Diarrhoeal diseases - British Medical Bulletin

Diarrhoeal diseases

V I MathanDepartment of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore, India

Diarrhoea is a symptom of the response of the intestinal tract to a variety ofprimary diseases. It can be clinically classified based on the duration of thesymptom and other associated features. In tropical regions, acute infectivediarrhoea is widely prevalent and is an important factor contributing tomorbidity and mortality, especially in children. The strategy of maintaininghydration by oral rehydration solutions has contributed significantly toreduction of mortality. Antibiotics are indicated only under specifiedcircumstances. Persistent diarrhoea with prolonged symptoms increases themorbidity and mortality. Chronic diarrhoea is often associated withmalabsorption of nutrients and an important component is tropical sprue, aprimary malabsorption syndrome. Since diarrhoea is the response of the host toa variety of factors, the detailed study of this symptom has furthered theunderstanding of intestinal physiology.

Correspondence toProf VI Mathan, Division

Director, LaboratorySciences Division,

International Centre forDiarrhoel Disease

Research, G.P.O. Box 128,Dhaka-1000, Bangladesh

Diarrhoea is defined as an increase in the number of stools (3 or moreper 24 h), an increase in the fluidity of the stool, and/or the presence ofblood and mucus with increased neutrophil polymorphs in the stool.Diarrhoea is a symptom of the secretory response of the gastrointestinalmucosa to a wide variety of stimuli. The increased secretion increasesthe water content and fluidity of the stool. If the primary disease causesinflammation or ulceration of the intestinal mucosa, particularly of thelarge intestine and rectum, blood and mucus may also be present in thefaeces. A wide variety of conditions including enteric infections,alteration in digestion and absorption of food, a variety of hormonalfactors or even a response to a parenteral infection can result in thesymptom of diarrhoea. However, acute infective diarrhoea is the majorclinical problem in tropical countries.

The excess loss of water and electrolytes in the stool can lead todehydration, hyponatraemia and hypokalaemia. Alterations in theepithelial barrier by inflammation, ulceration and altered circulation cancause a variety of complications. Diarrhoea is recognised as the mostfrequent cause of childhood death in many tropical countries1. Currentestimates worldwide are that at least 3.5 million children under the ageof 5 years, die each year due to diarrhoea. Death in the acute stage,especially with watery diarrhoea, is due to dehydration, complicated by

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Tropical medicine: achievements and prospects

widely prevalent malnutrition. The strategy of oral rehydration2, whichhas now been available for over 25 years, utilising the ability of thesmall intestine to absorb water and salt during glucose absorption evenin patients with cholera, can significantly reduce the mortality, but notthe morbidity, of acute diarrhoea. This strategy is not yet widelyaccepted in primary health care, due to sociological factors in thecommunities who are most vulnerable. A variety of infections secondaryto diarrhoea, septicaemia, pneumonia and meningitis, as well aspersistent diarrhoea and renal complications, contribute to themortality, especially when dehydration is corrected3.

Classification

Since diarrhoea is only a symptom of the response of the gastrointestinaltract to a wide variety of causes, particularly enteric infections, anetiologic classification is cumbersome. A clinical classification based onthe duration of diarrhoea and stool character is useful (Table 1). Acutediarrhoea is generally self-limited and lasts for less that 2 weeks. Acutediarrhoea which persists for longer than 14 days is classified aspersistent diarrhoea and if the duration of symptoms is longer than amonth chronic diarrhoea.

Acute infective diarrhoea

Definition

Acute infective diarrhoea should ideally be defined as diarrhoeaassociated with intestinal infection by a recognised enteric pathogen(viral, bacterial, parasitic or fungal). Unfortunately, in the bestlaboratories, using all currently available techniques, the rate ofidentification of enteric pathogens from patients is at best about 80%4.In 15-35% of such patients, more than one recognised enteric pathogencan be identified and it is often difficult to ascribe aetiology to a singlepathogen. The pathogens causal for acute infectious diarrhoea arefurther subdivided into invasive and noninvasive organisms. It isconventionally accepted that noninvasive organisms produce waterydiarrhoea, usually through an enterotoxin primarily affecting the smallintestine. In contrast, invasive organisms, primarily affect the largebowel, invade the mucosa and produce an inflammatory response andbloody, mucoid stools. This clear distinction is not always possible.

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Table 1 A clinical classification of diarrhoeal diseases

1 Acute infective diarrhoea1.1 Watery diarrhoea

1.1 Enterotoxin associated- CT, LT, ST, ZOT, ACE, etc.1.2 Enteroadhesive associated: aggregative, adherent E. coli1.3 Cytotoxin associated: EPEC, Shiga-like toxin, etc.1.4 Viral diarrhoeas: rota, adeno, Norwalk, etc.1.5 Parasite associated: Giardia, Cryptosporldium, Isospora1.6 Unknown mechanism: anaerobes, Giardia

1.2 Dysentery2.1 Invasive bacteria: Shigellae, Salmonellae, Campytobacter2.2 Parasites: E. histolytica

1.3 Mucoid diarrhoea: any of the pathogens which cause watery diarrhoea or dysentery1.4 Antibiotic-associated diarrhoea: Clostridium difidle1.5 Parenteral diarrhoea1.6 Travellers' diarrhoea

2 Persistent Diarrhoea

3 Chronic Diarrhoea3.1 Malabsorption syndromes

3.1.1 Secondary malabsorption syndromes

3.1.1.1 Luminal factors3.1.1.2 Mucosal factors3.1.1.3 Interference with vascular and lymphatic transport3 1.1.4 Pancreatic and biliary deficiency

3.1.2. Primary malabsorption syndrome: tropical sprue

3.2 Inflammatory bowel diseases3.3 Diarrhoea of the Irnmunocompromlsed

3.4 Irritable bowel syndrome

Epidemiology

Microbial enteric pathogens are demonstrable in faecal samples fromapparently healthy asymptomatic populations in tropical developingcountries5. In careful studies of groups of acute diarrhoea patients, withappropriate controls, the overall rate of isolation of enteric pathogens isusually significantly higher in the patients. In a report from southern India,more than one enteric pathogen was found in 15% of the controls and33% of the patients with diarrhoea6. This widespread prevalence of entericpathogen colonisation of the human gastrointestinal tract in asymptomaticcontrols in tropical developing countries is primarily a reflection ofenvironmental contamination, inadequate water supply and poor sani-tation. In contrast, in temperate zone industrialised countries, enteric path-ogens are seldom isolated from faecal samples of asymptomatic controls.

The high prevalence of enteric pathogens in asymptomatic populationsin tropical countries parallels the prevalence of an intestinal mucosal,morphological and functional abnormality. The small intestinal mucosaof residents in tropical countries is characterised by reduction in the

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villous height and increase in the thickness of the crypt layer associatedwith accelerated epithelial cell turn over7. There is also an increase in themononuclear cellular infiltrate of the lamina propria and the epitheliallayer. A similar lesion has also been described in the colon8. Thesemorphological abnormalities, designated tropical enteropathy andcolonopathy, are associated with a mild malabsorption, particularly ofxylose in 40% and fat in about 10% of the subjects9. Since fetal intestinesare identical in tropical and temperate zones and the morphologicalalterations begin within a few months of birth, these changes indicate aresponse to mild nonspecific injury associated with microbial colonisationof the gastrointestinal tract10.

Gut morphology and function revert to temperate zone patterns whenresidents of southern India migrate to temperate zones, even though thebasic diet does not change. These morphological and functional differencesbetween the intestinal mucosa of tropical residents and residents oftemperate zone countries is similar to the differences found between the gutepithelium of specific pathogen-free animals and conventionally rearedlitter mates11. Should the populations of the world be classified into'conventionally reared1 populations, who live in the contaminatedenvironment of tropical developing countries, and 'specific pathogen-free'populations resident in the temperate zones? The incidence of acutediarrhoea is similar in temperate and tropical zones1, but the associatedmorbidity and mortality is strikingly different. This difference is alsoinfluenced by nutritional status, socio-economic factors and access tomedical care.

Epidemics of acute infectious diarrhoea also occur frequently in tropicalregions. Many of the epidemics are confined to small circumscribedgeographic areas or populations and are usually related to contaminationof water or, rarely, food supply. They are inevitably associated withsecondary person-to-person spread. Of particular concern is large humanconglomerations for festivals, where outbreaks of cholera and shigellosiscan occur. In addition, some epidemics sweep across countries, sub-continents or continents. The cholera pandemic is the best example of this,but of more recent relevance is the outbreak of Vibrio cholerae serotype0139, which started near the city of Chennai (Madras) in southern India inOctober 1993, and then rapidly swept over the Indian sub-continent in aperiod of 6 months12. In the Indian sub-continent and in central America,there have been large epidemics of shigellosis, which involved severalcountries. These pandemics are usually spread by carriers.

Aetiological agents

The list of microbes considered causal for acute infectious diarrhoea,viral, bacterial, parasitic and fungal is ever growing. The chance of


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Diarrhoeal diseases

identifying a causal aetiological agent in the individual patient withacute infective diarrhoea increases with the variety and complexity ofidentification techniques that are used. Aerobic and anaerobic bacterialcultures, techniques to look for enterotoxins and other factors whichhave now been associated with diarrhoea such as the aggregative natureof the bacteria, the production of cytotoxins and the ability to invadetissue culture cells, techniques for directly identifying viruses by electronmicroscopic examination of suitably prepared faecal samples, examiningfaeces or mucosal biopsies for the more recently identified intra-cytoplasmic parasites such as isospora, the facility to culture entero-viruses in gut derived epithelial cells and appropriate facilities for fungalcultures, all can increase the rate of identification of enteric pathogensin individual patients. While the identification of these agents wouldhelp to understand the epidemiology and pathogenesis of acuteinfectious diarrhoea better, it contributes little to prevention or to themanagement of individual patients, especially as antibiotic therapy whenindicated should not wait for the culture report!

The prevalence of aetiological agents differs from area to area. Forexample, in the Gangetic delta (Bangladesh and West Bengal state ofIndia), V. cholerae is widely prevalent and has a seasonal pattern. Incontrast, in southern India, the prevalence of V. cholerae in endemicacute diarrhoea is low although, from time to time, large epidemicoutbreaks occur. Information about the predominant organisms ishelpful to plan appropriate antibiotic therapy and for developingvaccines to control diarrhoea. While it would be ideal to have a vaccineto prevent diarrhoea, the reality is that only vaccines to protect againstindividual aetiological agents can be developed13. With more than ahundred different aetiological agents implicated in acute infectiousdiarrhoea and with the pattern of prevalence of aetiological agents, evenin a single geographic location, varying over a period of time,aetiological agent based vaccines would be primarily useful only tocontrol the problem in specific age groups, where single predominantpathogens such as the rotavirus occur. It may also be relevant forpreventive vaccination when large human conglomerations with poorsanitary facilities are likely to occur. The multiplicity of entericpathogens suggest that it would be worth considering a strategy basedon identifying common pathways of host response and modifying them.

A clinical classification

There are three clinical issues to be considered in patients withdiarrhoea: (i) is there significant dehydration?; (ii) is there an infectionrequiring antibiotic therapy?; and (iii) what are the complications -nutritional deficiency, associated infections, renal failure, etc.}

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Clinically acute infective diarrhoea can be watery (including loosestools), mucoid or bloody (dysentery). The major microbial agentsassociated with these presentations are in general distinct (Table 1) butwith some overlap. Recent field experience, especially in Calcutta andDhaka, have shown that up to a third of patients could have small stoolswithout blood, but with an excess of mucus. Stool culture in suchpatients has shown that the majority have invasive pathogens14. Patientswith mucoid diarrhoea as well as with dysentery should be consideredfor appropriate antibiotic therapy. It is very important to keep in mindthat Entamoeba histolytica infection is widely prevalent in tropicaldeveloping countries. The possibility of amoebic dysentery must beconsidered when classical antibiotic management of a patient presentingwith dysentery is not successful. In a postmortem study from Dhaka,16% of the autopsied cases (total 140) had E. histolytica infectionswhich had been missed antemortem15.

Pathogenesis

The mechanisms underlying the symptom of diarrhoea are based onmicrobial pathogenic factors and complex host responses. The microbialfactors best understood at present are the enterotoxins and mucosal(epithelial) invasion. Several other mechanisms, such as enteroadhesive-ness, enteroaggregation and cytotoxins, have been identified but thesequence of events resulting in diarrhoea are not yet understood. Oneproblem in understanding pathogenesis has been the paucity of animalmodels for acute infectious diarrhoea. Much manipulation, such asadministration of opiates or removable intestinal ties, are necessarybefore an animal develops diarrhoea. Some enteric pathogens producenon diarrhoeal illnesses in animal hosts. Salmonella typhimurium animportant agent, associated with watery diarrhoea and occasionallydysentery, produces only an enteric fever (typhoid) like illness in mice.

Enterotoxins Cholera is the paradigm of enterotoxin induceddiarrhoea16. Following the demonstration by De in Calcutta17 that a cellfree culture supernatant of V. cholerae could induce intestinal secretionin rabbit ileal loops, the toxin has been identified, its structureestablished and the mechanism by which the pure toxin can stimulatesecretion by enterocytes worked out16. Cholera toxin (CT) has twosubunits, the active A subunit covalently bound to five B subunits whichare essential for the toxin to bind to its receptor, GMI ganglioside on theenterocyte and colonocyte surface membranes. After binding, the Asubunit is internalised and through a complex cascade involving Gproteins and protein kinases it induces adenyl cyclase in a non reversiblemanner. The resulting dramatic increase in the cAMP content of the cell


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Diarrhoeal diseases

is responsible for chloride secretion and associated loss of sodium andwater. Several other enterotoxins, the heat labile enterotoxin ofEscherichia coli (LT), similar in structure and mode of action to CT andheat stable enterotoxin of E. coli (ST), of which there are severalvariants, that apparently induces guanyl cyclase and cGMP, are alsofrequently associated with watery diarrhoea18. Other enterotoxins havebeen identified in V. cholera the best characterised of which is the zonulaoccludes toxin (ZOT) which affects the integrity of intestinal tightjunctions in the small bowel villus epithelium19. The exact mechanism ofaction of this toxin or of other toxins in V. cholerae are not yet wellunderstood.

Enteroinvasion The mechanism of enteroinvasion has been best workedout for Shigella flexneri20. The initial entry of the organism to theepithelial layer appears to be through the antigen sampling M cell,overlying mucosal lymphoid follicles. A series of invasion proteins,controlled by genes on the virulence plasmid of the organism, enables itto then invade epithelial cells through the basolateral cell membranes.Death of the epithelial cells occurs by the cytotoxins elaborated by theseorganisms, shigatoxin and shiga-like toxins (verotoxin), which inhibitribosomal protein synthesis. No evidence of direct invasion ofcolonocyte surface membrane has been found either in biopsies frompatients or in primate studies. The mechanism of invasion of organismssuch as Salmonellae and Catnpylobacter are not fully worked out21.Invasion of the epithelium and mucosa leads to inflammation, ulcerationand exudation. Why these organisms do not invade the small intestine,although there is an abundant supply of M cells is not clear.

Other microbial mechanisms Enterotoxins and invasion explain onlyabout a third of the cases of acute infective diarrhoea that reachhospitals. A wide variety of microbes which neither secrete recognisedenterotoxins nor invade the mucosa are still accepted as causal agents ofdiarrhoea on epidemiological grounds. Of particular interest are a groupof E. coli, many of which also possess cytotoxins, that adhere closely tothe surface of enterocytes and produce morphological alterations, suchas pedestal formation of the surface membrane22. How viral infectionscause acute infective diarrhoea is also not well understood23. A commonpathway of response by the host to a variety of agents may be theanswer to these issues.

The host response A detailed study of the rectal mucosal morphologyin adults with acute diarrhoea showed that a lamina propriamicrovascular lesion, resembling the local Schwartzman reactioncorrelated well with the clinical severity of the illness but not the


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prevalence of microbial pathogens24. This lesion appeared to be a responseto Gram-negative bacterial endotoxins and a murine model of acutediarrhoea was developed using endotoxin in appropriately primed mice25.Other workers studying murine rotavirus diarrhoea showed a correlationbetween the occurrence of a vascular lesion with temporary ischaemia andrecovery of enterocytes and the watery diarrhoea characteristic of theillness26. Recent studies on the duodenal mucosal pathology in patientswith cholera27 also showed a vascular lesion but, in addition, there wasevidence of involvement of the enteric nonmyelimated nerves and theenteric endocrine system. Mucosal mast cell abnormalities were present inthe rectal and duodenal mucosa in cholera and in shigellosis, althoughshigellosis is not thought to affect the small bowel. Cholera was alsofound to result in water secretion by the colon as well as histopathologicallesions, an area which was not thought to be affected in cholera. Thepattern emerging of a common response pathway in patients withdiarrhoea, involving the small and large intestine, with a role for the gutvascular, neural and endocrine systems as well as inflammatorymediators28, opens exciting possibilities of modifying this response toreduce the severity and morbidity of diarrhoea.

Clinical management

The four corner stones of clinical management of acute infectiousdiarrhoea are: (i) the correction of dehydration; (ii) the maintenance ofnutrition; (iii) the management of secondary complications; and (iv) theappropriate use of antibiotics. Nearly 40 years ago, it was shown thatthe administration of tetracycline to patients with cholera reduced theduration of diarrhoea and the volume of supplemental fluids needed formaintenance of hydration. In invasive organism related diarrhoea, therole of appropriate antibiotics is well accepted, while in other patientsantibiotics are not advocated. However, the ground reality is that mostpatients are given antibiotics, usually inappropriately. In the majority ofpatients, dehydration can be corrected orally by giving water with saltand sugar29. This oral rehydration solution, while correctingdehydration and reducing the mortality, does not reduce the volume orfrequency of stool. This factor had led to its limited acceptability,especially at the community level. Food should not be withheldespecially in children, as growth retardation may occur.

Primary health care approach

The high mortality associated with diarrhoea has led to its managementbeing a major priority in primary health care. Improvement in economic


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Diarrhoeal diseases

status, water supply and environmental sanitation would ultimatelyreduce the significance of acute infective diarrhoea as a major publichealth problem in tropical countries. In the interim, strategies to educatemothers and grandmothers in the appropriateness of oral rehydrationand the use of home available fluids, especially cereal based fluids, formaintenance of hydration is essential. An understanding of the socialand cultural background of communities is necessary to devise strategiesfor this. Health care workers have to be also educated in the proper useof oral rehydration and to recognise patients who would need to bereferred to well equipped hospitals early. Oral rehydration powderpackets should not only be widely available, people should be preparedto use them!

Travellers' diarrhoea

Travellers' diarrhoea is the result of exposure of naive gastrointestinaltracts to enteric pathogens in a different environment. Prophylactic useof antibiotics by short-term travellers to diarrhoea endemic countrieshas been advocated30. This practice would need the use of an everchanging spectrum of newer antibiotics and could contribute to theemergence of drug resistant pathogens. Care in ensuring clean water andhot foods and the avoidance of salads, etc. in diarrhoea-endemiccountries would be a more appropriate way of prevention.

Persistent diarrhoea

Persistent diarrhoea is operationally defined as an episode of acuteinfectious diarrhoea that lasts for 14 days or longer31. This ispredominantly a problem of children below 3 years of age and occurs in3-21% of diarrhoeal episodes. It gives rise to major problems ofnutritional management, growth faltering and mortality and con-siderably increases the cost of national programmes for control ofdiarrhoeal diseases.

A specific microbial etiology has not been found although anassociation with aggregatively adherent E. coli, and repeated infectionsmay be important. Malnutrition, particularly of micronutrients andprior illness, especially measles, may be risk factors. The strategies ofmanagement of the acute episode does not contribute to persistence andit is difficult to predict persistence in the individual patient. Antibioticsare of limited use. Specific nutritional deficiencies should be corrected.Fluid and dietary management is important. Algorithms have beendeveloped and are currently being tested in several centres.


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Chronic diarrhoea

Tropical sprue

Diarrhoea persisting for periods longer than a month is found in a widevariety of conditions. A clinical approach to these could divide them intomalabsorption syndromes, chronic diarrhoea without malabsorptionand chronic diarrhoea of the immunocompromised. A common present-ation of human immunodeficiency virus infected individuals is withchronic diarrhoea, usually associated with a variety of opportunisticinfections. In addition, morphological studies have suggested thepossibility of an HTV enteritis32. Patients with irritable bowel syndromemay present with a history of chronic diarrhoea which usually reflectsfrequent small stools without increase in faecal water and nomalabsorption. The commonest type of chronic diarrhoea in tropicalcountries are the malabsorption syndromes (Table 1).

The absorption of nutrients is a complex process involving digestion offood, absorption of the simple molecules produced by digestion by theenterocytes and the transport of the nutrients from the gut. Carefulgastrointestinal investigations, including radiological contrast studies,mucosal biopsies and cultures of the intestinal luminal fluid can diagnoseunderlying diseases and show when malabsorption is secondary to aprimary disease. In many tropical countries, when patients withmalabsorption syndromes are investigated, all conditions that give rise tosecondary malabsorption can be excluded and the remaining patients aredesignated idiopathic tropical malabsorption syndrome or tropical sprue.

Tropical sprue is defined as a primary malabsorption syndrome ofresidents of, or visitors to, certain tropical countries33.

Epidemiology Tropical sprue has been reported from South and SouthEast Asia, Caribbean islands other than Jamaica, but not from sub-Saharan Africa. During the colonial era, it was considered a diseasewhich exclusively affected expatriates from temperate zones. It is nowrecognised that it affects indigenous populations. There is a good clinicaldescription of malabsorption in an ancient Indian text book of medicinewritten sometime between 600 and 1300 BC! Several epidemics oftropical sprue have been reported from the Indian subcontinent34.During the second world war, such epidemics affected British and Indiantroops and was a major cause of repatriations from the Assam theatreof war. The epidemiological features of the more recent epidemics insouthern India suggest an infectious aetiology but detailed micro-biological investigations have not yet identified any causal agent.


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Diarrhoeal diseases

Diagnosis Patients may present with chronic diarrhoea or only with thenutritional sequelae, especially megaloblastic anaemia. The diagnosis oftropical sprue is by demonstration of malabsorption (fat, d-xylose,vitamin B12) and the exclusion of conditions that can give rise tosecondary malabsorption35. The increasing prevalence of HIV infectionand the occurrence of granulomatous enteritis (Crohn's disease) intropical countries add to the complexities of diagnosis.

Pathophysiology Several mechanisms underlying malabsorption havebeen described in different patient groups. In expatriates returning totemperate zones with post-infective diarrhoea, persistence of entericpathogens, including parasites, such as Giardia, and marginal folk aciddeficiency may play a role36. In the Caribbean islands colonisation of thesmall bowel by enterotoxin producing conforms, particularly followingseasonal dietary indiscretions, has been shown to be important37. Apersistent enterocyte stem cell lesion, with accelerated turnover ofenterocytes and extrusion of damaged cells from all levels of the crypt-villus unit has been shown in patients from southern India38. While it ispostulated that the stem cell lesion may be due to an infective agent,none has been as yet demonstrated. The background of nutritionaldeficiency widely prevalent in many tropical countries may be apredisposing factor which many also contribute to the persistence andseverity of malabsorption

Management Symptomatic control of diarrhoea and correction ofnutritional deficiencies including dehydration and electrolyteabnormalities is essential. Diarrhoea may be controlled by bismuth salts,loperamide or opiates, as necessary. In expatriates from temperate zones,therapy with folk acid and antibiotics, usually tetracycline, has beenfound to cure the malabsorption. In indigenous populations, the results oftetracycline therapy have not been so clear cut, but is advocated.

Conclusion

Diarrhoea is only a symptom of the response of the large and smallintestines to a variety of factors, acting at an important epithelial barrierbetween the internal environment of the body and the externalenvironment in the lumen of the gastrointestinal tract. This symptom isone of the major causes of morbidity and mortality, especially inchildren, in many tropical countries. The oral rehydration strategy hasthe potential to save many more thousands of lives than it already has,if appropriate and acceptable strategies can be developed to ensure theinitiation and maintenance of hydration in the home situation.


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Diarrhoea, the result of the complex interaction of a variety of microbialand other factors and the intestinal epithelium, has also helped tounderstand gastrointestinal physiology better.

References

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Diarrhoeal diseases - British Medical Bulletin