Infectious Diarrhoea, gastroenteritis or food posioning accounts for a large proportion of visits to family physicians and emergency departments. I discuss the main causes, diagnosis and management.

1. INFECTIOUS
DIARRHOEA
DR MARK FERNANDES
CONSULTANT GASTROENTEROLOGIST

2. SCOPE
• DEFINITION
• INCIDENCE
• AETIOLOGY
• PATHOGENESIS
• DIAGNOSTIC TESTING
• MANAGEMENT

3. DEFINITIONS
• Passage of 3 unformed stools in 24 h plus an enteric symptoms (nausea,
vomiting, abdominal pain/cramps, tenesmus, fecal urgency, moderate to
severe flatulence)
• Acute Diarrhoea (≤14 days), Persistent diarrhea (15 – 30 days), Chronic
Diarrhoea (>30 days)
• Watery Diarrhoea or
• Inflammatory diarrhoea/Dysentery -
inflammation and ulceration of the colon, with diarrhoea,
mucous and hemorrhage.

4. INCIDENCE

5. RATES IN SINGAPORE
WEEKLY INFECTIOUS DISEASE BULLETIN
EPIDEMIOLOGICAL WEEK 39 23 - 29 Sep 2018

6. AETIOLOGY

7. Lancet Infect Dis 2018; 18: 1211–28
GLOBAL BURDEN

8. GOBAL BURDEN OF DISEASE
Pathogen Millions Of Episodes Deaths
Rotavirus 591.73 228437
Shigella 269.19 212438
Enterotoxigenic E Coli 222.64 51186
Non-typhoidal Salmonella sp 197.35 84799
Campylobacter 172.33 75135
Norovirus 139.63 19496
Cryptosporidium 69.52 57203
Lancet Infect Dis 2018; 18: 1211–28

9. Main Pathogens

10. Causes of acute infectious diarrhea
in adults in resource-rich settingsLikely pathogens Mean incubation period Classic/common food sources Other epidemiologic clues
Watery diarrhea
Norovirus 24 to 48 hours
Shellfish, prepared foods, vegetables,
fruit
•Outbreaks in:
• Restaurants
• Health care facilities
• Schools and childcare centers
• Cruise ships
• Military populations
Clostridioides (formerly Clostridi
um) difficile*
N/A N/A
•Antibiotic use
•Hospitalization
•Cancer chemotherapy
•Gastric acid suppression
•Inflammatory bowel disease
Clostridium perfringens 8 to 16 hours
Meat, poultry, gravy, home-canned
goods
Enterotoxigenic Escherichia coli 1 to 3 days Fecally contaminated food or water •Travel to resource-limited settings
Other enteric viruses (rotavirus,
enteric adenovirus, astrovirus,
sapovirus)
10 to 72 hours Fecally contaminated food or water
•Daycare centers
•Gastroenteritis in children
•Immunocompromised adults
Giardia lamblia 7 to 14 days Fecally contaminated food or water
•Daycare centers
•Swimming pools
•Travel, hiking, camping (particularly when there is contact with
water in which beavers reside)
Cryptosporidium parvum 2 to 28 days Vegetables, fruit, unpasteurized milk
•Daycare centers
•Swimming pools and recreational water sources
•Animal exposure
•Chronic diarrhea in advanced HIV infection
Listeria monocytogenes 1 day (gastroenteritis)
Processed/delicatessen meats, hot
dogs, soft cheese, pâtés, and fruit
•Pregnancy
•Immunocompromising condition
•Extremes of age
Cyclospora cayetanensis 1 to 11 days Imported berries, herbs •Chronic diarrhea in advanced HIV infection

11. Causes of acute infectious diarrhea
in adults in resource-rich settings
Likely pathogens Mean incubation period Classic/common food sources Other epidemiologic clues
Inflammatory diarrhea
(fever, mucoid or bloody stools)
¶
Nontyphoidal Salmonella 1 to 3 days
Poultry, eggs, and egg products, fresh
produce, meat, fish, unpasteurized
milk or juice, nut butters, spices
•Animal contact (petting zoos, reptiles,
live poultry, other pets)
•Travel to resource-limited settings
Campylobacter spp 1 to 3 days Poultry, meat, unpasteurized milk
•Travel to resource-limited settings
•Animal contact (young puppies or
kittens, occupational contact)
Shigella spp 1 to 3 days Raw vegetables
•Daycare centers
•Crowded living conditions
•Men who have sex with men
•Travel to resource-limited settings
Enterohemorrhagic E. coli 1 to 8 days
Ground beef and other meat, fresh
produce, unpasteurized milk and juice
•Daycare centers
•Nursing homes
•Extremes of age
Yersinia spp 4 to 6 days
Pork or pork products, untreated
water
•Abnormalities of iron-metabolism (eg,
cirrhosis, hemochromatosis,
thalassemia)
•Blood transfusion
Vibrio parahemolyticus 1 to 3 days Raw seafood and shellfish •Cirrhosis
Entamoeba histolytica 1 to 3 weeks Fecally contaminated food or water
•Travel to resource-limited settings
•Men who have sex with men

12. Major foodborne microbes by the principal
presenting gastrointestinal symptom
Major presenting symptom Likely microbes Incubation period Likely food sources
Vomiting
S. aureus 1 to 6 hours Prepared food, eg, salads, dairy, meat
B. cereus 1 to 6 hours Rice, meat
Norwalk-like viruses 24 to 48 hours
Shellfish, prepared foods, salads, sandwiches,
fruit
Watery diarrhea
C. perfringens 8 to 16 hours Meat, poultry, gravy
Enterotoxigenic E. coli 1 to 3 days Fecally contaminated food or water
Enteric viruses 10 to 72 hours Fecally contaminated food or water
C. parvum 2 to 28 days Vegetables, fruit, unpasteurized milk, water
C. cayetanensis 1 to 11 days Imported berries, basil
Inflammatory diarrhea
Campylobacter spp 2 to 5 days Poultry, unpasteurized milk, water
Nontyphoidal Salmonella 1 to 3 days
Eggs, poultry, meat, unpasteurized milk or
juice, fresh produce
Shiga toxin-producing E. coli 1 to 8 days
Ground beef, unpasteurized milk and juice,
raw vegetables, water
Shigella spp 1 to 3 days Fecal contamination of food and water
V. parahemolyticus 2 to 48 hours Raw shellfish

13. PATHOGENESIS

14. INOCULAM SIZE
PATHOGEN INOCULUM SIZE
Rotavirus <10 viral copies
Norovirus <100 viral copies
Cryptosporidium parvum 1-103
Entamoeba histolytica 10-102
Giardia lamblia 10-102
Shigella 10-102
Campylobacter jejuni 102-106
Salmonella 105
Escherichia coli 108
Vibrio cholerae 108

15. Gut Physiology
• 1. Sodium/hydrogen exchangers (NHEs)
• 2. Sodium/glucose cotransporter (SGLT1,
SLC5A1)
• 3. Down-regulated in adenoma (DRA
[SLC26A3)
• 4. Epithelial sodium channel (ENaC)
• 5. Ca-activated chloride channels
• 6. Sodium/potassium/chloride
cotransporter 1 (NKCC1, [SLC12A2])
• 7. Cystic fibrosis transmembrane
conductance regulator (CFTR)
• 8. Na,K ATPase:
Intestinal physiology is an interplay between absorption and secretion regulated by ion
transporters

16. Pathophysiology of Infective Diarrhoea
• Osmotic/Malabsorptive (various mechanisms)
• Secretory (toxin mediated)
• Intestinal tight junction dysruption(leak-flux)
• Inflammatory (Mucosal invasion)
• Intestinal Motility (through the enteric nervous system)

17. Osomotic/Malabsorptive
• Rotavirus - results of villous epithelial cell
destruction with resulting brush border
enzyme deficiency and complex sugar
malabsorption
• Rotaviirus also inhibit SGLT ion transporter
• Giardia tropozoites strongly adhere to the
epithelial surface of the intestine via a
ventral adhesive disc. Giardia causes a loss
of the absorptive surface similar to EPEC.
It decreases NaCl and glucose absorption
owing to this loss of absorptive surface
area
• Mainly Small Intestinal
• Mechanism
– Enterotoxin –ion channel mediated
– Adherence
– Superficial invasion
• Features
– Large volume watery
– No fecal WBC
– Minimal/NO lactoferrin

18. Malabsorption -Ion Channel Mediated
Sodium/hydrogen exchangers (NHEs)
Sodium/glucose cotransporter (SGLT1)
Down-regulated in adenoma (DRA)
Epithelial sodium channel ENaC)
Das et al Cellular and Molecular Gastroenterology and Hepatology Vol. 6, No. 1

19. Figure 1. Localization of absorptive ion transporters (discussed in text) in the small intestine and colon, and their regulation by pathogens or their
secreted toxins. The red bars indicate inhibitory effects. CT, cholera toxin; DRA, down-regulated in adenoma; ENaC, epithelial sodium
channel; EPEC, enteropathogenic E. coli; KCC1, potassium chloride cotransporter-1; NHE, sodium hydrogen exchanger; NSP4, Rotavirus non-structural
protein 4; SGLT1, sodium glucose cotransporter-1; ST, heat-stable toxin of E. coli; LT, heatlabile toxin of E. coli; TcdB, C. difficile toxin B.
Das et al Cellular and Molecular Gastroenterology and Hepatology Vol. 6, No. 1

20. Secretory Diarrhoea
• Movement of water and ions into the bowel lumen resulting in watery diarrhoea.
• Secretory diarrhea
– continues despite fasting,
– is associated with stool volumes >1 liter/day,
– occurs day and night in contrast to osmotic diarrhea in which these
characteristics are uncommon.
• The osmotic gap is determined by subtracting the sum of the sodium and potassium
concentration in stool multiplied by a factor of 2 from 290 mOsm/kg to account for
unmeasured anions (ie, 290 - 2 ({Na+} + {K+})).
• An osmotic gap of >125 mOsm/kg suggests an osmotic diarrhea while a gap of
<50 mOsm/kg suggests a secretory diarrhea.
Lundgren O et al Science. 2000;287(5452):491.

21. Secretory Diarrhoea - Toxin
• Enterotoxin mediated
– Heat Stable – activate cGMP -
activate enterocyte cyclic GMP,
increases chloride secretion and
inhibits of sodium chloride
absorption
– Heat labile (similar to cholera
toxin)- activate cAMP – increases
chloride secretion
– Cholera Toxin - CFTR mediated –
increases chloride secreation
Das et al Cellular and Molecular Gastroenterology and Hepatology Vol. 6, No. 1

22. Secretory Diarrhoea
Das et al Cellular and Molecular Gastroenterology and Hepatology Vol. 6, No. 1

23. Intestinal Barrier/Leak-flux
• Many inflammatory cytokines
also impact tight junction
integrity and permeability
• Eg Rotavirus, EPEC
Ramig R JOURNAL OF VIROLOGY, Oct. 2004,

24. Intestinal Motility
• Increased intestinal motility results in
reduced time to absorb electrolytes
and nutrients, leading to excessive
unabsorbed substrates in the
intestine and reduced fluid
absorption, leading to diarrhea.
• Stimulation of the enteric
neurosystem
• Eg Rotavirus
Ramig R JOURNAL OF VIROLOGY, Oct. 2004,

25. Inflammatory Diarrhoea
• Causes destruction or impairment of epithelial cells resulting in loss of surface area and transports
resulting impaired nutrient absorption and increased osmotic load in the intestinal lumen
• Inflammatory cytokines/chemokines can influence cell proliferation and the census of ion transporters
varies in less vs more differentiated epithelial cells, with a predominance of secretory transporters in the
former cells.
• Many inflammatory cytokines also impact tight junction integrity, which indirectly alters ion transport.
• the inflammatory process also can lead to the breakdown in intestinal barrier function resulting in
exudation of mucus, protein, and blood into the gut lumen (eg protein-losing enteropathy).
• Features:
– Mainly affects the terminal ileum or colon
– Faecal WBC +
– Faecal lactoferrin+

26. Inflammatory Diarrhoea
• Involves invasion of the mucosa

27. Systemic Complications Associated
with Infectious Diarrhoea
Complication Associated Pathogen
Bacteremia Salmonellosis(non-typhoidal)
Hemolytic-uremic syndrome Shiga-toxin (Shigella and EHEC)
Guillain-Barré syndrome Campylobacter
Reactive arthritis Salmonella sp, Shigella, Yersinia, Campylobacter, C.
difficile

28. DIAGNOSTIC TESTING

29. Indications For Further Testing●Severe illness
-Profuse watery diarrhea with signs of hypovolemia
-Passage of >6 unformed stools per 24 hours
-Severe abdominal pain
-Need for hospitalization
●Other signs or symptoms concerning for inflammatory diarrhea
-Bloody diarrhea
-Passage of many small volume stools containing blood and mucus
-Temperature ≥38.5ºC (101.3ºF)
●High-risk host features
-Age ≥70 years
-Comorbidities(e.g. IHD), which may be exacerbated by hypovolemia or rapid infusion of fluid
-Immunocompromising condition (including advanced HIV infection)
-Inflammatory bowel disease
-Pregnancy
-Symptoms persisting for more than one week
-Public health concerns

30. Molecular Diagnostic Testing

31. Stool Diagnostic Tests
• Stool diagnostic studies may be used if available in cases of dysentery, moderate-
to-severe disease, and symptoms lasting >7 days
• Stool Ova cysts parasites – microscopic evaluation, poor sensitivity
• Stool culture - Poor 30% sensitivity
• Toxin identification -Shiga toxin (EIA, RT-PCR), C. Diff Toxin (GDH, Toxin EIA, RT-PCR)
• Immunological Detection Methods (EIA)
• Molecular Detection Methods - >70% sensitivity, false positives

32. MANAGEMENT

33. Management
• Fluid Replacement
• Anti-diarrhoeals
• Antibiotics
• Probiotics/Prebiotics/Synbiotics

34. ASSESSMENT FOR DEHYDRATION

35. ORAL REHYDRATION SOLUTIONS

36. Basis of ORT
• ORT drives water reabsorption in diseases such as cholera by
taking advantage of the fact that although the electroneutral
NaCl absorptive process is impaired by the disease, the
function of SGLT1 is intact and can mediate sodium ion and
fluid absorption if glucose is provided.
• This addresses acute water loss caused by diarrhea, even if it
does not combat the root cause of the diarrheal episode

37. Starch Based ORT
• Starch-based ORT drives Na absorption by
providing short-chain fatty acids in the colon
and has been shown to be more effective than
conventional ORT.

38. Anti-Diarrhoeals
• Anti-Motility
• Absorbent
• Future prospects

39. Anti-Motility Agents
·Loperamide also allows
greater absorption through a
secondary effect - inhibition
of calmodulin leading to
reduced mucosal secretion.

40. LOPERAMIDE
• In patients receiving antibiotics for TD, adjunctive loperamide therapy can
be administered to decrease duration of diarrhea and increase chance for
a cure.
• The recommended dose of loperamide for therapy for adults with
diarrhea is 4 mg initially
• followed by 2 mg after subsequently passed watery stools not to exceed 8
mg per day.
• Loperamide is not given for more than 48 hrs.
Riddle M Am J Gastroenterol 2016; 111:602–622

41. BISMUTH SALICYLATES
Riddle M Am J Gastroenterol 2016; 111:602–622
The recommended dose of BSS for therapy of acute diarrhea is 30 ml (525 mg) of liquid
formulation or two tablets (263 mg per tablet) chewed well each 30–60 min not to
exceed eight doses in 24 h.

42. Empiric Antibiotic therapy
Riddle M Am J Gastroenterol 2016; 111:602–622

43. Anti-Microbial Therapy For
Persistent Infectious Diarrhoea

44. Probiotics
• Several meta-analyses and clinical studies in developed countries suggest that
probiotics prevent or reduce the duration of diarrhoea in children.
• However, the use of probiotics or prebiotics for treatment of acute diarrhea in
adults is currently not recommended, except in cases of postantibiotic-associated
illness.
• Lactobacillus GG has been shown to decrease duration of childhood infectious
diarrhea and
• Saccharomyces boulardii may be effective in decreasing the duration of C.
difficile infection. Riddle M Am J Gastroenterol 2016; 111:602–622

45. Future Targetted Therapies
Das et al Cellular and Molecular Gastroenterology and Hepatology Vol. 6, No. 1

46. Summary

47. www.gutcare.com.sg
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