Infecção e leucemia infantil: revisão das evidências

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) • Dez 2013 • https://doi.org/10.1590/S0034-8910.2013047004753 copiar

Infecção e leucemia infantil: revisão das evidências

Autoria SCIMAGO INSTITUTIONS RANKINGS

OBJETIVO

: Analisar estudos que avaliaram o papel de infecções e de medidas indiretas de exposição às infecções no risco de leucemia infantil, principalmente da leucemia linfocítica aguda.

MÉTODOS

: A busca nas bases de dados Medline, Lilacs e SciELO utilizando-se inicialmente os descritores “leucemia infantil” e “infecção” e, posteriormente, pesquisando-se as palavras “leucemia infantil” e “infecção ou doença materna” ou “aleitamento materno” ou “frequência à creche” ou “vacinação” recuperou 62 publicações que atenderam aos seguintes critérios de inclusão: amostra composta por sujeitos com idade inferior ou igual a 15 anos; análise específica de casos diagnosticados com leucemia linfocítica aguda ou todas as leucemias; avaliação de exposição materna ou infantil a infecções (ou medidas indiretas de exposição à infecção) e risco de leucemia.

RESULTADOS

: Globalmente, os 23 estudos que avaliaram infecções nas crianças suportam a hipótese de que a ocorrência de infecções no início da infância reduz o risco de leucemia, mas existem discordâncias intra e entre estudos. A avaliação por meio das medidas indiretas de exposição à infecção mostrou evidências de redução do risco de leucemia associado principalmente com frequência à creche. Mais de 50,0% dos 16 estudos que avaliaram exposição materna à infecção observaram aumento do risco de leucemia associado com episódios de gripe, pneumonia, varicela, herpes zoster, infecção do trato genital inferior, doença de pele, doenças sexualmente transmissíveis, vírus Epstein-Barr (EBV) e Helicobacter pylori .

CONCLUSÕES

: Embora nenhum agente infeccioso específico tenha sido identificado, as evidências científicas são sugestivas de que a exposição a infecções interfere na etiologia da leucemia infantil.

Crianças; Leucemia, etiologia; Causalidade; Infecção; Revisão

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