In the early 1980s, diarrhea was the leading cause of child mortality, accounting for 4.6 million deaths annually worldwide, excluding China and Latin America.[1] Efforts to control diarrhea over the past decades have been based on multiple, potentially powerful interventions implemented more or less simultaneously. Oral rehydration therapy (ORT) was introduced in 1979 and rapidly became the cornerstone of the program for the control of diarrheal diseases. Improved case management and disease awareness over the decades have contributed significantly to the control of diarrheal diseases, and the annual number of deaths attributable to diarrhea among children <5 years of age has fallen from the estimated 4.6 million in 1980 to about 1.5 million today.[2]

The objective of this article is to discuss the existing guidelines for the management of infectious diarrhea in children, and whether the antidiarrheal drugs tested so far have any beneficial effect. Three clinical forms of diarrhea (acute watery diarrhea, invasive diarrhea, and persistent diarrhea) are described under separate headings. The role of some antidiarrheal agents tested has also been discussed separately. To discuss other forms of chronic diarrhea of specific etiology (e.g. celiac disease, tropical sprue, cystic fibrosis, ulcerative colitis, Crohn’s disease, etc.) is beyond the scope of this article and readers may refer to the literature to obtain further information on these specific areas.

1. Definition

1.1 What is Diarrhea?

Diarrhea is defined as the passage of three or more abnormally loose or watery stools per 24 hours. However, recent change in consistency and character of the stools is more important rather than the number of stools. During the initial 2–3 months of life, infants, particularly those who are being breast-fed, may normally pass as many as 8–10 semi-formed stools daily that do not constitute diarrhea. Again, a recent change in character of stools should be given adequate attention in recognition of diarrhea.

1.2 What is Dysentery/Invasive Diarrhea?

Dysentery is usually defined as diarrhea characterized by the presence of visible blood in the stools, which is usually associated with abdominal cramps and fever. Gross blood in stools is the most reliable sign; its presence facilitates early recognition by mothers and health workers, and identifies a clinically severe form of the disease, although many cases of invasive diarrhea may not present with visible blood, particularly in young infants. In such cases, stool microscopy would disclose the invasive nature of the illness through the presence of pus cells, erythrocytes, and macrophages.

1.3 What is Not Diarrhea?

The following are often erroneously considered to be diarrhea: (i) passage of frequent formed stools; (ii) passage of pasty stools in a breast-fed infant; (iii) passage of a stool during or immediately after feeding due to initiation of gastro-colic reflex; and (iv) passage of frequent, loose greenish yellow stools on the third and fourth days of life.

1.4 What is Persistent Diarrhea?

Most episodes of acute diarrhea resolve within 7 days; progressively smaller proportions persist beyond 14, 21, or 28 days. The delineation of persistent diarrhea as a subgroup distinct from acute diarrhea is, as such, arbitrary. The most commonly used clinical definition is an acute episode of presumed infectious etiology that lasts for more than 14 days. The 14-day cut-off for defining persistent diarrhea, although arbitrary, is supported by observations of a significantly high fatality rate when diarrhea extends for ≥2 weeks. Persistent diarrhea is usually described in children <5 years of age, and excludes specific disease entities with known pathophysiology, such as celiac disease, tropical sprue, cystic fibrosis, Crohn’s disease, ulcerative colitis etc.

2. Acute Watery Diarrhea

2.1 Pathophysiology

The human intestine (both large and small) is a tube within which a large amount of water and electrolytes is delivered (in the form of drinks and through secretion); however, most of this is absorbed by processes of transport and exchange. Normally, absorption and secretion of water and electrolytes occur throughout the intestine. In a healthy adult, about 9 liters of fluid enters the lumen of the small intestine everyday; about 2 liters ingested by mouth and 7 liters secreted as salivary, gastric, pancreaticobiliary, and intestinal secretions. In the small intestine, water and electrolytes are simultaneously absorbed by the villus cells and secreted by the crypt cells of the intestinal epithelium, resulting in a bi-directional flow of water and electrolytes between the intestinal lumen and the blood. Since fluid absorption is normally greater than secretion, the net result is fluid absorption. Any change in the bi-directional flow of water and electrolytes in the small intestine (i.e. decreased absorption, increased secretion, or both) results in either reduced net absorption or actual net secretion, causing an increased volume of fluid entering the colon. The capacity of the small intestine to absorb a balanced electrolyte solution is about 18 liters, and that of a normal colon is 3.8 liters daily.[3] Glucose and other actively absorbed nonelectrolytes stimulate small intestinal fluid absorption, but the absorptive capacity of the colon cannot be enhanced by glucose.[3] Diarrhea ensues when the volume delivered to the large intestine exceeds the absorptive capacity of the colon.

2.2 Etiology

The important pathogens responsible for causing watery diarrhea in children in developing countries include rotavirus, enterotoxigenic E. coli, V. cholerae 01, V. cholerae 0139, and other noncholera vibrios. Other less common agents are: enteropathogenic E. coli, enteroadherent E. coli, Campylobacter jejuni and Cryptosporidium spp. (especially in immunocompromised patients). However, children of developed countries experience diarrhea mainly due to viruses, especially rotavirus.[4]

2.3 Mechanisms of Watery Diarrhea

2.3.1 Secretory Diarrhea

The secretory diarrheas are typically caused by Vibrio cholerae 01, V. cholerae 0139, enterotoxigenic Escherichia coli, and sometimes V. cholerae non-01. After passing through the gastric acid barrier, they colonize the lower part of the small intestine, where they produce enterotoxins. For example, after becoming attached to the small intestine, V. cholerae 01 liberates cholera toxin (CT). CT is a protein molecule (molecular weight 84 000 Daltons) that consists of five B-subunits arranged in a circular fashion and linked noncovalently to the A subunit containing 2 peptides, A1 and A2, linked by a disulfide bond. First, an irreversible binding occurs between the B-subunits of the toxin molecule and GM1 monosialogangliosides, the cell surface receptor for CT. Following this, the A subunit penetrates into the cell membrane and the active part (A1) is split off, which in turn stimulates the activity of the enzyme adenylate cyclase through cleavage of nicotinamide adenine dinucleotide. This increases cellular concentration of cyclic-AMP, which inhibits or blocks the chloride-linked neutral sodium absorption from the intestinal lumen by the villus cells (but not the glucose- or other carrier-mediated sodium absorption) and directly stimulates chloride secretion by the crypt cells into the intestinal lumen. The net effect is a massive outpouring of fluid and electrolytes, resulting in classical secretory diarrhea.[5]

2.3.2 Osmotic Diarrhea

The permeability of the small intestinal mucosa allows rapid movement of water and electrolytes to maintain the osmotic balance between the intraluminal contents and extracellular fluid. Presence of poorly absorbed, osmotically active substance will cause an increase in the intraluminal osmolality, resulting in movement of water from the extracellular fluid into the gut lumen, causing diarrhea. Osmotic diarrhea may occur due to ingestion of purgatives (e.g. magnesium sulphate), or the presence of lactose or glucose in conditions associated with poor absorption.

Rotavirus causes patchy damage to the small intestinal epithelium, resulting in blunting of the villi. This is associated with some reduction in the activity of lactase and other disaccharidases, leading to reduced absorption of carbohydrates; however, this is of less clinical significance because a large area still remains intact for absorptive function. The intestinal morphology and absorptive capacity returns to normal within 2–3 weeks.

2.4 Consequences of Watery Diarrhea

Stools of patients with watery diarrhea contain large amounts of sodium, chloride, potassium, and bicarbonate ions. The effects of watery diarrhea are due to this loss of water and electrolytes. Additional amounts of water and electrolytes are lost in the presence of vomiting and fever. These combined losses cause dehydration, base-deficit acidosis, and potassium depletion. Dehydration is the most dangerous consequence and needs immediate attention as it leads to hypovolemia, circulatory collapse, and death if not efficiently managed.

2.5 Management of Acute Diarrhea

Patients with diarrhea should first be assessed quickly to determine the nature and pattern of diarrhea, the degree of dehydration (no signs of dehydration, some or severe dehydration), and the presence of any other associated conditions, such as pneumonia and malnutrition, in order that appropriate treatment can be initiated without delay.

Modified World Health Organization (WHO) guidelines (table I) for the assessment of dehydration are presented in this article. These guidelines, developed in a workshop, proved to be simple, easily learnt, and were validated in two multicenter studies[6,7] of reduced osmolarity oral rehydration salts (ORS) solution. They are being practiced in the treatment center of the International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B).

Table I
figure Tab1

Clinical assessment of dehydration, as provided in the World Health Organization treatment guidelines[8]

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Although most patients with infectious diarrhea can be treated at an outpatient clinic or at home, some patients will still need hospitalization, mainly for intravenous rehydration. There are no established admission criteria for acute diarrhea. Thus, indications depend on the individual expert opinion and clinical judgment. Indications for hospitalization of children with acute diarrhea were elaborated in a recent report.[9] Severe dehydration, neurologic involvement, toxic state/shock, severe vomiting, and suspected surgical disease were labeled as an absolute indication, while neonatal age, febrile infant <6 months of age with mucus and blood in the stools, bloody diarrhea, immunodeficiency, malnutrition, and parents unable to manage the problem, were labeled as relative indications.

The three essential parts in the effective clinical management of acute diarrhea are: prevention of dehydration, if the patient is not already dehydrated; prompt rehydration therapy by oral or intravenous fluids when dehydration is present, followed by maintenance therapy; and maintaining the patient’s usual diet during and after diarrhea.

2.5.1 Prevention of Dehydration

Many patients with diarrhea do not show early evidence of dehydration during their illness. While such patients may not require the standard ORS solution, they should drink larger quantities of appropriate fluids at home to account for the ongoing losses of fluids and electrolytes, in addition to their normal daily requirements. Mothers should be taught how to treat diarrhea at home by giving the child increased amounts of fluids and continuing feeding, and should also be educated to recognize signs of dehydration that should prompt them to bring their children to a healthcare facility. In the healthcare facility, the physician must assess the child’s need for hospital care. ORT, if initiated early at home to prevent dehydration,[10,11] might substantially decrease the number of visits to treatment facilities, and also overall deaths from diarrheal diseases. The authors refer readers to treatment plan A in the WHO guidelines[8,12] for further information.

2.5.2 Rehydration Therapy

Fluids are administered to dehydrated patients with acute diarrhea in two phases, the rehydration and maintenace phases:

Rehydration Phase

The degree of dehydration should be clinically assessed according to the presence of symptoms and signs that reflect the magnitude of fluid loss, which in turn forms the basis for estimating the amount of fluid to be administered. After assessment of dehydration, patients should be rehydrated using the WHO guidelines as follows:[8,12] plan C for patients with severe dehydration (rapid correction with intravenous fluids); plan B for some dehydration (rehydration with ORS solution at a health center); and plan A for patients without any sign of dehydration (treatment at home to prevent dehydration).[8,12]

Rehydration therapy can usually be carried out with an ORS solution, the formulation of which has recently been recommended by WHO and the United Nations Children’s Fund (UNICEF) [sodium 75 mmol/L, potassium 20 mmol/L, chlorine 65 mmol/L, citrate 10 mmol/L, glucose 75 mmol/L, osmolarity 245 mosmol].[13] The newly recommended ORS solution is advantageous because the requirement for unscheduled intravenous fluid is significantly less, i.e. there is less ORT failure and less vomiting, particularly in children with noncholera diarrhea.[13] One disadvantage noted was the occurrence of more asymptomatic hyponatremia, especially in cholera.

In some conditions ORT may be contraindicated, or the patients are unable to drink (e.g. painful oral condition, lethargy, severe vomiting, paralytic ileus etc.). In such cases, intravenous therapy is needed, initially until the dehydration is corrected. The ORS solution can then be initiated as soon as patients are able to drink. The vast majority of patients with diarrheal dehydration can be treated successfully with ORT; however, success of ORT may also depend upon the experience of the treating nurses and physicians. ORT may not be effective in some conditions, such as severe dehydration, high rate of purging (>10 ml/kg/h), persistent vomiting (>3 times/h), inability or refusal to drink, glucose malabsorption, incorrect preparation of ORS solution, and abdominal distension (ileus).

Children with severe dehydration should initially be rehydrated using an appropriate intravenous fluid; 30 ml/kg of bodyweight should be administered over 1 hour in infants <1 year of age, and 30 minutes in older children and adults.[8,12] The remaining 70 ml/kg is to be infused over 5 hours in infants <1 year of age, and 2.5 hours in older children and adults. For severely malnourished children, rehydration should be slow, over 8–10 hours, to avoid overhydration or heart failure.[14,15] Ongoing loss of fluid in stools during this period should also be replaced.

The preferable intravenous infusion solution used in dehydrating diarrhea is either Ringer’s Lactate (sodium 130 mmol/L, potassium 4 mmol/L, chlorine 109 mmol/L, lactate 28 mmol/L)[8,12] or Cholera Saline (sodium 133 mmol/L, potassium 13 mmol/L, chlorine 98 mmol/L, lactate 48 mmol/L)[16] where available. Normal saline (0.9% sodium chloride) can be used as a life-saving measure when the above solutions are not available; however, in such cases it would be important to start ORS solution as soon as the patient is able to drink; this is required for replenishment of other important electrolytes, such as potassium and bicarbonate.

Maintenance Phase

This phase is for the replacement of ongoing losses of water and electrolytes due to continuing diarrhea; its purpose is to prevent dehydration. ORS solution is adequate for maintenance therapy and the main advantage of ORS solution is that it can be used alone to rehydrate ≥95% of patients with mild or moderate diarrheal dehydration.[12] In patients with severe dehydration following rehydration with intravenous fluids, ORT should be instituted as soon as they are able to drink. The disadvantages of intravenous therapy include high cost, the need for trained personnel for its administration, lack of availability in rural or inaccessible areas, high risk of local or systemic infections when nonsterile techniques or materials are used, and the chances of over- or underhydration when too much or inadequate amount of fluid is administered, respectively. On the other hand, ORT is effective, simpler, less expensive, comforting to mothers and children, and allows mothers active participation in the process of management of their children.

2.6 Feeding During and After Diarrhea

To prevent growth faltering, good nutrition must be maintained, both during and after an episode of diarrhea. Maintaining the patient’s usual diet is an integral part in the management of patients with acute diarrhea, and there is no physiologic basis for ‘resting’ the bowel during or following a bout of acute diarrhea. In fact, fasting during diarrhea has been shown to impair the ability of the small intestine to absorb a variety of nutrients. Sixty percent or more of nutrients are absorbed during acute and persistent diarrhea.[17,18] Grading diet during diarrhea, starting with one-fourth strength and gradually moving up to full strength is unnecessary.[19] In general, the foods that should be given during diarrhea are the same as those the child should receive when he/she is well. It has also been observed that children breast-fed throughout the illness, and fed soon after initial rehydration, tend to gain more weight on recovery compared with those who are not fed, or fed restricted amounts of food.[20] Thus, breast-feeding should continue throughout episodes of diarrhea, and normal feeding should be initiated as soon as initial rehydration is accomplished.

Children on mixed diets, e.g. cows’ milk, cooked cereal, and vegetables, do not have increased stool output. However, those taking only animal milk or formula may have some increase in stool volume. Food is usually well tolerated during diarrhea, the major exception being clinically significant intolerance of lactose and, occasionally, protein in animal milk. This is unusual in acute diarrhea, but can be a significant problem in children with persistent diarrhea.

3. Invasive Diarrhea

Invasive diarrhea is caused by infection due to pathogens having an ability to invade the mucosa of the distal small intestine and colon, producing local and systemic inflammatory response, with ulceration of mucosa and hemorrhage, which clinically manifests as dysentery. Some invasive pathogens, such as Entamoeba histolytica, Shigella spp., and Salmonella spp., have the ability to invade the blood stream or may be carried by the lymphatic system to systemic circulation to affect distant organs, e.g. liver, spleen, central nervous system, and joints. The important pathogens that cause invasive diarrhea, mainly in developing countries, include: Shigella spp., Campylobacter spp., Salmonella spp., Entamoeba histolytica, enteroinvasive E. coli, and enterohemorrhagic E. coli.[21]

3.1 Shigellosis

Shigella species are the cause of approximately 10% of acute diarrhea in children aged 5 years or younger, but is also an important cause of diarrhea in older children and adults.[12] It is the most common cause of dysentery (visible blood in the stool) in developing countries. Shigella is classified under four species or groups, each of which, with the exception of S. sonnei, has several serotypes as follows: Group A — S. dysenteriae; Group B — S. flexneri; Group C — S. boydii; Group D — S. sonnei. The infective dose of Shigella is very low; only 10 bacteria may cause infection in healthy adults. The transmission of shigellosis often occurs by person-to-person contact, as the infective dose is low. Food- and water-borne transmission can also occur, and the incubation period is 1–7 days. The convalescent, carrier state usually ceases within 4 weeks of onset of the illness, even without therapy, and a chronic carrier state extending for more than 1 year is rare.

Shigella species multiply in the small intestine where they liberate the enterotoxin that is initially believed to be responsible for watery diarrhea. They finally settle in the colon where they enter and multiply into the colonic epithelium, spread to adjacent cells, and cause cell death, leading to shallow ulcerations of the gut. Most patients develop anorexia, fever, abdominal pain, and tenesmus, starting a day or two after they are exposed to the bacterium. The diarrhea is often bloody, particularly when due to S. dysenteriae type 1 (S. shiga); however, blood may be absent in neonates and small infants. Shigellosis generally has a self-limited course and the diarrhea usually resolves within 5–7 days. Severe infections with high fever may be associated with seizures in children <2 years of age. A classical patient with shigellosis appears acutely ill, febrile, exhausted, and often has toxemia. The abdomen is tender over the inflamed colon, or there may be diffuse tenderness. The patient may present with various degrees of rectal prolapse, which is more common in malnourished children; third degree rectal prolapse commonly occurs in severely malnourished children.[22]

Antimicrobial therapy plays a central role in the case management of shigellosis, and treatment options have changed markedly over the years due to the increasing resistance of Shigella organisms to standard antibacterials.[23] Eradication of this invasive organism by effective therapy shortens the duration of illness and hastens early recovery.[24,25] Of all Shigella species, S. dysenteriae type 1 is the most virulent serotype, and the serotype associated with epidemics in many developing countries. It is also the most efficient in acquiring resistance, and epidemics are often caused by strains resistant to agents in common use for treatment of shigellosis. Currently, most strains are resistant to ampicillin, trimethoprim-sulfamethoxazole and, recently, nalidixic acid.[26,27]

3.2 Campylobacter Infections

There are many species of Campylobacter, but only some are pathogens in humans, e.g. C. jejuni, C. coli, C. laridis, C. fetus, C. pylori, etc.[28] Most Campylobacter-infected diarrhea illness in humans is caused by only one species — C. jejuni. It was the most common invasive pathogen isolated from the 2% surveillance sampling during the year 2000 at the Dhaka Hospital of the ICDDR,B - Centre for Health and Population Research (Faruque ASG, personal communication). It is also the most common bacterial cause of diarrheal illness in the US.[29] The incubation period is 2–7 days, and it affects both the small and large intestine. A very small number of Campylobacter organisms (<500) can cause illness in humans. Most people who become ill get diarrhea, cramping, abdominal pain and fever within 2–5 days of exposure to the organism. The diarrhea may be bloody, and can be accompanied by nausea and vomiting. The illness typically lasts 1 week. The organism produces two types of toxin: a heat labile-like enterotoxin that activates cyclic AMP and causes fluid secretion resulting in watery diarrhea; and a cytotoxin that causes bloody diarrhea.

All persons infected with Campylobacter species will recover without any specific treatment. In persons with compromised immunity, Campylobacter occasionally spreads to the bloodstream and may cause serious life-threatening infection. Patients should drink plenty of fluids as long as diarrhea lasts. In more severe cases (e.g. persistent diarrhea, prolonged dysenteric illness, severe malnutrition etc.), antibacterials such as erythromycin or a fluoroquinolone can be used to shorten the duration of symptoms if given early in the illness.

3.3 Salmonella Infections

Salmonella spp. represent a large group of organisms having more than 40 serogroups and over 2000 serotypes, about 6–10 of which account for salmonella gastroenteritis. Salmonella spp. can be broadly classified as typhoidal and nontyphoidal. S. typhi and S. paratyphi A and B cause enteric fever and are classified under typhoidal Salmonella, while the others are collectively called nontyphoidal Salmonella, and are responsible for gastroenteritis and satellite infections. Typhoid fever may or may not be associated with diarrhea. Salmonella enteritis is common in industrialized countries where dairy products and canned foods are frequently consumed. Salmonella gastroenteritis usually presents as acute watery diarrhea, cramps, and fever, and may present as dysentery in about 5% of patients. Oral rehydration is effective in most patients, except for those presenting with severe dehydration who require initial intravenous rehydration.

Salmonella infections usually resolve within 5–7 days and often do not require specific drug treatment. However, there are conditions where antimicrobial therapy using an appropriate agent is indicated, e.g. dysenteric presentation, infection in small infants, hosts with compromised immunity, etc. Globally, the strains are currently resistant to ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole.[30]

3.4 Amebiasis

Several species of the protozoan parasite of the genus Entamoeba infect humans, but E. histolytica is the only species known to cause disease. The other (nonpathogenic) species are important because they may be confused with E. histolytica in stool microscopy, which is frequently applied in their diagnosis. Infection by E. histolytica occurs by ingestion of mature cysts in food, water, or hands contaminated with feces. Excystation occurs in the small intestine and trophozoites are released, which then migrate to the large intestine. The trophozoites multiply by binary fission and produce cysts, which are passed in the feces. The cysts can survive days, or even weeks, in the external environment and are responsible for transmission. Trophozoites can also be eliminated in diarrheal stools, but are rapidly destroyed once outside the body, and if ingested do not survive the passage through the acidic gastric environment. In many patients, the trophozoites remain confined to the intestinal lumen (noninvasive infection) and these individuals act as asymptomatic carriers, passing cysts in their stool. In some patients the trophozoites invade the intestinal mucosa (intestinal disease) or through the bloodstream to extraintestinal sites, such as the liver[31,32] and lungs[33] (extraintestinal disease), with resultant pathogenic manifestations.

It has been established that the invasive and noninvasive forms represent two separate species; E. histolytica and E. dispar, respectively. However, not all persons infected with E. histolytica will have invasive disease. These two species are morphologically indistinguishable. Worldwide, the incidence of amebiasis is higher in developing countries. In industrialized countries, risk groups include male homosexuals, travelers, recent immigrants, and institutionalized populations. On average, only 1/10 (10%) of people infected with E. histolytica become sick.[12] The symptoms are often quite mild and can include loose stools, stomach pain, and stomach cramping. Amebic dysentery is a severe form of amebiasis associated with blood in the stools, stomach pain, and fever.

3.5 Escherichia coli Infection

Enteroinvasive E. coli is not a common pathogen; however, it can cause sporadic food-borne cases and outbreaks of diarrhea in all ages worldwide. These organisms are similar to Shigella spp., both biochemically and serologically and, like Shigella spp., they are able to penetrate and multiply within the colonic epithelial cells and cause dysentery.

A newly recognized enteropathogen, E. coli serotype 0157, 0111:117, is a cause of sporadic hemorrhagic colitis in North America where improperly cooked meat has served as the major vehicle of transmission. The illness is characterized by the onset of acute cramps, fever and watery diarrhea that may rapidly progress to bloody diarrhea. Enterohemorrhagic E. coli produces a cytotoxin, which is responsible for edema and diffuse bleeding in the colon, as well as hemolytic uremic syndrome in children.[34]

4. Persistent Diarrhea

In developing countries, children <3 years of age may have as many as 10 diarrhea episodes per year, although a rate of 3–4 per year has been commonly reported.[35] The majority of attacks are of relatively short duration (<7 days) and can be treated easily and effectively by ORT, maintaining the patient’s usual diet, and antibiotics where indicated (e.g. cholera, shigellosis). Diarrhea sometimes lasts longer than usual; these ‘persistent’ diarrhea cases are associated with a deterioration of nutritional status and present a substantial risk of death. Relatively few studies have addressed the issue of its description, treatment, and prevention, and its reported incidence varies widely in different regions. Using the above definitions, studies in several developing countries have observed that overall, 3–20% of acute diarrhea episodes in children <5 years of age become persistent.[35] Episodes of persistent diarrhea, although fewer in number than those of acute diarrhea, are more likely to have severe consequences, such as increased mortality and malnutrition.

4.1 Etiology and Pathophysiology

The etiology and pathogenesis of persistent diarrhea is complex and multifactorial, and infective, nutritional, and allergic factors are usually associated with its causation. There is no specific microbial cause. Most pathogens causing acute diarrhea might also cause persistent diarrhea, with the notable exception being V. cholerae. Bacteria that are isolated more frequently in persistent diarrhea include enteroaggregative E. coli; however, Cryptosporidium spp. may also be important in severely undernourished and/or immunodeficient children. Undernutrition delays the repair of damaged intestinal epithelium, causing diarrhea to be prolonged, which is also suggested by epidemiologic data.[36] Allergies to animal proteins, especially cows’ milk protein, are also responsible for sustained damage to intestinal mucosa and prolongation of diarrhea. It has been postulated that the ingestion of cows’ milk protein during and after diarrhea, especially in early infancy, leads to absorption of intact protein, sensitization, and secondary damage to the epithelium.[37]

Irrespective of its cause, persistent diarrhea is associated with extensive changes in the bowel mucosa, particularly flattening of the villi and reduced production of disaccharidase enzymes, causing reduced absorption of nutrients and perpetuation of the illness after elimination of the original infectious cause. Young age (<1 year), malnutrition, and impaired cell-mediated immunity have been identified as risk factors for the development of persistent diarrhea in children.[35]

4.2 Management of Persistent Diarrhea

Despite the passage of several loose stools per day, the majority of patients with persistent diarrhea remain well hydrated; such children can be treated at home. Children with persistent diarrhea with one or more of the following features should be treated in a hospital: <4 months of age, presence of dehydration, severe malnutrition, and presence of systemic infection.

4.2.1 Rehydration Therapy

The principles of fluid and electrolyte replacement have been well established for acute diarrhea and do not differ in persistent diarrhea. The aim of treatment is to restore the initial fluid deficit and replace ongoing stool-related fluid losses until the diarrhea stops. In most patients this can be done with the use of standard ORS solution. On the basis of the presence of signs of dehydration (table I), fluids should be given according to the WHO-recommended diarrhea treatment plans A, B, or C as appropriate[8,12] (discussed earlier in section section 2.5.2).

4.2.2 Antimicrobial Agents

Antimicrobial agents are not usually indicated, except in some cases of specific enteric infection, such as those that are due to Shigella, Salmonella, and Vibrios species, where eradication therapy is indicated in acute, as well as persistent, diarrhea. Antimicrobial therapy is also indicated in associated nonenteric infection, such as urinary tract, respiratory tract and ear infection. Antiparasitic agents should also be prescribed for amebiasis and giardiasis.

4.2.3 Nutritional Management

Breast-Milk

It is recommended that breast-feeding should be continued, and even encouraged, during episodes of persistent diarrhea.

Other Foods

In prescribing other foods (to partially or fully weaned children), the algorithmic approach recommended by WHO[38] is followed by most treatment centers, including ICDDR,B. This begins with a diet that is simple, locally available, cheap, and culturally acceptable, and also devoid of common dietary components that are responsible for continuing mucosal injury or malabsorption, such as lactose and cows’ milk protein. In ICDDR,B, a low-lactose formula (diet A — cows’ milk, sugar, and rice powder mixture containing 67 Kcal/100ml) is used as the initial diet for 5–7 days. If there is no improvement, a lactose and cows’ milk protein-free diet (diet B — rice powder, egg albumin, and glucose mixture of 70 Kcal/100ml) is initiated. A small proportion (5–10%) of patients may not recover from diarrhea with these diets, in which case a chicken-based diet is advised that is free from cows’ milk and complex carbohydrates (diet C — minced chicken meat, glucose, and vegetable oil mixture containing 60 Kcal/100ml). These formulations (table II) might be used by others, or can be modified according to their local culture and the availability of foods.

Table II
figure Tab2

Composition of different diets for patients with persistent diarrhea

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Vitamins and Minerals

All patients with persistent diarrhea should get supplemental vitamins and minerals (retinol [vitamin A], folic acid, zinc, etc.), at about twice the dose of the recommended daily allowance, for 2–3 weeks, to help mucosal repair and improve intestinal functions, as well as to replace the existing deficiency, if any. As a guide, one recommended daily allowance for a child aged 1 year is folic acid 50μg, zinc 10mg, and retinol 400μg.[8,39] Other vitamins and minerals, including pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), ascorbic acid (vitamin C), ergocalciferol (vitamin D2), tocopherol (vitamin E), phytomenadione (vitamin K), thiamine (vitamin B1), nicotinic acid, riboflavin (vitamin B2), calcium pantothenate, biotin, calcium, phosphorus, magnesium, iron, copper, iodine, selenium, manganese, cobalt, and molybdenum, at about twice the dose of the recommended daily allowance, should also be supplemented in persistent diarrhea.[38,40] Locally available commercial preparations of vitamin/mineral mixture are usually suitable for use.

5. Role of Drugs in the Management of Diarrheal Disease

Since the majority of episodes of diarrhea are caused by intestinal infections, drugs capable of significantly reducing stool volume and/or frequency would be useful in the treatment of infectious enteritis. Unfortunately, such drugs have not yet been developed. However, the potential roles of the following categories of drugs in the management of diarrheal diseases deserve discussion: antimicrobial agents, antimotility drugs, antisecretory drugs, immunotherapy, probiotics, unabsorbed carbohydrate, other agents.

5.1 Antimicrobial Agents

Currently, the most important aspects in the management of diarrheal diseases include prevention and treatment of dehydration, maintaining the patient’s usual diet, and antimicrobial therapy for specific indications, if any. In the management of infectious disease, including infective diarrhea, antimicrobial therapy is indicated to meet one or more of the following objectives: reduction in mortality, shortening the duration of illness, to prevent/reduce transmission of infection, and to prevent or reduce complications. Besides potential advantages, there are also concerns regarding the use of antimicrobial therapy, e.g. cost of therapy, adverse effects, development of resistance, and diversion of attention from other important aspects, such as ORT and maintaining the patient’s usual diet (this may be a special problem in the management of patients with diarrhea where other therapies may be more important).

Appropriate use of antimicrobial agents requires making a diagnosis (infectious etiology) and having a clear understanding of the role of antimicrobial therapy in their management. However, an etiologic diagnosis of infectious disease requires laboratory confirmation, i.e. identification of infectious agents by direct visualization by simple microscopy of stained specimen, or isolation and identification by culture of body fluids or tissues, or by other recently developed sophisticated techniques such as enzyme-linked immunosorbent assay and polymerase chain reaction. As mentioned earlier, this is often not possible for various reasons, including cost and the lack of reliable laboratory facilities, including experienced technicians. Thus, empiric antimicrobial therapy in severe illness (suspected cholera, evidence of severe colitis with toxicity, suspected sepsis, etc.) is required when laboratory tests cannot be performed or when the results of laboratory tests are awaited. It needs to be mentioned here that antimicrobial therapy should not be delayed until availability of the laboratory results, as the outcome of interest (resolution of disease, development of complications, or an adverse outcome) may occur earlier than that.

Before selection of antimicrobial agents, the following factors should also be considered: proven efficacy of the antimicrobial agents against the etiologic agent, tolerability, availability, cost, formulation (oral, intramuscular, intravenous, etc.), and compliance. Assessment of the need and selection of the appropriate agent needs to be individualized to meet the specific requirements of the patients; however, this is time consuming and expensive, and requires well equipped laboratory facilities, supported by well experienced staff, particularly in developing countries where the magnitude of diarrheal disease is the greatest. However, it may be possible to make some generalization when a group of patients with similar infectious conditions, and coming from the same community, are considered. Applications of this method, which may not be perfect, require some knowledge and understanding, such as prevalence and incidence of various infectious agents causing diarrhea in the community, age-specific susceptibility of the population, risk factors for infection and death, seasonal variation in the incidences of infectious diseases, assessment of host defense status (previous exposure, immunization), nutritional status, and conditions that influence efficacy and antimicrobial susceptibility of common pathogens.

Most infectious diarrheas have a self-limiting course, i.e. they resolve over a period of time, during which supportive measures such as management of dehydration and maintaining the patient’s usual diet are important. However, the course of the illness and an adverse outcome may be significantly modified by antimicrobial therapy for some specific etiologic diarrhea. Taking into consideration the risks and costs versus the benefits, the WHO recommends routine use of antimicrobial agents for shigellosis, severe cholera, invasive intestinal amebiasis, and giardiasis.[8,12] Antimicrobial agents recommended for the above infectious diarrheas are listed in table III and table IV.

Table III
figure Tab3

Antimicrobial treatment of cholera

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Table IV
figure Tab4

Antimicrobial treatment for shigellosis, amebiasis and giardiasis

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5.2 Antimotility Drugs

The antimotility category of drugs includes the synthetic opiates, such as diphenoxylate and loperamide. The mechanism of action of these opiates is to reduce stool output, primarily by affecting intestinal motility.

Although diphenoxylate is effective in relieving symptoms of mild chronic diarrhea in adults, there is no clear evidence of its usefulness in acute diarrhea in children or adults.[41] There is evidence that the antimotility effects of diphenoxylate may actually worsen bacillary dysentery.[42] Potentially fatal adverse effects of diphenoxylate on the central nervous system are not uncommon;[43,44] therefore, there is no role for diphenoxylate in the treatment of childhood diarrhea.

Loperamide has not been shown to reduce losses of fluid and electrolytes in acute diarrhea.[45] The drug may have a modest effect on the duration of diarrhea,[45] probably as a result of reduced gastrointestinal motility; however, this effect is dose-dependent[46,47] and of questionable clinical importance. Abdominal distension and potentially fatal paralytic ileus have been reported in infants and young children treated with loperamide.[48–50] Toxic effects on the central nervous system have most commonly been observed in children <6 months of age. In conclusion, loperamide has no place in the routine management of diarrhea in children.

5.3 Antisecretory Drugs

Of all enteric pathogens that produce acute diarrhea in humans, V. cholerae induces the most dramatic illness, and the diarrhea produced by this pathogen is a classical example of infective secretory diarrheas. Other noninfectious secretory diarrhea will not be discussed in this review. The mechanism of fluid loss in cholera has been discussed in section 2.3.2.[5] In experimental animal studies, several drugs have been shown to have an antisecretory effect, some of which have been tested in patients.[51–58] Although some have been shown to reduce stool volume, these are not suitable for practical use because of adverse effects. Although antisecretory drugs could potentially assist in the treatment of patients with cholera, none have been shown to be beneficial in routine clinical management to date.

Enkephalins, the endogenous opiate substances first discovered in 1975, play an important physiologic role by acting as neurotransmitters, most notably along the digestive tract where they elicit intestinal antisecretory activity without affecting intestinal transit time or motility. However, activity is limited by an enzyme (enkephalinase) present throughout the gastrointestinal tract. Racecadotril, an enkephalinase inhibitor, reinforces the physiologic activity of endogenous enkephalins and shows intestinal antisecretory activity without affecting the intestinal transit time.[59–61] In addition to animal studies, some clinical studies[62–64] have demonstrated the efficacy of racecadotril in acute noncholera diarrhea compared with placebo and loperamide. A study was recently conducted in adult patients with cholera to examine the effect of racecadotril as an adjunct therapy to standard therapy (rehydration and antimicrobial). However, the drug failed to show any beneficial effect compared with placebo (Alam NH, unpublished data).

Therefore, none of the antisecretory drugs have been recommended in the routine management of acute diarrhea in children, although racecadotril has been marketed in some countries in Europe.

5.4 Immunotherapy

As a consequence of disappointing results from clinical trials with various ‘antisecretory drugs’ and the absence of a suitable rotavirus vaccine, there is scope for new approaches to address the major global health problem of diarrhea in children. Administering hyperimmune bovine colostrums containing a very high titer of antibodies against the pathogens presents a potentially attractive immunologic approach to treating enteric infections.[65–67] Although some intervention studies conducted in rotavirus-infected diarrhea have shown positive results,[65–67] studies[68,69] in bacterial diarrhea failed to prove their efficacy. Interpretation of the mechanism of action in rotavirus diarrhea is notably speculative. There is evidence that milk immunoglobulin concentrate neutralizes a very high dose of infectious rotavirus,[70] and the efficacy has also shown to be dose- and time-dependent.[71] Hyperimmune bovine colostrums given orally to patients infected with rotavirus clear the rotavirus isolates that are excreted into feces earlier than placebo.[65,66] However, more studies, including cost-effective analysis, are required before a firm conclusion can be reached in recommending use of hyperimmune bovine colostrums in the management of diarrhea in children.

5.5 Probiotics

Probiotic is defined as a ‘live microbial food ingredient’ that is beneficial to health. A number of health-related effects are documented in association with probiotic therapy, such as alleviation of symptoms of lactose intolerance, immune enhancement, shortening of the duration of diarrhea, decreased mutagenicity of intestinal contents, decreased fecal bacterial enzyme activity, and prevention of the recurrence of superficial bladder cancer.[72] The potential for probiotic therapy in acute infectious diarrhea has recently been studied. A number of studies[73–76] have documented the beneficial effects of lactic acid bacteria on diarrhea, particularly on rotavirus diarrhea. Some studies[77,78] have demonstrated that ingestion of Bifidobacterium longum and Lactobacillus casei strain GG reduced the duration of antibacterial-induced diarrhea. Oral bacterial therapy reduced the stool frequency in Pakistani children with acute, nonbloody diarrhea.[73] Similar results were also demonstrated by Isolauri et al.[74] and Shornikova et al.[75] in the treatment of rotavirus diarrhea in Finnish children, and Guarino et al.[76] demonstrated the reduction of duration of diarrhea with rotavirus-positive and -negative ambulatory children in Italy. The possible mechanism of bacterial effect of live bacteria is augmentation of immune response.[79]

Although probiotics have been found to be beneficial in the treatment of rotavirus diarrhea, the cost-effectiveness needs to be defined. As it is the children of developed countries who mostly experience rotavirus diarrhea, the use of probiotics may have potential as an antidiarrheal agent in those countries; however, more studies are needed before it is recommended for use as an antidiarrheal agent in developing countries.

5.6 Unabsorbed Carbohydrates (Short Chain Fatty Acids)

In recent years, considerable interest has been generated in unabsorbed carbohydrates, such as dietary fibers and amylase resistant starch, as a subject of research in health and disease. In humans, these products are mainly fermented in the colon by the resident bacterial flora producing short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate.[80] These compounds serve as a metabolic fuel for the colonocytes,[81] stimulate epithelial cell proliferation,[82] and exert a trophic effect on colonic mucosa.[83] SCFAs are also absorbed through the colon,[84,85] and their absorption is associated with stimulation of sodium transport from the colon in several species, including humans.[86–88] Thus, luminal SCFA levels in the colon may be a factor determining the clinical course of acute diarrheal diseases.[89,90]

Cereal-based ORS solutions have been shown to reduce stool volume by about 30–40% in cholera.[91] A part of the effect on stool volume reduction might be attributed to SCFAs produced by unabsorbed carbohydrates, including dietary fibers and amylase-resistant starch in the colon. To improve glucose-containing ORS, two recent studies have been conducted; one evaluating the addition of amylase-resistant starch to WHO-ORS in the treatment of adult cholera,[92] and the other[93] evaluating the addition of soluble fibers, specifically partially hydrolyzed guar gum (Benefiber®Footnote 1) in the treatment of acute noncholera, watery diarrhea in children. In both studies, stool output and duration of diarrhea were significantly reduced. In another study, Benefiber® was added to a comminuted chicken-based diet in the treatment of persistent diarrhea,[94] and a similar effect was observed. One study[95] in the ICDDR,B assessed the effect of green banana- and pectin-containing diets in the treatment of persistent diarrhea in children. Both were found to reduce stool output, as well as the duration of diarrhea in children with persistent diarrhea. In Bangladesh, cooked green banana and half ripe wood apple are traditionally used as antidiarrheal agents for hastening recovery from diarrhea. The results of these studies support their use in the treatment of diarrhea.

5.7 Other Agents

Zinc and folic acid, among others, are important agents considered to have antidiarrheal properties. Although these micronutrients are recommended for routine use in the treatment of persistent diarrhea,[8] their use in acute diarrhea is yet to be considered. A number of studies have evaluated the therapeutic effect of zinc supplementation in acute diarrhea and the findings were reviewed in a recent report.[96] Zinc supplementation given at a dosage of two recommended daily allowances per day (10–20 mg/day) for 14 days is efficacious in significantly reducing the severity of diarrhea and duration of the episode. As the studies were mostly carried out in developing countries, where many children were undernourished, its use can only be recommended in developing countries. The therapeutic effect of folic acid has also been evaluated in the treatment of acute diarrhea in children. Although some previous studies[97,98] have shown its beneficial effect, a recent well designed study[99] failed to show any effect.

6. Conclusions

The management of dehydration (prevention and treatment) and maintaining the patient’s usual diet during and after diarrhea remain the mainstay in the management of diarrheal diseases, irrespective of etiology, while antimicrobial therapy is indicated for specific etiologic diarrheas. Antidiarrheal drugs, although commonly used, have not been seen to provide any practical benefit and most of them are contraindicated, particularly for use in children.

While probiotics have potential as antidiarrheal agents in the treatment of children in developed countries, zinc might be recommended for children in developing countries who have diarrhea. However, efforts should continue in search of effective, well tolerated, and cheap antidiarrheal drugs.

For better management of diarrhea in children, every treatment center can formulate their own treatment protocol according to their needs, determined on the basis of epidemiologic knowledge of the disease and sociocultural background, although most centers in developing countries follow WHO recommended treatment guidelines.