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Helminth Infections: Soil-Transmitted Helminth Infections and Schistosomiasis

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Helminth Infections: Soil-Transmitted Helminth Infections and Schistosomiasis
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  467 Helminth infections caused by soil-transmitted helminths(STHs) and schistosomes are among the most prevalent afflic-tions ofhumans who live in areas ofpoverty in the developingworld.The morbidity caused by STHs and schistosomes is mostcommonly associated with infections ofheavy intensity.Approximately 300 million people with heavy helminth infec-tions suffer from severe morbidity that results in more than150,000 deaths annually (Crompton 1999;Montresor and oth-ers 2002).In addition to their health effects,helminth infectionsalso impair physical and mental growth in childhood,thwarteducational advancement,and hinder economic development.Because ofthe geographic overlap ofthese afflictions and theirimpact on children and adolescents,the World HealthOrganization (WHO);the World Bank;and other UnitedNations agencies and bilaterals;and civil society are working tointegrate STH and schistosome control through a program of periodic school-based,targeted anthelmintic drug treatments. CAUSES AND CHARACTERISTICS OF HELMINTH INFECTIONS Emphasis is placed on the four most common STH infectionsand the three most common schistosome infections.Together,these infections account for most ofthe global helminth dis-ease burden. Soil-Transmitted Helminths ThefourmostcommonSTHsareroundworm( Ascarislumbri-coides  ),whipworm( Trichuristrichiura  ),andtheanthropophilichookworms( Necatoramericanus  and Ancylostomaduodenale  ).Recentestimatessuggestthat A.lumbricoides  infects1.221bil-lionpeople, T.trichiura  795million,andhookworms740million(deSilvaandothers2003)(table24.1).Thegreatestnumbersof STHinfectionsoccurintheAmericas,ChinaandEastAsia,andSub-Saharan Africa. Strongyloides stercoralis  is also a com-monSTHinsomeoftheseregions,althoughdetailedinforma-tionontheprevalenceofstrongyloidiasisislackingbecauseof thedifficultiesindiagnosinghumaninfection.Thelifecyclesof  Ascaris,Trichuris, andhookwormfollowageneralpattern.Theadultparasitestagesinhabitthegastrointestinaltract( Ascaris  andhookworminthesmallintestine; Trichuris  inthecolon),reproducesexually,andproduceeggs,whicharepassedinhumanfecesanddepositedintheexternalenvironment.STHinfectionsrarelycausedeath.Instead,theburdenof diseaseisrelatedlesstomortalitythantothechronicandinsid-iouseffectsonthehosts’healthandnutritionalstatus(Stephenson,Latham,andOttesen2000;Stoltzfusandothers1997).Hookwormshavelongbeenrecognizedasanimportantcauseofintestinalbloodlossleadingtoirondeficiencyandpro-teinmalnutrition.Theirondeficiencyanemiathataccompaniesmoderateandheavyhookwormburdensissometimesreferredtoas hookwormdisease  (Hotezandothers2004).Whenhost Chapter 24 Helminth Infections: Soil-TransmittedHelminth Infections and Schistosomiasis Peter J. Hotez, Donald A. P. Bundy, Kathleen Beegle, Simon Brooker,Lesley Drake, Nilanthi de Silva, Antonio Montresor, Dirk Engels,Matthew Jukes, Lester Chitsulo, Jeffrey Chow, RamananLaxminarayan, Catherine M. Michaud, Jeff Bethony, RodrigoCorrea-Oliveira, Xiao Shu-Hua, Alan Fenwick, and Lorenzo Savioli  ironstoresaredepleted,theextentofirondeficiencyanemiaislinearlyrelatedtotheintensityofhookworminfection(Stoltzfusandothers1997).Becauseoftheirunderlyingpoorironstatus,children,womenofreproductiveage,andpregnantwomenarefrequentlytheonesmostsusceptibletodevelopinghookwormanemia(Brooker,Bethony,andHotez2004).Irondeficiencyanemiaduringpregnancyhasbeenlinkedtoadversematernal-fetalconsequences,includingprematurity,lowbirth-weight,andimpairedlactation(WHO2002).Chronic STH infections resulting from Ascaris,Trichuris, and hookworm can dramatically affect physical and mentaldevelopment in children (WHO 2002).Studies have alsoshown that the growth and physical fitness deficits caused by chronic STH infections are sometimes reversible followingtreatment with anthelmintic drugs (Stephenson,Latham,andOttesen 2000).The effects on growth are most pronounced inchildren with the heaviest infections,but light infections may also contribute to growth deficits ifthe nutritional status ofthecommunity is poor (Stephenson,Latham,and Ottesen 2000). Schistosomiasis Five major species ofparasitic trematodes ofthe family Schistosomatidae— Schistosoma haematobium,S.intercalatum , S.japonicum,S.mansoni, and S.mekongi—  infect humans.These parasites have a complex,indirect life cycle involving anintermediate snail host.Disease is caused primarily by schisto-some eggs,which are deposited by adult worms in the bloodvessels surrounding the bladder or intestines.Urinary schisto-somiasis,in which the bladder is affected,is caused by infectionwith S.haematobium, which occurs mainly in Africa.Intestinalschistosomiasis results from infection with S.mansoni  ,whichoccurs in the Middle East,South America,and Africa,and frominfection with S.japonicum, which occurs in parts ofChinaand the Philippines (Ross and others 2002).Two other schisto-some species are known to cause intestinal schistosomiasis inrestricted geographical areas: S.intercalatum ,found in CentralAfrica,and S.mekongi  ,found in Cambodia and the LaoPeople’s Democratic Republic.Schistosomiasis is estimated toaffect 187 million people worldwide (table 24.1).A serious acute illness accompanied by fever and lym-phadenopathy,known as Katayama Syndrome,can result fromheavy schistosome infections.Chronic disease is mostly due toperforation ofblood vessels and entrapment ofeggs by hosttissues.The host’s reaction to entrapped eggs results in gran-uloma formation. S.haematobium causes bladder wallpathology,leading to ulcer formation,hematuria,and dysuria.Granulomatous changes and ulcers ofthe bladder wall andureter can lead to bladder obstruction,dilatation,secondary urinary tract infections and subsequent bladder calcification,renal failure,lesions ofthe female and male genital tracts,andhydronephrosis. S.haematobium is also associated withincreased risk ofbladder cancer.The morbidity commonly associated with S.mansoni  infection includes lesions oftheliver,portal vein,and spleen,leading to periportal fibrosis,portal hypertension,hepatosplenomegaly,splenomegaly,andascites.Schistosomiasis also causes chronic growth falteringand can contribute to anemia (Ross and others 2002). EPIDEMIOLOGY OF STH INFECTIONSANDSCHISTOSOMIASIS Themoststrikingepidemiologicalfeaturesofhumanhelminthinfectionsareaggregateddistributionsinhumancommunities,predispositionofindividualstoheavy(orlight)infection,rapidreinfectionfollowingchemotherapy,andage-intensityprofilesthataretypicallyconvex(withtheexceptionofhookworm).For all the major human STH and schistosome infectionsstudied to date,worm burdens exhibit a highly aggregated(overdispersed) distribution so that most individuals harbor just a few worms in their intestines,although a few hosts har-bor disproportionately large worm burdens (Anderson andMay 1991).As a rule,20 percent ofthe host population harborsapproximately 80 percent ofthe worm population.Thisoverdispersion has many consequences,both with regard to thepopulation biology ofthe helminths and the public health con-sequence for the host,because heavily infected individuals aresimultaneously at highest risk ofdisease and the major sourceofenvironmental contamination.One feature that may helpexplain overdispersion is that individuals tend to be predis-posed to heavy (or light) infections.Predisposition has beendemonstrated for all four major STHs and the schistosomes.The underlying cause ofsuch predisposition remains poorly understood.However,a combination ofheterogeneity in 468 |Disease Control Priorities in Developing Countries|Peter J. Hotez, Donald A. P. Bundy, Kathleen Beegle, and others Table 24.1 Global Prevalence and Distribution of HelminthInfections Helminth infectionsTotal cases Major geographic areas STH infections   2 billionAscariasis1.221 billionSub-Saharan Africa, India,China and East AsiaTrichuriasis795 millionSub-Saharan Africa, India,China and East AsiaHookworm740 millionSub-Saharan Africa, Americas,China and East AsiaSchistosomiasis187 million S. haematobium  119 millionSub-Saharan Africa S. mansoni  67 millionSub-Saharan Africa, Americas S. japonicum  1 millionChina and East Asia Source:  de Silva and others 2003.  linked to morbidity,the age-intensity profiles provide a clearerunderstanding ofwhich populations are vulnerable to thedifferent helminths (figure 24.1).For A.lumbricoides and T.trichiura infections,the age-intensity profiles are typically convex in form,with the highest intensities in children 5 to Helminth Infections: Soil-Transmitted Helminth Infections and Schistosomiasis| 469 exposure to infection or differences in susceptibility to infec-tion and the ability to mount effective immunity (genetic andnutritional factors) is likely to be important.People ofall ages rapidly reacquire infection following treat-ment,but in schistosomiasis,older people reacquire infectionat slower rates than younger ones (Kabatereine and others1999).The rate ofreinfection is specific to certain species of helminths and depends on the life expectancy ofthat species(short-lived helminths reinfect more rapidly),on the intensity oftransmission within a given community,and on the treat-ment efficacy and coverage.The basic reproductive rate ( R  o )describes the transmission potential ofa parasite (and thus itsability to reinfect the host).It defines the average number of female offspring produced during the life span ofthe parasitethat survive to reproductive maturity in the absence ofdensity dependence. R  o is determined by parasite immigration anddeath rates as well as by host density (and,inschistosomiasis,also snail density).A parasite will fail to become establishedunless R  o is greater than unity (Anderson and May 1991).Adultworms usually survive between one and four years,whereaseggs can sometimes remain viable for several more years in theenvironment.Therefore,reinfection rates will remain highuntil adults are removed with chemotherapy and until infectivestages,through time,become uninfective.In reality,density-dependent processes regulate parasite populations;at endemicequilibrium,the effective reproductive ratio equals unity (thatis,each female replaces herself).Control programs rely onreducing the effective reproductive ratio long enough for theparasite population to be driven to local elimination.Theoretically, R  o provides useful insights,and it is helpful tothink ofcontrol programs attempting to break the transmis-sion cycle by reducing R  o to less than unity.Therefore,estimates can be madeabouthowlongandhowmanyroundsofchemotherapyare required to treat intestinal helminths.Forexample, A.lumbricoides  with an R  o ofthree and a lifeexpectancy ofone year will need to be treated annually withadrug that is 95 percent efficacious and with coverage ofmorethan 91 percent ofthe population.Where R  o is five—that is,inareas where transmission is higher—treatment must begiven more frequently than once a year (Anderson and May 1991).The age-dependent patterns ofinfection prevalence are gen-erally similar among the major helminth species,exhibiting arise in childhood to a relatively stable asymptote in adulthood(figure 24.1).Maximum prevalence of  A.lumbricoides and T.trichiura  is usually attained before five years ofage,and themaximum prevalence ofhookworm and schistosome infec-tions is usually attained in adolescence or in early adulthood.The nonlinear relationship between prevalence and intensity has the consequence that the observed age-prevalence profilesprovide little indicationofthe underlying profiles ofage inten-sity (age in relation towormburden).Because intensity is 001020304050102030405060708090100 Percentage infected  a. Prevalenceb. Intensity Age (years)005152535451020304050102030405060708090100110 Mean number of worms  Age (years)   Source:    Bundy 1995; reproduced and modified from Hotez, Ardra, and others 2005. A. lumbricoides T. trichiuraS. haematobium  Hookworm A. lumbricoides  (worms   2) T. trichiura (actual numbers) S. haematobium  Hookworm(worms   7) Figure 24.1 Age-Associated Prevalence and Intensity Profiles ofSTH and Schistosome Infections: Typical Age Profiles of Prevalenceand Intensity of STH Infections and Schistosomiasis  15years ofage (Bundy 1995).For schistosomiasis,a convex pattern is also observed,with a similar peak but with a plateauin adolescents and young adults 15 to 29 years ofage(Kabatereine and others 1999).In contrast,the age-intensity profile for hookworm exhibits considerable variation,althoughintensity typically increases with age until adulthood and thenplateaus (Brooker,Bethony,and Hotez 2004).In East Asia it isalso common to find the highest intensities among the elderly.However,more generally,children and young adults are athigher risk ofboth harboring higher levels ofinfection (thusgreater levels ofmorbidity) and becoming reinfected morequickly.Both may occur at vital stages in a child’s intellectualand physical development. Risk Factors Both host-specific and environmental factors have been identi-fied that may affect the risk ofacquiring or harboring heavy-intensity helminth infections. Genetics. No genes that control for human helminth infectionhave yet been identified.However,recent genome scans haveidentified a locus possibly responsible for controlling S.man-soni  infection intensity on chromosome 5q31-33 and locicontrolling A.lumbricoides  intensity on chromosomes 1 and13.There is also evidence for genetic control ofpathology attributable to S.mansoni, with linkage reported to a regioncontaining the gene for the interferon gamma receptor 1 sub-unit (Quinnell 2003). Behavior, Household Clustering, and Occupation. Specificoccupations,household clustering,and behaviors influence theprevalence and intensity ofhelminth infections (Bethony andothers 2001),particularly for hookworm,in which the highestintensities occur among adults (Brooker,Bethony,and Hotez2004).Engagement in agricultural pursuits,for example,remains a common denominator for hookworm infection.Behavioral and occupational factors,through their effect onwater contact,interact with environmental factors to producevariation in the epidemiology ofschistosomiasis. Poverty, Sanitation, and Urbanization. STH and schistoso-miasisdependfortransmissiononenvironmentscontaminatedwithegg-carryingfeces.Consequently,helminthsareintimately associated with poverty,poor sanitation,and lack ofcleanwater.The provision ofsafe water and improved sanitation areessential for the control ofhelminth infection.Although theSTH and schistosome infections are neglected diseases thatoccur predominantly in rural areas,the social and environ-mental conditions in many unplanned slums and squatter set-tlements ofdeveloping countries are ideal for the persistence of  A.lumbricoides (Crompton and Savioli 1993).Schistosomiasistransmission can also occur in urban areas. Climate,Water, and Season. Adequate warmth and moistureare key features for each ofthe STHs.Wetter areas exhibitincreased transmission,and in some endemic areas,both STHand schistosome infections exhibit marked seasonality (Brooker and Michael 2000).Recent use ofgeographical infor-mation systems and remote sensing has identified the distribu-tional limits ofSTH and schistosomes on the basis oftemper-ature and rainfall patterns (Brooker and Michael 2000).Forschistosomiasis,specific snail intermediate hosts prefer certaintypes ofaquatic environments.Construction ofdams is knownto extend the range ofsnail habitats,thereby promoting thereemergence ofschistosomiasis. BURDEN OF THE DISEASE The revised estimates in 2003 (de Silva and others 2003) use themethodology developed by Chan and others (1994) and buildon recent applications ofgeographical information systems toderive updated atlases ofhelminth infections.To reflect recentchanges in the epidemiology ofinfection,de Silva and othersused data from only 1990 onward.These data confirm thatSTH infections are the most prevalent infections ofhumansand that a large proportion ofthe population in developingcountries is at risk.Ofthe 187 million cases ofschistosomiasisestimated to occur worldwide,most are caused by S.haemato-bium in Sub-Saharan Africa (table 24.1).WHO (2002) estimates that 27,000 people die annually from STH infections and schistosomiasis (case fatality rate of 0.0014 percent).Many investigators,however,believe that thisfigure is an underestimate.Crompton (1999) estimated that155,000 deaths annually occur from these infections (case fatal-ity rate of0.08 percent),whereas Van der Werfand others(2003),using the limited data available from Africa,estimatedthe schistosomiasis mortality alone at 280,000 per year (casefatality rate of0.014 percent) because ofnonfunctioningkidneys (from S.haematobium ) and hematemesis (from S.mansoni  ).Therefore,the difference between estimates forhelminth-associated mortality is more than 10-fold.Because it is uncommon for STHs and schistosomes to killtheir human host,citing mortality figures provides only a smallwindow on their health impact.Instead,measurements ofdis-ease burden using disability-adjusted life years (DALYs) andsimilar tools portray a more accurate picture for helminthicdisease burden.WHO estimates the global burden ofdiseasefrom STH infections and schistosomiasis on the basis oftheenormous number ofinfected individuals,together with anassociated low disability weight (Van der Werfand others2003).However,because an estimated 2 billion people areinfected with STHs and schistosomes,even minor adjustmentsto the disability weights produce enormous variations inDALYs or other measurements ofdisease burden.This helps to 470 |Disease Control Priorities in Developing Countries|Peter J. Hotez, Donald A. P. Bundy, Kathleen Beegle, and others  explain why,for instance,in 1990 the disease burden for theSTH infections and schistosomiasis was almost 18 millionDALYs,whereas the 2001 estimate was only 4.7 million DALYs.In the intervening 11 years,the DALYs were as low as 2.6 mil-lion.Such disparities are substantial when one considers thatthe 1990 estimate ranks helminths close to major disease enti-ties such as tuberculosis,measles,and malaria,whereas thelowest estimate during the 1990s ranks helminth infections ona par with gonorrhea,otitis media,and iodine deficiency.TheDisease Control Priorities Project helminth working grouphasdetermined that the WHO global burden ofdiseaseestimates are low because they do not incorporate the full clin-ical spectrum ofhelminth-associated morbidity and chronicdisability,including anemia,chronic pain,diarrhea,exerciseintolerance,and undernutrition (King,Dickman,and Tisch2005).However,for this chapter,the average disability weightsestimated by WHO are used throughout.Some ofthe specificcontroversies are described below. A. Lumbricoides and T. Trichiura  infections Because the most significant physical and intellectual growthdisturbances occur as a consequence ofmoderate and heavy worm burdens,the age-associated epidemiology of  A.lumbricoides  and T.trichiura  infections has focused attentionon infected school-age children in developing countries(Bundy 1995).In a revised estimate ofthe probable number of ascariasisinfections worldwide and a better categorization of the morbidity,de Silva,Chan,and Bundy (1997) indicated that59 million ofthe 1.2 billion people infected (including 51 mil-lion children less than 15 years ofage) were at risk offalteringgrowth,decreased physical fitness,or both as aresult ofinfec-tion.They estimated that about 1.5 million children wouldnever make up the deficit in growth,even iftreated.In additionto these chronic,insidious effects,they estimated that about11.5 million individuals (almost all ofthem children) were atrisk ofmore acute clinical illness.Their figures also indicatedthat at least 10,500 deaths annually were directly attributable toone ofthe serious complications ofascariasis;children accountfor more than 90 percent ofthose deaths.The actual thresholdat which A.lumbricoides  and T.trichiura  worm burdens resultin childhood morbidity is controversial because ofthe nonlin-ear relationship between intensity and pathogenesis and thedifficulties ofmeasuring and attributing morbidity in under-served populations suffering from other underlying conditions(Bundy 1995). Hookworm Infection HookworminfectioncausesmoreDALYslostthananyotherhelminthiasiswiththeexceptionoflymphaticfilariasis.EventheseDALYmeasurementsmaystillunderestimatethetruediseaseburdenofirondeficiencyanemiaandproteinmalnutritionresultingfromhookwormdisease.Irondeficiency anemiaaloneresultsinapproximately12millionDALYslostannually,makingittheworld’smostimportantnutritionprob-lem.DataontheepidemiologyofirondeficiencyanemiainEastAfricaandelsewherepointtotheimportantcontributionofhookwormstothiscondition(Stoltzfusandothers1997).InTanzania,wherehosts’ironstoresareoftendepleted,thereisacorrelationbetweenthenumberofadulthookwormsintheintestineandtheamountofhostbloodloss(Stoltzfusandothers1997).However,itisunclearwhethercurrentdisability weightseffectivelyincorporatethefullcontributionofhook-wormtosevereirondeficiencyanemiaamongiron-depletedpopulationsorwhethertheytakehostproteinlossesandmalnutritionintoaccount.Thereisincreasinginterestintheimportanceofhookwormanemiainpreschoolchildren,espe-ciallyinAfrica(Brooker,Bethony,andHotez2004),whereinfantsandpreschoolchildrenareparticularlyvulnerabletothedevelopmentalandbehavioraldeficitscausedbyirondeficien-cyanemia(Stephenson,Latham,andOttesen2000).Closerassessmentoftheimpactofhookwormonanotherimportantiron-deficientpopulation—namely,womenofreproductiveage—couldalsosignificantlyincreasecurrentDALYestimates.Approximately44millionofthesewomenharborhookworms(Bundy,Chan,andSavioli1995).Inaddition,severeanemiainpregnancyisassociatedwithneonatalprematurity,reducedbirthweight,andimpairedlactation(Christian,Khatry,andWest2004). Schistosomes Scientists and public health workers disagree on the currentassessments ofboth morbidity and mortality attributable toschistosomiasis.Several investigators have now initiated aprocess to recalculate the burden ofdisease attributable toschistosomiasis,focusing much more on the clinical course of the different types ofschistosomiasis and chronic sequelae(King,Dickman,and Tisch 2005;Michaud,Gordon,and Reich2003).Through a comprehensive literature review combinedwith mathematical modeling,Van der Werfand others (2003)estimate that urinary schistosomiasis in Africa results inapproximately18 million cases ofbladder wall pathology and20 million cases ofhydronephrosis,and African intestinalschistosomiasis results in approximately 8.5 million cases of hepatomegaly.Mortality in Africa attributable to urinary andintestinal schistosomiasis was extrapolated from these figuresusing a limited number ofstudies reporting case fatality ratesfor nonfunctioning kidney and hematemesis.From theseextrapolations,Fenwick and others (2003) conclude that inAfrica the mortality attributable to urinary schistosomiasiscould be as high as 150,000 per year,and the number dying asa result ofintestinal schistosomiasis could be as high as 130,000per year. Helminth Infections: Soil-Transmitted Helminth Infections and Schistosomiasis| 471
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