1. Introduction and epidemiologic features
2. Clinical manifestations and diagnosis
3. Treatment options and prevention
4. Clinical practice
List of Tables
Table 1 Clinical features of infection with selected diarrheal pathogens
Table 2 Assessment of dehydration using the “Dhaka method”
Table 3 Nonspecific antidiarrheal agents
Table 4 Antimicrobial agents for the treatment of specific causes of diarrhea
List of Figures
Figure 1 Therapeutic approach to acute bloody diarrhea in children
Figure 2 Cascade for acute, severe, watery diarrhea—cholera-like, with severe dehydration. See above for the recipe for home-made oral fluid
Figure 3 Cascade for acute, mild/moderate, watery diarrhea—with mild/moderate dehydration. See above for the recipe for home-made oral fluid
Figure 4 Cascade for acute bloody diarrhea—with mild/moderate dehydration
INTRODUCTION AND EPIDEMIOLOGIC FEATURES
According to the World Health Organization (WHO) and UNICEF, there are about 2 billion cases of diarrheal disease worldwide every year, and 1.9 million children younger than 5 years of age perish from diarrhea each year, mostly in developing countries. This amounts to 18% of all the deaths of children below the age of 5 and means that >5000 children are dying every day as a result of diarrheal diseases. Of all child deaths from diarrhea, 78% occur in the African and Southeast Asian regions.
Each child below 5 years of age experiences an average of 3 annual episodes of acute diarrhea. Globally in this age group, acute diarrhea is the second leading cause of death (after pneumonia), and both the incidence and the risk of mortality from diarrheal diseases are greatest among children in this age group, particularly during infancy—thereafter, rates decline incrementally. Other direct consequences of diarrhea in children include growth faltering, malnutrition, and impaired cognitive development in resource-limited countries.
During the past 3 decades, changes in water supply, sanitation, and personal hygiene are believed to have contributed to a decline in the mortality rate in developing countries. In some countries, such as Bangladesh, the reduction in the case fatality rate can be attributed largely to improved case management, rather than changes in water supply, sanitation, or personal hygiene. Oral rehydration salts (ORS) and nutritional improvements probably have a greater impact on mortality rates than the incidence of diarrhea. Interventions such as exclusive breastfeeding (which prevents diarrhea), continuation of breastfeeding until 24 months of age, and improved complementary feeding (by way of improved nutrition), along with improved sanitation, are expected to affect mortality and morbidity simultaneously. The recommended routine use of zinc in the management of childhood diarrhea, not currently practiced in many countries, is expected to reduce disease incidence.
In industrialized countries, relatively few patients die from diarrhea, but it continues to be an important cause of morbidity that is associated with substantial health care costs. However, the morbidity from diarrheal diseases has remained relatively constant during the past 2 decades.
In this guideline, specific pediatric details are provided in each section as appropriate.
Cascades—a Resource-sensitive Approach
A gold standard approach is feasible for regions and countries in which the full scale of diagnostic tests and medical treatment options are available. However, such resources are not available in large parts of the world. With their diagnostic and treatment cascades, the WGO guidelines provide a resource-sensitive approach.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Although there may be clinical clues, a definitive etiological diagnosis is not possible clinically (Table 1).
The initial clinical evaluation of the patient should focus on:
* Assessing the severity of the illness and the magnitude (degree) of dehydration (Table 2)
* Determining likely causes on the basis of the history and clinical findings, including stool characteristics
For acute enteritis and colitis, maintaining adequate intravascular volume and correcting fluid and electrolyte disturbances take priority over identifying the causative agent. Presence of visible blood in febrile patients generally indicates infection due to invasive pathogens, such as Shigella, Campylobacter jejuni, Salmonella, or Entamoeba histolytica. Stool cultures are usually unnecessary for immune-competent patients who present with watery diarrhea, but may be necessary to identify Vibrio cholerae when there is a clinical and/or epidemiological suspicion of cholera, particularly during the early days of outbreaks/epidemics (also to determine antimicrobial susceptibility) and to identify the pathogen causing dysentery.
Epidemiologic clues to infectious diarrhea can be found by evaluating the incubation period, history of recent travel in relation to the regional prevalence of different pathogens, unusual food or eating circumstances, professional risks, recent use of antimicrobials, institutionalization, and human immunodeficiency virus infection risks.
Stool analysis and culture costs can be reduced by improving the selection and testing of the specimens submitted on the basis of interpreting the case information—such as patient history, clinical aspects, visual stool inspection, and estimated incubation period.
Screening usually refers to noninvasive fecal tests. Certain laboratory studies may be important when the underlying diagnosis is unclear or diagnoses other than acute gastroenteritis are possible. Where applicable, rapid diagnostic tests may be considered for quick cholera testing at the patient’s bedside.
Identification of a pathogenic bacterium, virus, or parasite in a stool specimen from a child with diarrhea does not indicate in all cases that it is the cause of illness.
Measurement of serum electrolytes may be required in some children with a longer duration of diarrhea with moderate or severe dehydration, particularly with an atypical clinical history or findings. Hypernatremic dehydration is more common in well-nourished children and those infected with rotavirus and features irritability, increased thirst disproportionate to clinical dehydration, and a doughy feel to the skin. This requires specific rehydration methods.
TREATMENT OPTIONS AND PREVENTION
Rehydration in Adults and Children
Oral rehydration therapy (ORT) is the administration of appropriate solutions by mouth to prevent or correct diarrheal dehydration. ORT is a cost-effective method of managing acute gastroenteritis and it reduces hospitalization requirements in both developed and developing countries.
Global ORS coverage rates are still <50%, and efforts must be made to improve coverage.
ORS, used in ORT, contain specific amounts of important salts that are lost in diarrhea stool. The new lower-osmolarity ORS (recommended by the WHO and UNICEF) has reduced concentrations of sodium and glucose and is associated with less vomiting, less stool output, lesser chance of hypernatremia, and a reduced need for intravenous infusions in comparison with standard ORS. This formulation is recommended irrespective of age and the type of diarrhea, including cholera.
ORT consists of:
* Rehydration—water and electrolytes are administered to replace losses.
* Maintenance fluid therapy to take care of ongoing losses once rehydration is achieved (along with appropriate nutrition).
ORT is contraindicated in the initial management of severe dehydration and also in children with paralytic ileus, frequent and persistent vomiting (>4 episodes per hour), and painful oral conditions such as moderate to severe thrush (oral candidiasis). However, nasogastric administration of ORS solution is potentially lifesaving when intravenous rehydration is not possible and the patient is being transported to a facility where such therapy can be administered.
Rice-based ORS is superior to standard ORS for adults and children with cholera and can be used to treat such patients wherever its preparation is convenient. It is not superior to standard ORS in the treatment of children with acute noncholera diarrhea, especially when food is given shortly after rehydration, as is recommended to prevent malnutrition.
Supplemental Zinc Therapy, Multivitamins, and Minerals in Children
Zinc deficiency is widespread among children in developing countries. Routine zinc therapy as an adjunct to ORT is useful for modest reduction of the severity but more importantly to reduce diarrhea episodes in children in developing countries. The recommendation for all children with diarrhea is 20 mg of zinc per day for 10 days. However, infants aged 2 months or younger should receive 10 mg/d for 10 days.
Supplementation with zinc sulfate in recommended doses reduces the incidence of diarrhea during the following 3 months and reduces nonaccidental deaths by as much as 50%. It is more important in the management of diarrhea in malnourished children and in persistent diarrhea. The WHO and UNICEF recommend routine zinc therapy for children with diarrhea, irrespective of the type.
All children with persistent diarrhea should receive supplementary multivitamins and minerals, including magnesium, each day for 2 weeks. Locally available commercial preparations are often suitable; tablets that can be crushed and given with food are least costly. These should provide as broad a range of vitamins and minerals as possible, including at least 2 recommended daily allowances of folate, vitamin A, zinc, magnesium, and copper (WHO 2005).
The practice of withholding food for >4 hours is inappropriate—normal feeding should be continued for those with no signs of dehydration, and food should be started immediately after correction of some (moderate) and severe dehydration, which usually takes 2 to 4 hours, using ORT or intravenous rehydration.
Breastfed infants and children should continue to receive food, even during the rehydration phase. However, for nonbreastfed, dehydrated children and for adults, rehydration is the first priority and can be accomplished in 2 to 4 hours.
Probiotics are live microorganisms, such as Lactobacillus GG (ATCC 53103), with demonstrated beneficial health effects in humans. However, the effects are strain specific and need to be verified for each strain in human studies. Extrapolation from the results of even closely related strains is not possible, and significantly different effects have been reported. Use of probiotics may not be appropriate in resource-constrained settings, mostly in developing countries.
Controlled clinical intervention studies and meta-analyses support the use of specific probiotic strains and products in the treatment and prevention of rotavirus diarrhea in infants.
Probiotics for the Treatment of Acute Diarrhea
It has been confirmed that different probiotic strains (see tables 8 and 9 in WGO’s Guideline on probiotics at http://www.worldgastroenterology.org/probiotics-prebiotics.html) including Lactobacillus reuteri ATCC 55730, Lactobacillus rhamnosus GG, Lactobacillus casei DN-114 001, and Saccharomyces cerevisiae (boulardii) are useful in reducing the severity and duration of acute infectious diarrhea in children. The oral administration of probiotics shortens the duration of acute diarrheal illness in children by approximately 1 day.
Several meta-analyses of controlled clinical trials have been published that show consistent results in systematic reviews, suggesting that probiotics are safe and effective. The evidence from studies on viral gastroenteritis is more convincing than the evidence on bacterial or parasitic infections. Mechanisms of action are strain specific: there is evidence for efficacy of some strains of lactobacilli (eg, L. casei GG and L. reuteri ATCC 55730) and for S. boulardii. The timing of administration is also of importance.
Prevention of Acute Diarrhea
In the prevention of adult and childhood diarrhea, there is only suggestive evidence that Lactobacillus GG, L. casei DN-114 001, and S. boulardii are effective in some specific settings (see tables 8 and 9 in WGO’s Guideline on probiotics at http://www.worldgastroenterology.org/probiotics-prebiotics.html).
In antibiotic-associated diarrhea, there is strong evidence of efficacy for S. boulardii or L. rhamnosus GG in adults or children who are receiving antibiotic therapy. One study indicated that L. casei DN-114 001 is effective in hospitalized adult patients for preventing antibiotic-associated diarrhea and Clostridium difficile diarrhea.
There is inadequate research evidence to be certain that VSL#3 (L. casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, and Streptococcus thermophilus) is effective in the treatment of radiation-induced diarrhea.
Nonspecific Antidiarrheal Treatment
None of these drugs addresses the underlying causes or effects of diarrhea (loss of water, electrolytes, and nutrients). Antiemetics are usually unnecessary in acute diarrhea management, and some that have sedative effects may make ORT difficult.
In general, antidiarrheals have no practical benefits for children with acute or persistent diarrhea (Table 3).
Antimicrobials in Adults and Children
* All doses shown are for oral administration.
* Selection of an antimicrobial should be based on the susceptibility patterns of strains of the pathogens in the locality/region.
* Antimicrobials are reliably helpful and their routine use is recommended in the treatment of severe (clinically recognizable):—Cholera, shigellosis, typhoid, and paratyphoid fevers.—Dysenteric presentation of campylobacteriosis and nontyphoidal salmonellosis when they cause persistent diarrhea, and when host immune status is compromised for any reason such as severe malnutrition, chronic liver disease, or lymphoproliferative disorders.—Invasive intestinal amebiasis.—Symptomatic giardiasis (anorexia and weight loss, persistent diarrhea, failure to thrive).
* Consider antimicrobial treatment for:—Shigella, Salmonella, Campylobacter (dysenteric form), or parasitic infections.—Nontyphoidal salmonellosis among at-risk populations (malnutrition, infants and elderly, immunocompromised patients, and those with liver diseases and lymphoproliferative disorders) and in dysenteric presentation.—Moderate/severe traveler’s diarrhea or diarrhea with fever and/or with bloody stools.—Antimicrobials are also indicated for associated health problems such as pneumonia.
* If drugs are not available in liquid form for use in young children, it may be necessary to use tablets and estimate the doses given.
* Consider antimicrobial treatment for:—When Shigella, Salmonella, Campylobacter (dysenteric form) are the only pathogen isolated from children with persistent diarrhea.—Nontyphoidal salmonellosis in infants.
* Alternative antimicrobials for treating cholera in children are trimethoprim/sulfamethoxazole (TMP/SMX; 5 mg/kg TMP+25 mg/kg SMX, 12-hourly for 3 d) and norfloxacin.
Prevention of Diarrhea With Vaccines
* Salmonella typhi: 2 typhoid vaccines (with limited cost effectiveness) are currently approved for clinical use.
* Shigella organisms: 3 vaccines have been shown to be immunogenic and protective in field trials. Parenteral vaccines may be useful for travelers and military personnel but are impractical for use in developing countries. More promising is a single-dose live-attenuated vaccine currently under development in several laboratories.
* V. cholerae: the current price and need for multiple doses (at least 2) and shorter protective efficacy are limitations. A new, cheaper killed-cell vaccine is likely to be available soon; oral cholera vaccines are still being investigated, and their use is recommended only in complex emergencies such as epidemics. Their use in endemic areas remains controversial. In traveler’s diarrhea, oral cholera vaccine is only recommended for those working in refugee or relief camps, because the risk of cholera for the usual traveler is very low.
* Enterotoxigenic Escherichia coli vaccines: the most advanced enterotoxigenic E. coli vaccine candidate consists of a killed whole-cell formulation plus a recombinant cholera toxin B subunit. No vaccines are currently available for protection against Shiga toxin–producing E. coli infection.
* Salmonella typhi: no available vaccine is currently suitable for routine use for children in developing countries.
* Rotavirus: in 1998, a rotavirus vaccine, RotaShield (Wyeth), was licensed in the United States for routine immunization of infants. In 1999, production was stopped after the vaccine was causally linked to intussusception in infants. Other rotavirus vaccines are being developed, and preliminary trials are promising. Currently, 2 vaccines have been approved: a live oral vaccine, RotaTeq, made by Merck for use in children, and GSK’s Rotarix.
* Measles immunization can substantially reduce the incidence and severity of diarrheal diseases. Every infant should be immunized against measles at the recommended age.
Approach in Adults With Acute Diarrhea
1. Perform initial assessment.
2. Manage dehydration.
3. Prevent dehydration in patients with no signs of dehydration, using home-based fluids or ORS solution.
* Rehydration of patients with some dehydration using ORS and correct dehydration of a severely dehydrating patient with an appropriate intravenous fluid.
* Maintain hydration using ORS solution.
* Treat symptoms (if necessary, consider bismuth subsalicylate or loperamide in cases of nondysenteric traveler’s diarrhea).
4. Stratify subsequent management:
* Epidemiological clues: food, antibiotics, sexual activity, travel, day care attendance, other illness, outbreaks, season.
* Clinical clues: bloody diarrhea, abdominal pain, dysentery, wasting, fecal inflammation.
5. Obtain a fecal specimen for analysis:
* If there is severe, bloody, inflammatory, or persistent diarrhea, and at the beginning of an outbreak/epidemic.
6. Consider antimicrobial therapy for specific pathogens.
7. Report to the public health authorities.
* In outbreaks, save culture plates and isolates; freeze fecal specimens and food or water specimens at −70°C
* Notifiable in the United States: cholera, cryptosporidiosis, giardiasis, salmonellosis, shigellosis, and infection with Shiga toxin–producing E. coli.
Approach in Children With Acute Diarrhea
In 2002, WHO and UNICEF revised their recommendations for routine use of hypoosmolar ORS, and in 2004 recommended routine use of zinc as an adjunct to ORT for treatment of childhood diarrhea, irrespective of etiology. Since then, >40 countries throughout the world have adopted the recommendations. In countries where both the new ORS and zinc have been introduced, the rate of ORS usage has dramatically increased. The principles of appropriate treatment for children with diarrhea and dehydration are:
1. No unnecessary laboratory tests or medications.
2. Use ORS for rehydration:
—Perform ORT rapidly, within 3 to 4 hours.
—Routine adjunct zinc therapy for children aged 5 years or younger.
3. When dehydration is corrected, rapid realimentation:
—Normal food or age-appropriate unrestricted diet.
4. Administer additional ORS for ongoing losses through diarrhea (Fig. 1).
Home Management of Acute Diarrhea in Adults and Children
Milder and uncomplicated cases of nondysenteric diarrhea in both adults and children can be treated at home, regardless of the etiologic agent, using home-based fluid or ORS as appropriate. Parents/caregivers of children should be educated to recognize signs of dehydration and when to take children to a health facility for treatment. Early intervention and administration of home-based fluids/ORS reduces dehydration, malnutrition, and other complications and leads to fewer clinic visits and potentially fewer hospitalizations and deaths.
Self-medication is safe in otherwise healthy adults. It relieves discomfort and social dysfunction. There is no evidence that it prolongs the illness. However, this may not be appropriate in developing countries, where diarrhea requiring specific interventions is more prevalent and people may not be competent in assessing their conditions.
Principles of self-medication:
* Maintain adequate fluid intake.
* Consumption of solid food should be guided by appetite in adults; small, but more frequent meals for children.
* Antidiarrheal medication with loperamide (flexible dose according to loose bowel movements) may diminish diarrhea and shorten the duration.
* Antimicrobial treatment is reserved for prescription only in residents’ diarrhea or for inclusion in travel kits (add loperamide).
Where feasible, families in localities with a high prevalence of diarrheal diseases should be encouraged to store a few ORS packets and zinc tablets if there are children below the age of 5 in the family, so that home therapy can be initiated as soon as diarrhea starts.
Home-made Oral Fluid Recipe
Preparing 1 L of oral fluid using salt, sugar, and water at home. The ingredients to be mixed are:
* One level teaspoon of salt.
* Eight level teaspoons of sugar.
* One liter (5 cupfuls) of clean drinking water or water that has been boiled and then cooled.
Among hundreds of over-the-counter products promoted as antidiarrheal agents, only loperamide and bismuth subsalicylate have sufficient evidence of efficacy and safety.
Family knowledge about diarrhea must be reinforced in areas such as prevention, nutrition, ORT/ORS use, zinc supplementation, and when and where to seek care.
Indications for medical consultation or in-patient care are:
* Caregiver’s report of signs consistent with dehydration
* Changing mental status
* History of premature birth, chronic medical conditions, or concurrent illness
* Young age ( less than 6 mo or <8 kg weight)
* Fever ≥38°C for infants less than 3 months old or ≥39°C for children aged 3 to 36 months
* Visible blood in stool
* High-output diarrhea, including frequent and substantial volumes
* Persistent vomiting, severe dehydration, persistent fever
* Suboptimal response to ORT or inability of caregiver to administer ORT
* No improvement within 48 hours—symptoms exacerbate and overall condition gets worse
* No urine in the previous 12 hours
A cascade is a hierarchical set of diagnostic or therapeutic techniques for the same disease, ranked by the resources available. Cascades for acute diarrhea are shown in Figures 2–4.
* If facilities for referral are available, patients with severe dehydration (at risk of acute renal failure or death) should be referred to the nearest health care facility with access to intravenous fluids (levels 5 and 6 cannot replace the need for referral in case of severe dehydration).
* Levels 5 and 6 must be seen as interim measures and are better than no treatment if no intravenous facilities are available.
* When intravenous therapy is used, it must be ensured that disposable sterile syringes, needles, and drip sets are used, to avoid the risk of hepatitis B and C.
* Nasogastric therapy requires skilled staff.
* Often, intravenous fluid treatment is more easily available than nasogastric tube feeding. (Caution: there is a risk of infection with contaminated intravenous infusion equipment.)
* Nasogastric feeding is not very feasible for healthy and active older children, but it is suitable for malnourished, lethargic children.
* Nasogastric administration (ORS and diet) is especially helpful in long-term severely malnourished children (anorexia).