Infection and childhood leukemia: review of evidence

Maia, Raquel da Rocha Paiva; Wünsch Filho, Victor

doi:10.1590/S0034-8910.2013047004753

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Sumário

Revisões • Rev. Saúde Pública 47 (6) • Dec 2013 • https://doi.org/10.1590/S0034-8910.2013047004753 copy

Infection and childhood leukemia: review of evidence

Infecção e leucemia infantil: revisão das evidências

Infección y leucemia infantil: revisión de las evidencias

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVE

: To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia.

METHODS

: A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors “childhood leukemia” and “infection” and later searching for the words “childhood leukemia” and “maternal infection or disease” or “breastfeeding” or “daycare attendance” or “vaccination” resulted in 62 publications that met the following inclusion criteria: subject aged ≤ 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers’ or infants’ to infections (or proxy of infection), and risk of leukemia.

RESULTS

: Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori .

CONCLUSIONS

: Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology.

Children; Leukemia, etiology; Causality; Infection; Review

Reference	Place	Study design	Infectious agent or disease	Disease	Risk (95%CI)
Increased risk
Hakulinen et al²¹(1973)	Finland	BC	Asian influenza	CL	Exposed incidence: 68.1/million Unexposed incidence: 4.2/million; P = 0.048
Austin et al² (1975)	Los Angeles	BC	Influenza	CL	RR 3.4
Vianna & Polan⁸³ (1976)	USA	ECO	Chicken pox	CL	Expected incidence < 1 Observed incidence = 3
Till et al⁷⁸ (1979)	England	CC	Varicella and herpes zoster	ALL	Number cases higher than expected (2 of 54)
Mckinney et al⁴³ (1987)	IREESC	CC	Skin disease	CL	RR 2.3 (1.1;4.7)
Buckley et al⁸ (1994)	USA Canada	CC	Any maternal infection	ALL	OR 1.5 (p < 0.05)
Naumburg et al⁴⁷ (2002)	Sweden	CC	Lower genital tract infection	ALL CL	OR 1.63 (1.04;2.53) OR 1.78 (1.17;2.72)
Lehtinen et al³⁵ (2003)	Finland Iceland	CC	Epstein-Barr virus	ALL	OR 2.9 (1.5;5,8)
Lehtinen et al³⁶ (2005)	Finland Iceland	CC	Helicobacter pylori	CL	OR 2.8 (1.1;6.9)
Kwan et al³³ (2007)	California	CC	Influenza/pneumonia Sexually transmitted diseases	ALL CL ALL CL	OR 1.89 (1.24;2.89) OR 1.74 (1.18;2.57) OR 4.85 (1.24;18.96) OR 6.33 (1.65;24.27)
Tedeschi et al⁷⁷ (2007)	Finland Iceland	CC	Epstein-Barr virus	ALL	OR 1.9 (1.2;3.0)

Non-significant effect or no association

Randolph & Heath⁵⁹ (1974)	USA	BC	Influenza	CL	No consistent increased incidence
Curnen et al¹² (1974)	Connecticut	ECO	Influenza, chickenpox, whooping…	CL	No significant positive correlations
& Dockerty et al¹³ (1999)	New Zealand	CC	Influenza Cold sores/oral herpes	CL	OR 0.58 (0.24;1.41) OR 0.70 (0.25;1.99)
Mckinney et al⁴⁴ (1999)	Scotland	CC	Respiratory tract Genitourinary	ALL	OR 1.64 (0.60;4.46) OR 1.18 (0.50;2.79)
Infante-Rivard et al²⁴ (2000)	Quebec	CC	Recurrent infections	ALL	OR 1.09 (0.65;1.84)

Reference	Place	Study design	Infectious agent or disease	Disease	Risk (95%CI)
Infection in the first 2 years of life: protective effect
Dockerty et al^13,a (1999)	New Zealand	CC	Eye infection	ALL	OR 0.2 (0.1;0.7)
Mckinney et al⁴⁴ (1999)	Scotland	CC	Skin infection	ALL CL	OR 0.2 (0.05;0.87) OR 0.2 (0.05;0.87)
Neglia et al⁴⁸ (2000)	USA	CC	Ear infection	ALL	Ear infection episodes reduced the risk: p trend = 0.026
Chan et al^10,a (2002)	Hong Kong	CC	Roseola and/or fever + rash	ALL	OR 0.33 (0.16;0.68)
Perrilat et al^52,a (2002)	France	CC	Surgical procedures: ear, nose, throat	CL	OR 0.4 (0.2;0.9)
Jourdan-da Silva et al^25,a (2004)	France	CC	≥4 gastrointestinal infections	ALL	OR 0.1 (0.03;0.6)
Rosembaum et al^66,a (2005)	New York State	CC	Diarrhoea	ALL	OR 0.69 (0.48;0.99)
Simpson et al^75,a (2007)	UK	CC	Eye infection	ALL	OR 0.7 (0.5;0.9)
Rudant et al^67,a (2010)	France	CC	Otitis; Bronchiolitis/other lower respiratory tract infections; Gastroenteritis	ALL	OR 0.7 (0.5;1.0) OR 0.3 (0.2;0.6) OR 0.3 (0.1;0.8)
Urayama et al⁸¹ (2011)	California	CC	Ear infection: non-Hispanic children; Hispanic children	ALL	OR 0.39 (0.17;0.91) OR 0.48 (0.27;0.83)

Infection in the first 2 years of life: increased risk

Dockerty et al¹³ ^, ^a (1999)	New Zealand	CC	Influenza	CL ALL	OR 6.80 (1.81;25.66) OR 6.0 (1.4;26.2)
Perrilat et al^52,a (2002)	France	CC	Mumps	CL	OR 3.2 (1.1;9.0)
Rosembaum et al^66,a (2005)	New York State	CC	Otitis in the second year of life	ALL B lineage	OR 1.56 (1.02;2.37)
Roman et al⁶⁴ (2007)	UK	CC	Upper respiratory tract infection Fungal infection	ALL	OR 1.3 (1.0;1.7) OR 1.9 (1.1;3.2)
Simpson et al^75,a (2007)	UK	CC	At least one infection	ALL	OR 1.6 (1.1;2.2)
Cardwell et al⁹ (2008)	UK	CC	Upper respiratory tract infections; Chickenpox	ALL	OR 1.59 (1.02;2.49) OR 2.62 (1.12;6.13)
Rudant et al^67,a (2010)	France	CC	Upper respiratory tract infections	ALL	OR 1.6 (1.3;2.0)

Infection in the first 2 years of life: non-significant effects or no association

Van Steensel-Moll et al⁸² (1986)	Netherlands	CC	Common colds; Fever	ALL	RR 0.8; p > 0.05; RR 0.9; p > 0.05
Naumburg et al⁴⁷ (2002)	Sweden	CC	History of infection in the postpartum	CL	OR 1.0 (0.50;2.04)

Infection at any time prior to the diagnosis: protective effect

Schlehofer et al^68,a (1996)	Germany	CC	Herpes labialis	CL	RR 0.38 (0.15;0.96)
Schuz et al^70,a (1999)	Germany	CC	Chickenpox	AL	OR 0.8 (0.7;1.0)
Ma et al³⁸ 2(005)	California	CC	Ear infection (in non-Hispanic)	c-ALL	OR 0.32 (0.14;0.74)

Infection at any time prior to the diagnosis: increased risk

Mckinney et al⁴³ (1987)	UK	CC	Number of illness episodes	CL	RR 1.9 (1.0;3.4)
Jourdan-da Silva et al^25,a (2004)	France	CC	Rubella	ALL	OR 2.4 (1.4;4.1)

Infection at any time prior to the diagnosis: non-significant effect or no association

Macarthur et al⁴⁰ (2008)	Canada	CC	Mumps Measles	ALL	OR 0.57 (0.13;2.52) OR 0.62 (0.25;1.27)

Infection at diagnosis or in the year before diagnosis: increased risk

Schuz et al^70,a (1999)	Germany	CC	Bronchitis Pneumonia	c-ALL	OR 1.9 (1.3;2.7) OR 2.6 (1.4;4.8)
Chan et al^10,a (2002)	Hong Kong	CC	Tonsillitis	c-ALL	OR 2.96 (1.32;6.66)
Kroll et al²⁹ (2006)	Britain	ECO	Influenza	c-ALL	Influenza epidemic preceded peak of c-ALL

Infection at diagnosis or in the year before diagnosis: laboratory analysis

Schlehofer et al^68,a (1996)	Germany	CC	Epstein-Barr Virus Parvovirus B-19 Adeno-associated virus type 2 Human herpes virus type 6.	CL	RR 2.05 (0.99;4.23) RR 0.48 (0.14;1.69) RR 0.66 (0.29;1.50) RR 1.11 (0.54;2.28)
Petridou et al⁵⁶ (2001)	Greece	CC	Epstein-Barr virus Human herpes virus type 6 Mycoplasma Parainfluenza1,2,3	ALL	OR 0.4 (0.2;0.8) OR 0.5 (0.3;0.9) OR 0.1 (0.0;0.7) OR 1.9 (1.1;3.2)
Mahjour et al⁴¹ (2010)	Iran	CC	Herpes Simplex Viruses 1 and 2; Epstein-Barr Virus; hepatitis B Virus	ALL	The prevalence of antibodies against HBsAg (p = 0.002), HSV1 (p < 0.0001), VCA (p = 0.021) and EA (p < 0.0001) antigens of EBV were higher in ALL patients.
Sehgal et al⁷¹ (2010)	India	CC	Epstein Barr Virus	ALL	Significant increase in EBV in ALL patients (p < 0.05)

Reference	Place	Study design	Disease	Variables	Risk (95%CI)
Protective effect

Petridou et al⁵⁴ (1993)	Attica (Greece)	CC	CL	Attendance at day-care for > 3 months in the first two years of life	OR 0.28 (0.09;0.88)
Infante-Rivard et al²⁴ (2000)	Quebec	CC	ALL	Entry at ≤ 2 years old	OR 0.49 (0.31;0.77)
Perrilat et al⁵² (2002)	France	CC	AL	Age at start of day care ≤ 6 months versus no day-care	OR 0.5 (0.3;1.0)
Ma et al³⁷ (2002)	California	CC	ALL	Children who had more total child – hours of attendance at day-care	OR 0.64 (0.45;0.95)
Jourdan-Da Silva et al²⁵ (2004)	France	CC	ALL	Age at start of day-care < 3 months versus no day-care	OR 0.6 (0.4;0.8)
Ma et al³⁸ (2005)	California	CC	ALL	Children (non-Hispanic white) who had more time of attendance at day-care	OR 0.42 (0.18;0.99)
Gilham et al¹⁵ (2005)	UK	CC	ALL	Formal day care in the first year of life Age at start of day-care < 3 months versus no day-care	OR 0.48 (0.37;0.62) OR 0.56 (0.37;0.83)
Kamper-Jorgensen et al²⁶ (2008)	Denmark	CC	ALL	Childcare in the first 2 years	OR 0.68 (0.48;0.95)
Urayama⁸¹ (2011)	California	CC	ALL	Attendance day-care by age 6 months (non-Hispanic white)	OR 0.83 (0.73;0.94)

Non-significant effect or no association

Roman et al⁶³ (1994)	England	CC	ALL	Child’s attendance at preschool playgroup	OR 0.6 (0.2;1.8)
Petridou et al⁵⁵ (1997)	Greece	CC	CL	Day-care: Yes versus No	OR 0.83 (0.51;1.37)
Schuz et al⁷⁰ (1999)	Germany	CC	c-ALL	Deficit in social contact	OR 1.0 (0.8;1.2)
Neglia et al⁴⁸ (2000)	USA	CC	ALL	Age at start of day care < 6 months	OR 0.91 (0.72;1.15)
Rosenbaum et al⁶⁵ (2000)	New York State	CC	ALL	Duration of out-of-home care (months): stayed home ( versus > 36)	OR 1.32 (0.70;2.52)
Chan et al¹⁰ (2002)	Hong Kong	CC	c-ALL	Attendance at day-care during first year of life	OR 0.93 (0.63;1.36)
Abdul Rahman et al¹ (2008)	Malaysia	CC	AL	Attendance in day-care (Yes versus No)	OR 1.12 (0.65;1.92)
Rudant et al⁶⁷ (2010)	France	CC	ALL	Full-time day-care attendance in the first year of life	OR 0.8 (0.6;1.1)

Reference	Place	Study design	Disease	Variables	Risk (95%CI)
Negative association: protective effect associated with higher birth order/ increased risk associated with lower birth order

Van steensel-moll⁸² (1986)	Netherlands	CC	ALL	There were more first-born children in cases	RR 1.8 (1.1;2.7)
Infante-Rivard et al^24,a (2000)	Quebec	CC	ALL	Having older siblings in the 1^st year of life (in cases diagnosed at 4 years of age or later)	OR 0.46 (0.22;0.97)
Petridou et al⁵⁶ (2001)	Greece	CC	ALL	Birth order: other versus first	OR 0.5 (0.3;0.9)
Dockerty et al¹⁴ (2001)	England Wales	CC	ALL	Parity ≥ 5	OR 0.52 (0.34;0.80)
Rudant et al⁶⁷ (2010)	France	CC	ALL	Parity ≥ 4 versus 1	OR 0.5 (0.3;0.8)
Urayama⁸¹ (2011)	California	CC	ALL	Birth order ≥ 4 versus 1(in children non-Hispanic white)	OR 0.44 (0.21;0.92)

Positive association: increased risk associated with higher birth order/ protective effect associated with lower birth order

Infante-Rivard et al^24,a (2000)	Quebec	CC	ALL	Having older siblings at time of diagnosis (in children diagnosed before 4 years of age)	OR 4.54 (2.27;9.07)
Shu et al⁷³ (2002)	USA	CC	ALL	Birth order ≥ 4 versus 1	OR 2.0 (1.3;3.0)
Reynolds et al⁶¹ (2002)	California	CC	ALL	Number of previous live births ≥ 3 versus 0 (in children aged < 2 years)	OR 1.53 (1.00;2.34)
ourdan-Da Silva et al²⁵ (2004)	France	CC	ALL	Birth order ≥ 4 versus 1	OR 2.0 (1.1;3.7)
Abdul Rahman et al¹ (2008)	Malaysia	CC	AL	Number of elder siblings < 2 versus ≥ 2	OR 0.37 (0.22;0.64)

Non-significant effect or no association

Roman et al⁶³ (1994)	England	CC	ALL	Number of siblings ≥ 2 versus 0	OR 0.8 (0.2;3.0)
Westergaard et al⁸⁵ (1997)	Denmark	COH	ALL	Birth order ≥ 4 versus 1	RR 0.72 (0.46;1.13)
Petridou et al⁵⁵ (1997)	Greece	CC	CL	Risk decreases with increasing birth order	OR 0.74 (0.48;1.15)
Schuz et al⁷⁰ (1999)	German	CC	c-ALL	First-born child (yes versus no)	OR 1.1 (1.0;1.4)
Mckinney et al⁴⁴ (1999)	Scotland	CC	ALL CL	Parity (0 versus 1 or more)	OR 0.81 (0.52;1.25) OR 0.82 (0.55;1.23)
Neglia et al⁴⁸ (2000)	USA	CC	ALL	Number of older siblings ≥ 2 versus 0	OR 1.05 (0.88;1.26)
Perrilat et al⁵² (2002)	France	CC	ALL	Birth order ≥ 4 versus 1	OR 1.4 (0.7;2.8)
Murray et al⁴⁶ (2002)	Ireland	COH	ALL	First-born versus Not first born	RR 0.98 (0.71;1.36)
Okcu et al⁵⁰ (2002)	Texas	CC	ALL CL	Parity ≥ 5 versus 0	OR 1.0 (0.1;7.8) OR 0.5 (0.1;4.3)
Gilham et al¹⁵ (2005)	UK	CC	ALL	Number of siblings ≥ 3 versus none	OR 0.99 (0.74;1.30)
Kamper-Jorgensen et al²⁶ (2008)	Denmark	CC	ALL	Older siblings > 2 versus 0	RR 0.93 (0.72; 1.19)

Reference	Place or group	Study design	Disease	Time of breast feeding	Risk (95%CI)

Negative association: protective effect associated with longer breastfeeding period/increased risk associated with shorter breastfeeding period
Dockerty et al¹³ (1999)	New Zealand	CC	ALL	> 1 year	OR 0.5 (p = 0.04)
Shu et al⁷² (1999)	USA, Canada, Australia	CC	ALL	> 6 versus 0 More time breastfeeding	OR 0.72 (0.60;0.87) p trend = 0.0034
Infante-Rivard et al²⁴ (2000)	Quebec	CC	ALL	>3 months versus 0	OR 0.67 (0.47;0.94)
Bener et al⁶ (2001)	United Arab Emirates	CC	ALL	0-6 months versus > 6	OR 2.47 (1.17;5.25)
Perrilat et al⁵³ (2002)	France	CC	AL	≥ 6 months versus 0	OR 0.5 (0.2;0.9)
Bener et al⁷ (2008)	Qatar	CC	ALL	0-6 months versus > 6	Males: OR 3.1 (1.4;6.8) Females: OR 2.2 (0.8;6.32)
Rudant et al⁶⁷ (2010)	France	CC	ALL	≥ 6 months versus > 0	OR 0.7 (0.5;1.0)

Non-significant effect or no association

Petridou et al⁵⁵ (1997)	Greece	CC	CL	yes versus no	OR 0.85 (0.52;1.41)
Schuz et al⁷⁰ (1999)	Germany	CC	c-ALL	2-6 months versus > 6	OR 1.2 (0.9;1.6)
UKCCS⁷⁹ (2001)	UK	CC	ALL	≥ 7 months versus 0	OR 0.89 (0.75;1.05)
Murray et al⁴⁶ (2002)	Ireland	COH	ALL	no versus yes	RR 0.98 (0.68;1.42)
Chan et al¹⁰ (2002)	Hong Kong	CC	c-ALL	≥ 6 months (yes versus no)	OR 0.21 (0.03;1.76)
Lancashire & Sorahan³⁴ (2003)	UK	CC	ALL CL	ever versus never	OR 1.04 (0.86;1.26) OR 1.05 (0.89 ;1.23)
Jourdan-Da Silva et al²⁵ (2004)	France	CC	ALL	yes versus no	OR 1.1 (0.9;1.5)
Kwan et al³² (2005)	California	CC	ALL	ever versus never	OR 0.99 (0.64;1.55)
Macarthur et al⁴⁰ (2008)	Canada	CC	ALL CL	7-12 months (yes versus no)	OR 1.02 (0.68;1.53) OR 1.00 (0.67;1.50)
Waly et al⁸⁴ (2011)	Oman	CC	ALL	No statistically significant difference	χ2 = 3.816, P = 0.282

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[1] Correspondence
: Raquel da Rocha Paiva Maia. Rua Roque Garcia, 363 Loteamento. Santo Afonso. 69908-836 Rio Branco, AC, Brasil. E-mail: raquelmaia@usp.br