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Diarrheal Diseases - Detailed Microbiology

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1. Definition and Classification

• ROSEN's Emergency Medicine, p. 3245

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2. Physiology - How the Gut Normally Handles Fluid

• 90% is absorbed in the small bowel
• The remainder is absorbed in the large bowel

1. NaCl absorption in the small bowel via Na+/H+ and Cl-/HCO3- cation/anion exchange
2. Electrogenic Na+ absorption in the colon - often damaged during acute diarrhea
3. Na+ co-transport with glucose, amino acids, and peptides in the small bowel - usually intact during acute diarrhea, which is why oral rehydration therapy (ORT) works

• ROSEN's Emergency Medicine, p. 3245

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3. Pathophysiologic Mechanisms of Infectious Diarrhea

A. Secretory Diarrhea

• Stool volume does NOT decrease with fasting
• Stool pH > 6 (alkaline)
• No reducing substances in stool
• Stools often large-volume, watery, "rice-water" in cholera

B. Osmotic Diarrhea

• Altered gut bacterial flora
• Damage to the mucosal absorptive surface (typical in viral gastroenteritis - injury to small bowel epithelium disrupts microvilli, reducing absorptive area)
• Ingestion of non-absorbable substances

• Diarrhea stops/decreases with fasting
• Stool pH < 6 (acidic)
• Reducing substances present in stool

C. Inflammatory/Invasive Diarrhea (Dysentery)

• Loss of fluids, electrolytes, mucus, proteins, and blood in the intestinal lumen
• Infiltration by neutrophils → enzymes/cytokines cause both increased secretion and decreased absorption

D. Adherence

• ROSEN's Emergency Medicine, p. 3245-3246; Sleisenger & Fordtran's Gastrointestinal and Liver Disease

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4. Causative Organisms - Overview by Category

• ROSEN's Emergency Medicine, p. 3247

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5. Major Bacterial Pathogens - Detailed Microbiology

5.1 Vibrio cholerae (Cholera)

• Gram-negative curved rod (comma-shaped), facultative anaerobe
• Transmission: contaminated water and food, fecal-oral route; epidemic/pandemic potential
• Pathogenesis: Colonizes small intestine without invading. Produces cholera toxin (CT) - an AB toxin:
  • B subunit binds GM1 ganglioside on enterocytes
  • A subunit activates adenylate cyclase → ↑↑ cAMP → massive Cl- secretion and inhibition of NaCl absorption
• Clinical features: Profuse, painless, watery "rice-water" stools; rapid dehydration; electrolyte loss; can be fatal within hours if untreated
• Mechanism type: Secretory
• Treatment: Oral rehydration; doxycycline or azithromycin

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5.2 Salmonella Species

• Gram-negative bacilli, family Enterobacteriaceae; flagellated, non-spore forming
• Transmission: Food from animals (poultry, eggs, meat), contaminated water, milk, reptile contact
• Species:
  • S. enterica serotype Typhi → Typhoid fever (systemic illness)
  • Non-typhoidal Salmonella (NTS) → gastroenteritis
• Pathogenesis:
  • Invades intestinal epithelium, particularly in the ileum and colon
  • Triggers inflammatory response; produces enterotoxins
  • Can breach the mucosa and cause bacteremia (especially in young children, sickle cell, immunocompromised)
• Clinical features: Nausea, vomiting, abdominal cramps, diarrhea (may be bloody), fever; 1-3 days incubation; lasts up to 1-2 weeks
• Typhoid: Rose spots on trunk, relative bradycardia, splenomegaly, stepladder fever
• Mechanism type: Mixed - invasive + secretory
• Diagnosis: Stool culture; blood culture in systemic disease; CDT (culture-independent diagnostic tests)
• Treatment: Usually self-limiting in NTS; ampicillin, trimethoprim-sulfamethoxazole, or fluoroquinolones for severe cases or typhoid

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5.3 Shigella Species

• Gram-negative bacilli; non-motile, non-spore forming
• Species: S. dysenteriae (most severe), S. flexneri, S. boydii, S. sonnei (most common in developed countries)
• Transmission: Fecal-oral; very low infectious dose (~10-200 organisms); person-to-person spread common; contaminated food/water
• Pathogenesis:
  • Invades colonic epithelium; escapes from phagosomes and moves cell-to-cell via actin polymerization
  • S. dysenteriae type 1 produces Shiga toxin - inhibits protein synthesis (inactivates 60S ribosomal subunit) → cell death
  • Causes intense inflammatory colitis with neutrophil infiltration
• Clinical features: Incubation 48-72 hours; watery diarrhea initially, progresses to bloody, mucoid dysentery; fever, tenesmus, severe abdominal cramps
• Complications: Hemolytic Uremic Syndrome (HUS) with S. dysenteriae Shiga toxin, seizures (children), reactive arthritis
• Mechanism type: Invasive (dysenteric) + cytotoxin
• Diagnosis: Stool culture; PMNs in stool
• Treatment: Azithromycin or ciprofloxacin (resistance increasing)

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5.4 Campylobacter jejuni

• Gram-negative curved/spiral rod (S-shaped or "gull-wing"), microaerophilic
• Transmission: Undercooked poultry (most common source), unpasteurized milk, contaminated water, pets
• Pathogenesis:
  • Adheres to and invades intestinal epithelium (ileum and colon)
  • Produces cytolethal distending toxin (CDT) and other toxins
  • Triggers inflammatory response with neutrophils and macrophages
• Clinical features: Incubation 1-7 days; watery to bloody diarrhea; severe cramping; high fever (+++); may mimic appendicitis (mesenteric adenitis)
• Complications: Guillain-Barré syndrome (post-infectious demyelinating neuropathy, especially after C. jejuni serotypes with LPS mimicking peripheral nerve gangliosides); reactive arthritis
• Mechanism type: Invasive
• Diagnosis: Stool culture; CDT; requires microaerophilic culture conditions (42°C incubation)
• Treatment: Usually self-limiting; azithromycin or fluoroquinolone if severe

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5.5 Escherichia coli - Multiple Pathotypes

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5.6 Clostridioides (Clostridium) difficile

• Gram-positive spore-forming anaerobic bacillus
• Transmission: Spores survive on surfaces/hands; healthcare-associated; fecal-oral; linked to antibiotic use (disrupts normal flora)
• Risk factors: Recent antibiotics (especially broad-spectrum: clindamycin, cephalosporins, fluoroquinolones), advanced age, hospitalization, PPIs
• Pathogenesis:
  • Produces Toxin A (enterotoxin) and Toxin B (cytotoxin)
  • Both disrupt Rho GTPases → cytoskeletal disruption → colonocyte death → mucosal inflammation
  • Leads to pseudomembranous colitis (yellow-white plaques on colonoscopy)
• Clinical features: Watery diarrhea (not usually bloody), lower abdominal cramps, fever; severe cases → toxic megacolon, perforation, sepsis
• Complications: Toxic megacolon (emergency - tachycardia, hypotension, delirium, dilated colon >6 cm)
• Diagnosis: Stool toxin assay (GDH antigen + toxin EIA); PCR for toxin genes; colonoscopy (pseudomembranes)
• Treatment: Oral vancomycin or fidaxomicin (1st line); metronidazole (mild cases); fecal microbiota transplant (FMT) for recurrent disease

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5.7 Staphylococcus aureus - Food Poisoning

• Gram-positive cocci in clusters
• Mechanism: Preformed enterotoxins (heat-stable, type A most common) in contaminated food (creamy foods, meat, custard); no live organisms needed
• Onset: Very rapid - 1-6 hours after ingestion
• Clinical features: Sudden-onset nausea, profuse vomiting, watery diarrhea, cramps; short duration (24-48 hours); no fever usually
• Diagnosis: Clinical; food cultures; phage typing
• Treatment: Supportive

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5.8 Clostridium perfringens

• Gram-positive spore-forming anaerobic bacillus
• Mechanism: Enterotoxin produced in vivo during sporulation in the gut (ingested spores germinate in cooked meat/poultry)
• Onset: 8-16 hours after ingestion
• Clinical features: Watery diarrhea, crampy abdominal pain (epigastric); vomiting rare; self-limiting (~24 hours); no fever typically
• Diagnosis: Stool culture with spore count; food cultures
• Treatment: Supportive

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5.9 Yersinia enterocolitica

• Gram-negative coccobacillus; grows at 4°C (psychrophilic - grows in refrigerator)
• Transmission: Pork, unpasteurized milk, contaminated water; fecal-oral; pets (pigs)
• Pathogenesis: Invades terminal ileum; replicates in mesenteric lymph nodes
• Clinical features: Fever, diarrhea (may be bloody), severe right lower quadrant pain mimicking appendicitis (mesenteric adenitis/terminal ileitis); can occur in older children/adults
• Complications: Reactive arthritis, erythema nodosum, uveitis (HLA-B27 associated)
• Treatment: Self-limiting; TMP-SMX or fluoroquinolone for severe cases

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6. Major Viral Pathogens

6.1 Rotavirus

• Double-stranded RNA virus, family Reoviridae; wheel-shaped appearance on electron microscopy
• Leading cause of severe diarrhea and dehydration in children < 5 years worldwide (now largely controlled by vaccine in developed countries)
• Transmission: Fecal-oral; highly infectious; stable in environment
• Pathogenesis:
  • Infects and destroys mature villous enterocytes in the small intestine
  • Viral protein NSP4 acts as an enterotoxin, stimulating Cl- secretion
  • Reduces absorptive surface → osmotic diarrhea
  • May cause neurologic symptoms (seizures) in 2-3% of infected children
• Clinical features: Vomiting first, then watery diarrhea; fever; lasts 5-7 days
• Seasonal: Late winter/early spring in temperate climates
• Vaccine: RotaTeq (RV5, 2006) and Rotarix (RV1, 2008) - dramatically reduced hospitalizations
• Treatment: Oral rehydration therapy

6.2 Norovirus

• Single-stranded RNA virus (Caliciviridae family)
• Currently the most common cause of diarrheal illness in children in the US (post-rotavirus vaccine era); also the leading cause of foodborne illness across all ages
• Transmission: Fecal-oral; person-to-person; aerosolized vomitus; contaminated food (shellfish); very low infectious dose (~18 viral particles)
• Pathogenesis: Infects small intestinal epithelium; disrupts villous architecture
• Clinical features: Acute-onset nausea, vomiting (prominent), watery diarrhea, cramps; low-grade fever; lasts 24-72 hours ("24-hour stomach flu")
• Outbreaks: Cruise ships, nursing homes, hospitals, schools
• Treatment: Supportive

6.3 Other Viruses

• Astrovirus: Affects children and elderly; watery diarrhea; milder than rotavirus
• Enteric Adenovirus (types 40, 41): Second or third leading cause of viral gastroenteritis in children; longer incubation (8-10 days); prominent diarrhea

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7. Major Parasitic/Protozoal Pathogens

7.1 Giardia intestinalis (G. lamblia)

• Flagellated protozoan; binucleate trophozoite with "owl face" appearance; forms hardy cysts
• Transmission: Contaminated water (mountain streams - "beaver fever"), travel, daycare centers
• Pathogenesis: Colonizes duodenum and proximal jejunum; adheres via ventral sucker disk; disrupts brush border and impairs nutrient/fat absorption; does not invade mucosa
• Clinical features: Incubation 1-3 weeks; greasy, foul-smelling, floating stools; bloating, flatulence, abdominal cramps; no blood/mucus; can cause chronic malabsorption
• Diagnosis: Stool O&P (cysts and trophozoites); stool antigen assay (most sensitive)
• Treatment: Metronidazole or tinidazole

7.2 Entamoeba histolytica (Amebiasis)

• Enteric protozoan; invasive form causes amebic dysentery
• Transmission: Fecal-oral; contaminated food/water; endemic in developing countries
• Pathogenesis:
  • Trophozoites invade colonic epithelium; produce cysteine proteases that lyse tissue
  • "Flask-shaped" ulcers in colon
  • Can disseminate hematogenously → amebic liver abscess
• Clinical features: Bloody dysentery, tenesmus, crampy abdominal pain; amebic liver abscess (right upper quadrant pain, fever, no diarrhea usually)
• Diagnosis: Stool antigen test; serology (liver abscess); colonoscopy (flask ulcers)
• Treatment: Metronidazole followed by luminal agent (paromomycin or iodoquinol)

7.3 Cryptosporidium

• Coccidian protozoan; forms oocysts resistant to chlorination
• Transmission: Waterborne (swimming pools, contaminated drinking water - oocysts resist standard chlorination); fecal-oral; zoonotic
• Pathogenesis: Invades and resides within intestinal epithelial cells (intracellular but extracytoplasmic); destroys microvilli
• Clinical features: In immunocompetent: self-limiting watery diarrhea (1-2 weeks); in HIV/AIDS (CD4 <200): severe, life-threatening chronic diarrhea ("cholera-like") - may disseminate to biliary tract
• Diagnosis: Acid-fast stain of stool (pink oocysts); stool antigen test; PCR
• Treatment: Nitazoxanide in immunocompetent; no reliable treatment in AIDS (antiretroviral therapy is key)

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8. Special High-Yield Pathogens and Toxin Mechanisms

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9. Clinical Approach and Key Differentiating Features

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10. Diagnosis

• Stool culture: For bacterial pathogens; standard for Salmonella, Shigella, Campylobacter
• Stool ova and parasites (O&P): For Giardia, E. histolytica
• Stool antigen tests: Giardia, Cryptosporidium, H. pylori, C. difficile (GDH)
• Stool toxin assays: C. difficile toxin A and B EIA; PCR
• PCR/molecular panels (FilmArray GI panel): Multipathogen simultaneous testing - now increasingly standard
• Stool microscopy: WBCs (PMNs) suggest invasive/inflammatory diarrhea
• Acid-fast stain: Cryptosporidium oocysts
• Blood culture: For bacteremic Salmonella, severe Shigella, Yersinia

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11. General Management Principles

1. Oral Rehydration Therapy (ORT): First-line for most acute diarrhea. Works because the Na+-glucose co-transport mechanism is preserved even in severe secretory diarrhea. WHO/UNICEF low-osmolarity ORS (245 mOsm/L) is preferred.
2. IV fluids: For severe dehydration or shock - 20 mL/kg isotonic crystalloid boluses.
3. Antibiotics: Indicated for cholera, shigellosis, C. difficile, typhoid, traveler's diarrhea, Giardia/amebiasis. NOT indicated for EHEC O157:H7 (increases HUS risk) or most NTS (increases carrier state).
4. Zinc supplementation: WHO recommends for children in developing countries (reduces severity and duration).
5. Probiotics: Modest benefit in rotavirus and antibiotic-associated diarrhea.
6. Anti-motility agents (loperamide): Useful in secretory diarrhea in adults; contraindicated in bloody/dysenteric diarrhea and in children.

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• ROSEN's Emergency Medicine: Concepts and Clinical Practice, Chapter 167 (Diarrhea), pp. 3245-3250
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Chapter 16 (Diarrhea), pp. 1965-1966
• Goldman-Cecil Medicine, Chapter 126 and 401 (Diarrhea), p. 4227