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Acute watery diarrhea is one of the leading causes of gastrointestinal illness in returning travelers (Figure 1). Acute diarrhea is generally defined as the passage of ≥3 unformed stools per 24 hours plus at least one additional symptom (e.g., nausea, vomiting, abdominal cramps, fever, blood/mucus in the stools, or fecal urgency) (
). The clinically important acute enteropathogens include specific variants of Escherichia coli (including enterotoxigenic [ETEC] and enteroaggregative [EAEC] strains), Vibrio cholerae norovirus, rotavirus, Cyclospora, Cryptosporidium, Campylobacter, Shigella, and Salmonella (Table 1) (
). Most cases go unreported, however, and patients are typically treated at home. The disease is usually self-limiting, with about half of patients spontaneously cured within 48 hours (
WHO Product Development for Vaccines Advisory Committee Report from the World Health Organization's third Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 8–10th June 2016.
Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge.
Vaccines using virus-like particles is under development
Rotavirus
Worldwide
Faecal-oral
2 days
Fever, vomiting, diarrhoea 'yellow watery stools'
EIA, latex agglutination
Rehydration ORS
Rehydration ORS
Rotarix two-doses at 2 and 4 months Rotateq three-doses at 2, 4 and 6 months Rotavac three-doses at 2, 4 and 6 months Rotasiil three-doses at 6, 10, and 14 weeks
Crytosporidium
South Asia, South East Asia, Middle East, Afica, Oceania, Europe
Faecal-oral, uncooked foods, tap water
1-12 days
Fever, vomiting, diarrhoea, headache
PCR assay
Nitazoxanide, 500 mg twice a day for 3 days
Nitazoxanide 100-200 mg twice a day for 3 days
No vaccine is available
Cyclospora
South Asia, South East Asia, Middle East, Afica, Latin America, South America
Faecal-oral
7 days
Diarrhoea, fever, abdominal pain, myalgia
PCR assay Acid-fast staining
Trimethoprim, 160 mg Sulfamethoxazole 800 mg twice a day for 3 days
Trimethoprim 4 mg/kg Sulfamethoxazole 20 mg/kg twice a day for 3 days
No vaccine is available
Campylobacter
South Asia, Southest Asia
Poultry, milk, tap water
1-4 days
Acute watery diarrhoea, fever
Stool culture
Azithromycin, 500 mg/day for 3 days
Azithromycin 10 mg/kg/day for 3–5 days
C. jejuni capsular polysaccharide conjugate vaccine (under development)
Shigella
North Africa, South Asia Southeast Asia, Oceania
Human contact, food, tap water
1-8 days
Severe diarrhea, dysentery, fever
Stool culture
Ciprofloxacin, 500 mg twice a day for 3 days
Azithromycin, 10 mg/kg/day for 3 days
Shig. flexneria 2a conjugate (SF2a-TT15) vaccine Shig. sonnei (WRSS1) live attenuated vaccine (both under development)
Ciprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 days
Ciprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 days
Typbar-TCV® single dose conjugate vaccine PedaTyph™ single dose conjugate vaccine Vi polysaccharide (ViPS) single dose vaccine Ty21a four-dose live oral vaccine on day 1,3, 5, 7
In the initial assessment of a patient with acute diarrhea, a detailed history and physical examination are essential to determine the severity of dehydration (mild, moderate, or severe). The physician needs to carefully assess the patient's age (especially if <6 months), conscious state, capillary refill, skin turgor (retraction), respiratory rate, fluid intake, urine output, and body weight (>10% loss is severe) (
). Disease patterns vary greatly among countries, and within countries there can also be differences depending on environment, ecology, altitude, climate, vectors, and other factors (
). Other useful information to obtain from the patient includes types of foods and liquids consumed, exposure to ill people, vaccination history, and medications taken (
). A physician should also know the incubation periods of potential infections (Table 1). Acute clinical symptoms (appearing <7 days after exposure) could be indicative of enteric viral or bacterial infection, whereas chronic symptoms (appearing ≥14 days after exposure) may suggest an enteric protozoal or helminthic infection (
). Consideration of these factors, in combination with careful assessment of the timing of clinical signs and symptoms, should help the physician determine the appropriate laboratory test to order and whether empirical treatment should be initiated (
). Modern PCR approaches detect bacterial, viral, and protozoal pathogens with high sensitivity and specificity, but technical skills and equipped laboratories are required. Table 1 lists the diagnostic methods commonly used for select acute enteropathogens (
). Additional morphologic, typing, biochemical, phenotypic, and genotypic analysis is required for identification and confirmation of the specific pathotypes (
). For phenotypic detection of pathogen, the stool is examined in selective media with biochemical assays. Infection of cultured cells is determined through cytotoxicity assays, fluorescent staining, and adherence pattern assays (
). Various typing methods, such as O- and H-antigen serotyping, multilocus sequence typing, ribotyping, pulsed-field gel electrophoresis, and multiple-locus variable-number tandem repeat analysis are used (
Clinically distinguishing cholera in a patient infected with another enteric pathogen that causes acute watery diarrhea is very difficult without laboratory testing (
). Cary-Blair is the preferred transport medium for sample transportation from field settings to the laboratory, and selective thiosulfate-citrate-bile salts agar or taurocholate-tellurite-gelatin agar is preferred for isolation and identification (
Rotavirus can be detected in stool samples of patients with gastroenteritis through antigen-based ELISAs and immunochromatographic assays. These tests have high sensitivity and specificity (90-95%) (
Quantitation of group A rotavirus by real-time reverse-transcription-polymerase chain reaction: correlation with clinical severity in children in South India.
). In addition, a rapid chromatographic immunoassay for the qualitative detection of rotavirus in human stool specimens can be used for rapid detection (
). Because of a lack of accurate diagnostic methods and lack of available facilities in most developing countries, it is difficult to determine the true burden of disease (
The laboratory diagnosis of cryptosporidiosis is performed microscopically by detection of oocysts in stool samples using various techniques such as acid-fast staining, direct fluorescent antibody, and/or enzyme immunoassay for detection of Cryptosporidium spp. antigens (
). In reference diagnostic laboratories, PCR is widely used as the gold standard to identify Cryptosporidium at the species level, although this method is rather expensive (
Campylobacter, Shigella, and Salmonella are routinely detected using stool or blood culture (Table 1). Microarray on digital versatile disc is now being used for identification and genotyping of Salmonella and Campylobacter in meat products (
). Fluid replacement is critical in patients with profuse watery diarrhea and dysentery.Antibiotics play an important role in shortening the duration, frequency, and severe complications of bacterial diarrhea (
). Currently, the treatment includes the macrolide azithromycin, the third-generation cephalosporin ceftriaxone, and the fluoroquinolone ciprofloxacin (Table 1) (
). Mild cases of enteroinvasive E. coli (EIEC) are self-limiting, but sometimes this pathogen causes severe symptoms (mimicking shigellosis) that require antibiotic treatment (
). Antisecretory drugs such as loperamide, along with antibiotics such as fluoroquinolones, azithromycin, and rifaximin, can lessen the duration of infection and are commonly used in self-treatment (
). Recently, yeast-based probiotics have also been used. Diffusely adherent E. coli (DAEC) is susceptible to nalidixic acid, ceftazidime, gentamicin, lomefloxacin, and ofloxacin. Zinc and nutritional therapy are also beneficial for treating E. coli diarrhea (
). For children <1 year of age, the volume replacement plan is for administration during a 6-hour period (30 ml/kg in the first hour and 70 ml/kg in subsequent 5 hours) (
). Ringer's lactate solution (sodium chloride, sodium lactate, potassium chloride, and calcium chloride) and cholera saline (sodium chloride, potassium chloride, and sodium acetate) are the intravenous fluids commonly used for the management of cholera (
, “Patients who were treated in a clinical trial with azithromycin had a shorter duration of diarrhea than did patients treated with ciprofloxacin (median, 30 vs 78 hours); a lower frequency of vomiting (43% vs 67%); fewer stools (median, 36 vs 52); and a lower stool volume (median, 114 vs 322 ml/kg of body weight)”. Supplementation with vitamin A (VAS) and zinc can reduce the duration and severity of diarrhea in children up to 5 years of age (
). Rehydration can be performed with hypo-osmolar oral rehydration salts or, in patients with severe dehydration or vomiting, with intravenous fluids (
). Treatment with probiotics has a positive immunomodulatory effect that improves intestinal function in children and might decrease the episodes of diarrhea (
Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.
). In a recent trial of 124 children with diarrhea (82 rotaviral and 42 cryptosporidial), baseline and clinical parameters were comparable between children receiving Lactobacillus rhamnosus GG (LGG) and placebo (
Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.
). At the end of follow-up, fewer children with rotaviral diarrhea on LGG had repeated diarrheal episodes (25% vs 46%; P = .048) and impaired intestinal function (48% vs 72%; P = .027) (
Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.
). A pooled analysis of randomized controlled trials of zinc supplementation performed in nine low-income countries in Latin America and the Caribbean, South and Southeast Asia, and the Western Pacific demonstrated that supplemental zinc led to an 18% reduction in the incidence of diarrhea and a 25% reduction in the prevalence of diarrhea (
Most patients with cryptosporidiosis recover within 2 weeks without treatment. However, immunocompromised patients recover more slowly, and the disease can be life-threatening in a subset of patients (
). The management of patients is usually with fluid and electrolyte therapy (e.g., sodium, potassium, and calcium), antimotility drugs (e.g., loperamide), and supplemental zinc (
For Campylobacter and Shigella, antimicrobial therapy is indicated (Table 1). For nontyphoidal Salmonella, antibiotics are given to patients in whom bacteremic disease is suspected (
). Multidrug-resistant Salmonella serovar Typhi and Salmonella serovar Paratyphi are common in Asia and Sub-Saharan Africa, and there are increasing reports of reduced susceptibility to fluoroquinolones (
Currently, vaccines are available against EPEC, DAEC, AIEC, and EIEC. Studies have shown that breast milk contains antibodies against EPEC and protects infants from diarrhea (
Inhibition of localized adhesion of enteropathogenic Escherichia coli to HEp-2 cells by immunoglobulin and oligosaccharide fractions of human colostrum and breast milk.
). Because of the diverse strains of the ETEC pathogen, vaccines based on various formulations are being produced; these include live attenuated, inactivated whole-cell, hybrid toxin-producing, and fimbrial antigen-containing vaccines (
). The Dukoral oral cholera vaccine, composed of the B subunit of cholera toxin (CTB), provides short-term protection against ETEC diarrhea in travelers (Table 1). An oral inactivated vaccine with recombinant CTB (rCTB) and a mix of major colonization factors (CFs), rCTB-CF ETEC, has been studied and found to result in decreased severity of diarrhea when compared with placebo among vaccinated travelers (
Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge.
). A phase I/II clinical trial, conducted on the oral whole-cell inactivated ETEC vaccine ETVAX, showed that the vaccine was safe and immunogenic among all age groups in Bangladesh (
Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial.
). To date, however, there is no licensed vaccine available for protection against ETEC diarrhea.
Vaccination is considered the most effective way to prevent rotavirus infection among children. Currently, two WHO-prequalified vaccines are available globally: ROTARIX (GlaxoSmithKline Biologicals) and RotaTeq (Merck & Co., Inc.). RotaTeq is a live attenuated pentavalent vaccine that should be given orally in three doses at 2, 4 and 6 months of age. ROTARIX is a live attenuated monovalent vaccine that should be given orally in two doses at 2 and 4 months of age (Table 1) (
). The efficacy of RotaTeq was 98% in protection against severe rotavirus gastroenteritis and 74% in protection against gastroenteritis of any severity. ROTARIX gives 85-96% protection against severe rotavirus gastroenteritis among children from the “developed” world (Europe, USA) (
). Two new rotavirus vaccines, ROTAVAC (Bharat Biotech, Hyderabad, India) and ROTASIIL (Serum Institute of India Pvt. Ltd., Pune, India), are now WHO-prequalified (
). Viral diversity and short duration of immunity against the emerging genogroups of norovirus are major obstacles in vaccinating people against the virus (
WHO Product Development for Vaccines Advisory Committee Report from the World Health Organization's third Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 8–10th June 2016.
. There is currently no licensed vaccine for protection against cryptosporidiosis.
Three vaccines to protect against typhoid fever are licensed in the United States: a live attenuated strain Ty21a vaccine; a parenteral Vi capsular polysaccharide vaccine; and a parenteral killed whole-cell vaccine (
). A C. jejuni capsular polysaccharide conjugate vaccine, a Shigella flexneri 2a conjugate vaccine (SF2a-TT15), and a Shigella sonnei live attenuated vaccine (WRSS1) are in various stages of development (
Inhibition of localized adhesion of enteropathogenic Escherichia coli to HEp-2 cells by immunoglobulin and oligosaccharide fractions of human colostrum and breast milk.
Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge.
Quantitation of group A rotavirus by real-time reverse-transcription-polymerase chain reaction: correlation with clinical severity in children in South India.
Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial.
Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.
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