Objectives: The incidence of acute lymphoblastic leukemia (ALL) in children has shown temporal and geographic variation during the 20th century, with higher rates in developed nations appearing in the first half of the century, but with persisting low rates in developing nations. We sought to assess the relation of childhood ALL with hygiene conditions, an aspect of socioeconomic development affecting rates of exposure to infectious agents.
Methods: Infection patterns for hepatitis A virus (HAV), an agent with a fecal-oral route of transmission, were used to indicate hygiene conditions in different populations, with emphasis on instructive United States and Japanese data. A catalytic model was fit to these data, estimating the HAV force of infection and age-specific seroprevalence rates over time. These analyses were used to assess the temporal relationship of changes in HAV infection rates to changes in childhood leukemia mortality and incidence rates.
Results: We observed an inverse relationship between HAV infection prevalence and rates of childhood leukemia. Further, decreases in the HAV force of infection in the United States and Japan appear to have preceded increases in childhood leukemia rates. We describe a model based on a putative leukemia-inducing agent with a change in infection rate over time correlated with that of HAV that describes well the temporal trends in childhood leukemia rates for White children in the US and for Japanese children.
Conclusion: The data suggest that improved public hygiene conditions, as measured by decreased prevalence of HAV infection, are associated with higher childhood ALL incidence rates. The model that we present supports the plausibility of the hypothesis that decreased childhood exposure to a leukemia-inducing agent associated with hygiene conditions leads to higher rates of ALL in children by increasing the frequency of in utero transmission caused by primary infection during pregnancy (or by increasing the number of individuals infected in early infancy because of lack of protective maternal antibodies). Cancer causes and Control 1998, 9, 285-298
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Hewitt D. Some features of leukaemia mortality. Br J Prev Social Med 1955; 9: 81–8.
Gilliam A, Walter W. Trends of mortality from leukemia in the United States, 1921–55. Public Health Rep 1958; 73: 773–84.
Linet MS, Devesa SS. Descriptive epidemiology of childhood leukaemia. Br J Cancer 1991; 63: 424–9.
Fleming AF. Leukaemias in Africa. Leukemia 1993; 7Suppl 2: S138–41.
Slocumb J, MacMahon B. Changes in mortality rates from leukemia in the first five years of life. N Engl J Med 1963; 268: 922–5.
Stewart A, Webb J, Hewitt D. A survey of childhood malignancies. Br Med J 1958; 1: 1495–508.
Court-Brown W, Doll R. Leukemia in childhood and young adult life. Trends in mortality in relation to aetiology. Br Med J 1961; 1: 981–8.
Burnet M. Leukemia as a problem in preventive medicine. N Engl J Med 1958; 259: 423–31.
Fleming AF. Epidemiology of the leukaemias in Africa. Leuk Res 1979; 3: 51–9.
Greaves M, Pegram S, Chan L. Collaborative Group Study of the Epidemiology of Acute Lymphoblastic Leukaemia Subtypes: Background and First Report. In: Greaves M, Chan L, eds. Epidemiology of Leukaemia and Lymphoma. Oxford, UK: Pergamon Press, 1985: 55–73.
Greaves MF, Colman SM, Beard ME, et al. Geographical distribution of acute lymphoblastic leukaemia subtypes: second report of the collaborative group study. Leukemia 1993; 7: 27–34.
Pinkel D, Nefzger D. Some epidemiological features of childhood leukemia in the Buffalo, N.Y., area. Cancer 1959; 12: 351–8.
Browning D, Gross S. Epidemiological studies of acute childhood leukemia. A survey of Cuyahoga county, Ohio. Am J Dis Child 1968; 116: 576–85.
Fasal E, Jackson EW, Klauber MR. Birth characteristics and leukemia in childhood. J Natl Cancer Inst 1971; 47: 501–9.
Alexander FE, Ricketts TJ, McKinney PA, Cartwright RA. Community lifestyle characteristics and risk of acute lymphoblastic leukaemia in children [see comments]. Lancet 1990; 336: 1461–5.
Alexander FE, Cartwright RA, McKinney PA, Ricketts TJ. Leukaemia incidence, social class and estuaries: an ecological analysis. J Public Health Med 1990; 12: 109–17.
Bithell JF, Dutton SJ, Neary NM, Vincent TJ. Controlling for socioeconomic confounding using regression methods. J Epidemiol Community Health 1995; 49: S15–9.
McKinney PA, Alexander FE, Cartwright RA, Scott CS, Staines A. Acute lymphoblastic leukaemia incidence in the UK by immunophenotype. Leukemia 1993; 7: 1630–4.
McWhirter W. The relationship of incidence of incidence of childhood lymphoblastic leukaemia to social class. Br J Cancer 1982; 46: 640–5.
Draper G, Vincent T, O'Conor C, Stiller C. Socioeconomic factors and variation in incidence rates between county districts. In: Draper G, ed. The Geographical Epidemiology of Childhood Leukaemia and non-Hodgkin's Lymphoma in Great Britain. London, UK: OPCS, 1991: 37–46.
Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP. Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia. Cancer 1991; 68: 1351–5.
Stark CR, Mantel N. Maternal-age and birth-order effects in childhood leukemia: age of child and type of leukemia. J Natl Cancer Inst 1969; 42: 857–66.
Birch JM, Swindell R, Marsden HB, Morris Jones PH. Childhood leukaemia in North West England 1954–1977: epidemiology, incidence and survival. Br J Cancer 1981; 43: 324–9.
Swensen A, Ross J, Severson R, Pollock B, Robison L. The age peak in childhood acute lymphoblastic leukemia: Exploring the potential relationship with socioeconomic status. Cancer 1997; 79: 2045–51.
Muirhead CR. Childhood leukemia in metropolitan regions in the United States: a possible relation to population density? Cancer Causes Control 1995; 6: 383–8.
Liberatos P, Link BG, Kelsey JL. The measurement of social class in epidemiology. Epidemiol Rev 1988; 10: 87–121.
Greaves M. A natural history for pediatric acute leukemia. Blood 1993; 82: 1043–51.
Greaves MF, Alexander FE. An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia 1993; 7: 349–60.
Kinlen L. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain [see comments]. Lancet 1988; 2: 1323–7.
Alexander FE. Viruses, clusters and clustering of childhood leukaemia: a new perspective? Eur J Cancer 1993; 29A: 1424–43.
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia [Editorial]. Br J Cancer 1995; 71: 1–5.
Greaves M. Aetiology of acute leukemia. Lancet 1997; 349: 344–9.
Petridou E, Kassimos D, Kalmanti M, et al. Age of exposure to infections and risk of childhood leukaemia. Br Med J 1993; 307: 774.
Smith M. Considerations on a possible viral etiology for B-precursor acute lymphoblastic leukemia of childhood. J Immunother 1997; 20: 89–100.
Arthur RR, Shah KV. Occurrence and significance of papovaviruses BK and JC in the urine. Prog Med Virol 1989; 36: 42–61.
Rowe W, Huebner R, Hartley J. Ecology of a mouse tumor virus. In: Pollard M, ed. Perspectives in Virology. New Brunswick, NJ (USA): Rutgers University Press, 1961: 177–94.
Battegay M, Feinstone S. Hepatitis A virus. In: Willson R, ed. Viral Hepatitis: Diagnosis, Treatment, Prevention. New York, NY (USA): Marcel Dekker, Inc., 1997: 35–84.
McDowell A, Engel A, Massey JT, Maurer K. Plan and operation of the Second National Health and Nutrition Examination Survey, 1976–1980. Vital Health Stat  1981; Series 1: 1–144.
Forthofer RN. Investigation of nonresponse bias in NHANES II. Am J Epidemiol 1983; 117: 507–15.
Schenzle D, Dietz K, Frosner GG. Antibody against hepatitis A in seven European countries. II. Statistical analysis of cross-sectional surveys. Am J Epidemiol 1979; 110: 70–6.
Ikematsu H, Kashiwagi S, Hayashi J, et al. A seroepidemiologic study of hepatitis A virus infections: statistical analysis of two independent cross-sectional surveys in Okinawa, Japan. Am J Epidemiol 1987; 126: 50–4.
Sacks M, Seeman I. A statistical study of mortality from leukemia. Blood 1947; 2: 1–14.
Cooke J. The occurrence of leukemia. Blood 1954; 9: 340–7.
Ries L, Kosary C, Hankey B, Miller B, Harras A, Edwards B, eds. SEER Cancer Statistics Review, 1973–1994. Bethesda, MD (USA): National Cancer Institute, 1997.
Grove R, Hetzel A. Vital Statistics Rates in the United States 1940–1960 (Public Health Service Publication No. 1677). Washington, DC: US Government Printing Office, 1968.
Parkin DM, Whelan S, Ferlay J, Raymond L, Young J, eds. Cancer Incidence in Five Continents, Volume VII. Lyon, France: International Agency for Research on Cancer, 1997.
Fraumeni JF Jr, Miller R. Epidemiology of human leukemia: Recent observations. J Natl Cancer Inst 1967; 38: 593–605.
Parkin DM, Stiller C, Draper G, Bieber C. The international incidence of childhood cancer. Int J Cancer 1988; 42: 511–20.
Ajiki W, Hanai A, Tsukuma H, Hiyama T, Fujimoto I. Incidence of childhood cancer in Osaka, Japan, 1971–1988: reclassification of registered cases by Birch's scheme using information on clinical diagnosis, histology and primary site. Jpn J Cancer Res 1994; 85: 139–46.
Koff RS. Seroepidemiology of hepatitis A in the United States. J Infect Dis 1995; 171Suppl 1: S19–23.
Shapiro CN, Coleman PJ, McQuillan GM, Alter MJ, Margolis HS. Epidemiology of hepatitis A: seroepidemiology and risk groups in the USA. Vaccine 1992; 10Suppl 1: S59–62.
US Bureau of the Census. Historical Statistics of the United States, 1789–1945. Washington, DC: US Government Printing Office, 1949.
Hirst K, Butler N, Dawkings M. Infant and Perinatal Mortality in England and Wales. Washington, DC: US Government Printing Office 1968; Public Health Service Pub. No. 1000: Series 3, No. 12.
Szmuness W, Dienstag JL, Purcell RH, Harley EJ, Stevens CE, Wong DC. Distribution of antibody to hepatitis A antigen in urban adult populations. N Engl J Med 1976; 295: 755–9.
Soda T, Kimurra M, Hirayama T, Tsunoda R, Suganuma T, Ueda K. Recent Retardation of Mortality Rates in Japan. Washington, DC: US Government Printing Office, 1968; Public Health Service Pub. No. 1000: Series 3, No. 10.
Akbar SM, Onji M, Kanaoka M, et al. The seroepidemiology of hepatitis A and B in a Japanese town. Asia Pac J Public Health 1992; 6: 26–9.
Abdool Karim SS, Coutsoudis A. Sero-epidemiology of hepatitis A in black South African children. S Afr Med J 1993; 83: 748–50.
Botha JF, Blackburn NK, Schoub BD, Kew MC. The prevalence of antibodies to the hepatitis A virus in Owambo children. Trop Gastroenterol 1994; 15: 15–7.
Mohamud KB, Aceti A, Mohamed OM, et al. [The circulation of the hepatitis A and B viruses in the Somali population]. Ann Ital Med Int 1992; 7: 78–83.
Ayoola EA. Antibody to hepatitis A virus in healthy Nigerians. J Natl Med Assoc 1982; 74: 465–8.
Werner GT, Frosner GG, Fresenius K. Prevalence of serological hepatitis A and B markers in a rural area of northern Zaire. Am J Trop Med Hyg 1985; 34: 620–4.
Darwish M, Faris R, Clemens J, Rao M, Edelman R. High seroprevalence of hepatitis A, B, C, and E viruses in residents in an Egyptian village in The Nile Delta: a pilot study. Am J Trop Med Hyg 1996; 54: 554–8.
Thuring E, Joller-Jemelka HI, Sareth H, Sokhan U, Reth C, Grob P. Prevalence of markers of hepatitis viruses A, B, C and of HIV in healthy individuals and patients of a Cambodian province. Southeast Asian J Trop Med Public Health 1993; 24: 239–49.
Queiroz DA, Cardoso DD, Martelli CM, et al. Risk factors and prevalence of antibodies against hepatitis A virus (HAV) in children from day-care centers, in Goiania, Brazil. Rev Inst Med Trop Sao Paulo 1995; 37: 427–33.
Arankalle V, Tsarev S, Chadha M, et al. Age-specific prevalence of antibodies to hepatitis A and E viruses in Pune, India, 1982 and 1992. J Infect Dis 1995; 171: 447–50.
Fleming AF. Possible aetiological factors in leukaemias in Africa. Leuk Res 1988; 12: 33–43.
Kamel AM, Assem MM, Jaffe ES, Magrath I, Aboul Enein MI, Hindawy DS. Immunological phenotypic pattern of acute lymphoblastic leukaemia in Egypt. Leuk Res 1989; 13: 519–25.
Parkin DM, Stiller C, Draper G, Bieber C, Terracini B, Young J. International Incidence of Childhood Cancer. Lyon, France: International Agency for Research on Cancer, 1988.
Booth K, Amato D. Leukaemia in Papua New Guinea. Trop Geogr Med 1978; 30: 343–9.
Tu J, Li FP. Incidence of childhood tumors in Shanghai, 1973–77. J Natl Cancer Inst 1983; 70: 589–92.
Alert J, Jimenez J. Malignant tumors in Cuban children. Fourth triennial 1973–1975 of the national cancer registry. Neoplasma 1980; 27: 739–44.
Nandakumar A, Anantha N, Appaji L, et al. Descriptive epidemiology of childhood cancers in Bangalore, India. Cancer Causes Control 1996; 7: 405–10.
Mejia-Arangure JM, Fajardo-Gutierrez A, Bernaldez-Rios R, Farfan-Canto JM, Ortiz-Fernandez A, Martinez-Garcia MD. Incidence trends of acute leukemia among the children of Mexico City: 1982–1991. Arch Med Res 1996; 27: 223–7.
Barr RD, McCulloch PB, Mehta S, Kendall AG. Acute leukaemia in Kenya. Scott Med J 1972; 17: 330–3.
Kasili EG, Taylor JR. Leukaemia in Kenya. East Afr Med J 1970; 47: 461–8.
Nishi M, Miyake H, Takeda T, Shimada M. Epidemiology of childhood leukemia in Hokkaido, Japan. Int J Cancer 1996; 67: 323–6.
Knudson A. Ethnic differences in childhood leukemia as revealed by a study of antecedent variables. Cancer 1965; 18: 815–8.
Bhargava M, Kumar R, Karak A, Kochupillai V, Arya LS, Mohanakumar T. Immunological subtypes of acute lymphoblastic leukemia in north India. Leuk Res 1988; 12: 673–8.
Rajalekshmy KR, Abitha AR, Pramila R, Gnanasagar T, Maitreyan V, Shanta V. Immunophenotyping of acute lymphoblastic leukaemia in Madras, India. Leuk Res 1994; 18: 183–90.
Wilkinson R. The frequency of hepatitis A and B viruses as the offending viral type in suspected hepatitis. S Afr Med J 1983; 63: 82–5.
Rego EM, Garcia AB, Viana SR, Falcao RP. Characterization of acute lymphoblastic leukemia subtypes in Brazilian patients. Leuk Res 1996; 20: 349–55.
Kellett C. Acute leukaemia in one of identical twins. Arch Dis Child 1937; 12: 239.
Fraumeni JF Jr. Infectious mononucleosis and acute leukemia. JAMA 1971; 215: 1159.
Austin DF, Karp S, Dworsky R, Henderson BE. Excess leukemia in cohorts of children born following influenza epidemics. Am J Epidemiol 1975; 101: 77–83.
Fedrick J, Alberman ED. Reported influenza in pregnancy and subsequent cancer in the child. Br Med J 1972; 2: 485–8.
Hakulinen T, Hovi L, Karkinen J, Penttinen K, Saxen L. Association between influenza during pregnancy and childhood leukaemia. Br Med J 1973; 4: 265–7.
Shore RE, Pasternack BS, Curnen MG. Relating influenza epidemics to childhood leukemia in tumor registries without a defined population base: a critique with suggestions for improved methods. Am J Epidemiol 1976; 103: 527–35.
Vianna NJ, Polan AK. Childhood lymphatic leukemia: prenatal seasonality and possible association with congenital varicella. Am J Epidemiol 1976; 103: 321–32.
Adelstein AM, Donovan JW. Malignant disease in children whose mothers had chickenpox, mumps, or rubella in pregnancy. Br Med J 1972; 4: 629–31.
van 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 Epidemiol 1986; 124: 590–4.
Schlehofer B, Blettner M, Geletneky K, et al. Seroepidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer 1996; 65: 584–90.
Knox EG, Stewart AM, Kneale GW. Foetal infection, childhood leukaemia and cancer. Br J Cancer 1983; 48: 849–52.
Fleming A. Childhood leukaemia [Letter; Comment]. Lancet 1991; 337: 361.
Gold E, Nankervis G. Cytomegalovirus. In: Evans A, ed. Viral Infections of Humans: Epidemiology and Control, 3rd Ed. New York, NY (USA): Plenum Medical Book Company, 1989: 169–89.
Tookey PA, Ades AE, Peckham CS. Cytomegalovirus prevalence in pregnant women: the influence of parity. Arch Dis Child 1992; 67: 779–83.
Evans A, Cox F, Nankervis G, et al. A health and seroepidemiological survey of a community in Barbados. Int J Epidemiol 1974; 3: 167–75.
Evans AS, Cook JA, Kapikian AZ, Nankervis G, Smith AL, West B. A serological survey of St Lucia. Int J Epidemiol 1979; 8: 327–32.
Schopfer K, Lauber E, Krech U. Congenital cytomegalovirus infection in newborn infants of mothers infected before pregnancy. Arch Dis Child 1978; 53: 536–9.
Liu Z, Wang E, Taylor W, et al. Prevalence survey of cytomegalovirus infection in children in Chengdu. Am J Epidemiol 1990; 131: 143–50.
Kunitake T, Kitamura T, Guo J, Taguchi F, Kawabe K, Yogo Y. Parent-to-child transmission is relatively common in the spread of the human polyomavirus JC virus. J Clin Microbiol 1995; 33: 1448–51.
Gardner S, Knowles W. Human polyomaviruses. In: Zuckerman A, Bantvala J, Pattison J, eds. Principles and Practice of Clinical Virology. Chichester, UK: John Wiley & Sons, 1995: 635–51.
Bernal W, Smith HM, Williams R. A community prevalence study of antibodies to hepatitis A and E in inner-city London. J Med Virol 1996; 49: 230–4.
Tettmar RE, Masterton RG, Strike PW. Hepatitis A immunity in British adults-an assessment of the need for pre-immunisation screening. J Infect 1987; 15: 39–43.
Nandwani R, Caswell S, Boag F, Lawrence AG, Coleman JC. Hepatitis A seroprevalence in homosexual and heterosexual men. Genitourin Med 1994; 70: 325–8.
Stiller CA, Draper GJ. Trends in childhood leukaemia in Britain 1968–1978. Br J Cancer 1982; 45: 543–51.
Backer J, Aagenaes O. Infant Mortality Problems in Norway. Washington, DC: US Government Printing Office 1967; Public Health Service Pub. No 1000: Series 3, No. 8.
Bjelke E. Leukemia in children and young adults in Norway: Type distribution, incidence, and survival. Cancer 1964; 17: 248–55.
Ericsson JL, Karnstrom L, Mattsson B. Childhood cancer in Sweden, 1958–1974. I. Incidence and mortality. Acta Paediatr Scand 1978; 67: 425–32.
Lehmann NI, Gust ID. The prevalence of antibody to hepatitis A virus in two populations in Victoria. Med J Aust 1977; 2: 731–2.
Gust ID, Lehmann NI, Lucas CR, Ferris AA, Locarnini SA. Studies on the epidemiology of hepatitis A in Melbourne. In: GN V, Cohen S, Schmid R, eds. Viral hepatitis: A Contemporary Assessment of Etiology, Epidemiology, Pathogenesis, and Prevention. Philadelphia, PA (USA): Franklin Institute Press, 1978: 105–12.
Gust I, Lehmann N, Lucas C. Relationship between prevalence of antibody to hepatitis A antigen and age: A cohort effect? J Infect Dis 1978; 138: 425–6.
Petridou E, Revinthi K, Alexander FE, et al. Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology. Br J Cancer 1996; 73: 1278–83.
Kobayashi A. Changing patterns of parasitic infections in Japan. In: Croll N, Cross J, eds. Human Ecology and Infectious Diseases. New York, NY (USA): Academic Press, 1983: 137–68.
Kuni C. Parasite control activities in Japan: Government-expert-private sector partnership. In: Croll N, Cross J, eds. Human Ecology and Infectious Diseases. New York, NY (USA): Academic Press, 1983: 169–85.
Tominaga S, Aoki K, Fujimoto I, Kurihara M. Cancer Mortality and Morbidity Statistics. Tokyo, Japan: Japan Scientific Societies Press, 1994; Gann Monogr Cancer Res, Vol. 41.
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Smith, M.A., Simon, R., Strickler, H.D. et al. Evidence that Childhood Acute Lymphoblastic Leukemia is Associated with an Infectious Agent Linked to Hygiene Conditions. Cancer Causes Control 9, 285–298 (1998). https://doi.org/10.1023/A:1008873103921
- Acute lymphoblastic leukemia
- hepatitis A virus
- socioeconomic status
- United States