Early Childhood Diarrhea Predicts Cognitive Delays in Later Childhood Independently of Malnutrition

Relana Pinkerton Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.

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Reinaldo B. Oriá Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.
Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Institute of Biomedicine and Clinical Research Unit, University Hospital, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.

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Aldo A. M. Lima Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.
Institute of Biomedicine and Clinical Research Unit, University Hospital, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Physiology and Pharmacology Department, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.

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Elizabeth T. Rogawski Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.

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Mônica O. B. Oriá Department of Nursing, Federal University of Ceará, Fortaleza, Brazil.

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Peter D. Patrick Kluge Children Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.

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Sean R. Moore Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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Benjamin L. Wiseman Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.
Psychiatry, Johnston-Willis Hospital, Richmond, Virginia.

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Mark D. Niehaus Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.

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Richard L. Guerrant Center for Global Health, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, Virginia.
Institute of Biomedicine and Clinical Research Unit, University Hospital, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.

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Understanding the complex relationship between early childhood infectious diseases, nutritional status, poverty, and cognitive development is significantly hindered by the lack of studies that adequately address confounding between these variables. This study assesses the independent contributions of early childhood diarrhea (ECD) and malnutrition on cognitive impairment in later childhood. A cohort of 131 children from a shantytown community in northeast Brazil was monitored from birth to 24 months for diarrhea and anthropometric status. Cognitive assessments including Test of Nonverbal Intelligence (TONI), coding tasks (WISC-III), and verbal fluency (NEPSY) were completed when children were an average of 8.4 years of age (range = 5.6–12.7 years). Multivariate analysis of variance models were used to assess the individual as well as combined effects of ECD and stunting on later childhood cognitive performance. ECD, height for age (HAZ) at 24 months, and weight for age (WAZ) at 24 months were significant univariate predictors of the studies three cognitive outcomes: TONI, coding, and verbal performance (P < 0.05). Multivariate models showed that ECD remained a significant predictor, after adjusting for the effect of 24 months HAZ and WAZ, for both TONI (HAZ, P = 0.029 and WAZ, P = 0.006) and coding (HAZ, P = 0.025 and WAZ, P = 0.036) scores. WAZ and HAZ were also significant predictors after adjusting for ECD. ECD remained a significant predictor of coding (WISC III) after number of household income was considered (P = 0.006). This study provides evidence that ECD and stunting may have independent effects on children's intellectual function well into later childhood.

Author Notes

* Address correspondence to Richard L. Guerrant, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, 2507 Northfield Road, Charlottesville, VA 22901. E-mail: rlg9a@virginia.edu

Authors' addresses: Relana Pinkerton, Elizabeth T. Rogawski, Mark D. Niehaus, and Richard L. Guerrant, Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, E-mails: rcp3w@virginia.edu, etr5m@virginia.edu, mniehaus@lifespan.org, and rlg9a@virginia.edu. Reinaldo B. Oriá and Mônica O. B. Oriá, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil, E-mails: oria@ufc.br and oriarte@aol.com.br. Aldo A. M. Lima, Institute of Biomedicine and Clinical Research Unit, University Hospital, School of Medicine, Federal University of Ceará, Fortaleza, Brazil, E-mail: alima@ufc.br. Peter D. Patrick, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, E-mail: pdp2n@virginia.edu. Sean R. Moore, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, E-mail: sean.moore.md@gmail.com. Benjamin L. Wiseman, Psychiatry, CJW Medical Center, Johnston-Willis Hospital, Richmond, VA, E-mail: blw4u@virginia.edu.

  • 1.

    Kosek M, Bern C, Guerrant RL, 2003. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 81: 197204.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Keusch GT, Scrimshaw NS, 1986. Selective primary health care: strategies for control of disease in the developing world. XXIII. Control of infection to reduce the prevalence of infantile and childhood malnutrition. Rev Infect Dis 8: 273287.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Bryce J, Boschi-Pinto C, Shibuya K, Black RE, 2005. WHO estimates of the causes of death in children. Lancet 365: 11471152.

  • 4.

    Guerrant RL, Kosek M, Lima AA, Lorntz B, Guyatt HL, 2002. Updating the DALYs for diarrhoeal disease. Trends Parasitol 18: 191193.

  • 5.

    Moore SR, Lima AA, Conaway MR, Schorling JB, Soares AM, Guerrant RL, 2001. Early childhood diarrhoea and helminthiases associate with long-term linear growth faltering. Int J Epidemiol 30: 14571464.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Guerrant DI, Moore SR, Lima AA, Patrick PD, Schorling JB, Guerrant RL, 1999. Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil. Am J Trop Med Hyg 61: 707713.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Niehaus MD, Moore SR, Patrick PD, Derr LL, Lorntz B, Lima AA, Guerrant RL, 2002. Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown. Am J Trop Med Hyg 66: 590593.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Lorntz B, Soares AM, Moore SR, Pinkerton R, Gansneder B, Bovbjerg VE, Guyatt H, Lima AM, Guerrant RL, 2006. Early childhood diarrhea predicts impaired school performance. Pediatr Infect Dis J 25: 513520.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Patrick PD, Oria RB, Madhavan V, Pinkerton RC, Lorntz B, Lima AA, Guerrant RL, 2005. Limitations in verbal fluency following heavy burdens of early childhood diarrhea in Brazilian shantytown children. Child Neuropsychol 11: 233244.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Tarleton JL, Haque R, Mondal D, Shu J, Farr BM, Petri WA Jr, 2006. Cognitive effects of diarrhea, malnutrition, and Entamoeba histolytica infection on school age children in Dhaka, Bangladesh. Am J Trop Med Hyg 74: 475481.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Berkman DS, Lescano AG, Gilman RH, Lopez SL, Black MM, 2002. Effects of stunting, diarrhoeal disease, and parasitic infection during infancy on cognition in late childhood: a follow-up study. Lancet 359: 564571.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Bowen A, Agboatwalla M, Luby S, Tobery T, Ayers T, Hoekstra RM, 2012. Association between intensive handwashing promotion and child development in Karachi, Pakistan: a cluster randomized controlled trial. Arch Pediatr Adolesc Med 166: 10371044.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Rice D, Barone S Jr, 2000. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108 (Suppl 3): 511533.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Yehuda S, Rabinovitz S, Mostofsky DI, 2006. Nutritional deficiencies in learning and cognition. J Pediatr Gastroenterol Nutr 43 (Suppl 3): S22S25.

  • 15.

    Checkley W, Gilman RH, Epstein LD, Suarez M, Diaz JF, Cabrera L, Black RE, Sterling CR, 1997. Asymptomatic and symptomatic cryptosporidiosis: their acute effect on weight gain in Peruvian children. Am J Epidemiol 145: 156163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Bushen OY, Kohli A, Pinkerton RC, Dupnik K, Newman RD, Sears CL, Fayer R, Lima AA, Guerrant RL, 2007. Heavy cryptosporidial infections in children in northeast Brazil: comparison of Cryptosporidium hominis and Cryptosporidium parvum. Trans R Soc Trop Med Hyg 101: 378384.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Kohli A, Bushen OY, Pinkerton RC, Houpt E, Newman RD, Sears CL, Lima AA, Guerrant RL, 2008. Giardia duodenalis assemblage, clinical presentation and markers of intestinal inflammation in Brazilian children. Trans R Soc Trop Med Hyg 102: 718725.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Guerrant RL, Oria RB, Boissevain JR, Patrick PD, Lima AA, 2007. Infectious diseases, balanced polymorphisms, and human evolution: a declaration of interdependence. Curr Infect Dis Rep 9: 8385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Ley RE, Turnbaugh PJ, Klein S, Gordon JI, 2006. Microbial ecology: human gut microbes associated with obesity. Nature 444: 10221023.

  • 20.

    Oria RB, Patrick PD, Zhang H, Lorntz B, de Castro Costa CM, Brito GA, Barrett LJ, Lima AA, Guerrant RL, 2005. APOE4 protects the cognitive development in children with heavy diarrhea burdens in northeast Brazil. Pediatr Res 57: 310316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Prentice AM, Rayco-Solon P, Moore SE, 2005. Insights from the developing world: thrifty genotypes and thrifty phenotypes. Proc Nutr Soc 64: 153161.

  • 22.

    Lima AA, Moore SR, Barboza MS Jr, Soares AM, Schleupner MA, Newman RD, Sears CL, Nataro JP, Fedorko DP, Wuhib T, Schorling JB, Guerrant RL, 2000. Persistent diarrhea signals a critical period of increased diarrhea burdens and nutritional shortfalls: a prospective cohort study among children in northeastern Brazil. J Infect Dis 181: 16431651.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Wechsler D, Golombok S, Rust J, 1991. Weschler Intelligence Scale for Children (WISC–IIIUK). 3rd ed. The Psychological Corporation.

  • 24.

    Lima AA, Guerrant RL, 1992. Persistent diarrhea in children: epidemiology, risk factors, pathophysiology, nutritional impact, and management. Epidemiol Rev 14: 222242.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Pires AL, da Silveira TR, Scholl JG, 1999. Relationship between nutritional status and histologic findings in small bowel mucosa of children presenting with diarrhoea of more than 14 days' duration. J Trop Pediatr 45: 302304.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Chappell VL, Thompson MD, Jeschke MG, Chung DH, Thompson JC, Wolf SE, 2003. Effects of incremental starvation on gut mucosa. Dig Dis Sci 48: 765769.

  • 27.

    Lima AA, Brito LF, Ribeiro HB, Martins MC, Lustosa AP, Rocha EM, Lima NL, Monte CM, Guerrant RL, 2005. Intestinal barrier function and weight gain in malnourished children taking glutamine supplemented enteral formula. J Pediatr Gastroenterol Nutr 40: 2835.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Chen P, Soares AM, Lima AA, Gamble MV, Schorling JB, Conway M, Barrett LJ, Blaner WS, Guerrant RL, 2003. Association of vitamin A and zinc status with altered intestinal permeability: analyses of cohort data from northeastern Brazil. J Health Popul Nutr 21: 309315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Zhang Y, Lee B, Thompson M, Glass R, Cama RI, Figueroa D, Gilman R, Taylor D, Stephenson C; Diarrhea Working Group, Peru, 2000. Lactulose–mannitol intestinal permeability test in children with diarrhea caused by rotavirus and Cryptosporidium. J Pediatr Gastroenterol Nutr 31: 1621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Checkley W, Epstein LD, Gilman RH, Cabrera L, Black RE, 2003. Effects of acute diarrhea on linear growth in Peruvian children. Am J Epidemiol 157: 166175.

  • 31.

    Steiner TS, Lima AA, Nataro JP, Guerrant RL, 1998. Enteroaggregative Escherichia coli produce intestinal inflammation and growth impairment and cause interleukin-8 release from intestinal epithelial cells. J Infect Dis 177: 8896.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Checkley W, Epstein LD, Gilman RH, Black RE, Cabrera L, Sterling CR, 1998. Effects of Cryptosporidium parvum infection in Peruvian children: growth faltering and subsequent catch-up growth. Am J Epidemiol 148: 497506.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B, 2007. Developmental potential in the first 5 years for children in developing countries. Lancet 369: 6070.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Dillingham R, Guerrant RL, 2004. Childhood stunting: measuring and stemming the staggering costs of inadequate water and sanitation. Lancet 363: 9495.

  • 35.

    Jiang NM, Tofail F, Moonah SN, Scharf RJ, Taniuchi M, Ma JZ, Hamadani JD, Gurley ES, Houpt ER, Azziz-Baumgartner E, Haque R, Petri WA Jr, 2014. Febrile illness and pro-inflammatory cytokines are associated with lower neurodevelopmental scores in Bangladeshi infants living in poverty. BMC Pediatr 14: 50.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Kolb B, Whishaw IQ, 1985. Fundamentals of Human Neuropsychology, 2nd edition. New York, NY: W. H. Freeman.

  • 37.

    Mayneris-Perxachs J, Lima AA, Guerrant RL, Leite ÁM, Moura AF, Lima NL, Soares AM, Havt A, Moore SR, Pinkerton R, Swann JR, 2007. Light and confocal microscopic observations of adult Schistosoma mansoni from mice fed on a high-fat diet. J Helminthol 81: 361368.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI, 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444: 10271031.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Brocki KC, Bohlin G, 2004. Executive functions in children aged 6 to 13: a dimensional and developmental study. Dev Neuropsychol 26: 571593.

  • 40.

    Walter T, 2003. Effect of iron-deficiency anemia on cognitive skills and neuromaturation in infancy and childhood. Food Nutr Bull 24 (Suppl): S104S110.

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