Oakland, California (Marilyn L. Kwan, Kamala
diagnosed infection (14). Our results here are consistent Deosaransingh, Julie R. Munneke, Charles Quesenberry
with infection-related damage, like damage from chemical Jr.); Department of Laboratory Medicine, University of
exposures, inducing risk to AML. California San Francisco, San Francisco, California (Scott
Strengths of this study include the case-control design, Kogan); Helen Diller Family Comprehensive Cancer
with subjects selected from a well-defined cohort; the inte- Center, University of California San Francisco, San
grated health-care delivery system with clinical and admin- Francisco, California (Scott Kogan); and Center for
istrative information from the electronic medical record Genetic Epidemiology, Department of Preventive
mapped to a common format for accurate and efficient data Medicine, University of Southern California, Los Angeles,
extraction; and the large and ethnically diverse population California (Adam J. de Smith, Joseph L. Wiemels).
comprising approximately 23% of the Northern California This work was supported by the National Cancer
population (29). Some limitations should also be considered. Institute (grant R01CA185058).
Similar to other studies using medical record abstraction or Conflict of interest: none declared.
administrative databases, little data were available on other
childhood leukemia risk factors, and confounding might
have affected risk estimates. Specifically, geocoded income
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