child undernutrition, tropical enteropathy, toilets and handwashing

7/29/2019 Child undernutrition, tropical enteropathy, toilets and handwashing

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Child undernutrition, tropical enteropathy, toilets, and

handwashingJean H Humphrey

Of the 555 million preschool children in developingcountries, 32% are stunted and 20% are underweight. 1Child underweight or stunting causes about 20% of allmortality of children younger than 5 years of age andleads to long-term cognitive deficits, poorer performancein school and fewer years of completed schooling, andlower adult economic productivity.2 Child underweightstate or stunting mainly develops during the first 2 yearsof life, when mean weight-for-age and length-for-ageZ scores of children in Africa and Asia drop to about

20, with little or no recovery thereafter.3

Under the plausible assumption that children growpoorly because they do not eat enough of the right foods,research efforts have focused on identifying dietarysolutions. Numerous studies have tested manynutrient-dense foods and supplements, nutritioneducation interventions, and infant feeding behavioural-change strategies. A recent review4 of 38 of these studiesshowed that children receiving one of these dietaryinterventions gained up to 760 g more weight (00076weight-for-age Z score) and grew up to 17 cm taller(00064 length-for-age Zscore) than control childrenby 12 to 24 months. However, none of these interventionsachieved normal growth: the growth effect of even the

most successful of these studies (~ +07 Z) is equivalentto about a third of the average deficit of Asian and Africanchildren (~ 20 Z).

Diarrhoea has also been implicated as a cause of poorgrowth. In a pooled analysis of nine studies withdiarrhoea and growth data for 1393 children,5 theprobability of stunting at 24 months of age increased by25% per episode of diarrhoea, and 25% of all stunting in24-month-old children was attributable to having five ormore episodes of diarrhoea in the first 2 years of life.However, other authors have contended that the effect ofdiarrhoea on permanent stunting is small becausegrowth velocity can be faster than average for age betweenillness episodes resulting in catch-up growth.6 Hence,

the relative contribution of diarrhoea to undernutritionand, consequently, the potential effect that diarrhoeacontrol programmes (ie, sanitation and hygieneinterventions) could have on growth are still unresolved.The Lancet Maternal and Child Undernutrition Seriesestimated that sanitation and hygiene interventionsimplemented with 99% coverage would reduce diarrhoeaincidence by 30%, which would in turn decrease theprevalence of stunting by only 24%.7

This report suggests: that a key cause of childundernutrition is a subclinical disorder of the smallintestine known as tropical enteropathy, which ischaracterised by villous atrophy, crypt hyperplasia,

increased permeability, inflammatory cell infiltrate, andmodest malabsorption;8 that tropical enteropathy iscaused by faecal bacteria ingested in large quantities byyoung children living in conditions of poor sanitationand hygiene; that provision of toilets and promotion ofhandwashing after faecal contact could reduce orprevent tropical enteropathy and its adverse effects ongrowth; and that the primary causal pathway from poorsanitation and hygiene to undernutrition is tropicalenteropathy and not diarrhoea.

If this is true, the Lancet Maternal and ChildUndernutrition Series7 might have substantiallyunderestimated the contribution of sanitation andhygiene to growth because the effect was modelledentirely through diarrhoea. Importantly, because ofmortality, and cognitive and economic consequences ofchild undernutrition, sanitation and hygiene interventionsmight have been undervalued because they have beenmainly appraised for their effect on diarrhoea.Confirmation of these hypotheses might provide evidenceto accelerate provision of toilets to the 26 billion people(40% of the worlds population) who currently lack them,hasten progress towards the Millennium DevelopmentGoal to halve this number by 2015, and ultimately yield

improvements in child growth, health, and survival.Several studies done mostly in the 1960s in Asia, Africa,and Central America showed that almost all apparentlyhealthy adults and children in developing countriesworldwide had morphological changes or functionalsigns of tropical enteropathy.8 Although the cause oftropical enteropathy has not been clearly elucidated, mostof these investigators suggested that tropical enteropathyresults from exposure to poor environmental sanitation.Further evidence for an environmental cause comes fromstudies of asymptomatic American soldiers in Vietnamand Peace Corps volunteers in Pakistan who got tropicalenteropathy after a few months of residence in thesesettings and recovered soon after returning to the USA.8

Similar to other inflammatory bowel diseases, tropicalenteropathy results from unrestrained enteric T-cellactivation.9 However, unlike diseases caused by abnormalhyper-reactivity to a normal exposure (eg, in coeliacdisease, enteric T cells are phenotypically hyper-reactiveto gluten10), tropical enteropathy probably develops whennormalT cells are hyperstimulated by abnormally highconcentrations of ingested faecal bacteria in thesmall-intestinal lumen.11

Over the past 20 years, investigators at the MRC DunnNutritional Laboratory (Cambridge, UK, and Keneba, TheGambia) have studied growth in Gambian children.Dietary inadequacy and diarrhoea were not associated

Lancet 2009; 374: 103235

Center for Human Nutrition,

Johns Hopkins Bloomberg

School of Public Health,

Baltimore, MD, USA, and

ZVITAMBO project, Harare,

Zimbabwe (J H Humphrey ScD)

Correspondence to:

DrJean H Humphrey,

Johns Hopkins Bloomberg

School of Public Health, Center

for Human Nutrition, 615 N

Wolfe Street, Baltimore, MD21205, USA

[email protected]


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with growth failure, but the lactulose to mannitol urinaryexcretion ratioan indicator of intestinal permeabilityexplained 39% of ponderal and 43% of linear growth.12Moreover, gut hyperpermeability was a chronic condition:these children had diarrhoea on 73% of days betweenbirth and 2 years of life, but had lactulose to mannitol

urinary excretion ratios associated with growth suppres-sion on 76% of days during this period.

In a subsequent study,13 the same investigators alsomeasured plasma concentrations of total IgG andIgGendotoxin-core antibody (EndoCAb). Endotoxin is acomponent of gram-negative bacterial cell walls probablyderived from faecal contamination. A permeable gutallows endotoxin translocation into the body, where itstimulates an immune response that stimulatesproduction of EndoCAb. At 2 months of age, the weight-for-age Z score, height-for-age Z score, lactulose tomannitol ratio, and plasma IgG and EndoCAbconcentrations were similar to those in normal infants in

the UK. However, by 15 months of age, mean height-for-age Zscore fell from 06 to 18, mean weight-for-ageZscore fell from 04 to 24, the lactulose to mannitolratio almost tripled (in normal infants in the UK, thisratio declined during this period), and mean IgG andEndoCAb concentrations were 2-fold and 5-fold higher

than normal, respectively. The lactulose to mannitol ratioand IgG and EndoCAb concentrations were correlatedwith each other and all were negatively correlated withlinear and ponderal growth. Using semipartial regressionanalysis methods, the combined effects of IgG andEndoCAb concentrations explained 51% of linear growth,which increased to 56% when the lactulose to mannitolratio was also included.

Solomons and colleagues tell a similar story fromanimal husbandry.14 In controlled studies, chicks raisedamidst faeces, dust, and dander but fed antibiotics grewbetter than chicks living in similar conditions but notfed antibiotics, and grew as well as chicks raised in

Figure: Model of the mechanisms from poor sanitation and hygiene to tropical enteropathy, child undernutrition, and child development and survival

Thick lines indicate primary pathways and thin lines secondary pathways, as hypothesised in this report.

No toilet

No handwashingafter faecal contact

Faecal ingestion by infants and

young children

Tropical enteropathy

Chronic villus atrophy, crypt hyperplasia, inflammatory cell infiltrate

Child undernutrition

Increased child mortalityReduced cognitive development and adult economic productivity

Faecal contamination

of domestic environment

Faecal contamination

of infant hands

Increased pathogenic

bacteria ingestion

Intermittent diarrhoea

Anorexia

Reduced nutrient

absorption

Multiple socio-economic,climatic, political, and

behavioural factors

Inadequate diet

Faecal contamination of breast,infant food, drinking water,

utensils, toys

Faecal contamination ofchild caretakers hands

Reduced small-intestinalsurface area

Reduced nutrient

absorption

Microbial translocation

Increased intestinalpermeability

Enteric T-cell stimulation

High bacterial ingestion overwhelmsgastric barrier resulting in high bacteria

concentration in the small-intestinal lumen

Repartitioning of exogenous and endogenous nutrients away from growth for: increased synthesisof antibodies (including EndoCAb), acute-phase proteins, cytokines, and increased glucose oxidation

to fuel high metabolic rate


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steam-cleaned cages for whom antibiotics had no growtheffect.15 The poor growth of dirty chicks not fedantibiotics was accompanied by high plasmaconcentrations of interleukin 1, a major mediator of theimmune response, which was not observed in dirtychicks fed antibiotics or in clean chicks. On this basis,antibiotics (termed growth permitters in this context)have been used for decades on poultry farms to maximisemeat yield. Therefore, when confronted by incessantmicrobial challenge, both the Gambian infants andchicks studied entered a near-continuous state ofgrowth-suppressing immune response: dietary nutrientswere repartitioned away from anabolism in favour ofglucose oxidation and synthesis of acute-phase proteinsand other immune mediators.14

The figure shows a model of these pathways. Children

living in poor sanitary conditions ingest highconcentrations of faecal bacteria, which colonise thesmall intestine and induce tropical enteropathy througha T-cell-mediated process. The hyperpermeable gutfacilitates translocation of microbes, which trigger themetabolic changes of the immune response. Growthfalters when these changes coincide with reducednutrient absorption by atrophied villi, marginal dietaryintake, and the high growth demands of the first 2 yearsof life.

How can children be protected from faeces? Safedisposal of stools (ie, toilets) and handwashing with soapafter faecal contact are the primary barriers to faecal-oraltransmission because they prevent faeces from entering

the domestic environment. Many randomised trials ofhandwashing16 have shown substantial reductions indiarrhoea, although none included the effect of theseinterventions on tropical enteropathy or child growth.Surprisingly, there are no published randomised trials oftoilet provision on child growth or even diarrhoea.Almost all existing evidence that sanitation benefitshuman health comes from cross-sectional, prospectivecohort, case-control, and non-randomised interventionstudies. Thus, all have methodological issues, includingpotential confounding by socioeconomic status, lack ofadequate control in beforeafter programmeassessments, and inadequate statistical power when asingle control community is compared with a single

intervention community.17

Nonetheless, many of thesestudies have documented benefits on child growth.18Indeed, in an analysis of demographic and health surveydata from eight countries, Esrey19 estimated thatimprovements in sanitation were associated withlength-for-age Z score increments of 006062 inchildren living in rural areas and 026065 in childrenliving in urban areas, which are similar to the growtheffects of dietary interventions reviewed earlier in thisreport4 (ie, 000064). Moreover, from a meanlength-for-age Z score (SD) of 169 (145) in ruralchildren and 119 (145) in urban children, theseincrements correspond to 437% and 2046% decreases

in stunting prevalence in rural and urban children,respectively, suggesting a considerably greater effectthan the 24% decrease previously estimated in theLancetSeries.7

Undoubtedly, the complex problem of childundernutrition will not be solved with toilets andhandwashing alone. Interventions focused on gutmicrobial populations20 and improved drinking waterquality21 might be important, together with continuedefforts to improve infant diets. However, I hypothesisethat prevention of tropical enteropathy, which affl ictsalmost all children in the developing world, will becrucial to normalise child growth, and that this will notbe possible without provision of toilets. Randomisedcontrolled trials of toilet provision and handwashingpromotion that include tropical enteropathy and child

growth as outcomes will give valuable evidence for thispremise, and might offer a solution to the intractableproblem of child undernutrition.

Conflicts of interest

I declare that I have no conflicts of interest.

Acknowledgments

I thank Robert Ntozini for statistical support; Prof Rebecca Stoltzfus andProf Robert Black for helpful comments on earlier versions of this paper;and UK Department for International Development and US NationalInstitutes of Child Health and Human Development (grant number:1R01HD060338-01) for financial support.

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child undernutrition, tropical enteropathy, toilets and handwashing

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