key: cord-0953562-12l88oa8
authors: Bhutta, Z.; Syed, S.
title: Diarrheal Diseases
date: 2015-09-22
journal: Encyclopedia of Food and Health
DOI: 10.1016/b978-0-12-384947-2.00223-3
sha: 640187326d6e3fe0d1c22c39f754dc841854a518
doc_id: 953562
cord_uid: 12l88oa8

An estimated 700 000 children die annually due to diarrhea with majority of these occurring in children under the age of 5 years. Morbidity from diarrhea includes poor growth and development. The global diarrhea burden is primarily due to infections secondary to rotavirus, cryptosporidium, enterotoxigenic Escherichia coli, and Shigella species. Known interventions to effectively treat and prevent diarrhea include vaccines against rotavirus and cholera, zinc supplementation, and therapy with oral rehydration solution. The achievement of the fourth Millennium Development Goal requires reductions in mortality from diarrhea, and can only be accomplished by implementing evidence-based strategies.

The WHO defines diarrhea as the passage of three or more loose or liquid stools per day, or more frequently than is normal for the individual. Diarrhea is the leading cause of mortality among children under 5 years of age accounting for one in ten child deaths worldwide annually. It disproportionally affects young children in low-and middle-income countries ( Figure 1 ). In 2010, there were 1.731 billion episodes of diarrhea (36 million of which progressed to severe episodes) and in 2011, an estimated 700 000 deaths were due to diarrhea. Incidence and mortality from diarrhea and pneumonia vary by age ( Figure 2 ) with the burden of disease mainly concentrated in the younger age groups. The epidemiology of childhood diarrhea and pneumonia overlap, likely because of shared risk factors, such as undernutrition, suboptimum breastfeeding, and zinc deficiency. Children are at the highest risk during the first 2 years of life, with 72% of deaths being secondary to diarrhea. Diarrheal mortality rates are declining by about 4% annually with disease incidence decreasing from an estimated 3.4 episodes/child-year in 1990 to 2.9 episodes/child-year in 2010. The highest burden of disease has remained consistent with respect to age in the 6-11-month-old age group having the highest incidence. The burden of mortality due to diarrhea in children less than 5 years of age in 2010 was highest in the WHO regions of Africa and Southeast Asia. It is estimated that a third of severe diarrhea episodes is preventable by vaccination (i.e., against rotavirus and cholera). Furthermore, under nutrition is a key underlying risk factor for morbidity and mortality associated with both diarrhea and pneumonia. Diarrhea disease severity in children under-five is mostly mild ($65% cases for which no care was sought/no dehydration) lasting about 4 days or moderate ($35% cases for which care was sought/any dehydration on presentation) with only 0.5% of cases being severe (cases for which care was sought, with severe dehydration on presentation) and lasting 8 days. Older children and adults have predominantly mild episodes (95%) with 4.95% being moderate and 0.05% being severe. Among individuals 16 years or older, severe episodes typically last $3 days and cause dehydration in $93% of cases.

Despite reduction of diarrheal mortality by use of oral rehydration therapy, persistent global burden of enteric infections results in high morbidity of up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Children suffering from diarrhea during the first 2 years of life might have on average an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7-9 years old. The proposed link between enteric infections and child growth and development is a double burden of enteric infections and malnutrition, and the potential link of both of these factors to obesity later in life is an interrelated 'triple burden' (Figure 3) . Important risk factors for diarrhea include lack of exclusive breastfeeding in infants younger than 6 months, undernutrition and zinc deficiency. While evidence suggests that vitamin A deficiency increases the risk of severe diarrhea, it is not an important risk factor for the incidence of diarrhea. Associations of specific water and sanitation risk factors (i.e., unwashed hands and poor water quality) with diarrhea morbidity and mortality have been shown. However, for some outcomes such as inappropriate excreta disposal, poor availability of evidence permits only rough estimates of risk. In a stratified subgroup of infants aged less than 6 months, acute lower-respiratory-tract infections are a risk factor for diarrhea. Measles is an established risk factor for diarrhea. A study from the 1980s showed that with moderate coverage of the measles vaccine (45-90%) in infants, the incidence of diarrhea could be reduced by 0.6-3.8%, and diarrhea mortality reduced by 6-26% in children younger than 5 years. Table 1 shows the effect sizes for specific confirmed biological risk factors for diarrhea.

Diarrhea can be classified based on duration as prolonged/ acute (1-13 days) and persistent (14 days or more). Prolonged diarrhea can further be classified as prolonged/acute watery diarrhea which is loose or watery stools at least three times in a 24 h period or prolonged/acute invasive diarrhea which is gross blood (by history or inspection) in the stool of less than 14 days duration, typically accompanied by fever. Diarrhea can be secondary to one or more of the following pathophysiological processes: secretory, osmotic and inflammatory diarrhea. Secretory diarrhea occurs when there is a significant increase in the volume of intestinal fluid output which exceeds the reabsorptive ability of the gastrointestinal epithelium. Research initially done in patients with cholera revealed that while the secretory diarrhea in cholera does lead to significant fecal water and electrolytes loss, the gut still retains the ability to reabsorb water and electrolytes due to an intact Na-coupled solute cotransport mechanism. Chloride-mediated secretion is stimulated by second messengers in diarrheal infections secondary to Vibrio cholerae 01 and 139, Shigella, Salmonella, Escherichia coli strains and other bacterial pathogens who produce enterocyte receptor binding pathogens, causing chloride-mediated secretion stimulated by second messengers (e.g., cAMP, cGMP, and calcium). It is important to recognize that there may be a combination of osmotic and secretory diarrhea such as in the case of Rotavirus where there enterotoxin mediated secretory diarrhea along with osmotic diarrhea secondary to enterocyte damage. Phosphorylation-induced activation (by increase in cAMP, cGMP, or calcium) of these channels can be set off by exogenous or endogenous substances. Exogenous mediators include bacterial toxins such as cholera or shiga toxins, or parasites. Endogenous mediators can be endocrine, such as vasoactive intestinal peptide or serotonin, or released by the immune system, such as histamine, serotonin, prostaglandins, or interleukin-1. Lastly, increased intestinal permeability due to loss of cellular tight junctions can lead to increased intestinal fluid loss ( Figure 4) .

Poorly absorbed osmotically active substances in the gut lumen retain fluid, pull water and secondarily ions to maintain osmotic equilibrium with body fluids -this is the key underlying process behind osmotic diarrhea. This can occur secondary to an absorptive defect or enzyme deficiency from pancreas or intestinal wall causing maldigestion and/or malabsorption. An osmotic gradient is created that can only be neutralized by maintaining excessive amounts of water within the intestine. Examples include, malabsorption with congenital or acquired lactase deficiency, gluten-sensitive enteropathy (celiac disease) and maldigestion, as seen in pancreatic insufficiency ( Figure 5 ).

Gastrointestinal barrier disruption by bacteria (Salmonella, E. coli, Campylobacter), viruses (rotaviruses, coronaviruses), and protozoa (Cryptosporium, Giardia) in addition to idiopathic inflammatory bowel diseases are common causes of inflammatory diarrhea. Immune cells after activation release inflammatory mediators and cytokines which stimulate secretion and activate enteric nerves. Subepithelial myofibroblasts destroy the basement membrane by metalloproteinases, damaged enterocytes are extruded, and villous atrophy develops followed by regenerative crypt hyperplasia in the small intestine and colon. These surfaces are covered with immature enterocytes that typically are deficient in the brush border enzymes and transporters necessary for absorption of nutrients and water. 

Major etiologies for prolonged/acute and persistent diarrhea are outlined in Repeated and persisting infections Figure 3 The vicious cycles of diseases of poverty. Enteric infections, especially in the first 2-3 years of life, with or without overt diarrhea, can predispose an individual to malnutrition and stunted growth through multiple mechanisms. Stunting by 2 years of age, in turn, is associated with impaired cognitive development that extends into later childhood and even adulthood and adult productivity. In addition, malnourished children experience both greater frequency and duration of diarrheal illnesses, and, documented in animal models, heavier infections. The latter is documented with Cryptosporidium and with enteroaggregative E. coli. Finally, enteric infections or stunting can predispose to obesity and its comorbidities of diabetes, hypertension, cardiovascular disease, metabolic syndrome and burgeoning healthcare expenditures, contributing to individual and societal poverty in vicious cycles. Reproduced from Guerrant, R.L., DeBoer, M.D., Moore, S.R., Scharf, R.J., and Lima, A.A. (2013). The impoverished gut -a triple burden of diarrhoea, stunting and chronic disease. Nature Reviews Gastroenterology & Hepatology 10(4), 220-229.

Despite clinical clues, determining the causative agent of diarrhea in an individual patient on the basis of clinical grounds alone can be difficult. Both acute/prolonged and persistent diarrheas have similar initial evaluation and management. This chapter focuses on assessing the severity of illness and the need for rehydration. A brief history and directed clinical exam can help determine this and further guide the management.

Specific points in history include, time of onset of diarrhea, frequency, amount, consistency, and contents (blood, mucous, pus) of stool, associated signs and symptoms (fever, abdominal pain, nausea, vomiting, bloating, flatus, tenesmus), recent travel, dietary history, exposure to pets or cattle, drug history (specifically antibiotics and laxatives), pertinent past medical and surgical history, family history and day care attendance. For persistent diarrhea, the age of symptom onset and a detailed dietary history with relation between onset of symptoms and introduction to new foods is relevant.

The initial physical exam focuses on signs and symptoms of dehydration (discussed below) and sepsis (fever and toxic look) which are major complications of acute and chronic diarrhea and require urgent management. Nutritional assessment is necessary and includes height, weight, vital signs, and global nutritional appearance.

Early recognition of dehydration, which is the main cause of mortality, is the most critical part of diarrhea management. Loss of water and electrolytes (sodium, chloride, potassium, and bicarbonate) via liquid stools, emesis, sweat, urine, and breathing leads to dehydration if left unreplaced. The WHO suggests assessment of dehydration on a scale of three ( Figure 6 ).

1. Early dehydration with no signs or symptoms, 2. Moderate dehydration notable for thirst, restless, or irritable behavior, decreased skin elasticity, sunken eyes, 3. Severe dehydration when symptoms become more severe with diminished consciousness, lack of urine output, cool, moist extremities, a rapid and feeble pulse, low or undetectable blood pressure, and pale skin in the setting of clinical shock.

For acute diarrhea, maintaining adequate intravascular volume and correcting fluid and electrolyte disturbances take priority over the identification of the causative agent. Stool cultures are usually unnecessary for immune-competent patients who present within 24 h after the onset of acute, watery diarrhea. Lab testing including stool studies, blood tests, intestinal imaging, and immunologic and serologic evaluation are indicated in bloody diarrhea, high fever (>104 F), systemic illness, severe, or prolonged diarrhea, history suggestive of food poisoning, recent history of travel overseas or possibility of immune dysfunction. Supplementary laboratory studies, including serum electrolytes, to assess patients with acute diarrhea usually are unnecessary.

Dehydration is the primary cause of death in patients with diarrhea and effectively addressing this is the cornerstone of diarrhea treatment. Oral rehydration solution (ORS), developed in the 1960s and 1970s by researchers in South Asia, is a simple cost-effective solution containing glucose and electrolytes that can be used to prevent and treat dehydration due to diarrhea of any cause across all ages. Development of the ORS took advantage of the glucose-coupled intestinal sodium transport mechanism discovered in the 1960s by Robert Crane. Absorption of sodium and glucose molecules across the luminal membrane is facilitated by the protein sodium glucose co-transporter 1 (SGLT1). Although nutrientindependent sodium absorption across the intestinal epithelial brush border membrane is impaired in diarrhea, cotransport of sodium and glucose is preserved. This allows absorption of sodium and thus water as provided by ORSs (Figure 7) .

Once in the enterocyte, the transport of glucose into the blood is facilitated by GLUT2 (glucose transporter type 2) in the basolateral membrane with the Na þ Kþ ATPase provides the gradient that drives the process. Key in the success of use of ORS for rehydration is the fact that these physiological processes stay intact, even in the setting of severe diarrhea. Figure 4 Pathophysiology of secretory diarrhea: diarrhea secondary to cholera toxin cholera toxin induces secretion, in part, through activation of an intramural neural reflex. Toxin attaches to enterochromaffin cells in the epithelium, causing an increase in (cAMP) there. In response to the latter, serotonin (5-HT), neurotensin (NT), and possibly additional peptides are released. These activate afferent neurons (I), whose axons course from close to the epithelium to the myenteric neural plexus, where they connect with interneurons (II) that, in turn, through release of acetylcholine (ACh) and/or substance P (SP), activate secreto-motor neurons (III) in the submucosal neural plexus. Axons from these secreto-motor neurons reach the epithelial surface, in both the villus and the crypt regions, releasing VIP and thereby stimulating secretion in crypts and inhibiting nutrient-independent salt absorption in villi. Reproduced from Field, M. (2003) . Intestinal ion transport and the pathophysiology of diarrhea. The Journal of Clinical Investigation 111 (7), 931-943.

The original ORS recommended by the WHO in the 1970s had a formulation with a total osmolarity of 311 mmol l À1 (Table 4 ) but subsequent investigations lead to the current WHO recommendations from 2004 of a low osmolarity ORS (total osmolarity of 245 mmol l À1 , decreased concentrations of glucose and sodium). The current formulation when compared to the original formulation is associated with decrease in stool volume by about 25% when compared to the original World Health Organization/United Nations Children's Fund (WHO/UNICEF) ORS solution, reduced vomiting by almost 30%, and reduced need for unscheduled IV therapy by more than 30%. A 2010 review by Munos and colleagues assessed 205 studies and showed that universal coverage with ORS would reduce diarrhea-related deaths by 93%. There are two phases to treatment: rehydration and maintenance. In the rehydration phase, there is quick replacement of the fluid deficit over 3-4 h to achieve clinical hydration. In the maintenance phase, maintenance calories and fluids are administered with reintroductions of enteral feeding with an age-appropriate unrestricted diet, including solids. In children with mild to moderate dehydration, 50-100 ml of ORS/kg body weight during 2-4 h should be administered to replace the estimated fluid deficit, with additional ORS administered to replace ongoing losses. In the setting of severe dehydration, there is an emergent immediate need for IV rehydration. Lactated Ringer's solution, normal saline, or a similar solution should be administered (20 ml kg À1 body weight) until pulse, perfusion, and mental status return to normal.

Zinc deficiency is widespread among young children in lowand middle-income countries. It contributes to mortality and morbidity related to diarrhea, malaria, pneumonia, and restricts growth. Children with diarrhea suffer due to poor baseline dietary zinc intake with aggravated net losses of zinc during the period of illness. The WHO and UNICEF has recommended zinc for the treatment of diarrhea since 2004. Evidence suggests that zinc administration (20 mg per day until the diarrhea ceases) reduces the duration, severity and hospital admissions associated with diarrheal episodes in children in developing countries. Zinc for the treatment of diarrhea is estimated to decrease diarrhea mortality by 23% as well as significantly reducing the severity and duration of diarrheal episodes in children as well as a reduction in treatment failure or deaths in diarrheal episodes of longer duration (>14 days).

Current WHO guidelines for the management and treatment of diarrhea in children strongly recommend continued feeding alongside appropriate management. An extensive review on feeding strategies and food-based interventions in children younger than 5 years with diarrhea in low-and middle-income countries showed that although illness duration was shorter and risk of treatment failure 47% lower in children with acute diarrhea who consumed lactose-free diet, there was no effect of lactose avoidance on stool output or weight gain. WHO recommends the following: 

Antibiotics should not be used for relatively mild, self-limited infectious diarrhea to minimize development of drug resistance. When the diarrhea is hemorrhagic, seriously dehydrating, associated with serious systemic signs and symptoms, or of longer than 5 days' duration without improvement, antibiotic use is appropriate. A review by Traa and colleagues assessed the effectiveness of WHO-recommended antibiotics -ciprofloxacin, ceftriaxone, and pivmecillinam -for the treatment of dysentery, and concluded that antibiotics can be expected to If child has no other severe classification: Give fluid for severe dehydration (Plan C) OR If child also has another severe classification:

Refer URGENTLY to hospital with mother giving frequent sips of ORS on the way Advise the mother to continue breastfeeding Advise the mother to continue breastfeeding Advise the mother to return immediately Advise the mother to feeding a child who has PERSISTENT DIARRHOEA Give multivitamins and minerals (including zinc) for 14 days Advise mother when to return immediately decrease diarrhea mortality attributable to dysentery by more than 99%. There is evidence to recommend antibiotic use for reduction of morbidity and mortality due to cholera, Shigella spp. and cryptosporidium - Das et al. showed that in the developing country setting antibiotic management of cholera resulted in a 63% reduction in rates of clinical failure and a 75% reduction in rates of bacteriological failure. They also showed that antibiotic management of Shigella resulted in an 82% reduction in rates of clinical failure and a 96% reduction in rates of bacteriological failure. Antibiotics for treatment of cryptosporidiosis reduced mortality by 76%, rates of clinical failure by 52%, and rates of parasitological failure by 38%. The empiric antibiotic regimen should be determined by host factors, severity of illness, local resistance patterns, and history of travel to an area with increased resistance.

Probiotics are defined by the joint Food and Agriculture Organization/WHO Working Group as 'live microorganisms that when administered in adequate amount concern a health benefit on the host.' Recent Cochrane systematic reviews on the use of probiotics as an adjunct therapy to ORS have shown that probiotics shorten the duration of diarrhea and reduce stool frequency but the observation remains inconclusive due to few trials with small numbers of participants. Most commonly used probiotics in trials include Bifidobacterium, two genera of lactic acid bacteria (Lactobacillus and Streptococcus) and the yeast Saccharomyces. There is insufficient evidence to recommend their widespread use at this time.

Vomiting associated with diarrhea causes significant additional physical discomfort and is of concern for both parents and physicians. Additionally, vomiting can limit the success of ORS and can result in increased use of intravenous (IV) rehydration, need for prolonged emergency department stays and hospitalizations. A recent systematic review evaluated seven RCTs which used ondansetron, metoclopramide, dimenhydrinate, and dexamethasone in children aged 0-12 years. They found that use of antiemetics significantly reduced the incidence of vomiting and hospitalization by 54% and reduced IV fluid requirements by 60%. A 2011 Cochrane Review on the use of antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents concluded that oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing IV rehydration and immediate hospital admission. IV ondansetron and metoclopramide reduced the number of episodes of vomiting and hospital admission, and dimenhydrinate as a suppository reduced the duration of vomiting. Antiemetics are effective for the management of gastroenteritis in children and have the potential to decrease morbidity and mortality burden due to diarrhea.

Breast milk provides various immunological, psychological, social, economic, and environmental benefits, and is therefore recommended as the best feeding option for newborn babies and young infants in developing countries, including HIV-infected populations. Lamberti and colleagues reviewed 18 studies from developing countries reporting the effect of breastfeeding on diarrhea morbidity and mortality. The investigators estimated that not breastfeeding was associated with a 165% increase in diarrhea incidence and mortality in 0-23-month-olds.

Rotavirus is the most common cause of severe dehydrating diarrhea in infants worldwide. Rotavirus vaccines represent an important preventive approach to reducing the burden of diarrheal disease due to rotavirus. Since 2006 two rotavirus vaccines are currently licensed for vaccinating infants in North and South American, European, and Eastern Mediterranean countries: RotaTeq® (Merck) and Rotarix® (GlaxoS-mithKline). RotaTeq®/RV5 -is a live, oral vaccine that contains five reassortant rotaviruses developed from human and bovine parent rotavirus strains and is given orally in three doses at ages 2, 4, and 6 months. Rotarix®/RV1 is a live, oral vaccine licensed in 2008 for use in the United States that contains a human rotavirus strain, this is given orally in two doses at ages 2 and 4 months. This first dose of either vaccine is most effective if it is given before a child is 15 weeks of age and children should receive all doses of rotavirus vaccine before they turn 8 months old.

In the global health setting, there is evidence suggesting that rotavirus vaccine efficacy may vary by setting due to regional differences in circulating rotavirus vaccine strains, and reduced efficacy of oral vaccines in countries with high burden of malnutrition and enteric infections. A meta-analyses by Munos et al. assessed the effectiveness of two currently marketed vaccines the pentavalent human-bovine reassortant rotavirus vaccine and monovalent attenuated human rotavirus vaccine in Phase III trials in European and Latin American sites for both vaccines, as well as the United States (including Navajo and Apache populations) and Taiwanese sites for the pentavalent vaccine. The effectiveness studies of the monovalent and pentavalent vaccines were conducted in northern Australia and Nicaragua, respectively. The authors estimated that these rotavirus vaccines could prevent 

Although case management with oral rehydration therapy has substantially improved case-fatality rates for cholera, the infection can still kill rapidly, especially in outbreak settings. Oldgeneration injectable cholera vaccines, abandoned since the 1970s because of their restricted effectiveness and local side effects. However, studies have shown vaccines to be effective in reducing risk of cholera infection in children younger than 5 years by 52%, increase in vibriocidal antibodies by 124% and a relative risk of one or more adverse events of 1.4. Such evidence for the effectiveness of oral cholera vaccines makes them good candidates for cholera control in endemic areas.

Maintaining water quality (protection or treatment of water at source or point of use) is more effective than improving water supply (improved source of water or improved distribution, or both). Cairncross and colleagues estimated the effect of water, sanitation, and hygiene strategies and estimated risk reductions for diarrhea of 48% for hand washing with soap, 17% with improved water quality, and 36% with proper excreta disposal.

Although evidence confirms the efficacy and effectiveness of many interventions, many interventions are not accessible to people in need; hence, the focus on delivery strategies has increased. One method of community-based case management is to provide these amenities through community health workers with home visitation and community-based sessions for education and promotion of care seeking. These approaches have been assessed and concluded that that community-based interventions are associated with a 160% significant increase in the use of ORS and an 80% increase in the use of zinc in diarrhea. Furthermore, findings showed a 9% increase in care seeking for diarrhea and noted a 75% significant decline in inappropriate use of antibiotics for diarrhea.

The 2013 Lancet Childhood Pneumonia and Diarrhea series reviewed existing preventive and therapeutic interventions that could have a role in reducing the morbidity and mortality burden in children younger than 5 years due to diarrhea and pneumonia. The interventions with the maximum effect include breastfeeding, ORS, and community case management. The series concluded that despite a large global burden childhood diarrhea and pneumonia deaths are avoidable and 15 interventions delivered at scale can prevent most of these deaths (Figures 8 and 9 ). Estimates modeled with the Lives Saved Tool showed that if the interventions are scaled up by 80% in the 75 countdown countries, 95% of diarrheal, and 67% of pneumonia deaths in children younger than 5 years can be prevented by 2025. Scaling up of diarrheal and pneumonia interventions would cost US$ 6.715 billion, only $2.9 billion more than present levels of spending. Assessment is needed of the cost-effectiveness of these interventions in national health delivery frameworks.

We have a clear idea of effective interventions for both diarrhea and pneumonia and with community health-worker programs increasingly being employed to reach underserved populations, real opportunities exist to scale-up community advocacy/education programs, early case detection and management strategies. The series also included summary recommendations after a series of consultations with several hundred front line public health practitioners in target countries were held to identify key barriers to scaling up of evidence-based interventions to reduce pneumonia and diarrhea mortality. Critical barriers included: absence of national coordination within ministries and other stakeholders to deliver interventions, insufficient financial resources, inadequate training and support for health workers, poor systems for monitoring and assessment of key programmatic indicators and sporadic availability of key commodities. The final list of recommendations included: (1) Improve coordination between various groups working on preventive and treatment interventions to control pneumonia and diarrhea. (2) Substantially increase resources for child survival programs, with an emphasis on pneumonia and diarrhea control efforts. (3) Enhance efforts to attract, train, and retain a competent work force of caregivers. (4) Invest in better systems for harmonization of the collection of essential programmatic indicators, and ensure that this information is shared throughout the system. (5) Strengthen supply systems that deliver essential commodities. In summary, the cost to achieve the end of preventable deaths from pneumonia and diarrhea by 2025 is estimated to be around US$ 6.715 billion. Despite large reductions in child mortality between 2000 and 2010 (both in all-cause mortality, and specifically diarrhea and pneumonia associated), these diseases remain causes for preventable deaths. The achievement of the fourth Millennium Development Goal and the longerterm target of reduction of child mortality to 20 deaths or fewer per 1000 live births in all countries by 2035 requires significant decreases in mortality from both diarrhea and 

Clostridium: Occurrence and Detection of Clostridium perfringens; Colon: Structure and Function; Escherichia coli and Other Enterobacteriaceae: Food Poisoning and Health Effects; Escherichia coli and Other Enterobacteriaceae: Occurrence and Detection; Malnutrition: Concept, Classification and Magnitude; Malnutrition: Prevention and Management; Nutrition and Infection; Probiotics; Salmonella: Detection; Salmonella: Properties and Occurrence; Salmonella: Salmonellosis; Sanitization; Staphylococcus: Food Poisoning; World Health Organization; Zinc: Physiology and Health Effects

Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial

Probiotics for treating persistent diarrhoea in children

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, doubleblind, placebo-controlled trial

Interventions to address deaths from childhood pneumonia and diarrhoea equitably: what works and at what cost?

A clinical trial of oral therapy in a rural cholera-treatment center

The restrictions on possible mechanisms of intestinal transport of sugars

Antibiotics for the treatment of Cholera, Shigella and Cryptosporidium in children

The effect of antiemetics in childhood gastroenteritis

Vaccines for the prevention of diarrhea due to cholera, shigella, ETEC and rotavirus

Effect of community based interventions on childhood diarrhea and pneumonia: uptake of treatment modalities and impact on mortality

Scientific rationale for a change in the composition of oral rehydration solution

Role of antidiarrhoeal drugs as adjunctive therapies for acute diarrhoea in children

Intestinal ion transport and the pathophysiology of diarrhea

Bottlenecks, barriers, and solutions: results from multicountry consultations focused on reduction of childhood pneumonia and diarrhoea deaths

Ending preventable child death in a generation

The impoverished gut-A triple burden of diarrhoea, stunting and chronic disease

Managing acute gastroenteritis among children -oral rehydration, maintenance, and nutritional therapy

Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study

Breastfeeding and the risk for diarrhea morbidity and mortality

Global causes of diarrheal disease mortality in children <5 years of age: a systematic review

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since

Effect of human rotavirus vaccine on severe diarrhea in African infants

Effect of intragastric glucose-electrolyte infusion upon water and electrolyte balance in Asiatic cholera

Antibiotics for the treatment of dysentery in children

Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes

Diarrhoea treatment guidelines: including new recommendations for the use of ORS and zinc supplementation for clinic-based healthcare workers

Pediatric gastrointestinal and liver disease