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5.1 Introduction

Diarrhea as a clinical complaint has been with hominids long before our species emerged, but in man’s most natural state, infectious diarrhea may not have been a major health problem. Among small bands and tribes, infectious agents could have spread through the local population, engendered widespread immunity, then submerged to a subclinical existence, or perhaps failed to be sustained at all. With the rise of human cities, however, enteric pathogens may have found an opportunity for persistence, given continual replenishment of susceptible individuals, along with new opportunities provided by sewage systems and close proximity to domesticated livestock.

But historical records suggest that diarrhea emerged as a global scourge with widespread confluence of human populations brought about by colonization and frequent inter-continental transportation. Cholera spread dramatically across the globe in the ninteenth century in a series of pandemics [1]. No civilized area remained untouched. At the same time, cholera in the headlines drove breakthroughs in science and medicine from which we daily benefit. John Snow’s investigations into the source of London cholera epidemics founded the science of epidemiology [2]. Robert Koch’s seminal investigations, coupled with the infamous opposition by von Pettenkofer [3] and others, drove the final nails in the coffin of the miasma theory and established modern microbiology.

Realization that cholera derived from a microorganism spread through sewerage eventually drove development of modern urban sanitation systems. Sanitation finally stemmed the tide: deaths due to enteric diseases in industrialized cities declined dramatically around the turn of the twentieth century, long before we knew of antibiotics or oral rehydration therapy [4] . Unfortunately, however, while cities in the industrialized world reaped the benefits of cleaner living, the sprawling metropolae of the under-developed world continued to provide ripe opportunities for propagation of enteric diseases. In many parts of the world, this heritage persists.

5.2 Toward Effective Control of the Global Diarrhea Burden

The legacy of cholera also provided the first breakthrough in diarrhea therapy. In the 1950s and 1960s, physiologists described the phenomenon of coupled sodium-glucose co-transport across the mammalian intestine [5]. In the presence of glucose, animal perfusion models showed dramatically improved sodium uptake. Capt. Robert Phillips and others quickly exploited this fundamental breakthrough [6]. Working in Bangladesh (while others in Calcutta were making similar strides), Phillips’ team demonstrated that stool output of cholera patients was substantially reduced when oro-gastric sodium chloride infusions included glucose [7]. With astonishing rapidity, this observation led to the miracle of oral rehydration therapy (ORT) [8] .

ORT was propagated across the face of the globe throughout the decades of the 1970s, 1980s and 1990s, with remarkable success. Everywhere ORT reached, mortality rates from dehydrating diarrhea declined. Global data reflected the local effects. From an estimated 5 million deaths per year attributable to diarrhea among children under 5 years globally in 1980, this rate fell steadily to below 2 million, and data from the Child Health Research Group (CHERG) place the number of diarrhea-related deaths at 1.32 million in 2008 [9]. This still represents ca. 18 % of all deaths among children under 5 years (Fig. 5.1).

Fig. 5.1
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Major causes of death among children less than 5 years of age worldwide, 2008. (From [9])

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After rapid decline soon after the introduction of ORT , the rate of decline of diarrhea-related deaths has plateaued. Several causes can be postulated. First, the vigor accompanying early ORT implementation programs could not be sustained indefinitely, in view of new public health priorities. In addition, many enteric infections may be intrinsically refractory to ORT, or perhaps their pathophysiologic assault may involve derangements other than dehydration. Studies focused on the etiologic agents of childhood diarrhea now suggest that the story is complex.

5.3 Pathogenesis of Infectious Diarrhea

The fundamental derangement in human diarrhea is the reprogramming of the gastrointestinal tract from a net absorptive organ to one that eliminates feces with abnormally high water content. Molecular mechanisms may involve up-regulation of secretion channels and pumps, reduction of absorptive functions, and/or erosion of intestinal barrier function. Remarkably, pathogenesis research suggests that most enteric pathogens effect more than one (quite often all three) of these assaults . Enteropathogenic E. coli (EPEC) , a common pathogen of infants and toddlers in developing countries, provides a prominent example (reviewed in references [10–13]) (Fig. 5.2). EPEC attaches tightly to the brush border of small intestinal enterocytes, and injects a set of protein toxins directly into the cellular cytoplasm. The net effects of these toxins are astonishing, and only partly understood [14]. A subset of the proteins trigger signal transduction pathways in the afflicted cell, resulting in release of pro-inflammatory cytokines, including the chemokine IL-8, though pro-inflammatory responses are finely modulated [12]. Release of these cytokines results in recruitment of leukocytes to the tissue, leading to tight junction opening and tissue damage. Emerging evidence also suggests that some of the EPEC effector proteins may have direct pathologic effects on cellular absorptive and secretion channels in the apical membrane. Perhaps more remarkably, several proteins act in synergistic fashion to open tight junctions and stimulate leakage of fluid via the intercellular junctions [13]. One of the more intriguing effects of EPEC intoxication is the inhibition of the sodium-glucose co-transport apparatus [15] . It can be envisioned that damage to the epithelial layer, loss of absorptive driving force, and reduced function of the sodium-glucose contransporter could render EPEC infection relatively resistant to the effects of ORT . This hypothesis requires clinical validation, but there can be little doubt that the impact of some enteric pathogens extends well beyond loss of water and salts .

Fig. 5.2
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Pathogenetic effects of enteropathogenic E. coli infection on small bowel epithelial cells. Attachment of the pathogen to the apical membrane of enterocytes results in decreased absorptive and enhanced secretory mechanisms, along with impairment of normal barrier function. (Adapted from [13])

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5.4 Diarrhea, Growth and Cognition

The notion that diarrhea does more than simply dry out the host has gained increasing support from epidemiologic and clinical studies. Studies in Fortaleza Brazil and elsewhere show clearly that patients with diarrhea persisting longer than 7–14 days demonstrate shortfalls in growth and cognitive development, as well as increased mortality that may be due to factors other than diarrhea per se. Guerrant and others have accordingly suggested that enteric infection may trigger a vicious cycle in which damage to the intestinal mucosa leads to malabsorption of nutrients that are required for growth, cognitive development, maintenance of gut integrity and immune function [16, 17]. This relationship has complex and potentially devastating implications. Fig. 5.3 illustrates the diarrhea vicious cycle: infection leads to malabsorption, which predisposes to further infection. Each individual infection exacts its toll in terms of growth and development; eventually, the ability of the child to “catch up” is lost. The effect has been documented since the 1970s, starting with the famous studies of Leonardo Mata in Guatemala [18]. In growth curves of children in Mata’s study villages, he observed growth flattening accompanying each infection, followed by catch up growth that is increasingly meager as the child ages. The result is a child who is stunted, and likely abnormal in many more subtle ways. And as we rescue more and more of the word’s children from acute diarrhea-related death, this silent toll of diarrhea and malnutrition may emerge as the principle threat of enteric infection on human health.

Fig. 5.3
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The cycle of malnutrition and enteric infection. (Redrawn from [18])

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5.5 The Global Enteric Multisite Study (GEMS)

The urgency to understand the persistence of diarrhea-related death among the world’s poorest children has motivated the Bill & Melinda Gates Foundation to embark on the largest diarrhea case-control study every attempted. The study, coordinated by Dr. Myron M. Levine at the University of Maryland School of Medicine, has implemented an identical case-control design at seven sites in sub-saharan Africa and south Asia (Table 5.1). For a period of 3 years, the study enrolls children under 5 years of age who present to sentinel health centers with a complaint of acute moderate-to-severe diarrhea, defined as diarrhea within 7 days of onset accompanied by clinical dehydration, fecal blood, need for intravenous hydration, and/or admission to a medical facility. For each of the subjects enrolled, a matched control is recruited from the subject’s village.

Table 5.1 Sites represented in the global enteric multi-site research study
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Each GEMS case and control is studied in comprehensive fashion. A detailed questionnaire is administered to elucidate risk factors for enteric infection. Precise anthropometric data are acquired. A stool sample is collected and analyzed comprehensively for the major enteric pathogens, using validated microbiological methods. A household visit is conducted at 60 days post-enrollment for both cases and controls to ascertain survival, length of diarrhea, and growth during the follow-up period. Results of the study are expected in 2012.

5.6 The Future of Diarrhea Control

Future diarrhea prevention and therapy strategies must remain focused on the last ca. 1 million diarrhea-related deaths among children under 5 years of age, but also on diarrhea-related morbidities. The most fruitful approach to avoiding diarrhea-related deaths will require a multi-pronged approach. Rotavirus remains the most common cause of dehydrating diarrhea, and implementation of the new rotavirus vaccines has become an urgent global health priority. Successful deployment of the rotavirus vaccines to the world’s poorest will save many thousands of lives, though the precise impact will depend on complex epidemiologic and political factors [19, 20]. Beyond the rotavirus vaccine, it is essential to elucidate other specific etiologic agents that may be over-represented among fatal cases. These pathogens may become amenable to vaccines or control strategies targeted at their modes of transmission. The GEMS study should provide vital illumination of these important microorganisms. GEMS may also reveal information to guide sanitation and hygiene programs, particularly important in areas where pathogen-specific interventions are impractical.

Along with prevention of diarrhea-related deaths, we must become increasingly attuned to the silent morbidity attending diarrhea. Provision of zinc supplementation to children with diarrhea has already been shown to diminish the duration of diarrhea episodes. Providing anticipatory zinc to at risk populations may provide significant benefits in terms of diarrhea related morbidity and mortality [16, 21–31] . Several studies have examined the provision of zinc along with other nutrients (e.g. vitamin A), and inclusion of zinc in oral rehydration salts may be a practical way to target populations in greatest need [21, 23, 25, 30].

Understanding the effects of diarrhea on human cognition will become increasingly important as we prevent death and growth shortfalls. The studies in Fortaleza reveal not only that children with diarrhea are more likely to manifest cognitive disability, but that there may be a genetic predisposition to this adverse outcome [32]. These studies need to be replicated more widely, and the relative contribution of predisposition vs. insult needs to be elucidated. Beyond genetic predisposition, it will be important to understand the roles of intercurrent infections and the intestinal microbiome in conferring susceptibility to enteric-related morbidity and mortality.

A great deal of research remains devoted to improving oral rehydration. Oral rehydration salts (ORS) with low osmolarity [33], complex starch [34], amino acids [35], and other additives may ultimately provide a material improvement in our ability to avoid adverse outcomes in children who can receive these interventions. Ramakrishna et al. [36] conducted a prospective randomized clinical trial at a tertiary referral hospital in southern India to compare the effects of low osmolarity ORS incorporating amylase-resistant starch instead of glucose (Fig. 5.4) . These investigators reported significantly shorter duration of diarrhea in adult males given the maize-based ORT .

Fig. 5.4
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Compared with standard ORS, high amylase maize starch (HAMS-ORS) reduced diarrhea duration by 55 % and significantly reduced fecal weight after the first 12 h of ORS therapy in adults with cholera-like diarrhea. (From [36])

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Integration of multiple interventions is likely to produce the greatest benefit in terms of lives saved [37]. However, each additional intervention adds complexity to the problems of deployment. Despite decades of international effort, only an estimated 38 % of the world’s poorest children receive ORS when they develop diarrhea [38]. The causes for this are many, and include lack of delivery infrastructure, lack of resources for purchase and dissemination, and focus on other public health priorities. It is likely that developing countries will be able to leverage ORS dissemination programs to introduce other interventions against enteric diseases, providing programmatic synergy.

Fischer-Walker et al. [37] have recently applied a Lives Saved Tool (LiST) analysis to estimate the impact of various interventions in the management of diarrhea. The authors analysed the impact of implementing the following interventions in 68 high child mortality countries: ORS, zinc , antibiotics for dysentery , rotavirus vaccine, vitamin A supplementation and breastfeeding promotion, in addition to basic water, sanitation and hygiene. They found that diarrhea mortality would be reduced by 78 % and 92 %, respectively under an “ambitious” (feasible improvement in coverage of all interventions) and “universal” (assumes near 100 % coverage of all interventions) scale-up impact scenarios. With universal coverage, nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$ 12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$ 84.8 billion would be required for the addition of all water and sanitation interventions.

Following similar analyses, UNICEF has developed a comprehensive seven-point plan for diarrhea control (Table 5.2). Given the recognition that the burden of enteric disease extends far beyond death from dehydration, success in the UNICEF plan may realize dramatic improvements in child health.

Table 5.2 Seven point plan for diarrhea control
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Perhaps the final frontier in enteric pathogenesis research will be understanding the true cost of exposure to enteric pathogens . Studies in Guinea-Bissau [39] have documented frequent exposure of infants and children to enteric pathogens, with only a minority of the exposures resulting in frank diarrhea. But this observation compels us to ask the key question: Is asymptomatic exposure truly benign? It is well-established that children in developing countries exhibit increased intestinal permeability when compared to their counterparts in industrialized nations [40]. Is this the result of repeated subclinical exposure to pathogens? If so, what is the true cost of this malady?

Many important questions remain in the fight against enteric disease among the world’s poorest children. But perhaps for the first time, there exists a confluence of technology that will to bring to bear effective weapons. This effort will require continued application of energy and resources to benefit the majority of the world’s children.