Persistent diarrhea in children in resource-limited settings

INTRODUCTION — Persistent diarrhea is generally defined as diarrhea lasting 14 days or longer. In resource-limited settings, it is often associated with a chronic enteropathy, with impaired mucosal healing and diminished digestive and absorptive capacity [1], resulting in malabsorption or maldigestion [2]. Although less common than acute diarrhea in resource-limited settings, these prolonged episodes are important, because of their association with chronic complications, including malnutrition and increased risk of death [3,4].

The major causes and the prevalence of persistent diarrhea differ between resource-limited and resource-abundant settings, calling for different approaches to diagnosis and management:

●In resource-limited settings, persistent diarrhea usually follows an acute episode and typically is associated with serial enteric infections without sufficient time to recover between episodes. Children are at risk of malnutrition and often have other intercurrent illnesses, such as respiratory infections.

●In resource-abundant settings, children are less likely to be exposed to serial enteric infections and ensuing malnutrition. In these populations, chronic diarrhea is more likely to be caused by underlying disease. However, enteric infections (particularly in immunocompromised patients), malnutrition, food allergy, and other dietary factors can play a role in some cases. (See "Overview of the causes of chronic diarrhea in children in resource-abundant settings".)

The pathophysiology and management of persistent diarrhea in resource-limited settings will be reviewed here. UpToDate topics with related material are:

●(See "Malnutrition in children in resource-limited settings: Clinical assessment".)

●(See "Management of moderate acute malnutrition in children in resource-limited settings".)

●(See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings".)

DEFINITIONS

●Diarrhea – Objective definitions of diarrhea are based on stool weight or volume. For example, diarrhea can be defined as a stool volume of more than 10 grams/kg/day in infants and toddlers or more than 200 grams/day in older children [5]. However, because assessment of daily stool weights/volumes is difficult in the outpatient and/or resource-limited setting, changes in the frequency and consistency of stool compared with baseline can also be used as a practical clinical indicator of diarrhea. A change in stool consistency is a more accurate indicator of diarrhea than stool frequency [3]. (See "Approach to chronic diarrhea in children >6 months in resource-abundant settings".)

●Persistent diarrhea – Persistent diarrhea is generally defined as loose or watery stools occurring at least three times a day for 14 days or more. Although the 14-day threshold is used for the definition, there is evidence that diarrhea that lasts 7 to 13 days is also associated with adverse outcomes, including stunting, and identifies children at risk of developing persistent diarrhea in the future [6].

Some authors make a distinction between persistent diarrhea, which they define as having a sudden onset, and chronic diarrhea, which they define as having a gradual onset usually lasting more than 30 days. However, it is frequently difficult to identify the time of onset of the diarrhea and clearly delineate the two entities. Lack of consensus on symptom-based and duration-based definitions of diarrhea remains a challenge [7,8]. Consequently, for the purposes of this review, we will not differentiate between persistent and chronic diarrhea.

PREVALENCE AND MORBIDITY — In resource-limited settings, persistent diarrhea is a common condition. It is most common in infants and toddlers but can also occur in older children [6].

The extent to which diarrhea episodes become persistent is highly variable. Overall, fewer than 10 percent of episodes of diarrhea persist for two or more weeks, but reports range from 1.4 to 28.4 percent, and the risk depends on many factors, including the initial enteropathogen, nutritional status, geographical location, and socioeconomic conditions [9,10]. It is estimated that diarrhea lasting more than two weeks occurs in up to 3 to 5 percent of the infant population worldwide [11]. However, there is some evidence that the proportion of episodes of diarrhea that become persistent and the total number of children with persistent diarrhea is decreasing [12].

One report estimated that 1 million deaths could be averted annually by scaling up well-established preventive measures for diarrhea, including breastfeeding, vitamin A supplementation, handwashing with soap, improved sanitation, safe drinking water, and rotavirus vaccination, as well as specific therapies, including oral rehydration solutions (ORS), zinc, and antibiotics for dysentery [13]. More than one-half of these deaths are attributable to persistent diarrhea, and 30 to 50 percent of deaths occur among children younger than five years of age in resource-limited settings [14-16].

PATHOPHYSIOLOGY

General mechanisms of diarrhea — The basic pathophysiology underlying all diarrheas is incomplete absorption of water and electrolytes from the intestinal lumen, either because of a reduced rate of net water absorption (related to impaired electrolyte absorption or excessive electrolyte secretion) or due to osmotic retention of water within the lumen. Reduction of net water absorption by as little as 1 percent may be sufficient to cause diarrhea. Consequently, even relatively modest compromise of absorptive function can lead to loose stools [17].

Diarrhea may result from pathology in the small intestine, the colon, or both and may have secretory and/or osmotic components.

●Secretory diarrhea (also known as electrolyte transport-related diarrhea) occurs when pathogens produce toxins that stimulate small intestinal secretion of chloride ions, with concomitant fluid movement into the intestinal lumen that overwhelms the absorptive capacity of the colon. The classic example is cholera and enterotoxigenic Escherichia coli infections. Pathogens that directly damage the small intestinal mucosa, such as norovirus, have a similar effect. Diarrhea may be severe, especially in the first two to three days. (See "Pathogenesis of acute diarrhea in children", section on 'Electrolyte transport-related (secretory)'.)

●Osmotic diarrhea (also known as diet-induced diarrhea) occurs when unabsorbed nutrients (especially carbohydrates and sugars) or osmotically active medications cause an osmotic gradient that draws water into the intestinal lumen. This is by far the most common mechanism of acute infectious and persistent diarrhea. This may occur in the small or large intestine or both. This type of diarrhea is typically exacerbated by ingestion of carbohydrates or sugars, and stools may be acidic and contain reducing substances. Unabsorbed dietary fat does not exert the same osmotic effect, and steatorrhea is not necessarily associated with diarrhea. The colon has an important role in mitigating the effects of this type of diarrhea because much of the fluid secreted by the small intestine is reabsorbed in the colon. Additionally, short-chain fatty acids produced by bacteria are important because they facilitate fluid absorption by nonionic diffusion and serve as a metabolic fuel for colonocytes. Pathogens that cause inflammation of colonic mucosa classically cause frequent small diarrheal stools with blood and mucus. Inflammatory cells may be seen on microscopy of stools. All of these processes may occur together. (See "Pathogenesis of acute diarrhea in children", section on 'Diet-induced (osmotic)'.)

Persistent diarrhea — In resource-limited settings, most cases of persistent diarrhea are triggered by enteric infections but the condition is perpetuated by other factors such as malnutrition or immune suppression, as illustrated in the figure (figure 1).

●First, the original infectious agent may be particularly virulent and difficult to clear. Some bacteria such as Shigella spp contain plasmids capable of downregulating the host cell expression of antibacterial peptides, thus delaying clearance of the bacteria [18].

●Second, the infection may cause intestinal damage that leads to continuing diarrhea (figure 2). The most common example of this is secondary lactose intolerance, resulting from destruction of the villus tips where the enzyme lactase is located. Studies have also shown that intestinal damage leads to a decrease in intestinal absorptive surface area, which in turn interferes with the absorption of nutrients, particularly sugars [19,20]. Disturbance of the intestinal flora, such as occurs in antibiotic-associated diarrhea, is another example of a secondary effect. Also, irritable bowel syndrome develops in susceptible travelers following acute traveler's diarrhea.

●Third, delayed healing of the intestine may prolong the diarrhea. Host factors, such as zinc, vitamin A, or folate deficiency or generalized malnutrition impair the host response to the infection, resulting in longer duration. Recovery may be further impaired in individuals with underlying immunodeficiency conditions such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS).

●Finally, exposure to enteropathogens may be so common that new infections with different pathogens occur before the child has had a chance to recover, and these sequential acute episodes merge into one episode of persistent diarrhea.

These mechanisms are not exclusive and often exacerbate each other; for instance, delayed recovery makes it more likely that a new infection will lead to continuing symptoms.

Infection, malnutrition, and impaired immunity exacerbate one another (figure 2). Infection, anorexia, and food withdrawal or dilution reduce nutrient intake and cause increased net loss of nutrients, altered permeability, immune dysregulation, mucosal injury, altered intestinal microflora, and nutritional deficits [21-23]. These factors create a vicious cycle that leads to persistent diarrhea, with increasing malnutrition, and risk of death [24].

Environmental enteric dysfunction — Environmental enteric dysfunction (EED), also known as environmental enteropathy, is a subclinical syndrome of altered enteric structure and function resulting in poor absorption, increased intestinal permeability, and chronic mucosal inflammation in individuals who live in resource-limited settings. In infants and children, EED has been implicated in both chronic childhood stunting and decreased immunogenicity of live oral vaccines [25]. It is caused by the interaction of enteric infections, malnutrition, and impaired host defense mechanisms (figure 1).

Although subclinical, EED is often associated with persistent low-grade malabsorption and is characterized by abnormalities and altered permeability of the small intestinal mucosa [26]. There is evidence of an inflammatory response in the mucosa with a variety of immunologic abnormalities [14]. In severe cases, the chronic enteropathy typically exhibits villous atrophy, with crypt cell hypoplasia with decreased mitotic figures [27,28]. The latter feature appears to be associated with protein malnutrition and sometimes helps to distinguish the disorder morphologically from celiac disease. The increased intestinal permeability, especially in children younger than 12 months, may lead to enhanced sensitization to dietary antigens and subsequent allergic enteropathy (see "Food protein-induced allergic proctocolitis of infancy"). In studies of EED patients in Bangladesh, Pakistan, and Zambia, intestinal biopsies reveal intestinal inflammation that is driven by an altered gut microbiome [29-31]. This appears to result in hypermethylation of genes related to epithelial metabolism and barrier function and hypomethylation of genes related to immune response and cell proliferation [31].

The enteropathy contributes to malnutrition by causing malabsorption of macronutrients and micronutrients due to reduced surface area for absorption, reduced bile acid production and function, impaired intestinal motility, and bacterial overgrowth. Small intestinal bacterial overgrowth (SIBO) is associated with increased intestinal permeability, especially in children younger than 12 months, which in turn may lead to enhanced sensitization to dietary antigens and an allergic enteropathy (see "Food protein-induced allergic proctocolitis of infancy"). However, SIBO is very common in children living in unhygienic environments and is found in asymptomatic children as well as those with acute and persistent diarrhea [32]. Although associated with nutrient malabsorption [33], it is not clear if and when SIBO per se causes diarrhea. It rapidly clears when clean food and water are provided.

Gut microbiota (the communities of bacteria present in the intestine) appear to play an important role in the pathogenesis of EED. This was shown in a group of Bangladeshi toddlers (mean age 18 months) with EED confirmed by an abnormal small bowel histology and characterized by linear growth stunting that was unresponsive to a nutritional intervention with no identifiable causative illness [29]. These children harbored strains of duodenal bacteria that are not classified as pathogens but were correlated with biomarkers of intestinal inflammation and stunting of growth. When these strains of bacteria were transferred to germ-free mice maintained on a multinutrient-deficient Bangladeshi diet, they induced histologic changes consistent with EED, supporting a causal mechanism; the control germ-free mice received cecal flora from conventional mice because ethical limitations precluded acquisition of duodenal bacteria from healthy children. In a subsequent study, targeted manipulation of gut flora in Bangladeshi children with moderate acute malnutrition using microbiota-directed complementary foods improved weight-for-age and weight-for-length recovery over a three-month trial [34]. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings", section on 'Formulations'.)

Gut microbiota, interacting with dietary factors, also appear to be involved in the pathogenesis of acute malnutrition, particularly kwashiorkor [35]. Together, these findings suggest that gut dysbiosis may be involved in the pathogenesis of EED, persistent diarrhea, and acute or chronic malnutrition. (See "Malnutrition in children in resource-limited settings: Clinical assessment", section on 'Pathophysiology'.)

Contributing factors

Enteric pathogens — A large variety of bacterial pathogens have been isolated from stools of children with persistent diarrhea in resource-limited settings. Some pathogens have been associated with more prolonged episodes, although results of studies are inconsistent. A literature review identified more than 30 bacterial, viral, and parasitic potential pathogens in persistent digestive disorders including persistent diarrhea. Among the most commonly cited culprits are enteroaggregative E. coli (also known as enteroadherent E. coli) [14,36-38], enteropathogenic E. coli in infants younger than six months [3,39-41], Shigella [42], Cryptosporidium [43], Yersinia, and Campylobacter. (See "Pathogenic Escherichia coli associated with diarrhea" and "Approach to the child with acute diarrhea in resource-limited settings", section on 'Infectious causes'.)

Intestinal parasites such as Cyclospora, Isospora, Microsporidium, Entamoeba histolytica, and Strongyloides may also play a role [14]. Among the intestinal parasites, Cryptosporidium has been found in chronic episodes of diarrhea in Bangladesh but not in Peru, while Giardia lamblia showed similar incidence rates in acute and chronic diarrhea [24,44-46]. (See "Giardiasis: Treatment and prevention".)

Twelve different types of viruses have been implicated, including adenovirus, norovirus, cytomegalovirus, human rotavirus, and HIV [38,42]. Viral pathogens such as rotavirus and cytomegalovirus have been associated with protracted diarrhea, usually following particularly severe acute episodes [44,47,48]. Rotavirus is the principal cause of severe acute, dehydrating diarrhea in young children, but most episodes of rotavirus infection are short lived and self-limited. Nevertheless, rotavirus has been implicated in protracted diarrhea syndrome in both immunodeficient and immunocompetent hosts [49,50]. The reduction in diarrheal episodes associated with introduction of a vaccine against rotavirus in the infant vaccine schedules of many countries will allow a better estimate of the effect of this virus in persistent diarrhea. (See "Acute viral gastroenteritis in children in resource-abundant countries: Clinical features and diagnosis" and "Clinical manifestations and diagnosis of rotavirus infection", section on 'Clinical manifestations'.)

Torovirus and Astrovirus also have been associated with chronic diarrhea [51,52]. Some viral infections such as measles or HIV cause chronic diarrhea through immunosuppression [53,54]. Immunosuppressed children are more likely to develop enteric infections with multiple pathogens and/or with opportunistic pathogens such as Mycobacterium avium complex, Isospora, and microsporidia [55]. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Other'.)

However, serial stool cultures during episodes of chronic diarrhea suggest that sequential infections with the same or different pathogens are more often responsible for prolonged diarrhea [44,45] than persistence of a single etiologic agent. When complete analyses are undertaken, multiple pathogens often are identified. Studies in resource-limited settings where fecal contamination is common show high rates of enteropathogens, even in stools of children without diarrhea [36]. Therefore, the presence of a particular bacteria, virus, or parasite does not mean it is the causal agent, perhaps explaining some apparent treatment failures. On the other hand, no enteropathogens are detected in many cases of persistent diarrhea [14,36]. This may be because it is almost impossible to test for all possible pathogens, particularly in resource-limited settings; because the pathogen is intermittently excreted or was present during the acute phase of the diarrhea; or because the diarrhea has a noninfectious cause.

Advances in genetics are increasing understanding of the interaction between the virulence mechanisms of enteropathogens and the host immune response, and are likely to explain why some children have persistent diarrhea, whereas others harboring the same pathogens remain symptom-free [56].

Malnutrition — Chronic and acute undernutrition impair the development and function of the immune system [57]. This leads to suboptimal immune responses that are also associated with a generalized increase in inflammatory mediators, which can contribute to the tissue damage caused by enteric infection. Malnutrition also impairs tissue repair mechanisms so that infections tend to be more severe and of longer duration.

Specific nutrient deficiencies, such as vitamin A and zinc deficiencies, are associated with persistent diarrhea [58-60]. Randomized controlled studies in a variety of populations have shown that zinc supplementation given during an episode of diarrhea reduces the severity and duration of acute and persistent diarrhea in children over six months of age [61]. Zinc supplements given prophylactically in populations where zinc deficiency is common also reduce the incidence of diarrhea, including persistent diarrhea [62-64]. (See "Zinc deficiency and supplementation in children".)

Breastfeeding, especially exclusive breastfeeding, protects against diarrhea through reduced exposure to enteropathogens and provides protective substances including lactoferrin, lysozyme, and oligosaccharides against enteropathogens, as well as maternal antibodies and white blood cells. Both acute and persistent diarrhea is less common in breastfed children. The positive effects of breastfeeding continue even after other foods are introduced; breastfeeding to two years old is the recommendation by the World Health Organization (WHO) and other agencies [65,66].

HIV disease — Persistent diarrhea is commonly associated with HIV and provides a paradigm for the complex interactions between the immunocompromised host, malnutrition, and enteric infection. Malnutrition is often an early manifestation of HIV disease and is associated with a rapid decrease in the CD4+ cell number and an increased rate of opportunistic infections [67]. Combined dysfunctions of the digestive-absorptive processes are common in children with HIV infection and may involve the intestine, liver, and pancreas [68]. Iron and lactose malabsorption are particularly common [69].

Several cellular mechanisms appear to be directly affected by HIV infection. As an example, the HIV transactivating factor protein (Tat) released by the virus can directly impact enterocytes, both as a viral cytotoxin and an enterotoxin. This protein-cell interaction impairs cell growth and proliferation and inhibits ion transport [70]. In the setting of immunosuppression, superinfection with opportunistic agents such as Cryptosporidium, Blastocystis hominis, Candida albicans, and others can lead to diarrhea and mucosal injury. Consequently, HIV infection both directly and indirectly induces intestinal dysfunction, malnutrition, and immune impairment. Antiretroviral therapy may also cause persistent diarrhea [71].

DIAGNOSTIC APPROACH — Because persistent diarrhea following an acute infection is the predominant type of diarrhea seen in resource-limited settings and because diagnostic resources often will be limited, an diagnostic and management algorithm is practical and usually effective. This approach requires categorical assessment of the child's nutritional status and type of diarrhea, specific testing for pathogens when possible, and, in some cases, empiric therapy based on the clinical findings and prevalence rates.

Assess for complications and comorbid conditions — The first step in the evaluation is to assess the child for dehydration and sepsis, as both require urgent treatment.

●Dehydration – Follow standard guidelines to diagnose and treat hypovolemia (dehydration) (see "Clinical assessment of hypovolemia (dehydration) in children"). Children with mild or no dehydration should be given extra fluids and can be managed at home; moderate dehydration should be treated orally or by nasogastric tube, using a rehydration fluid consisting of glucose, sugar or rice flour, sodium, potassium chloride, and a base such as bicarbonate or citrate. It is important to continue oral feeding even if the diarrhea continues. (See 'Rehydration' below.)

●Malnutrition – Children should be weighed, measured, and examined for bilateral edema in order to recognize severe malnutrition that will require special attention (table 1). (See "Malnutrition in children in resource-limited settings: Clinical assessment".)

Children with diarrhea and severe malnutrition (<70 percent of median reference weight for height or mid-upper arm circumference <115 mm), and especially those with edematous malnutrition, fever, or other signs of medical complications, should be evaluated and managed in a specialized treatment center whenever possible. Management of children with malnutrition is discussed in detail in separate topic reviews. (See "Management of moderate acute malnutrition in children in resource-limited settings" and "Management of uncomplicated severe acute malnutrition in children in resource-limited settings" and "Management of complicated severe acute malnutrition in children in resource-limited settings".)

●Infections – All children should be evaluated for nonintestinal infections, including otitis media, pneumonia, urinary tract infections, and sepsis. Treatment of these infections should follow standard protocols.

Clinicians should look for comorbid conditions that may be the underlying cause of the malnutrition, such as cerebral palsy, cystic fibrosis, congenital heart disease, HIV disease, and tuberculosis. These diseases may cause or complicate the child’s illness and nutritional status. Tuberculosis may be difficult to diagnose in severely malnourished children. (See "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis".)

Categorize the diarrhea — The next step is to classify the diarrhea based on its appearance; this is not essential as a first step but narrows the range of likely infectious agents and provides some estimate of risk.

●Watery diarrhea – Most cases of persistent watery diarrhea in children in resource-limited settings are caused by acute infections with enteric pathogens, usually in combination with undernutrition. These children usually respond to interventions designed to improve nutrition and reduce the likelihood of reinfection. Because serial infections are common, enteropathogens not usually associated with persistent diarrhea may present as acute or chronic infections. As an example, cholera typically presents with acute-onset watery diarrhea in children or adults (often with vomiting). In children younger than two years of age, the clinical presentation is not readily distinguishable from that of rotavirus. Cholera should be suspected in a child presenting with an acute exacerbation of watery, chronic diarrhea if other cases of cholera are reported in the area.

●Bloody diarrhea – In resource-limited settings, most cases of acute bloody diarrhea are caused by Shigella spp (45 to 67 percent of cases) and Campylobacter (35 to 37 percent of cases) [72]. E. histolytica is the most important nonbacterial pathogen but is responsible for fewer than 3 percent of episodes. Most infections with these organisms result in acute diarrhea illnesses and cause low-volume bloody stools, often associated with fever. However, in children with underlying malnutrition or immunodeficiency, these pathogens may cause chronic diarrhea and may be associated with higher-volume diarrhea and dehydration. Children presenting with bloody diarrhea are at particularly high risk for morbidity and mortality [15].

Laboratory testing — Specific laboratory testing is not essential for the management of persistent diarrhea in resource-limited settings. Essential fluid, electrolyte, and dietary management are not dependent on etiology. There are rarely facilities for a complete enteropathic screen, and results of stool cultures are generally not available in time to be clinically valuable for these patients.

Nonetheless, some simple bedside laboratory tests may be helpful. In cases where diarrhea has persisted for more than two weeks, testing the stool for glucose and pH can be helpful in identifying those children with severe villous atrophy. This can be done easily at the bedside with a urine dipstick if available. Glucose test tape, nitrazine paper, and Clinitest tablets also have been used. A stool glucose of greater than 2+ or a pH of less than 5.0 suggests substantial villous atrophy.

In selected cases, laboratory testing also can help identify enteropathogens that respond to antimicrobial therapy. If the diarrhea contains red blood or blood mixed with mucus and facilities are available, the stool should be cultured for bacterial pathogens (particularly Shigella spp and Campylobacter). In these cases, antibiotic treatment for Shigella infection, based on local resistance patterns, should be started empirically (see 'Antimicrobials' below). In some clinical settings, laboratory testing is used as surveillance for epidemiologic reasons, such as the detection of cholera outbreaks.

For children with persistent watery stools, stool microscopy can be performed to detect trophozoites or cysts of E. histolytica or other parasites. However, microscopy typically over-diagnoses amoebiasis because of the difficulty of distinguishing pathologic from nonpathologic Entamoeba. If available, fecal antigen assays also may be used to detect Giardia infection. Rotavirus should also be sought, and rapid tests are now available in many locales. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Intestinal Entamoeba histolytica amebiasis".)

If cholera is suspected (eg, in a child presenting with an acute exacerbation of diarrhea, with "rice-water" stools and vomiting), dark-field or phase-contrast microscopy can be performed to identify the organism. Antimicrobial therapy generally is not necessary for individuals with mild symptoms, so there is no benefit to specific testing for these patients. (See "Cholera: Epidemiology, clinical features, and diagnosis".)

TREATMENT — Treatment of chronic diarrhea includes supportive measures, nutritional rehabilitation, and drug therapy. Children with diarrhea and moderate malnutrition, evidence of dehydration, or systemic infections; infants younger than six months of age; and children with severe persistent diarrhea should be treated in an inpatient setting if possible [73]. Children with severe malnutrition also should be treated as inpatients until stable, as described separately. (See "Management of complicated severe acute malnutrition in children in resource-limited settings".)

Rehydration — Death in the context of persistent diarrhea is usually caused either by hypovolemia (dehydration) and/or severe acute malnutrition (defined as <70 percent of median reference weight for height or mid-upper arm circumference <115 mm). Consequently, replacement of fluid and electrolyte losses is the major early intervention.

Rehydration is ideally given through the oral or nasogastric route with an oral rehydration solution (ORS) [74]. The World Health Organization (WHO) recommends different formulations of ORS for different groups of children:

●No malnutrition, uncomplicated malnutrition, and/or cholera – For these children, use standard low-osmolarity ORS to treat diarrheal episodes [73]. This solution contains 75 mmol/L glucose, 75 mEq/L sodium, and 20 mEq/L potassium, at an osmolarity of 245 mOsm/L [75]. Severe acute malnutrition is considered uncomplicated if the child is clinically well, alert, and has retained their appetite.

●Complicated severe acute malnutrition – For children with complicated severe acute malnutrition (ie, with clinical features of infection or metabolic disturbance, severe edema, or poor appetite), the preferred rehydration solution is ReSoMal (Rehydration Solution for Malnourished children) [76,77]. This formula contains 55 mmol/L glucose, 45 mEq/L sodium, and 40 mEq/L potassium, at an osmolarity of 294 mEq/L. This is because severely malnourished children are potassium depleted. If ReSoMal is not available, additional sucrose and potassium chloride can be added to the standard low-osmolarity ORS fluid to provide 40 mEq/L of potassium; the method is described separately. (See "Management of complicated severe acute malnutrition in children in resource-limited settings", section on 'Rehydration Solution for Malnutrition (ReSoMal)'.)

If ReSoMal (or the formulated equivalent) is not available, it is acceptable to use standard low-osmolarity ORS for children with complicated severe acute malnutrition [73]. (See "Management of complicated severe acute malnutrition in children in resource-limited settings", section on 'Oral rehydration solution'.)

In most cases, breastfeeding should be continued. The evaluation of a child for dehydration and treatment with ORS according to the degree of dehydration are discussed separately. (See "Oral rehydration therapy" and "Malnutrition in children in resource-limited settings: Clinical assessment".)

Children with severe dehydration (eg, hypovolemic shock) may require intravenous fluids, as described separately and in standard protocols. For those with severe acute malnutrition, and especially for those with edematous malnutrition, intravenous fluids should be carefully monitored to avoid overhydration and risk for heart failure. (See "Management of complicated severe acute malnutrition in children in resource-limited settings", section on 'Rehydration methods'.)

Dietary management — Nutritional compromise plays a role in most cases of persistent diarrhea in resource-limited settings and is the primary target for treatment.

●General approach – It is essential to start oral feeding as soon as the child has been rehydrated. Delays in starting feeding worsen malnutrition. At first, the diet should be given in frequent small amounts (for instance, every three hours), in which the total amount mentioned above is divided into eight feedings. If children refuse food, a nasogastric tube may be necessary. Feeding should be continued, either orally or by nasogastric tube, during the night to avoid long periods without food. This approach is similar to that used for nutritional rehabilitation in other children with malnutrition.

For patients with severe malnutrition, management typically includes a gradual increase to full caloric intake, with a course of broad-spectrum antibiotics. Hypophosphatemia is common during the early phases of refeeding (known as "refeeding syndrome") and can be mitigated by feeds that are relatively high in phosphorus (eg, milk-based feeds). Measurement of serum phosphorus concentrations is not routinely available in most centers managing acute malnutrition in resource-limited settings. (See "Management of complicated severe acute malnutrition in children in resource-limited settings".)

●Diet composition – Most children will respond to dietary management using locally available foods designed to provide approximately 150 kcals/kg/day and 10 percent of calories from protein [78]. If possible, at least one-half the protein should come from an animal source such as milk, egg, or chicken. Additional potassium should be added to the diet to provide at least 5 mEq/kg per day. Breastfeeding may provide some of these nutrients and is continued when possible.

Many infants and children with chronic diarrhea have secondary disaccharidase deficiencies caused by mucosal damage. Consequently, a low-lactose diet and sometimes a diet also low in sucrose or total carbohydrates may be necessary. It is often sufficient to reduce lactose by mixing milk with cereals such as rice or noodles and giving small frequent feedings. However, a minority of children benefit from a lactose-free diet. Egg or pureed chicken has been successfully used and is palatable. Yogurt-based diets have also been used successfully [79]. Lactose-free formulas are an alternative if available, but it is important to ensure that the family can afford these formulas and will not dilute or give less than the required amounts in order to save money.

There is no need to limit fat intake; indeed, fat can be beneficial because it provides concentrated calories and enables less carbohydrate to be included in the diet. Ready-to-use therapeutic food (RUTF) is not contraindicated. In a randomized trial of 250 children in southern India with acute watery diarrhea, supplementation with cooked green bananas hastened recovery and reduced the risk of progression to persistent diarrhea by 70 percent [80]. In a similar trial of 153 children in eastern India, supplementation with green bananas reduced the duration of diarrhea by 1.5 days and reduced the risk of progression to persistent diarrhea by 60 percent [81]. Green bananas are a rich source of pectin, a starch that resists digestion and is converted in the colon to short-chain fatty acids, which are thought to have cytoprotective effects and enhance colonic fluid absorption.

●Efficacy – The efficacy of dietary management, with an algorithm for lactose inclusion, was demonstrated in a multinational trial designed by the WHO [78]. After evaluation and treatment for acute comorbidities (including hypovolemia, sepsis, and pneumonia), all children were treated with a low-lactose diet, containing <3.7 grams of lactose/150 kcals, as compared with approximately 10 grams of lactose/150 kcals in the standard WHO full-milk diet. The ingredients varied by region but consisted of cereals, legumes, vegetable oil, and milk products, with added micronutrient supplements and an energy density of 65 to 100 kcals/100 grams. Children who did not respond to this low-lactose diet within seven days were advanced to a lactose-free diet, in which the protein component was supplied by chicken or egg white. The overall success rate for the treatment algorithm was 80 percent (95% CI 76-84 percent). Sixty-five percent of children recovered with a low-lactose diet alone. Among the 35 percent of children who failed the low-lactose diet and moved on to treatment with a lactose-free diet, 71 percent recovered on this diet.

Micronutrients and vitamins — Micronutrient and vitamin supplementation are part of nutritional rehabilitation, especially in malnourished children from resource-limited settings [59,60]. Children with chronic diarrhea and malnutrition are often deficient in vitamin A, zinc, folic acid, copper, and other vitamins and minerals [82]. Deficiencies in these micronutrients can impair the function of the immune system and have a direct effect on small intestinal function and recovery.

The WHO recommends zinc supplementation for children with diarrhea in resource-limited settings, at a dose of 10 mg daily for infants up to six months of age and 20 mg daily for older infants and children, for 14 days [62,83]. These recommendations are based on a variety of randomized trials in resource-limited settings, demonstrating that zinc supplementation reduced the severity and duration of acute and persistent diarrhea in children [63,64,84]. A subsequent large trial found that lower doses of zinc (10 mg or 5 mg daily for children >6 months) were equally effective for treating the diarrhea compared with the standard 20 mg dose and reduced the risk of vomiting [85]. In July 2019, the WHO added zinc to its Model List of Essential Medicines for Children listings, both as co-packaged oral rehydration salts (with 5 mg elemental zinc/sachet) and as zinc sulfate for acute diarrhea (20 mg) [86]. (See "Zinc deficiency and supplementation in children", section on 'Treatment of acute or persistent diarrhea'.)

In addition to zinc, the WHO also recommends providing at least two times the recommended daily allowance for folate, vitamin A, iron, copper, and magnesium for two weeks [87]. Vitamin A and zinc supplementation may have synergistic effects [60]. In addition, children with concomitant measles infection or ophthalmologic signs of vitamin A deficiency should be treated with a high dose of vitamin A. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Vitamin A'.)

Antimicrobials — Although nutritional rehabilitation is effective alone for most children with chronic diarrhea, specific antibiotic treatment for enteric pathogens is indicated in some cases, particularly children with bloody diarrhea (usually caused by Shigella, Campylobacter, or parasites) [88].

Children with bloody diarrhea are likely to have a Shigella or Campylobacter infection and can be treated empirically [89]. Empiric therapy generally should be directed against Shigella, based on the known sensitivities of local strains. Ciprofloxacin, ceftriaxone, and pivmecillinam have been shown to be generally effective [90]. If no improvement is seen within two days, treatment should be changed to another agent known to be effective against local strains of Shigella [87]. Antimicrobial therapy for Campylobacter is only indicated in patients who are at increased risk or have severe disease, with bloody stools, high fever, or symptoms lasting longer than one week. (See "Shigella infection: Treatment and prevention in children", section on 'Antibiotic therapy' and "Campylobacter infection: Clinical manifestations, diagnosis, and treatment".)

Antibiotics are not essential for treatment of cholera but may hasten recovery and reduce the duration of infectivity. Thus, antimicrobial therapy directed against cholera is recommended for cases of suspected or proven cholera with severe dehydration [87]. (See "Cholera: Epidemiology, clinical features, and diagnosis".)

If enteric parasites are identified by laboratory testing, these should be treated according to standard guidelines. Empiric therapy for intestinal parasites is not recommended, except that empiric treatment for amoebiasis may be considered in a child with persistent bloody diarrhea, who has failed trials of two different antimicrobials known to be effective against local strains of Shigella [87]. In addition, nitazoxanide has been shown to have partial efficacy in treatment of cryptosporidiosis in undernourished children in low-resource settings but not in children with HIV/AIDS. (See "Giardiasis: Treatment and prevention" and "Intestinal Entamoeba histolytica amebiasis" and "Cyclospora infection" and "Cryptosporidiosis: Treatment and prevention".)

Extraintestinal infections such as acute lower respiratory infections, urinary tract infections, sepsis, and others are commonly associated with chronic diarrhea and should be evaluated carefully and treated promptly [78,91,92].

Antidiarrheal drugs — Drugs that alter intestinal motility, including loperamide, codeine, and paregoric, are not recommended, because they lack efficacy, are associated with potentially serious side effects, and possibly prolong the excretion of enteric pathogens [15,83]. Similarly, some antiemetics may cause sedation that could interfere with oral rehydration therapy and should not be given to children with diarrhea [87]. (See "Approach to chronic diarrhea in children >6 months in resource-abundant settings", section on 'Medications'.)

Probiotics — A Cochrane review of clinical trials reported that probiotics reduced the stool frequency and duration of persistent diarrhea [93]. The authors concluded that probiotics appeared to hold promise as adjuvant therapy for persistent diarrhea, but there was insufficient evidence to recommend their use at this time. The probiotics used in the trials were Lactobacillus strains plus Saccharomyces boulardii and Lactobacillus rhamnosus GG. A subsequent randomized, double-blind, placebo-controlled study in Uganda involved 400 children admitted to the hospital with severe acute malnutrition [94]. Bifidobacterium animalis subsp. lactis and L. rhamnosus had no effect on diarrhea during the hospitalization for severe acute malnutrition but reduced the number of days with diarrhea after discharge to outpatient treatment by 26 percent.

Pancreatic enzyme replacement therapy — A small study from Indonesia used fecal elastase-1 to identify pancreatic exocrine insufficiency in 31 children with persistent diarrhea with or without malnutrition and randomized them to treatment with pancreatic enzyme replacement therapy (8371 United States Pharmacopeia [USP] units of lipase three times daily for one month) versus placebo, as an adjunct to standard treatment [95,96]. Patients treated with pancreatic enzymes had significantly shorter duration of diarrhea compared with placebo (3 versus 10 days; p = 0.019).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in children" and "Society guideline links: Pediatric malnutrition".)

SUMMARY AND RECOMMENDATIONS

●Definition – Persistent diarrhea is defined as loose or watery stools occurring at least three times a day for 14 days or more, where the change in stool consistency is more important than stool frequency. This typically translates to a stool volume of more than 10 grams/kg/day in infants and toddlers, or more than 200 grams/day in older children. (See 'Definitions' above.)

●Causes – In resource-limited settings, most cases of persistent diarrhea are caused by a combination of enteric infections, undernutrition, and impaired immunity (figure 2). These factors interact to cause a chronic enteropathy and diarrhea. (See 'Pathophysiology' above.)

●Evaluation

•The first step in evaluating a child with persistent diarrhea is to diagnose comorbid conditions that may cause or complicate the diarrheal illness, including dehydration, malnutrition, and associated nonenteric infections, including sepsis and HIV disease. (See 'Assess for complications and comorbid conditions' above.)

•The next step is to classify the diarrhea based on its appearance. Bloody diarrhea is most likely caused by Shigella, confers a worse prognosis, and requires antimicrobial treatment. An acute exacerbation of watery diarrhea should raise the possibility of cholera in children older than two years of age. (See 'Categorize the diarrhea' above.)

•Laboratory testing of stool is not essential for management. When available, it may be helpful to test the stools for the presence of glucose or acidic pH, culture bloody stools for Shigella and Campylobacter, and examine stools for parasites including Giardia, Cryptosporidium, and Entamoeba histolytica. (See 'Laboratory testing' above.)

●Stabilization – The first step in treatment is to stabilize children with dehydration or intercurrent infections:

•Rehydration – Children with mild or moderate dehydration and all children with suspected cholera should be treated with standard low-osmolarity oral rehydration solution (ORS). For those with complicated severe acute malnutrition, the preferred rehydration solution is ReSoMal, which has higher potassium content compared with standard ORS. Children with severe dehydration and hypovolemic or septic shock may require intravenous repletion. (See 'Rehydration' above.)

•Treatment of intercurrent infections – Intercurrent infections (otitis media, pneumonia, urinary tract infections) should be managed according to standard protocols.

●Treatment of diarrhea

•Antibiotics – For treatment of the diarrhea, we generally suggest not treating empirically with antibiotics (Grade 2B). However, in children with bloody diarrhea, we suggest empiric therapy directed against Shigella (Grade 2B). We also suggest antimicrobial treatment for patients with severe symptoms and suspected or proven cholera or Cryptosporidium (Grade 2C). Antibiotics should be selected based on sensitivities of local strains. If this information is not available, ciprofloxacin, ceftriaxone, or pivmecillinam is recommended. (See 'Antimicrobials' above.)

•Nutritional rehabilitation – The main component of treatment is nutritional rehabilitation. Breastfeeding is continued when possible and supplemented with a balanced diet of locally available foods, including an animal protein source such as yogurt, milk, chicken, or egg. Many children with chronic enteropathy have a secondary carbohydrate intolerance and respond better to a low-lactose or low-carbohydrate diet. (See 'Dietary management' above.)

•Zinc – Children with chronic diarrhea in resource-limited settings should be treated with zinc supplements, consistent with guidance from the World Health Organization (WHO). The evidence and implementation are discussed separately. (See 'Micronutrients and vitamins' above and "Zinc deficiency and supplementation in children", section on 'Treatment of acute or persistent diarrhea'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mary E Penny, MBChB, MRCP, who contributed to earlier versions of this topic review.