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Diagnosis and management of acute enteropathogens in returning travelers

Open AccessPublished:August 04, 2022DOI:https://doi.org/10.1016/j.ijid.2022.08.001

      Highlights

      • Acute enteropathogens are a common cause of gastrointestinal illness in travelers
      • Initial clinical assessment is critical in determining the severity of disease
      • Diagnosis typically comprises culture, enzyme-linked immunosorbent assay, or polymerase chain reaction
      • Management depends on the severity of dehydration and the infectious organism
      • Vaccines are available for only some of the acute enteropathogens

      Keywords

      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) (
      • Jiang ZD
      • DuPont HL.
      Etiology of travellers’ diarrhea.
      ;
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Steffen R.
      Epidemiology of travellers’ diarrhea.
      ). 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) (
      • Jiang ZD
      • DuPont HL.
      Etiology of travellers’ diarrhea.
      ;
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Steffen R.
      Epidemiology of travellers’ diarrhea.
      ). 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 (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). However, in approximately 20% diarrhea persists, requiring further investigation and intervention (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ).
      Figure 1
      Figure 1Global incidence of traveler's diarrhea. Note: figure obtained from the public domain.
      Table 1Acute enteropathgens and the returning traveler (
      • Aliabadi N
      • Lopman BA
      • Parashar UD
      • Hall AJ.
      Progress toward norovirus vaccines: considerations for further development and implementation in potential target populations.
      ,
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      Development, evaluation, and application of lateral-flow immunoassay (immunochromatography) for detection of rotavirus in bovine fecal samples.
      ,
      • Bajait C
      • Thawani V.
      Role of zinc in pediatric diarrhea.
      ,

      Rotavirus vaccination: what everyone should know. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/rotavirus/public/index.html, 2021 (accessed 21 January 2021).

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      Gastroenteritis in children: Part II. Prevention and management.
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      • Das S
      • Gupta PK
      • Das RR.
      Efficacy and safety of Saccharomyces boulardii in acute rotavirus diarrhea: double blind randomized controlled trial from a developing country.
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      • DuPont HL.
      Approach to the patient with infectious colitis.
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      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
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      • Giersing BK
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      • Kaslow DC
      • Moorthy V
      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.
      ,
      • Harris JB
      • LaRocque RC
      • Qadri F
      • Ryan ET
      • Calderwood SB
      Cholera.
      ,
      • Harro C
      • Louis Bourgeois A
      • Sack D
      • Walker R
      • DeNearing B
      • Brubaker J
      • Maier N
      • Fix A
      • Dally L
      • Chakraborty S
      • Clements JD
      • Saunders I
      • Darsley MJ
      Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge.
      ,
      • Huq A
      • Haley BJ
      • Taviani E
      • Chen A
      • Hasan NA
      • Colwell RR.
      Detection, isolation, and identification of Vibrio cholerae from the environment.
      ,
      • Jiang X
      • Wang M
      • Graham DY
      • Estes MK.
      Expression, self-assembly, and antigenicity of the Norwalk virus capsid protein.
      ,
      • Li J
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      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ).
      Acute EnteropathogenAreas of High RiskMode of TransmissionIncubation PeriodCommon SymptomsDiagnostic MethodAdult TreatmentPediatric TreatmentVaccine
      Escherichia coli

      ETEC

      EAEC

      EIEC
      South Asia, South East Asia, Middle East, Afica, Latin America, South AmericaDairy products, uncooked meats, tap water3-4 daysDiarrhoea, fever, abdominal pain, vomiting, nausea 'yellow watery stools'Stool cultureCiprofloxacin, 750 mg/day x 3 days or Azithromycin 1 g as single doseAzithromycin 10 mg/kg/day x 3 days or Ceftriaxone 50 mg/kg/day od x 3 daysDukoral OCV is given to travellers 7 days before departure
      Vibrio choleraeSouth Asia, South East Asia, Middle East, Afica, CaribbeanFecal-oral, tap water, seafood, human contact1-5 daysDiarrhoea, fever, abdominal pain, vomiting, nausea 'rice water stool'Stool cultureORS + Zn

      Doxycycline, 300 mg single dose or Azithromycin 1 g single dose
      ORS + Zn

      Doxycycline 2 mg/kg single dose or Azithromycin 20 mg/kg
      Shanchol OCV two-doses 14 days apart)

      Euvichol OCV two-doses 14 days apart)

      Dukoral OCV two-dose regimen (7 days apart)
      NorovirusWorldwideFecal-oral, human contact, respiratory1-2 daysDiarrhoea, fever, abdominal pain, vomiting, nauseaPCR assayRehydrationRehydrationVaccines using virus-like particles is under development
      RotavirusWorldwideFaecal-oral2 daysFever, vomiting, diarrhoea 'yellow watery stools'EIA, latex agglutinationRehydration ORSRehydration ORSRotarix 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
      CrytosporidiumSouth Asia, South East Asia, Middle East, Afica, Oceania, EuropeFaecal-oral, uncooked foods, tap water1-12 daysFever, vomiting, diarrhoea, headachePCR assayNitazoxanide, 500 mg twice a day for 3 daysNitazoxanide 100-200 mg twice a day for 3 daysNo vaccine is available
      CyclosporaSouth Asia, South East Asia, Middle East, Afica, Latin America, South AmericaFaecal-oral7 daysDiarrhoea, fever, abdominal pain, myalgiaPCR assay Acid-fast stainingTrimethoprim, 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
      CampylobacterSouth Asia, Southest AsiaPoultry, milk, tap water1-4 daysAcute watery diarrhoea, feverStool cultureAzithromycin, 500 mg/day for 3 daysAzithromycin 10 mg/kg/day for 3–5 daysC. jejuni capsular polysaccharide conjugate vaccine (under development)
      ShigellaNorth Africa, South Asia Southeast Asia, OceaniaHuman contact, food, tap water1-8 daysSevere diarrhea, dysentery, feverStool cultureCiprofloxacin, 500 mg twice a day for 3 daysAzithromycin, 10 mg/kg/day for 3 daysShig. flexneria 2a conjugate (SF2a-TT15) vaccine

      Shig. sonnei (WRSS1) live attenuated vaccine (both under development)
      Salmomella
      Serovar TyphiSouth Asia, AfricaHuman contact, food, tap water5-14 daysFever, headache, malaise, abdominal pain, diarrheaBlood and stool cultureCiprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 daysCiprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 daysTypbar-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
      NontyphoidalSoutheast Asia, OceaniaPoultry, egg, meat8-24 hoursFever, headache, malaise, abdominal pain, diarrheaBlood and stool cultureCiprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 daysCiprofloxacin, 20 mg/kg/day for 7 days; or azithromycin, 20 mg/kg/day for 7 days
      Note: All figures were obtained from public domain. ORS + Zn = oral rehydration solution + Zinc.

      What should I consider in my initial assessment?

      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) (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). Disease patterns vary greatly among countries, and within countries there can also be differences depending on environment, ecology, altitude, climate, vectors, and other factors (
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). Other useful information to obtain from the patient includes types of foods and liquids consumed, exposure to ill people, vaccination history, and medications taken (
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). 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 (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). 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 (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ).

      How do I make a diagnosis?

      Current methods for detecting acute enteropathogens comprise stool and blood cultures, enzyme-linked immunosorbent assays (ELISAs), and polymerase chain reaction (PCR) (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). 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 (
      • Leung AKC
      • Leung AAM
      • Wong AHC
      • Hon KL.
      Travelers' diarrhea: a clinical review.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ).
      There is no single method available for the diagnosis of all six pathogenic strains of E. coli (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). Additional morphologic, typing, biochemical, phenotypic, and genotypic analysis is required for identification and confirmation of the specific pathotypes (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). Currently, molecular techniques are preferred for more rapid detection and identification (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). Fresh stool, rectal swabs, or surgical specimens are collected and transferred in buffered glycerol or Cary-Blair transport medium (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). 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 (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). Molecular detection is based on PCR, microarray, or enzyme-linked immunoassay (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). 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 (
      • DebRoy C
      • Roberts E
      • Fratamico PM.
      Detection of O antigens in Escherichia coli.
      ;
      • Noller AC
      • McEllistrem MC
      • Pacheco AGF
      • Boxrud DJ
      • Harrison LH.
      Multilocus variable-number tandem repeat analysis distinguishes outbreak and sporadic Escherichia coli O157:H7 isolates.
      ;
      • Wang L
      • Rothemund D
      • Curd H
      • Reeves PR.
      Species-wide variation in the Escherichia coli flagellin (H-antigen) gene.
      ).
      Clinically distinguishing cholera in a patient infected with another enteric pathogen that causes acute watery diarrhea is very difficult without laboratory testing (
      • Harris JB
      • LaRocque RC
      • Qadri F
      • Ryan ET
      • Calderwood SB
      Cholera.
      ;
      • Learoyd TP
      • Gaut RM.
      Cholera: under diagnosis and differentiation from other diarrhoeal diseases.
      ). Stool culture is the gold-standard diagnostic method for the isolation and identification of Vibrio cholerae serogroup O1 or O139 (
      • Huq A
      • Haley BJ
      • Taviani E
      • Chen A
      • Hasan NA
      • Colwell RR.
      Detection, isolation, and identification of Vibrio cholerae from the environment.
      ;
      • Ramamurthy T
      • Das B
      • Chakraborty S
      • Mukhopadhyay AK
      • Sack DA.
      Diagnostic techniques for rapid detection of Vibrio cholerae O1/O139.
      ). Proper sample collection (stool/rectal swabs) and transportation to the laboratory is the key to increasing the efficacy of the test (
      • Huq A
      • Haley BJ
      • Taviani E
      • Chen A
      • Hasan NA
      • Colwell RR.
      Detection, isolation, and identification of Vibrio cholerae from the environment.
      ;
      • Ramamurthy T
      • Das B
      • Chakraborty S
      • Mukhopadhyay AK
      • Sack DA.
      Diagnostic techniques for rapid detection of Vibrio cholerae O1/O139.
      ). 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 (
      • Huq A
      • Haley BJ
      • Taviani E
      • Chen A
      • Hasan NA
      • Colwell RR.
      Detection, isolation, and identification of Vibrio cholerae from the environment.
      ;
      • Ramamurthy T
      • Das B
      • Chakraborty S
      • Mukhopadhyay AK
      • Sack DA.
      Diagnostic techniques for rapid detection of Vibrio cholerae O1/O139.
      ). PCR is another sensitive method for the diagnosis of cholera, but improved laboratory capacity is required for performing such a test (
      • Huq A
      • Haley BJ
      • Taviani E
      • Chen A
      • Hasan NA
      • Colwell RR.
      Detection, isolation, and identification of Vibrio cholerae from the environment.
      ;
      • Ramamurthy T
      • Das B
      • Chakraborty S
      • Mukhopadhyay AK
      • Sack DA.
      Diagnostic techniques for rapid detection of Vibrio cholerae O1/O139.
      ).
      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%) (
      • Parashar UD
      • Nelson EAS
      • Kang G.
      Diagnosis, management, and prevention of rotavirus gastroenteritis in children.
      ). Rotavirus strain characterization can be performed using reverse transcriptase-PCR (RT-PCR) to identify both G and P types (
      • Kang G
      • Iturriza-Gomara M
      • Wheeler JG
      • et al.
      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 (
      • Al-Yousif Y
      • Anderson J
      • Chard-Bergstrom C
      • Kapil S
      Development, evaluation, and application of lateral-flow immunoassay (immunochromatography) for detection of rotavirus in bovine fecal samples.
      ). The test is based on antibodies specific to rotavirus and gives results in 10 min (
      • Al-Yousif Y
      • Anderson J
      • Chard-Bergstrom C
      • Kapil S
      Development, evaluation, and application of lateral-flow immunoassay (immunochromatography) for detection of rotavirus in bovine fecal samples.
      ). As for rotavirus, ELISA and RT-PCR are commonly used to detect norovirus in either stool or vomit specimens (
      • Patel MM
      • Hall AJ
      • Vinjé J
      • Parashar UD.
      Noroviruses: a comprehensive review.
      ). The sensitivity of the test depends on viral load and detection capacity for various genetic subtypes (
      • Patel MM
      • Hall AJ
      • Vinjé J
      • Parashar UD.
      Noroviruses: a comprehensive review.
      ). 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 (
      • Patel MM
      • Hall AJ
      • Vinjé J
      • Parashar UD.
      Noroviruses: a comprehensive review.
      ).
      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 (
      • Smith H
      Diagnostics.
      ). The detection of oocysts in the stool is difficult; hence, fecal samples should be collected on three separate days and examined microscopically (
      • Smith H
      Diagnostics.
      ). 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 (
      • Smith H
      Diagnostics.
      ).
      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 (
      • Tortajada-Genaro LA
      • Rodrigo A
      • Hevia E
      • Mena S
      • Niñoles R
      • Á Maquieira
      Microarray on digital versatile disc for identification and genotyping of Salmonella and Campylobacter in meat products.
      ). In patients with bloody diarrhea, stool culture and fecal toxin assay with commercial ELISAs are recommended (
      • DuPont HL.
      Clinical practice. Bacterial diarrhea.
      ).

      What should be my management strategy?

      Management will depend on the severity of dehydration and the organism identified or suspected (
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Steffen R.
      Epidemiology of travellers’ diarrhea.
      ). 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 (
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Steffen R.
      Epidemiology of travellers’ diarrhea.
      ). Currently, the treatment includes the macrolide azithromycin, the third-generation cephalosporin ceftriaxone, and the fluoroquinolone ciprofloxacin (Table 1) (
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Steffen R.
      Epidemiology of travellers’ diarrhea.
      ). Mild cases of enteroinvasive E. coli (EIEC) are self-limiting, but sometimes this pathogen causes severe symptoms (mimicking shigellosis) that require antibiotic treatment (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). ETEC can cause severe diarrhea; intravenous rehydration may be necessary (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). 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 (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ). Enteropathogenic E. coli (EPEC) shows a high degree of multidrug resistance to recommended antibiotics (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). However, adherent-invasive E. coli (AIEC) can be treated with a wide range of antibiotics (e.g., ciprofloxacin or fluoroquinolones) (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ). 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 (
      • Croxen MA
      • Law RJ
      • Scholz R
      • Keeney KM
      • Wlodarska M
      • Finlay BB.
      Recent advances in understanding enteric pathogenic Escherichia coli.
      ).
      Rapid assessment and management of dehydration are crucial for cholera management, and the treatment plan is chosen according to dehydration status (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). Patients with some signs of dehydration can be effectively treated with oral rehydration solution (ORS) (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). Patients with severe dehydration need immediate intravenous fluid replacement with 100 ml/kg during a 3-hour administration period (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). One-third of the total volume should be given in the first 30 minutes (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). 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) (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). 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 (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Ross AGP
      • Olds GR
      • Cripps AW
      • Farrar JJ
      • McManus DP.
      Enteropathogens and chronic illness in returning travelers.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). According to the World Health Organization (WHO) guideline, antibiotics should be used only in patients with severe dehydration (
      • Pietroni MAC.
      Case management of cholera.
      ). The choice of antibiotic should be based on availability and local antibiotic susceptibility (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). The antibiotic options include macrolides, fluoroquinolones, and tetracycline (
      • Davies HG
      • Bowman C
      • Luby SP.
      Cholera–management and prevention.
      ;
      • Pietroni MAC.
      Case management of cholera.
      ;
      • Sousa FBM
      • Nolêto IRSG
      • Chaves LS
      • et al.
      A comprehensive review of therapeutic approaches available for the treatment of cholera.
      ). However, a single dose of azithromycin (1 g for adults or 20 mg/kg for children) is effective for the treatment of cholera (
      • Saha D
      • Karim MM
      • Khan WA
      • Ahmed S
      • Salam MA
      • Bennish ML.
      Single-dose azithromycin for the treatment of cholera in adults.
      ). According to
      • Saha D
      • Karim MM
      • Khan WA
      • Ahmed S
      • Salam MA
      • Bennish ML.
      Single-dose azithromycin for the treatment of cholera in adults.
      , “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 (
      • Bajait C
      • Thawani V.
      Role of zinc in pediatric diarrhea.
      ;
      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
      ). The findings from a systematic review by
      • Imdad A.
      • Herzer K.
      • Mayo-Wilson E.
      • Yakoob M.Y.
      • Bhutta Z.A.
      Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age.
      included 43 studies and 230,354 children (
      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
      ). VAS led to a 24% reduction in all‐cause mortality (risk ratio 0.76 [95% CI 0.69, 0.83]) (
      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
      ). The benefits of VAS were strongest in high‐risk populations (
      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
      ). Approximately one death was prevented for every 45 children who received the supplement (
      • Francis DK.
      Vitamin A supplementation for preventing death and illness in children 6 months to 5 years of age.
      ).
      Most rotavirus cases are self-limiting (
      • Crawford SE
      • Ramani S
      • Tate JE
      • Parashar UD
      • Svensson L
      • Hagbom M
      • Franco MA
      • Greenberg HB
      • O'Ryan M
      • Kang G
      • Desselberger U
      • Estes MK.
      Rotavirus infection.
      ). Severe dehydration in children becomes life-threatening if not treated (
      • Crawford SE
      • Ramani S
      • Tate JE
      • Parashar UD
      • Svensson L
      • Hagbom M
      • Franco MA
      • Greenberg HB
      • O'Ryan M
      • Kang G
      • Desselberger U
      • Estes MK.
      Rotavirus infection.
      ). Rehydration can be performed with hypo-osmolar oral rehydration salts or, in patients with severe dehydration or vomiting, with intravenous fluids (
      • Crawford SE
      • Ramani S
      • Tate JE
      • Parashar UD
      • Svensson L
      • Hagbom M
      • Franco MA
      • Greenberg HB
      • O'Ryan M
      • Kang G
      • Desselberger U
      • Estes MK.
      Rotavirus infection.
      ). Continuation of regular diet and adequate fluid intake are recommended for children with minimal or ongoing dehydration (
      • Crawford SE
      • Ramani S
      • Tate JE
      • Parashar UD
      • Svensson L
      • Hagbom M
      • Franco MA
      • Greenberg HB
      • O'Ryan M
      • Kang G
      • Desselberger U
      • Estes MK.
      Rotavirus infection.
      ). Treatment with probiotics has a positive immunomodulatory effect that improves intestinal function in children and might decrease the episodes of diarrhea (
      • Das S
      • Gupta PK
      • Das RR.
      Efficacy and safety of Saccharomyces boulardii in acute rotavirus diarrhea: double blind randomized controlled trial from a developing country.
      ;
      • Sindhu KNC
      • Sowmyanarayanan TV
      • Paul A
      • Babji S
      • Ajjampur SSR
      • Priyadarshini S
      • Sarkar R
      • Balasubramanian KA
      • Wanke CA
      • Ward HD
      • Kang G.
      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 (
      • Sindhu KNC
      • Sowmyanarayanan TV
      • Paul A
      • Babji S
      • Ajjampur SSR
      • Priyadarshini S
      • Sarkar R
      • Balasubramanian KA
      • Wanke CA
      • Ward HD
      • Kang G.
      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) (
      • Sindhu KNC
      • Sowmyanarayanan TV
      • Paul A
      • Babji S
      • Ajjampur SSR
      • Priyadarshini S
      • Sarkar R
      • Balasubramanian KA
      • Wanke CA
      • Ward HD
      • Kang G.
      Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial.
      ). In settings with evidence of mortality, zinc supplementation has been shown to be effective in reducing the duration and severity of diarrhea (
      • Telmesani AM.
      Oral rehydration salts, zinc supplement and rota virus vaccine in the management of childhood acute diarrhea.
      ). 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 (
      • Telmesani AM.
      Oral rehydration salts, zinc supplement and rota virus vaccine in the management of childhood acute diarrhea.
      ). Norovirus patients are treated in a similar manner (
      • Churgay CA
      • Aftab Z.
      Gastroenteritis in children: Part II. Prevention and management.
      ). Patients are given supportive treatment for diarrhea along with adjunctive treatments such as antiemetics, analgesics, and antimotility agents (
      • Churgay CA
      • Aftab Z.
      Gastroenteritis in children: Part II. Prevention and management.
      ;
      • Thorne L
      • Arias A
      • Goodfellow I.
      Advances toward a norovirus antiviral: from classical inhibitors to lethal mutagenesis.
      ). Rehydration with ORS or intravenous fluids is sometimes performed in patients who are moderately or severely dehydrated (
      • Churgay CA
      • Aftab Z.
      Gastroenteritis in children: Part II. Prevention and management.
      ;
      • Thorne L
      • Arias A
      • Goodfellow I.
      Advances toward a norovirus antiviral: from classical inhibitors to lethal mutagenesis.
      ).
      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 (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ;
      • Sparks H
      • Nair G
      • Castellanos-Gonzalez A
      • White Jr., AC
      Treatment of Cryptosporidium: what we know, gaps, and the way forward.
      ). 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 (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ;
      • Sparks H
      • Nair G
      • Castellanos-Gonzalez A
      • White Jr., AC
      Treatment of Cryptosporidium: what we know, gaps, and the way forward.
      ). The antiparasitic drug nitazoxanide can help relieve diarrhea by targeting the parasite (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ;
      • Sparks H
      • Nair G
      • Castellanos-Gonzalez A
      • White Jr., AC
      Treatment of Cryptosporidium: what we know, gaps, and the way forward.
      ). To reduce viral load and boost immune response in patients who are immunocompromised with HIV/AIDS, antiretroviral therapies are required (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ;
      • Sparks H
      • Nair G
      • Castellanos-Gonzalez A
      • White Jr., AC
      Treatment of Cryptosporidium: what we know, gaps, and the way forward.
      ). Trimethoprim-sulfamethoxazole (TMP-SMX) is a combination drug used to treat patients with Cyclospora infection (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ). TMP 160 mg/SMX 800 mg for adults and TMP 4 mg/SMX 20 mg per kg body weight for pediatric patients, twice daily for 3 days, are recommended (
      • Li J
      • Cui Z
      • Qi M
      • Zhang L.
      Advances in cyclosporiasis diagnosis and therapeutic intervention.
      ).
      For Campylobacter and Shigella, antimicrobial therapy is indicated (Table 1). For nontyphoidal Salmonella, antibiotics are given to patients in whom bacteremic disease is suspected (
      • DuPont HL.
      Approach to the patient with infectious colitis.
      ). 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 (
      • Meiring JE
      • Shakya M
      • Khanam F
      • Voysey M
      • Phillips MT
      • Tonks S
      • Thindwa D
      • Darton TC
      • Dongol S
      • Karkey A
      • Zaman K
      • Baker S
      • Dolecek C
      • Dunstan SJ
      • Dougan G
      • Holt KE
      • Heyderman RS
      • Qadri F
      • Pitzer VE
      • Basnyat B
      • Gordon MA
      • Clemens J
      • Pollard AJ
      STRATAA Study Group
      Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study.
      ). Campylobacter jejuni resistance to fluoroquinolones has become a concern in Southeast Asia, with rates of resistance of 80% reported in Thailand (
      • Sproston EL
      • Wimalarathna HML
      • Sheppard SK.
      Trends in fluoroquinolone resistance in Campylobacter.
      ;
      • Whelan MVX
      • Ardill L
      • Koide K
      • Nakajima C
      • Suzuki Y
      • Simpson JC
      • Ó Cróinín T.
      Acquisition of fluoroquinolone resistance leads to increased biofilm formation and pathogenicity in Campylobacter jejuni.
      ). Multidrug resistance in a distinct genotype of Salmonella serovar Typhimurium (ST313) has also emerged in Africa (
      • Van Puyvelde S
      • Pickard D
      • Vandelannoote K
      • Heinz E
      • Barbé B
      • de Block T
      • Clare S
      • Coomber EL
      • Harcourt K
      • Sridhar S
      • Lees EA
      • Wheeler NE
      • Klemm EJ
      • Kuijpers L
      • Mbuyi Kalonji L
      • Phoba MF
      • Falay D
      • Ngbonda D
      • Lunguya O
      • Jacobs J
      • Dougan G
      • Deborggraeve S
      An African Salmonella Typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation.
      ).

      What vaccines are currently available?

      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 (
      • Cravioto A
      • Tello A
      • Villafán H
      • Ruiz J
      • del Vedovo S
      • Neeser JR.
      Inhibition of localized adhesion of enteropathogenic Escherichia coli to HEp-2 cells by immunoglobulin and oligosaccharide fractions of human colostrum and breast milk.
      ;
      • Parissi-Crivelli A
      • Parissi-Crivelli JM
      • Girón JA.
      Recognition of enteropathogenic Escherichia coli virulence determinants by human colostrum and serum antibodies.
      ). For Shiga toxin-producing E. coli, vaccines are being developed in mice and cattle (
      • Fingermann M
      • Avila L
      • De Marco MB
      • Vázquez L
      • Di Biase DN
      • Müller AV
      • Lescano M
      • Dokmetjian JC
      • Fernández Castillo S
      • Pérez Quiñoy JL
      OMV-based vaccine formulations against Shiga toxin producing Escherichia coli strains are both protective in mice and immunogenic in calves.
      ). ETEC vaccines containing heat-labile toxins exert protection against EAEC (
      • Sack DA
      • Shimko J
      • Torres O
      • Bourgeois AL
      • Francia DS
      • Gustafsson B
      • Kärnell A
      • Nyquist I
      • Svennerholm AM.
      Randomised, double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhoea of travellers to Guatemala and Mexico.
      ). 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 (
      • Sack DA
      • Shimko J
      • Torres O
      • Bourgeois AL
      • Francia DS
      • Gustafsson B
      • Kärnell A
      • Nyquist I
      • Svennerholm AM.
      Randomised, double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhoea of travellers to Guatemala and Mexico.
      ). 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 (
      • Sack DA
      • Shimko J
      • Torres O
      • Bourgeois AL
      • Francia DS
      • Gustafsson B
      • Kärnell A
      • Nyquist I
      • Svennerholm AM.
      Randomised, double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhoea of travellers to Guatemala and Mexico.
      ). A live attenuated ETEC vaccine, ACE527, when coadministered with the mucosal adjuvant double-mutant heat-labile toxin, showed strong protection (
      • Harro C
      • Louis Bourgeois A
      • Sack D
      • Walker R
      • DeNearing B
      • Brubaker J
      • Maier N
      • Fix A
      • Dally L
      • Chakraborty S
      • Clements JD
      • Saunders I
      • Darsley MJ
      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 (
      • Qadri F
      • Akhtar M
      • Bhuiyan TR
      • Chowdhury MI
      • Ahmed T
      • Rafique TA
      • Khan A
      • Rahman SIA
      • Khanam F
      • Lundgren A
      • Wiklund G
      • Kaim J
      • Löfstrand M
      • Carlin N
      • Bourgeois AL
      • Maier N
      • Fix A
      • Wierzba T
      • Walker RI
      • Svennerholm AM.
      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) (

      Rotavirus vaccination: what everyone should know. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/rotavirus/public/index.html, 2021 (accessed 21 January 2021).

      ). 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) (
      WHO
      Detailed review paper on rotavirus vaccines to be presented to the WHO Strategic Advisory Group of Experts (SAGE) on Immunization.
      ). Two new rotavirus vaccines, ROTAVAC (Bharat Biotech, Hyderabad, India) and ROTASIIL (Serum Institute of India Pvt. Ltd., Pune, India), are now WHO-prequalified (
      • Skansberg A
      • Sauer M
      • Tan M
      • Santosham M
      • Jennings MC.
      Product review of the rotavirus vaccines ROTASIIL, ROTAVAC, and Rotavin-M1.
      ). The WHO recommends using the rotavirus vaccine in national immunization programs in South and Southeast Asia and in Sub-Saharan Africa (). Viral diversity and short duration of immunity against the emerging genogroups of norovirus are major obstacles in vaccinating people against the virus (
      • Parrino TA
      • Schreiber DS
      • Trier JS
      • Kapikian AZ
      • Blacklow NR.
      Clinical immunity in acute gastroenteritis caused by Norwalk agent.
      ). However, several vaccines using virus-like particles are currently in preclinical development (
      • Jiang X
      • Wang M
      • Graham DY
      • Estes MK.
      Expression, self-assembly, and antigenicity of the Norwalk virus capsid protein.
      ;
      • Johnson PC
      • Mathewson JJ
      • DuPont HL
      • Greenberg HB.
      Multiple-challenge study of host susceptibility to Norwalk gastroenteritis in US adults.
      ). Clinical trials examining various routes of administration (e.g., intranasal, oral, and intramuscular) are ongoing (
      • Aliabadi N
      • Lopman BA
      • Parashar UD
      • Hall AJ.
      Progress toward norovirus vaccines: considerations for further development and implementation in potential target populations.
      ;
      • Giersing BK
      • Vekemans J
      • Nava S
      • Kaslow DC
      • Moorthy V
      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 (
      • Khanam F
      • Ross AG
      • McMillan NAJ
      • Qadri F.
      Toward typhoid fever elimination.
      ;
      • Pasetti MF
      • Simon JK
      • Sztein MB
      • Levine MM.
      Immunology of gut mucosal vaccines.
      ). 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 (
      • Riddle MS
      • Guerry P.
      Status of vaccine research and development for Campylobacter jejuni.
      ;
      • Sarker P
      • Mily A
      • Ara A
      • Haque F
      • Maier N
      • Wierzba TF
      • Walker RI
      • Venkatesan MM
      • Raqib R.
      Functional antibodies and innate immune responses to WRSS1, a live oral Shigella sonnei vaccine candidate, in Bangladeshi adults and children.
      ;
      • van der Put RMF
      • Smitsman C
      • de Haan A
      • Hamzink M
      • Timmermans H
      • Uittenbogaard J
      • Westdijk J
      • Stork M
      • Ophorst O
      • Thouron F
      • Guerreiro C
      • Sansonetti PJ
      • Phalipon A
      • Mulard LA.
      The first-in-human synthetic glycan-based conjugate vaccine candidate against Shigella.
      ).

      Further educational resources for professionals

      • WHO. Diarrhea.
      https://www.who.int/health-topics/diarrhoea#tab=tab_1
      • Centers for Disease Control and Prevention. Guidelines for the management of acute diarrhea after a disaster.
      https://www.cdc.gov/disasters/disease/diarrheaguidelines.html
      • World Gastroenterology Organisation. Acute diarrhea in adults and children: a global perspective.

      Contributors’ Statement

      All authors contributed to writing the article and approved the final submission.

      Declarations of competing interest

      The authors have no competing interests to declare.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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