• View in gallery

    Examples of normal growth patterns for children: Left panels indicate Centers for Disease Control and Prevention (CDC) curves for normal weight and height values at different ages during childhood, indicating growth-related gains up to 20 years of age. Right panels indicate their corresponding normal age-specific rates of change (“growth velocity”), based on National Center for Health Statistics (NCHS) data available at: http://www.cdc.gov/growthcharts/percentile_data_files.htm.30 Representative data for boys' height and linear growth velocity are shown in the upper panels. Data for girls' weight and weight gain at different ages are shown in the lower panels. Graphed lines, from bottom to top, represent the observed 3rd, 10th, 50th, 90th, and 97th percentiles of normal childhood growth, respectively.

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    Envelopes of Schistosoma infection intensity (worm burden, approximated by counts of excreted eggs)47 and related effects on growth patterns (in terms of height and weight) for the modeled heterogeneous endemic population. Boys are indicated in the upper panels and girls are indicated in the lower panels. Each hypothetical gender cohort was assembled from five quantile groups, reflecting the range of their initial potential for healthy growth, i.e., normally capable of reaching the 5th, 25th, 50th, 75th, or 95th percentiles, respectively. Left panels indicate the range of likely egg counts for each age group. Middle panels indicate the range of likely heights, and right panels indicate the likely range of weights at different ages among the affected childhood populations. In each height and weight plot, the thick solid curve represents the desired United States median growth, dashed lines from bottom to top represent, respectively, the community minimum and maximum values as affected by recurrent Schistosoma infection; small dots represent calibration data from field studies,31 and the thin solid line is the best-fit curve with the parameters shown in Table 1.

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    Projected effects of treatment at 6, 9, and 12 years of age (with the fraction of worms killed in each session being 90%) on worm burden and developmental growth of an individual randomly selected from the modeled community. Solid curves are for baseline state (untreated infection) and dashed lines show the expected impact of the three treatment schedule.

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    Projected impact of different schistosomiasis treatment regimens on accrued growth (relative to normal) at 20 years of age for infected girls and boys exposed to possible reinfection in endemic areas, based on model simulations of growth, reinfection, and potential for catch-up growth after treatment. In each panel, clustered bars for girls and boys compare the projected outcomes of five proposed strategies: 1) no treatment; 2) treatment at the time of school entry and completion (ages 5 and 15 yr); 3) treatment at 6, 9, and 12 years of age; 4) treatment every 2 years; and 5) treatment every year during school ages from 4 up to 15 years of age. Upper panels show substantially reduced impact when community participation is low (20%), as compared with where projected uptake and adherence are high (80%, lower panels). This figure appears in color at www.ajtmh.org.

  • 1.

    Chitsulo L, Engels D, Montresor A, Savioli L, 2000. The global status of schistosomiasis and its control. Acta Trop 77: 4151.

  • 2.

    Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J, 2006. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 6: 411425.

    • Search Google Scholar
    • Export Citation
  • 3.

    King CH, Mahmoud AA, 1989. Drugs five years later: praziquantel. Ann Intern Med 110: 290296.

  • 4.

    Fenwick A, 2006. New initiatives against Africa's worms. Trans R Soc Trop Med Hyg 100: 200207.

  • 5.

    Molyneux DH, Hotez PJ, Fenwick A, 2005. “Rapid-impact interventions”: how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med 2: e336.

    • Search Google Scholar
    • Export Citation
  • 6.

    Satayathum SA, Muchiri EM, Ouma JH, Whalen CC, King CH, 2006. Factors affecting infection or reinfection with Schistosoma haematobium in coastal Kenya: survival analysis during a nine-year, school-based treatment program. Am J Trop Med Hyg 75: 8392.

    • Search Google Scholar
    • Export Citation
  • 7.

    King CH, 2007. Lifting the burden of schistosomiasis-defining elements of infection-associated disease and the benefits of antiparasite treatment. J Infect Dis 196: 653655.

    • Search Google Scholar
    • Export Citation
  • 8.

    King CH, Sturrock RF, Kariuki HC, Hamburger J, 2006. Transmission control for schistosomiasis—why it matters now. Trends Parasitol 22: 575582.

    • Search Google Scholar
    • Export Citation
  • 9.

    King CH, 2001. Epidemiology of schistosomiasis: determinants of transmission of infection. Mahmoud AA, ed. Schistosomiasis. London, UK: Imperial College Press, 115132.

    • Search Google Scholar
    • Export Citation
  • 10.

    Smith JH, Christie JD, 1986. The pathobiology of Schistosoma haematobium infection in humans. Hum Pathol 17: 333345.

  • 11.

    Richter J, Correia Dacal AR, Vergetti Siqueira JG, Poggensee G, Mannsmann U, Deelder A, Feldmeier H, 1998. Sonographic prediction of variceal bleeding in patients with liver fibrosis due to Schistosoma mansoni. Trop Med Int Health 3: 728735.

    • Search Google Scholar
    • Export Citation
  • 12.

    van der Werf MJ, de Vlas SJ, Brooker S, Looman CWN, Nagelkerke NJD, Habbema JDF, Engels D, 2003. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 86: 125139.

    • Search Google Scholar
    • Export Citation
  • 13.

    Koukounari A, Gabrielli AF, Toure S, Bosque-Oliva E, Zhang Y, Sellin B, Donnelly CA, Fenwick A, Webster JP, 2007. Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso. J Infect Dis 196: 659669.

    • Search Google Scholar
    • Export Citation
  • 14.

    Olveda RM, 2001. Disease in schistosomiasis japonica. Mahmoud AA, ed. Schistosomiasis. London: Imperial College Press, 361390.

  • 15.

    King CH, Dickman K, Tisch DJ, 2005. Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365: 15611569.

    • Search Google Scholar
    • Export Citation
  • 16.

    Friedman JF, Kanzaria HK, Acosta LP, Langdon GC, Manalo DL, Wu H, Olveda RM, McGarvey ST, Kurtis JD, 2005. Relationship between Schistosoma japonicum and nutritional status among children and young adults in Leyte, the Philippines. Am J Trop Med Hyg 72: 527533.

    • Search Google Scholar
    • Export Citation
  • 17.

    King CH, Dangerfield-Cha M, 2008. The unacknowledged impact of chronic schistosomiasis. Chronic Illn 4: 6579.

  • 18.

    Ezeamama AE, Friedman JF, Acosta LP, Bellinger DC, Langdon GC, Manalo DL, Olveda RM, Kurtis JD, McGarvey ST, 2005. Helminth infection and cognitive impairment among Filipino children. Am J Trop Med Hyg 72: 540548.

    • Search Google Scholar
    • Export Citation
  • 19.

    Nokes C, McGarvey ST, Shiue L, Wu G, Wu H, Bundy DA, Olds GR, 1999. Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren. Am J Trop Med Hyg 60: 556565.

    • Search Google Scholar
    • Export Citation
  • 20.

    King CH, 2010. Parasites and poverty: the case of schistosomiasis. Acta Trop 113: 95104.

  • 21.

    King CH, Bertino AM, 2008. Asymmetries of poverty: why global burden of disease valuations underestimate the burden of neglected tropical diseases. PLoS Negl Trop Dis 2: e209.

    • Search Google Scholar
    • Export Citation
  • 22.

    WHO, 2006. Preventive Chemotherapy in Human Helminthiasis: Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 23.

    Medley GF, Bundy DAP, 1996. Dynamic modeling of epidemiologic patterns of schistosomiasis morbidity. Am J Trop Med Hyg 55: 149158.

  • 24.

    Chan MS, Guyatt HL, Bundy DA, Booth M, Fulford AJ, Medley GF, 1995. The development of an age structured model for schistosomiasis transmission dynamics and control and its validation for Schistosoma mansoni. Epidemiol Infect 115: 325344.

    • Search Google Scholar
    • Export Citation
  • 25.

    Gurarie D, King CH, 2005. Heterogeneous model of schistosomiasis transmission and long-term control: the combined influence of spatial variation and age-dependent factors on optimal allocation of drug therapy. Parasitology 130: 4965.

    • Search Google Scholar
    • Export Citation
  • 26.

    Gurarie D, King CH, Wang X, 2010. A new approach to modelling schistosomiasis transmission based on stratified worm burden. Parasitology 137: 19511965.

    • Search Google Scholar
    • Export Citation
  • 27.

    Stephenson LS, Latham MC, Kurz KM, Kinoti SN, 1989. Single dose metrifonate or praziquantel treatment in Kenyan children. II. Effects on growth in relation to Schistosoma haematobium and hookworm egg counts. Am J Trop Med Hyg 41: 445453.

    • Search Google Scholar
    • Export Citation
  • 28.

    Stephenson LS, Latham MC, Kurz KM, Kinoti SN, Oduori ML, Crompton DW, 1985. Relationships of Schistosoma haematobium, hookworm and malarial infections and metrifonate treatment to growth of Kenyan school children. Am J Trop Med Hyg 34: 11091118.

    • Search Google Scholar
    • Export Citation
  • 29.

    Parraga IM, Assis AM, Prado MS, Barreto ML, Reis MG, King CH, Blanton RE, 1996. Gender differences in growth of school-aged children with schistosomiasis and geohelminth infection. Am J Trop Med Hyg 55: 150156.

    • Search Google Scholar
    • Export Citation
  • 30.

    de Onis M, Garza C, Onyango AW, Borghi E, 2007. Comparison of the WHO child growth standards and the CDC 2000 growth charts. J Nutr 137: 144148.

    • Search Google Scholar
    • Export Citation
  • 31.

    Olds GR, King CH, Hewlett J, Olveda R, Wu G, Ouma JH, Peters PA, McGarvey S, Koech D, Liu CY, Aligui G, Gachihi G, Kombe Y, Parraga I, Ramirez B, Whalen C, Horton RJ, Reeve P, 1999. Double-blind placebo controlled study of concurrent administration of albendazole and praziquantel in school children with schistosomiasis and geohelminths. J Infect Dis 179: 9961003.

    • Search Google Scholar
    • Export Citation
  • 32.

    Blanton RE, Salam EA, Ehsan A, King CH, Goddard KA, 2005. Schistosomal hepatic fibrosis and the interferon gamma receptor: a linkage analysis using single-nucleotide polymorphic markers. Eur J Hum Genet 13: 660668.

    • Search Google Scholar
    • Export Citation
  • 33.

    Dessein AJ, Hillaire D, Elwali NE, Marquet S, Mohamed-Ali Q, Mirghani A, Henri S, Abdelhameed AA, Saeed OK, Magzoub MM, Abel L, 1999. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 65: 709721.

    • Search Google Scholar
    • Export Citation
  • 34.

    Koukounari A, Fenwick A, Whawell S, Kabatereine NB, Kazibwe F, Tukahebwa EM, Stothard JR, Donnelly CA, Webster JP, 2006. Morbidity indicators of Schistosoma mansoni: relationship between infection and anemia in Ugandan schoolchildren before and after praziquantel and albendazole chemotherapy. Am J Trop Med Hyg 75: 278286.

    • Search Google Scholar
    • Export Citation
  • 35.

    Leenstra T, Acosta LP, Langdon GC, Manalo DL, Su L, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Schistosomiasis japonica, anemia, and iron status in children, adolescents, and young adults in Leyte, Philippines. Am J Clin Nutr 83: 371379.

    • Search Google Scholar
    • Export Citation
  • 36.

    Klumpp RK, Webbe G, 1987. Focal, seasonal and behavioural patterns of infection and transmission of Schistosoma haematobium in a farming village at the Volta Lake, Ghana. J Trop Med Hyg 90: 265281.

    • Search Google Scholar
    • Export Citation
  • 37.

    Kloos H, Fulford AJ, Butterworth AE, Sturrock RF, Ouma JH, Kariuki HC, Thiongo FW, Dalton PR, Klumpp RK, 1997. Spatial patterns of human water contact and Schistosoma mansoni transmission and infection in four rural areas in Machakos District, Kenya. Soc Sci Med 44: 949968.

    • Search Google Scholar
    • Export Citation
  • 38.

    Kvalsvig JD, Schutte CH, 1986. The role of human water contact patterns in the transmission of schistosomiasis in an informal settlement near a major industrial area. Ann Trop Med Parasitol 80: 1326.

    • Search Google Scholar
    • Export Citation
  • 39.

    Hagan P, Blumenthal UJ, Chaudri M, Greenwood BM, Hayes RJ, Hodgson I, Kelly C, Knight M, Simpson AJ, Smithers SR, Wilkins HA, 1987. Resistance to reinfection with Schistosoma haematobium in Gambian children: analysis of their immune responses. Trans R Soc Trop Med Hyg 81: 938946.

    • Search Google Scholar
    • Export Citation
  • 40.

    Etard JF, Audibert M, Dabo A, 1995. Age-acquired resistance and predisposition to reinfection with Schistosoma haematobium after treatment with praziquantel in Mali. Am J Trop Med Hyg 52: 549558.

    • Search Google Scholar
    • Export Citation
  • 41.

    Kurtis JD, Friedman JF, Leenstra T, Langdon GC, Wu HW, Manalo DL, Su L, Jiz M, Jarilla B, Pablo AO, McGarvey ST, Olveda RM, Acosta LP, 2006. Pubertal development predicts resistance to infection and reinfection with Schistosoma japonicum. Clin Infect Dis 42: 16921698.

    • Search Google Scholar
    • Export Citation
  • 42.

    Naus CW, Kimani G, Ouma JH, Fulford AJ, Webster M, van Dam GJ, Deelder AM, Butterworth AE, Dunne DW, 1999. Development of antibody isotype responses to Schistosoma mansoni in an immunologically naive immigrant population: influence of infection duration, infection intensity, and host age. Infect Immun 67: 34443451.

    • Search Google Scholar
    • Export Citation
  • 43.

    Olveda RM, Daniel BL, Ramirez BD, Aligui GD, Acosta LP, Fevidal P, Tiu E, de Veyra F, Peters PA, Romulo R, Domingo E, Wiest PM, Olds GR, 1996. Schistosomiasis japonica in the Philippines: the long-term impact of population-based chemotherapy on infection, transmission, and morbidity. J Infect Dis 174: 163172.

    • Search Google Scholar
    • Export Citation
  • 44.

    Boersma B, Wit JM, 1997. Catch-up growth. Endocr Rev 18: 646661.

  • 45.

    Coutinho HM, Acosta LP, McGarvey ST, Jarilla B, Jiz M, Pablo A, Su L, Manalo DL, Olveda RM, Kurtis JD, Friedman JF, 2006. Nutritional status improves after treatment of Schistosoma japonicum-infected children and adolescents. J Nutr 136: 183188.

    • Search Google Scholar
    • Export Citation
  • 46.

    Coutinho HM, McGarvey ST, Acosta LP, Manalo DL, Langdon GC, Leenstra T, Kanzaria HK, Solomon J, Wu H, Olveda RM, Kurtis JD, Friedman JF, 2005. Nutritional status and serum cytokine profiles in children, adolescents, and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines. J Infect Dis 192: 528536.

    • Search Google Scholar
    • Export Citation
  • 47.

    Wilson RA, van Dam GJ, Kariuki TM, Farah IO, Deelder AM, Coulson PS, 2006. The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in non-human primates. Int J Parasitol 36: 12411244.

    • Search Google Scholar
    • Export Citation
  • 48.

    WHO, 2002. Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee. WHO Tech Rep Ser 912: 157.

    • Search Google Scholar
    • Export Citation
  • 49.

    Assis AM, Barreto ML, Prado MS, Reis MG, Parraga IM, Blanton RE, 1998. Schistosoma mansoni infection and nutritional status in schoolchildren: a randomized, double-blind trial in northeastern Brazil. Am J Clin Nutr 68: 12471253.

    • Search Google Scholar
    • Export Citation
  • 50.

    Kirigia JM, 1997. Economic evaluation in schistosomiasis: using the delphi technique to assess effectiveness. Acta Trop 64: 175190.

  • 51.

    Bustinduy AL, King CH, 2009. Parasitic helminths. Fratamico PM, Smith JL, Brogden KA, eds. Post-Infectious Sequelae and Long-Term Consequences of Infectious Diseases. Washington, DC: American Society for Microbiology Press, 291329.

    • Search Google Scholar
    • Export Citation
  • 52.

    Warren KS, 1982. Selective primary health care: strategies for control of disease in the developing world. I. Schistosomiasis. Rev Infect Dis 4: 715726.

    • Search Google Scholar
    • Export Citation
  • 53.

    Beasley NM, Tomkins AM, Hall A, Kihamia CM, Lorri W, Nduma B, Issae W, Nokes C, Bundy DA, 1999. The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania. Trop Med Int Health 4: 744750.

    • Search Google Scholar
    • Export Citation
  • 54.

    Leenstra T, Coutinho HM, Acosta LP, Langdon GC, Su L, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation. Infect Immun 74: 63986407.

    • Search Google Scholar
    • Export Citation
  • 55.

    Kjetland EF, Ndhlovu PD, Kurewa EN, Midzi N, Gomo E, Mduluza T, Friis H, Gundersen SG, 2008. Prevention of gynecologic contact bleeding and genital sandy patches by childhood anti-schistosomal treatment. Am J Trop Med Hyg 79: 7983.

    • Search Google Scholar
    • Export Citation
  • 56.

    Ouma JH, King CH, Muchiri EM, Mungai P, Koech DK, Ireri E, Magak P, Kadzo H, 2005. Late benefits 10–18 years after drug therapy for infection with Schistosoma haematobium in Kwale District, Coast Province, Kenya. Am J Trop Med Hyg 73: 359364.

    • Search Google Scholar
    • Export Citation
  • 57.

    Coutinho HM, Leenstra T, Acosta LP, Olveda RM, McGarvey ST, Friedman JF, Kurtis JD, 2007. Higher serum concentrations of DHEAS predict improved nutritional status in helminth-infected children, adolescents, and young adults in Leyte, the Philippines. J Nutr 137: 433439.

    • Search Google Scholar
    • Export Citation
  • 58.

    Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL, 2002. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 May: 1190.

    • Search Google Scholar
    • Export Citation
  • 59.

    de Onis M, Habicht JP, 1996. Anthropometric reference data for international use: recommendations from a World Health Organization Expert Committee. Am J Clin Nutr 64: 650658.

    • Search Google Scholar
    • Export Citation
  • 60.

    WHO, 2006. Assessment of differences in linear growth among populations in the WHO Multicentre Growth Reference Study. Acta Paediatr Suppl 450: 5665.

    • Search Google Scholar
    • Export Citation
  • 61.

    Woolhouse ME, Watts CH, Chandiwana SK, 1991. Heterogeneities in transmission rates and the epidemiology of schistosome infection. Proc R Soc Lond B Biol Sci 245: 109114.

    • Search Google Scholar
    • Export Citation
  • 62.

    Kvalsvig JD, 1986. The effects of schistosomiasis haematobium on the activity of school children. J Trop Med Hyg 89: 8590.

  • 63.

    Gryseels B, 1989. The relevance of schistosomiasis for public health. Trop Med Parasitol 40: 134142.

  • 64.

    Tanner M, 1989. Evaluation of public health impact of schistosomiasis. Trop Med Parasitol 40: 143148.

  • 65.

    Warren KS, Mahmoud AA, 1976. Targeted mass treatment: a new approach to the control of schistosomiasis. Trans Assoc Am Physicians 89: 195204.

    • Search Google Scholar
    • Export Citation
  • 66.

    Mott KE, 2004. Schistosomiasis. Murray CJ, Lopez A, Mathers CD, eds. The Global Epidemiology of Infectious Diseases. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 67.

    de Lima e Costa MF, Leite ML, Rocha RS, de Almeida Magalhaes MH, Katz N, 1988. Anthropometric measures in relation to schistosomiasis mansoni and socioeconomic variables. Int J Epidemiol 17: 880886.

    • Search Google Scholar
    • Export Citation
  • 68.

    McGarvey ST, Wu G, Zhang S, Wang Y, Peters P, Olds GR, Wiest PM, 1993. Child growth, nutritional status, and schistosomiasis japonica in Jiangxi, People's Republic of China. Am J Trop Med Hyg 48: 547553.

    • Search Google Scholar
    • Export Citation
  • 69.

    Blas BL, Lipayon IL, Tormis LC, Portillo LA, Hayashi M, Matsuda H, 2006. An attempt to study the economic loss arising from Schistosoma japonicum infection and the benefits derived from treatment. Southeast Asian J Trop Med Public Health 37: 2632.

    • Search Google Scholar
    • Export Citation
  • 70.

    Strauss J, Thomas D, 1998. Health, nutrition, and economic development. J Econ Lit 36: 766817.

  • 71.

    Florencio TT, Ferreira HS, Cavalcante JC, Assuncao ML, Sawaya AL, 2008. Short stature and food habits as determining factors for the low productivity of sugarcane laborers in the State of Alagoas, north-eastern Brazil. Arch Latinoam Nutr 58: 3339.

    • Search Google Scholar
    • Export Citation
  • 72.

    Coly AN, Milet J, Diallo A, Ndiaye T, Benefice E, Simondon F, Wade S, Simondon KB, 2006. Preschool stunting, adolescent migration, catch-up growth, and adult height in young Senegalese men and women of rural origin. J Nutr 136: 24122420.

    • Search Google Scholar
    • Export Citation
  • 73.

    Lwambo NJ, Brooker S, Siza JE, Bundy DA, Guyatt H, 2000. Age patterns in stunting and anaemia in African schoolchildren: a cross-sectional study in Tanzania. Eur J Clin Nutr 54: 3640.

    • Search Google Scholar
    • Export Citation
  • 74.

    Coutinho HM, Leenstra T, Acosta LP, Su L, Jarilla B, Jiz MA, Langdon GC, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Pro-inflammatory cytokines and C-reactive protein are associated with undernutrition in the context of Schistosoma japonicum infection. Am J Trop Med Hyg 75: 720726.

    • Search Google Scholar
    • Export Citation
  • 75.

    Golden MH, 1994. Is complete catch-up possible for stunted malnourished children? Eur J Clin Nutr 48 (Suppl 1): S5870; discussion S71.

  • 76.

    Stothard JR, Gabrielli AF, 2007. Schistosomiasis in African infants and preschool children: to treat or not to treat? Trends Parasitol 23: 8386.

    • Search Google Scholar
    • Export Citation
  • 77.

    Carabin H, Marshall CM, Joseph L, Riley S, Olveda R, McGarvey ST, 2005. Estimating the intensity of infection with Schistosoma japonicum in villagers of Leyte, Philippines. Part I: a Bayesian cumulative logit model. The Schistosomiasis Transmission & Ecology Project (STEP). Am J Trop Med Hyg 72: 745753.

    • Search Google Scholar
    • Export Citation
  • 78.

    de Vlas SJ, Gryseels B, 1992. Underestimation of Schistosoma mansoni prevalences. Parasitol Today 8: 274277.

  • 79.

    Savioli L, Hatz C, Dixon H, Kisumku UM, Mott KE, 1990. Control of morbidity due to Schistosoma haematobium on Pemba Island: egg excretion and hematuria as indicators of infection. Am J Trop Med Hyg 43: 289295.

    • Search Google Scholar
    • Export Citation
  • 80.

    Shane HL, Verani JR, Abudho B, Montgomery SP, Blackstock AJ, Mwinzi PN, Butler SE, Karanja DM, Secor WE, 2011. Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in western Kenya. PLoS Negl Trop Dis 5: e591.

    • Search Google Scholar
    • Export Citation
  • 81.

    Stothard JR, Sousa-Figuereido JC, Betson M, Adriko M, Arinaitwe M, Rowell C, Besiyge F, Kabatereine NB, 2011. Schistosoma mansoni infections in young children: when are schistosome antigens in urine, eggs in stool and antibodies to eggs first detectable? PLoS Negl Trop Dis 5: e938.

    • Search Google Scholar
    • Export Citation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

Modeling the Effect of Chronic Schistosomiasis on Childhood Development and the Potential for Catch-Up Growth with Different Drug Treatment Strategies Promoted for Control of Endemic Schistosomiasis

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  • Department of Mathematics, Department of Pediatrics, and Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio

In areas endemic for schistosomiasis having limited healthcare, targeted drug treatment of school-age children is recommended for control of Schistosoma-associated morbidity. However, optimal timing, number, and frequency of treatments are not established. Because longitudinal studies of long-term impact of treatment are few, for current policy considerations we performed quantitative simulation (based on calibrated modeling of Schistosoma-associated disease formation) to project the impact of different school-age treatment regimens. Using published efficacy data from targeted programs, combined with age-specific risk for growth retardation and reinfection, we examined the likely impact of different strategies for morbidity prevention. Results suggest the need for early, repeated treatment through primary school years to optimally prevent the disabling sequelae of stunting and undernutrition. Dynamics of infection/reinfection during childhood and adolescence, combined with early treatment effects against reversible infection-associated morbidities, create a need for aggressive retreatment of preadolescents to achieve optimal suppression of morbidity where drug-based control is used.

Introduction

Schistosomiasis remains one of the most serious and prevalent diseases worldwide. In 2003, there were an estimated 207 million people infected, with 89% of these people living in the less-developed areas of sub-Saharan Africa and South America.1,2 Although highly effective anti-schistosomal drugs have been marketed for over 25 years,3 there remain significant challenges to providing treatment (or preventive therapy) to those who are at highest risk for disease.4,5 Because, until recently, implementation of a large-scale of anti-schistosomal treatment has been very limited, there remain significant gaps in our knowledge about the expected benefits of repeated treatment in areas that continue to have high risk for Schistosoma reinfection after therapy.6 These communities, which often have the highest prevalence and intensity of infection, pose a particular challenge to program development for schistosomiasis morbidity control.7,8 Clinical and epidemiologic studies indicate that 10–15 year old children typically carry the highest rates of schistosome infection and the highest risk of inflammation-related disease associated with infection.9,10 The more lethal, late outcomes of infection are more common among adult age groups, and result from progressive infection-associated fibrosis of vital organs.11,12 However, of recent note, researchers and policy-makers have come to appreciate that schistosomiasis can also be a significant risk factor for chronic anemia, childhood growth stunting, protein calorie malnutrition, cognitive disability, and poor school performance.1319 These sub-clinical morbidities are physiologically important but more subtle than the easily recognized, advanced forms of schistosomiasis.12 Nevertheless, these “subtle morbidities” can have serious day-to-day consequences in the setting of rural poverty,17,20 and may, in fact, given the substantial numbers of persons who are affected by these pathologies, represent the bulk of schistosomiasis-associated disability and health burden among endemic populations.21

How can available resources be best allocated to prevent both the prevalent sub-clinical morbidity associated with schistosomiasis and the more severe forms of advanced disease (including developmental stunting)? In this analysis, we use a calibrated computer simulation to estimate the relative benefits of different treatment strategies for school-age schistosomiasis control programs. The World Health Organization (WHO) presently advocates schistosomiasis control by a strategy of periodic drug treatment of affected populations, focusing on school-age children as the highest risk group for infection and consequent disease formation.22 Large-scale control programs have already begun in many countries,4 but important operational questions regarding the optimal timing and distribution of treatment efforts still remain. To address these questions in greater detail, our present modeling approach builds partly on earlier modeling efforts of Medley and Bundy,23 Chan and others,24 and Gurarie and others.25,26 Those articles focused on late-term Schistosoma-related morbidity outcomes and the analysis of the optimal timing for targeted or population-based therapy for control or prevention of “classical” forms of schistosomiasis. The current article takes a different approach, focusing instead on predicting the best means to use available therapy for prevention of the detrimental impact of schistosomiasis on childhood growth and development.15,16,2729 Because available field data are presently quite limited, we calibrated a growth-development model for ages 0–20 yr using the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics (NCHS) database (see Figure 1),30 and evaluated the age-dependent impact of “schistosomiasis-like” chronic infection that causes growth retardation. The model was benchmarked using detailed anthropometric and infection data collected for Kenyan villagers in a Schistosoma haematobium endemic area.31 In addition, the approach was nuanced to include innate age- and gender-related differences in individual risk for growth-related disease formation,32,33 and the projected impact of preventing reversible nutritional morbidities of childhood.13,15,34,35

Figure 1.
Figure 1.

Examples of normal growth patterns for children: Left panels indicate Centers for Disease Control and Prevention (CDC) curves for normal weight and height values at different ages during childhood, indicating growth-related gains up to 20 years of age. Right panels indicate their corresponding normal age-specific rates of change (“growth velocity”), based on National Center for Health Statistics (NCHS) data available at: http://www.cdc.gov/growthcharts/percentile_data_files.htm.30 Representative data for boys' height and linear growth velocity are shown in the upper panels. Data for girls' weight and weight gain at different ages are shown in the lower panels. Graphed lines, from bottom to top, represent the observed 3rd, 10th, 50th, 90th, and 97th percentiles of normal childhood growth, respectively.

Citation: The American Society of Tropical Medicine and Hygiene 84, 5; 10.4269/ajtmh.2011.10-0642

As a basis for discussion in current program planning, we addressed the unanswered questions about long-term treatment impacts by developing outcome predictions based on a bounded modeling system that accounted for 1) age-related parasite exposure3638; 2) the kinetics for development of inflammation-related disease3942; 3) the impact of infection on early and mid-childhood growth retardation17,43; and 4) a child's potential for catch-up growth at different stages of childhood and adolescence.44 Our analysis indicates that optimal drug-based control strategies have the potential to substantially reduce developmental morbidities found among schistosomiasis-affected populations.

Materials and Methods

Modeling approach.

Given the limited amount of data on long-term clinical outcomes of schistosomiasis control programs, and to estimate and compare the potential long-term benefits of different operational approaches to drug-based control of schistosomiasis, we sought to simulate the deleterious effect of chronic infection on early-life development (0 to 20 yr) by a dynamic model that coupled parasite worm acquisition during childhood to observed deviations from normal human growth patterns among children with schistosomiasis27,29,45,46 (see Figure 2 and the Supplemental Appendix for details). This linked system allowed us to explore the relative quantitative impacts of different age-targeted control strategies on cumulative schistosomiasis-associated nutritional morbidity at 20 years of age, although in a stationary population with a stable environmental transmission pattern.6,8

Figure 2.
Figure 2.

Envelopes of Schistosoma infection intensity (worm burden, approximated by counts of excreted eggs)47 and related effects on growth patterns (in terms of height and weight) for the modeled heterogeneous endemic population. Boys are indicated in the upper panels and girls are indicated in the lower panels. Each hypothetical gender cohort was assembled from five quantile groups, reflecting the range of their initial potential for healthy growth, i.e., normally capable of reaching the 5th, 25th, 50th, 75th, or 95th percentiles, respectively. Left panels indicate the range of likely egg counts for each age group. Middle panels indicate the range of likely heights, and right panels indicate the likely range of weights at different ages among the affected childhood populations. In each height and weight plot, the thick solid curve represents the desired United States median growth, dashed lines from bottom to top represent, respectively, the community minimum and maximum values as affected by recurrent Schistosoma infection; small dots represent calibration data from field studies,31 and the thin solid line is the best-fit curve with the parameters shown in Table 1.

Citation: The American Society of Tropical Medicine and Hygiene 84, 5; 10.4269/ajtmh.2011.10-0642

Table 1

Simulation parameter descriptions (see the Supplemental Appendix) and their best-fit values based on infection and anthropometric data from Kajiwe village, Kenya31

TypeSymbolDescriptionGirlsBoys
Height/weightHeight/weight
Worm burdenS0Maximum force of infection among ages31.252.6
a0Age (in years) when the rate of new infections begins to decline8.77.1
pExponential in contact pattern15.132.96
Morbidityν0Maximum morbidity resolution rate10.180.75
αRate of min/max of resolution rate0.20.07
a1Threshold age for resolution jump11.38.3
q1Hill exponent for morbidity resolution5.471.0
Remedial growthThreshold of stunting factor φ/morbidity accretion rate7.67/9.85122.96/103.61
φ0Maximum stunting (growth reduction) rates caused by morbidity0.5/0.130.52/0.18
φ1Baseline stunting rates (norm = 1), caused by factors other than schisto infection)0.99/0.820.96/0.8
mHill exponent in φ7.1/5.154.93/1.7
KRatio of age-specific remedial growth rate to normal growth rate11.13/8.09.37/7.84

Age plays an important role in the schistosome transmission, as it is strongly correlated with behavioral factors linked to risk for transmission (water contact rate, snail contamination, and new infection),3638 and to the phenomenon of gradual acquisition of age- or experience-dependent partial resistance to new infection.3942 The modeling system used for this analysis can be viewed as the average state of growth, infection, and disease (mean worm burden, accumulated damage, and resulting developmental impairment) of an age cohort for whom infection and disease state are then “perturbed” by various treatment intervention strategies.23,24

Because morbidity and developmental stunting in schistosomiasis are linked to infection intensity and its cumulative duration,10 chemotherapy-based disease control can take its cues from two different perspectives: 1) a global reduction of community intensity of infection (average worm burden) at a given time t, to be effected in the short term through broad-based drug treatment intervention; or 2) a targeted, age-based reduction of infection, based on a person's year of life (as a surrogate of his or her current infection intensity and projected exposure to infection over the near future).25 In this work, we focused on the latter, i.e., age-targeted treatment and its effects on age-dependent patterns of development.

Details of the mathematical modeling approach, and its programming and calibration are presented in the Supplemental Appendix. The related Mathematica programming used for this analysis is available from authors DG and XW.

Results

On the basis of modeling of schistosomiasis-associated growth retardation observed among untreated children (shown in Figure 2), Figure 3 shows potential remediation of growth deficits by a hypothetical, three-session praziquantel (PZQ) treatment regimen (given at 6, 9, and 12 years of age) for a typical resident of a schistosomiasis-endemic area. The analysis indicates that, despite continuing transmission and risk of reinfection, improvements can occur gradually by the end of childhood (age 20 yr) in terms of height and weight among treated as compared with untreated children (Table 2). Results of the modeling analysis, which quantified potential recovery from infection-associated weight deficits for both girls and boys, indicate that treatment campaigns with greater adherence (i.e., 80% as compared with 20% yearly coverage) would result in the greatest improvement in growth outcomes (Figure 4).

Figure 3.
Figure 3.

Projected effects of treatment at 6, 9, and 12 years of age (with the fraction of worms killed in each session being 90%) on worm burden and developmental growth of an individual randomly selected from the modeled community. Solid curves are for baseline state (untreated infection) and dashed lines show the expected impact of the three treatment schedule.

Citation: The American Society of Tropical Medicine and Hygiene 84, 5; 10.4269/ajtmh.2011.10-0642

Figure 4.
Figure 4.

Projected impact of different schistosomiasis treatment regimens on accrued growth (relative to normal) at 20 years of age for infected girls and boys exposed to possible reinfection in endemic areas, based on model simulations of growth, reinfection, and potential for catch-up growth after treatment. In each panel, clustered bars for girls and boys compare the projected outcomes of five proposed strategies: 1) no treatment; 2) treatment at the time of school entry and completion (ages 5 and 15 yr); 3) treatment at 6, 9, and 12 years of age; 4) treatment every 2 years; and 5) treatment every year during school ages from 4 up to 15 years of age. Upper panels show substantially reduced impact when community participation is low (20%), as compared with where projected uptake and adherence are high (80%, lower panels). This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 84, 5; 10.4269/ajtmh.2011.10-0642

Table 2

Predicted community height and weight values (relative to United States median at age 20 yr), ensuing from different school-age treatment regimens*

StrategyFemaleMale
HeightWeightHeightWeight
A. Untreated0.962 (0.036)0.939 (0.138)0.924 (0.033)0.757 (0.115)
B. Treat at school entry and completion (ages 5 and 15 yr) with:
20% adherence0.962 (0.036)0.939 (0.138)0.926 (0.033)0.771 (0.122)
50% adherence0.962 (0.036)0.940 (0.138)0.930 (0.033)0.792 (0.121)
80% adherence0.963 (0.036)0.941 (0.138)0.933 (0.033)0.812 (0.122)
C. Treat at ages 6, 9, and 12 yr, with:
20% adherence0.968 (0.037)0.948 (0.142)0.934 (0.040)0.793 (0.135)
50% adherence0.976 (0.038)0.963 (0.146)0.950 (0.043)0.846 (0.146)
80% adherence0.985 (0.034)0.978 (0.144)0.967 (0.041)0.896 (0.145)
D. Treat every other year beginning age 6 yr, with:
20% adherence0.968 (0.038)0.949 (0.143)0.935 (0.042)0.799 (0.142)
50% adherence0.979 (0.039)0.965 (0.147)0.954 (0.046)0.861 (0.154)
80% adherence0.989 (0.035)0.980 (0.145)0.973 (0.043)0.919 (0.150)
E. Treat every other year beginning age 4 yr, with:
20% adherence0.968 (0.038)0.949 (0.143)0.935 (0.042)0.799 (0.142)
50% adherence0.979 (0.035)0.965 (0.147)0.955 (0.046)0.861 (0.155)
80% adherence0.989 (0.035)0.980 (0.145)0.974 (0.043)0.920 (0.151)
F. Treat every year beginning age 6 yr, with:
20% adherence0.969 (0.039)0.949 (0.143)0.936 (0.043)0.802 (0.146)
50% adherence0.980 (0.040)0.965 (0.148)0.956 (0.048)0.868 (0.160)
80% adherence0.991 (0.035)0.982 (0.145)0.976 (0.044)0.930 (0.155)
G. Treat every year beginning age 4 yr, with:
20% adherence0.969 (0.039)0.949 (0.143)0.936 (0.043)0.802 (0.146)
50% adherence0.980 (0.040)0.965 (0.148)0.957 (0.048)0.869 (0.160)
80% adherence0.991 (0.035)0.982 (0.145)0.977 (0.044)0.931 (0.155)

Shown are projected mean values, with standard deviations in parentheses, for the fraction of normal growth obtained by boys and girls under each regimen.

We next explored the relative impact of three different regimens currently recommended by WHO for school-age treatment of schistosomiasis in high, medium, and low prevalence areas.48 These regimens were 1) treat children every year from age 5 to 15 yr (recommended in high [≥ 50%] prevalence areas); 2) treat children every 2 years from age 5 to 15 yr (recommended in medium [10–30%] prevalence areas); and 3) treat children on school entry and at primary school completion (recommended in low [< 10%] prevalence areas). We also examined differences in outcomes among programs that commenced treatment either at age 4 or 6 yr. As compared with United States median values, Table 2 shows the mean relative heights and weights obtained at 20 years of age by boys and girls living in communities following these different strategies, and compares results obtained for different levels of community participation (adherence). Figure 4 shows the same results from a different point of view, i.e., the resulting deficits (as a percentage of normal growth) in height and weight for boys and girls either after no therapy, or after participation in differently timed treatment programs during the childhood years from 5 to 15 yr. From Table 2 we see that for the benchmark population, starting treatment at age 4 yr instead of age 6 yr appears to make little difference in ultimate outcomes, both for the every-1 year and every-2 year strategies. The model also suggests that treatment at 6, 9, and 12 years of age has comparable benefits to those of an every-2 year treatment program. In contrast, the 2-session regimen (i.e., at only ages 5 and 15 yr) appears not to be very effective in improving net growth outcomes, no matter how high the adherence with this regimen. Overall, boys, who are often more wasted or stunted than girls when untreated,29,49 were predicted to experience greater benefits after treatment than girls, for whatever strategy used.

As shown in the lower panels of Figure 4, in communities with 80% or higher adherence to repeated annual treatment, cumulative deficits (estimated for 20-year-old individuals in the face of continuing risk for reinfection with S. haematobium) were reduced in magnitude for height outcomes by 70% in boys and by about 76% in girls. Corresponding weight deficits at 20 years of age were reduced by 72% for boys and by 70% in girls. Where treatment was less frequent (only 2–3 treatments in childhood) or where adherence was less good (e.g., 20%; see Figure 4, upper panels) the impact of drug-based treatment campaigns on the childhood population's growth and development profile was projected to be much more modest, on the order of only 3–60% reductions in the cumulative height and weight deficits overall.

Discussion

The nonlinear dynamics of Schistosoma transmission and the complexity of age- and time-related factors influencing infection-related disease formation have made it difficult for experts to gauge the potential lifetime benefits of repeated anti-schistosomal treatments in endemic communities.50 Risk of infection-associated morbidity increases with both the duration and the intensity of infection, reflecting an aggregate effect of local tissue injury from granulomatous inflammation to parasite eggs deposited in host tissues, and the systemic effects of chronic inflammation.15,21,51 In particular, chronic anemia and growth stunting during childhood are believed to be the result of chronic anti-parasite inflammation that persists throughout childhood and adolescence.16 Although school-based treatment has long been recommended as a means to suppress the heaviest burden of Schistosoma infection that occurs during childhood,52 field studies indicate that such programs may fail to suppress transmission in high- and medium-risk communities, such that reinfection remains highly likely despite repeated treatments given during school age.6 Although inflammation may subside after successful elimination of infection (with substantial benefits in terms of improved hemoglobin levels and rebound growth)8,13,27,45,53 early reinfection appears to reactivate these inflammation-associated morbidities, resulting in only limited benefits from any single round of therapy.34,54

It is only recently that growth and nutrition-related morbidities have become more widely recognized as significant components of the schistosomiasis-associated disease burden.17 Notably, only two studies have examined the long-term effects of repeated anti-schistosomal treatments (given during childhood) on later adult health.55,56 For now, because the data on the late benefits of treatment are limited, and considering the need for informed policy formulation in this area, it is appropriate at this point to use established modeling techniques (calibrated on available data) to estimate the benefits of repeated treatment campaigns on Schistosoma-associated growth deficits that may occur during childhood. Our modeling analysis, benchmarked to available individual-level field data, was based on the well-recognized potential of children for “catch-up growth” following recovery from chronic diseases.44 Individuals can acutely increase their post-insult growth velocity up to 4-fold after the growth restriction ceases. This is known as type A catch-up growth. In another form of catch-up growth, known as type B, puberty can be delayed by several years, allowing linear bone growth to continue for an extended compensatory period.44 However, for schistosomiasis, the net impact of any type B recovery is likely to be complex, in that pubertal hormonal changes per se have been shown to down-modulate anti-parasite inflammation and reduce nutritional deficits associated with Schistosoma japonicum infection.57 We recognize that one of the limitations of our simulation model is that we are not able to distinguish the relative contributions of these two types of growth recovery. Future longitudinal studies, using careful Tanner staging for sexual maturity57 will be needed to clarify the relative effects of type A and type B recovery following treatment. Other factors, such as diet quality and co-infection with other parasitic worms, including soil-transmitted helminths, may serve to limit actual catch-up growth in treatment campaigns. Our study is limited in that it focused primarily on schistosomiasis and data on the impact of S. haematobium infection. Outcomes of mass-treatment may prove different for Schistosoma mansoni- or S. japonicum-affected areas,29,45,49 particularly if the risk for reinfection is highly episodic or changes significantly during the treatment campaign.

Like other studies of the growth impact of schistosomiasis,27,29,45,49 we have used CDC/NCHS growth standards58 as our norms for affected children. Even though their formulae were developed on the basis of sampling children within the United States population, these 2000 CDC/WHO standards are widely accepted as reference parameters for childhood growth among most other populations.30,59 New reference standards based on sampling in six countries are being developed by the WHO,60 but, at the time of this study, they had not been implemented for children > 5 years of age. Undoubtedly, for future research, the use of these newer international standards should be considered.

We should stress that, as constructed, our model gives a lower bound estimate of growth remediation, and the real benefits could be higher. Indeed, mass drug administration (MDA) may have a double effect in some communities—it can lower human infection levels and may also reduce transmission in some locales, particularly if high-risk adults are included in the treatment campaign. Our present simulation does not account for the coupled process of “human-to-snail transmission” (only its “snail-to-human” part), so that part (1) of the model system could underestimate the effect of drug treatments on the process of contamination and snail infection. However, human-to-snail transmission remains a patchy, nonlinear phenomenon in which a single infected individual (alone) can continue to contaminate one or more snail contact sites and maintain transmission for several months within any given community. This is the likely reason that MDA programs have not reliably reduced transmission in many high-prevalence areas.8,61 Nevertheless, our projections do suggest an increasing benefit from repeated treatments during childhood, even in the face of continuing reinfection.

Our results suggest that repeated treatment during childhood has the potential to reverse most, but not all, growth impairment associated with schistosomiasis. In particular, early treatment of S. haematobium with PZQ beginning at or before 6 years of age, with repeated treatments into the adolescent years, appears likely to be most effective in facilitating catch-up growth among repeatedly infected children. The gender-specific differences in growth observed among our benchmark Kenyan population (Figure 2) were consistent with those found in treatment studies of S. mansoni infection in Brazil.29,49 In those studies, infected males were found to suffer more undernutrition, but they also had more dramatic improvements after anti-schistosome therapy.49 Among our calibration sample of children, boys had higher average egg burdens than girls (geometric mean = 96 eggs/10 mL urine versus 36 eggs/10 mL urine), which might explain a higher risk of inflammation with corresponding worsening of growth-related morbidity outcomes. Another possible factor contributing to gender difference may be a difference in daily activity patterns, with higher rates of caloric consumption and/or higher rates of reinfection among boys.62 More research on the question of the relative gender-specific, growth-related disease risk is needed.

Historically, policy-makers have tended to underestimate the health impact of non-lethal morbidities associated with schistosomiasis (compare, e.g., the conclusions stated in References 6366 to the meta-analysis in Reference 15). However, multiple cross-sectional studies have documented growth retardation in children infected with all species of Schistosoma parasites.45,49,67,68 In terms of policy implications, there are likely to be important economic effects of childhood growth retardation that results in permanent stunting of adults. Short stature is associated with a decrease in productivity in many settings: previous studies estimate that a 1% decrease in adult stature is associated with a 1.4% decrease in productivity in less-developed economies.6971 Unmeasured confounders, such as differences in food availability, undoubtedly exist,13 but the reproducibility of the benefits of specific anti-schistosomal therapy suggest a significant growth effect of chronic schistosomiasis wherever it occurs.27,28,45,49 Although the durable long-term impact of anti-schistosomal treatment in reversing wasting or stunting has not been as well studied, treatment outcomes studies, including randomized-placebo controlled trials, indicate the potential for growth improvement with specific anti-schistosomal therapy. In the Philippines, in villages endemic for S. japonicum, children who were most wasted or stunted at baseline had the best relative outcomes after treatment.45 In Kenya, marked improvement in growth was observed after a single dose of an anti-schistosomal drug (metrifonate or PZQ) for the treatment of S. haematobium at follow-up after 8 months.27 Of note, an inflammatory response related to growth impairment has been shown when reinfection occurs after successful primary treatment of S. japonicum.54 This association, however, has not been examined in areas endemic for S. haematobium or S. mansoni, and the potential importance of this link to later growth impairments remains an important area for future study.

Other aspects of schistosomiasis-related morbidity and impairment were not included in our model. However, the age dynamics and reversibility of outcomes such as anemia and learning-related disabilities could easily be incorporated into future modeling efforts to identify the optimal timing and frequency for their prevention. Other modifications may need to be considered as new data emerge. Children's growth patterns exhibit different rates according to levels of bone maturity and sexual development.44,57,72,73 Retardation in growth will continue if inflammation persists or quickly recurs,74 but there is a potential for regaining a normal growth velocity.75 Changes in environment and nutrient availability are not necessarily sufficient to reverse early growth impairment.72 However, the effect of a delayed puberty, sometimes seen in low resource settings, can be beneficial for catch-up growth if the causative insult has ceased.75 Our results suggest that in the typical setting of endemic schistosomiasis, where reinfection can rapidly occur after treatment, mass administration campaigns that include periodic retreatment through adolescence may be needed to obtain a healthy rate of growth.

Data are scarce on the true prevalence of schistosomiasis among preschool-age children.76 Our analysis was calibrated on detailed information from school-age children (5–20 yr) in one affected village. In the future, to assess the potential benefit of anti-schistosomal treatment during preschool years, it will be important to include these younger subjects in community-based studies, including more sensitive diagnostics for Schistosoma infection than the standard, relatively insensitive assays based on egg-detection in stool and urine.7781 Quantifying pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) among preschool-age children with serologic evidence of early infection could provide evidence of early effects of infection before egg numbers reach their threshold to be reliably detected in the excreta.47,80,81 Our simulations indicate that if growth deficits are associated with infection in preschool years, then starting treatment at earlier ages (preschool years) might yield the best results for achieving near-normal growth in high-risk areas. As structured, our model did not indicate a benefit for early age therapy. However, it was based only on data for children 5 years of age and older, and in areas where earlier growth deficits can be tied to schistosomiasis, then initiation of treatment in preschool years will likely prove beneficial. For now, and for the particular type of village setting studied here, our model clearly suggests that every other year treatments during school age (6–20 yrs) and high community adherence to treatment (> 50%) will provide the best aggregate growth outcomes among at-risk individuals.

ACKNOWLEDGMENTS:

We thank Isabel Parraga of the CWRU Department of Nutrition for her invaluable guidance on the performance and interpretation of anthropometric studies.

  • 1.

    Chitsulo L, Engels D, Montresor A, Savioli L, 2000. The global status of schistosomiasis and its control. Acta Trop 77: 4151.

  • 2.

    Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J, 2006. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 6: 411425.

    • Search Google Scholar
    • Export Citation
  • 3.

    King CH, Mahmoud AA, 1989. Drugs five years later: praziquantel. Ann Intern Med 110: 290296.

  • 4.

    Fenwick A, 2006. New initiatives against Africa's worms. Trans R Soc Trop Med Hyg 100: 200207.

  • 5.

    Molyneux DH, Hotez PJ, Fenwick A, 2005. “Rapid-impact interventions”: how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med 2: e336.

    • Search Google Scholar
    • Export Citation
  • 6.

    Satayathum SA, Muchiri EM, Ouma JH, Whalen CC, King CH, 2006. Factors affecting infection or reinfection with Schistosoma haematobium in coastal Kenya: survival analysis during a nine-year, school-based treatment program. Am J Trop Med Hyg 75: 8392.

    • Search Google Scholar
    • Export Citation
  • 7.

    King CH, 2007. Lifting the burden of schistosomiasis-defining elements of infection-associated disease and the benefits of antiparasite treatment. J Infect Dis 196: 653655.

    • Search Google Scholar
    • Export Citation
  • 8.

    King CH, Sturrock RF, Kariuki HC, Hamburger J, 2006. Transmission control for schistosomiasis—why it matters now. Trends Parasitol 22: 575582.

    • Search Google Scholar
    • Export Citation
  • 9.

    King CH, 2001. Epidemiology of schistosomiasis: determinants of transmission of infection. Mahmoud AA, ed. Schistosomiasis. London, UK: Imperial College Press, 115132.

    • Search Google Scholar
    • Export Citation
  • 10.

    Smith JH, Christie JD, 1986. The pathobiology of Schistosoma haematobium infection in humans. Hum Pathol 17: 333345.

  • 11.

    Richter J, Correia Dacal AR, Vergetti Siqueira JG, Poggensee G, Mannsmann U, Deelder A, Feldmeier H, 1998. Sonographic prediction of variceal bleeding in patients with liver fibrosis due to Schistosoma mansoni. Trop Med Int Health 3: 728735.

    • Search Google Scholar
    • Export Citation
  • 12.

    van der Werf MJ, de Vlas SJ, Brooker S, Looman CWN, Nagelkerke NJD, Habbema JDF, Engels D, 2003. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 86: 125139.

    • Search Google Scholar
    • Export Citation
  • 13.

    Koukounari A, Gabrielli AF, Toure S, Bosque-Oliva E, Zhang Y, Sellin B, Donnelly CA, Fenwick A, Webster JP, 2007. Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso. J Infect Dis 196: 659669.

    • Search Google Scholar
    • Export Citation
  • 14.

    Olveda RM, 2001. Disease in schistosomiasis japonica. Mahmoud AA, ed. Schistosomiasis. London: Imperial College Press, 361390.

  • 15.

    King CH, Dickman K, Tisch DJ, 2005. Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365: 15611569.

    • Search Google Scholar
    • Export Citation
  • 16.

    Friedman JF, Kanzaria HK, Acosta LP, Langdon GC, Manalo DL, Wu H, Olveda RM, McGarvey ST, Kurtis JD, 2005. Relationship between Schistosoma japonicum and nutritional status among children and young adults in Leyte, the Philippines. Am J Trop Med Hyg 72: 527533.

    • Search Google Scholar
    • Export Citation
  • 17.

    King CH, Dangerfield-Cha M, 2008. The unacknowledged impact of chronic schistosomiasis. Chronic Illn 4: 6579.

  • 18.

    Ezeamama AE, Friedman JF, Acosta LP, Bellinger DC, Langdon GC, Manalo DL, Olveda RM, Kurtis JD, McGarvey ST, 2005. Helminth infection and cognitive impairment among Filipino children. Am J Trop Med Hyg 72: 540548.

    • Search Google Scholar
    • Export Citation
  • 19.

    Nokes C, McGarvey ST, Shiue L, Wu G, Wu H, Bundy DA, Olds GR, 1999. Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren. Am J Trop Med Hyg 60: 556565.

    • Search Google Scholar
    • Export Citation
  • 20.

    King CH, 2010. Parasites and poverty: the case of schistosomiasis. Acta Trop 113: 95104.

  • 21.

    King CH, Bertino AM, 2008. Asymmetries of poverty: why global burden of disease valuations underestimate the burden of neglected tropical diseases. PLoS Negl Trop Dis 2: e209.

    • Search Google Scholar
    • Export Citation
  • 22.

    WHO, 2006. Preventive Chemotherapy in Human Helminthiasis: Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 23.

    Medley GF, Bundy DAP, 1996. Dynamic modeling of epidemiologic patterns of schistosomiasis morbidity. Am J Trop Med Hyg 55: 149158.

  • 24.

    Chan MS, Guyatt HL, Bundy DA, Booth M, Fulford AJ, Medley GF, 1995. The development of an age structured model for schistosomiasis transmission dynamics and control and its validation for Schistosoma mansoni. Epidemiol Infect 115: 325344.

    • Search Google Scholar
    • Export Citation
  • 25.

    Gurarie D, King CH, 2005. Heterogeneous model of schistosomiasis transmission and long-term control: the combined influence of spatial variation and age-dependent factors on optimal allocation of drug therapy. Parasitology 130: 4965.

    • Search Google Scholar
    • Export Citation
  • 26.

    Gurarie D, King CH, Wang X, 2010. A new approach to modelling schistosomiasis transmission based on stratified worm burden. Parasitology 137: 19511965.

    • Search Google Scholar
    • Export Citation
  • 27.

    Stephenson LS, Latham MC, Kurz KM, Kinoti SN, 1989. Single dose metrifonate or praziquantel treatment in Kenyan children. II. Effects on growth in relation to Schistosoma haematobium and hookworm egg counts. Am J Trop Med Hyg 41: 445453.

    • Search Google Scholar
    • Export Citation
  • 28.

    Stephenson LS, Latham MC, Kurz KM, Kinoti SN, Oduori ML, Crompton DW, 1985. Relationships of Schistosoma haematobium, hookworm and malarial infections and metrifonate treatment to growth of Kenyan school children. Am J Trop Med Hyg 34: 11091118.

    • Search Google Scholar
    • Export Citation
  • 29.

    Parraga IM, Assis AM, Prado MS, Barreto ML, Reis MG, King CH, Blanton RE, 1996. Gender differences in growth of school-aged children with schistosomiasis and geohelminth infection. Am J Trop Med Hyg 55: 150156.

    • Search Google Scholar
    • Export Citation
  • 30.

    de Onis M, Garza C, Onyango AW, Borghi E, 2007. Comparison of the WHO child growth standards and the CDC 2000 growth charts. J Nutr 137: 144148.

    • Search Google Scholar
    • Export Citation
  • 31.

    Olds GR, King CH, Hewlett J, Olveda R, Wu G, Ouma JH, Peters PA, McGarvey S, Koech D, Liu CY, Aligui G, Gachihi G, Kombe Y, Parraga I, Ramirez B, Whalen C, Horton RJ, Reeve P, 1999. Double-blind placebo controlled study of concurrent administration of albendazole and praziquantel in school children with schistosomiasis and geohelminths. J Infect Dis 179: 9961003.

    • Search Google Scholar
    • Export Citation
  • 32.

    Blanton RE, Salam EA, Ehsan A, King CH, Goddard KA, 2005. Schistosomal hepatic fibrosis and the interferon gamma receptor: a linkage analysis using single-nucleotide polymorphic markers. Eur J Hum Genet 13: 660668.

    • Search Google Scholar
    • Export Citation
  • 33.

    Dessein AJ, Hillaire D, Elwali NE, Marquet S, Mohamed-Ali Q, Mirghani A, Henri S, Abdelhameed AA, Saeed OK, Magzoub MM, Abel L, 1999. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 65: 709721.

    • Search Google Scholar
    • Export Citation
  • 34.

    Koukounari A, Fenwick A, Whawell S, Kabatereine NB, Kazibwe F, Tukahebwa EM, Stothard JR, Donnelly CA, Webster JP, 2006. Morbidity indicators of Schistosoma mansoni: relationship between infection and anemia in Ugandan schoolchildren before and after praziquantel and albendazole chemotherapy. Am J Trop Med Hyg 75: 278286.

    • Search Google Scholar
    • Export Citation
  • 35.

    Leenstra T, Acosta LP, Langdon GC, Manalo DL, Su L, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Schistosomiasis japonica, anemia, and iron status in children, adolescents, and young adults in Leyte, Philippines. Am J Clin Nutr 83: 371379.

    • Search Google Scholar
    • Export Citation
  • 36.

    Klumpp RK, Webbe G, 1987. Focal, seasonal and behavioural patterns of infection and transmission of Schistosoma haematobium in a farming village at the Volta Lake, Ghana. J Trop Med Hyg 90: 265281.

    • Search Google Scholar
    • Export Citation
  • 37.

    Kloos H, Fulford AJ, Butterworth AE, Sturrock RF, Ouma JH, Kariuki HC, Thiongo FW, Dalton PR, Klumpp RK, 1997. Spatial patterns of human water contact and Schistosoma mansoni transmission and infection in four rural areas in Machakos District, Kenya. Soc Sci Med 44: 949968.

    • Search Google Scholar
    • Export Citation
  • 38.

    Kvalsvig JD, Schutte CH, 1986. The role of human water contact patterns in the transmission of schistosomiasis in an informal settlement near a major industrial area. Ann Trop Med Parasitol 80: 1326.

    • Search Google Scholar
    • Export Citation
  • 39.

    Hagan P, Blumenthal UJ, Chaudri M, Greenwood BM, Hayes RJ, Hodgson I, Kelly C, Knight M, Simpson AJ, Smithers SR, Wilkins HA, 1987. Resistance to reinfection with Schistosoma haematobium in Gambian children: analysis of their immune responses. Trans R Soc Trop Med Hyg 81: 938946.

    • Search Google Scholar
    • Export Citation
  • 40.

    Etard JF, Audibert M, Dabo A, 1995. Age-acquired resistance and predisposition to reinfection with Schistosoma haematobium after treatment with praziquantel in Mali. Am J Trop Med Hyg 52: 549558.

    • Search Google Scholar
    • Export Citation
  • 41.

    Kurtis JD, Friedman JF, Leenstra T, Langdon GC, Wu HW, Manalo DL, Su L, Jiz M, Jarilla B, Pablo AO, McGarvey ST, Olveda RM, Acosta LP, 2006. Pubertal development predicts resistance to infection and reinfection with Schistosoma japonicum. Clin Infect Dis 42: 16921698.

    • Search Google Scholar
    • Export Citation
  • 42.

    Naus CW, Kimani G, Ouma JH, Fulford AJ, Webster M, van Dam GJ, Deelder AM, Butterworth AE, Dunne DW, 1999. Development of antibody isotype responses to Schistosoma mansoni in an immunologically naive immigrant population: influence of infection duration, infection intensity, and host age. Infect Immun 67: 34443451.

    • Search Google Scholar
    • Export Citation
  • 43.

    Olveda RM, Daniel BL, Ramirez BD, Aligui GD, Acosta LP, Fevidal P, Tiu E, de Veyra F, Peters PA, Romulo R, Domingo E, Wiest PM, Olds GR, 1996. Schistosomiasis japonica in the Philippines: the long-term impact of population-based chemotherapy on infection, transmission, and morbidity. J Infect Dis 174: 163172.

    • Search Google Scholar
    • Export Citation
  • 44.

    Boersma B, Wit JM, 1997. Catch-up growth. Endocr Rev 18: 646661.

  • 45.

    Coutinho HM, Acosta LP, McGarvey ST, Jarilla B, Jiz M, Pablo A, Su L, Manalo DL, Olveda RM, Kurtis JD, Friedman JF, 2006. Nutritional status improves after treatment of Schistosoma japonicum-infected children and adolescents. J Nutr 136: 183188.

    • Search Google Scholar
    • Export Citation
  • 46.

    Coutinho HM, McGarvey ST, Acosta LP, Manalo DL, Langdon GC, Leenstra T, Kanzaria HK, Solomon J, Wu H, Olveda RM, Kurtis JD, Friedman JF, 2005. Nutritional status and serum cytokine profiles in children, adolescents, and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines. J Infect Dis 192: 528536.

    • Search Google Scholar
    • Export Citation
  • 47.

    Wilson RA, van Dam GJ, Kariuki TM, Farah IO, Deelder AM, Coulson PS, 2006. The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in non-human primates. Int J Parasitol 36: 12411244.

    • Search Google Scholar
    • Export Citation
  • 48.

    WHO, 2002. Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee. WHO Tech Rep Ser 912: 157.

    • Search Google Scholar
    • Export Citation
  • 49.

    Assis AM, Barreto ML, Prado MS, Reis MG, Parraga IM, Blanton RE, 1998. Schistosoma mansoni infection and nutritional status in schoolchildren: a randomized, double-blind trial in northeastern Brazil. Am J Clin Nutr 68: 12471253.

    • Search Google Scholar
    • Export Citation
  • 50.

    Kirigia JM, 1997. Economic evaluation in schistosomiasis: using the delphi technique to assess effectiveness. Acta Trop 64: 175190.

  • 51.

    Bustinduy AL, King CH, 2009. Parasitic helminths. Fratamico PM, Smith JL, Brogden KA, eds. Post-Infectious Sequelae and Long-Term Consequences of Infectious Diseases. Washington, DC: American Society for Microbiology Press, 291329.

    • Search Google Scholar
    • Export Citation
  • 52.

    Warren KS, 1982. Selective primary health care: strategies for control of disease in the developing world. I. Schistosomiasis. Rev Infect Dis 4: 715726.

    • Search Google Scholar
    • Export Citation
  • 53.

    Beasley NM, Tomkins AM, Hall A, Kihamia CM, Lorri W, Nduma B, Issae W, Nokes C, Bundy DA, 1999. The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania. Trop Med Int Health 4: 744750.

    • Search Google Scholar
    • Export Citation
  • 54.

    Leenstra T, Coutinho HM, Acosta LP, Langdon GC, Su L, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation. Infect Immun 74: 63986407.

    • Search Google Scholar
    • Export Citation
  • 55.

    Kjetland EF, Ndhlovu PD, Kurewa EN, Midzi N, Gomo E, Mduluza T, Friis H, Gundersen SG, 2008. Prevention of gynecologic contact bleeding and genital sandy patches by childhood anti-schistosomal treatment. Am J Trop Med Hyg 79: 7983.

    • Search Google Scholar
    • Export Citation
  • 56.

    Ouma JH, King CH, Muchiri EM, Mungai P, Koech DK, Ireri E, Magak P, Kadzo H, 2005. Late benefits 10–18 years after drug therapy for infection with Schistosoma haematobium in Kwale District, Coast Province, Kenya. Am J Trop Med Hyg 73: 359364.

    • Search Google Scholar
    • Export Citation
  • 57.

    Coutinho HM, Leenstra T, Acosta LP, Olveda RM, McGarvey ST, Friedman JF, Kurtis JD, 2007. Higher serum concentrations of DHEAS predict improved nutritional status in helminth-infected children, adolescents, and young adults in Leyte, the Philippines. J Nutr 137: 433439.

    • Search Google Scholar
    • Export Citation
  • 58.

    Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL, 2002. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 May: 1190.

    • Search Google Scholar
    • Export Citation
  • 59.

    de Onis M, Habicht JP, 1996. Anthropometric reference data for international use: recommendations from a World Health Organization Expert Committee. Am J Clin Nutr 64: 650658.

    • Search Google Scholar
    • Export Citation
  • 60.

    WHO, 2006. Assessment of differences in linear growth among populations in the WHO Multicentre Growth Reference Study. Acta Paediatr Suppl 450: 5665.

    • Search Google Scholar
    • Export Citation
  • 61.

    Woolhouse ME, Watts CH, Chandiwana SK, 1991. Heterogeneities in transmission rates and the epidemiology of schistosome infection. Proc R Soc Lond B Biol Sci 245: 109114.

    • Search Google Scholar
    • Export Citation
  • 62.

    Kvalsvig JD, 1986. The effects of schistosomiasis haematobium on the activity of school children. J Trop Med Hyg 89: 8590.

  • 63.

    Gryseels B, 1989. The relevance of schistosomiasis for public health. Trop Med Parasitol 40: 134142.

  • 64.

    Tanner M, 1989. Evaluation of public health impact of schistosomiasis. Trop Med Parasitol 40: 143148.

  • 65.

    Warren KS, Mahmoud AA, 1976. Targeted mass treatment: a new approach to the control of schistosomiasis. Trans Assoc Am Physicians 89: 195204.

    • Search Google Scholar
    • Export Citation
  • 66.

    Mott KE, 2004. Schistosomiasis. Murray CJ, Lopez A, Mathers CD, eds. The Global Epidemiology of Infectious Diseases. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 67.

    de Lima e Costa MF, Leite ML, Rocha RS, de Almeida Magalhaes MH, Katz N, 1988. Anthropometric measures in relation to schistosomiasis mansoni and socioeconomic variables. Int J Epidemiol 17: 880886.

    • Search Google Scholar
    • Export Citation
  • 68.

    McGarvey ST, Wu G, Zhang S, Wang Y, Peters P, Olds GR, Wiest PM, 1993. Child growth, nutritional status, and schistosomiasis japonica in Jiangxi, People's Republic of China. Am J Trop Med Hyg 48: 547553.

    • Search Google Scholar
    • Export Citation
  • 69.

    Blas BL, Lipayon IL, Tormis LC, Portillo LA, Hayashi M, Matsuda H, 2006. An attempt to study the economic loss arising from Schistosoma japonicum infection and the benefits derived from treatment. Southeast Asian J Trop Med Public Health 37: 2632.

    • Search Google Scholar
    • Export Citation
  • 70.

    Strauss J, Thomas D, 1998. Health, nutrition, and economic development. J Econ Lit 36: 766817.

  • 71.

    Florencio TT, Ferreira HS, Cavalcante JC, Assuncao ML, Sawaya AL, 2008. Short stature and food habits as determining factors for the low productivity of sugarcane laborers in the State of Alagoas, north-eastern Brazil. Arch Latinoam Nutr 58: 3339.

    • Search Google Scholar
    • Export Citation
  • 72.

    Coly AN, Milet J, Diallo A, Ndiaye T, Benefice E, Simondon F, Wade S, Simondon KB, 2006. Preschool stunting, adolescent migration, catch-up growth, and adult height in young Senegalese men and women of rural origin. J Nutr 136: 24122420.

    • Search Google Scholar
    • Export Citation
  • 73.

    Lwambo NJ, Brooker S, Siza JE, Bundy DA, Guyatt H, 2000. Age patterns in stunting and anaemia in African schoolchildren: a cross-sectional study in Tanzania. Eur J Clin Nutr 54: 3640.

    • Search Google Scholar
    • Export Citation
  • 74.

    Coutinho HM, Leenstra T, Acosta LP, Su L, Jarilla B, Jiz MA, Langdon GC, Olveda RM, McGarvey ST, Kurtis JD, Friedman JF, 2006. Pro-inflammatory cytokines and C-reactive protein are associated with undernutrition in the context of Schistosoma japonicum infection. Am J Trop Med Hyg 75: 720726.

    • Search Google Scholar
    • Export Citation
  • 75.

    Golden MH, 1994. Is complete catch-up possible for stunted malnourished children? Eur J Clin Nutr 48 (Suppl 1): S5870; discussion S71.

  • 76.

    Stothard JR, Gabrielli AF, 2007. Schistosomiasis in African infants and preschool children: to treat or not to treat? Trends Parasitol 23: 8386.

    • Search Google Scholar
    • Export Citation
  • 77.

    Carabin H, Marshall CM, Joseph L, Riley S, Olveda R, McGarvey ST, 2005. Estimating the intensity of infection with Schistosoma japonicum in villagers of Leyte, Philippines. Part I: a Bayesian cumulative logit model. The Schistosomiasis Transmission & Ecology Project (STEP). Am J Trop Med Hyg 72: 745753.

    • Search Google Scholar
    • Export Citation
  • 78.

    de Vlas SJ, Gryseels B, 1992. Underestimation of Schistosoma mansoni prevalences. Parasitol Today 8: 274277.

  • 79.

    Savioli L, Hatz C, Dixon H, Kisumku UM, Mott KE, 1990. Control of morbidity due to Schistosoma haematobium on Pemba Island: egg excretion and hematuria as indicators of infection. Am J Trop Med Hyg 43: 289295.

    • Search Google Scholar
    • Export Citation
  • 80.

    Shane HL, Verani JR, Abudho B, Montgomery SP, Blackstock AJ, Mwinzi PN, Butler SE, Karanja DM, Secor WE, 2011. Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in western Kenya. PLoS Negl Trop Dis 5: e591.

    • Search Google Scholar
    • Export Citation
  • 81.

    Stothard JR, Sousa-Figuereido JC, Betson M, Adriko M, Arinaitwe M, Rowell C, Besiyge F, Kabatereine NB, 2011. Schistosoma mansoni infections in young children: when are schistosome antigens in urine, eggs in stool and antibodies to eggs first detectable? PLoS Negl Trop Dis 5: e938.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Charles H. King, Center for Global Health and Diseases, Wolstein Research Building 4126, 2103 Cornell Road, Cleveland, OH 44106-7286. E-mail: chk@cwru.edu

Financial support: This work was supported by National Institutes of Health Research grant R01TW008067 funded by the Ecology of Infectious Diseases Program of the Fogarty International Center. Funding support was also provided to ALB through an NIH T32 Ruth L. Kirschstein-National Service Research Award-Training Grant.

Authors' addresses: David Gurarie and Xiaoxia Wang, Department of Mathematics, Yost Hall, Case Western Reserve University, Cleveland, OH, E-mails: dxg5@cwru.edu and xxw@cwru.edu. Amaya L. Bustinduy, Division of Infectious Diseases, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, E-mail: axb342@case.edu. Charles H. King, Center for Global Health and Diseases, Wolstein Research Building, Cleveland, OH, E-mail: chk@cwru.edu.

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