Gastroenteritis

Overview

Epidemiology

• The 2nd leading cause of morbidity and mortality worldwide
• 3 million deaths annually (> 8,400 per day)
• Mostly affects young children in developing countries
• International travelers are particularly susceptible.
• In the United States:
  • 179 million cases per year (17 million cases are foodborne)
  • Approximately 2 million hospitalizations

Etiology

• Viral:
  • Norovirus (common)
  • Rotavirus (common)
  • Enteric adenovirus
  • Astrovirus
  • Immunocompromised patients:
    • Cytomegalovirus
    • Enterovirus
• Bacterial:
  • Salmonella (common)
  • Campylobacter (common)
  • Shigella
  • Escherichia coli (E. coli)
  • Clostridium
  • Yersinia
• Parasitic:
  • Giardia lamblia
  • Entamoeba histolytica
  • Cryptosporidium
  • Cyclospora

Pathogenesis

• Modes of infection:
  • Foodborne (toxin accumulation in food products)
  • Fecal-oral (bacterial contamination)
  • Direct or indirect animal transmission
• Mechanism of diarrhea, associated findings, and etiology are described in the table below.

Clinical presentation

• Common symptoms:
  • Abdominal pain and cramps
  • Diarrhea (watery, mucoid, or bloody)
  • Vomiting 
  • Fever
  • Anorexia
  • Headache
  • Myalgia
• Evidence of severe dehydration: 
  • Tachycardia
  • Hypotension

Diagnosis

• Stool testing:
  • Most patients do not require stool testing.
  • Guided by clinical history and findings:
    • Blood or pus in the stool
    • Persistent fever
    • Severe symptoms
    • Prolonged course
    • High-risk patients
  • Fecal leukocytes or lactoferrin → inflammatory diarrhea
  • Stool culture and polymerase chain reaction (PCR) panel
  • Stool ova and parasites 
  • Direct viral antigen (rarely indicated)
  • C. difficile toxin enzyme immunoassay
• General testing:
  • Generally only done in severe disease with evidence of dehydration
  • Basic metabolic panel → assesses for acute kidney injury and electrolyte abnormalities
  • Complete blood count → leukocytosis may be seen; eosinophilia may signal a parasitic infection

The following algorithm summarizes the workup of gastroenteritis:

Management

• Supportive care:
  • Most infections are self-limiting and only require oral rehydration therapy.
  • Intravenous (IV) fluid hydration may be required for severe disease.
  • Oral and IV solutions should contain replacement electrolytes.
• Antidiarrheal agents (loperamide, bismuth salicylate): 
  • Reduce the duration of diarrhea
  • Can delay the excretion of the causative pathogens or toxins, and are contraindicated in:
    • Diarrhea with fever
    • Bloody or mucoid stool
    • Diarrhea caused by C. difficile and Shigella
• Antibiotic therapy:
  • Not routinely used
  • The decision to use antibiotics is often empirical, because enteric pathogen testing is not always expedient.
  • Possible indications: 
    • Dysentery (passage of bloody stools)
    • Fever > 38°C (100.4°F)
    • Severe symptoms and hospitalization
    • High-risk population group (infants, elderly, immunocompromised, patients with comorbidities)
    • C. difficile infection
  • Contraindicated if Shiga toxin–producing E. coli is suspected (risk of hemolytic-uremic syndrome (HUS))
  • Frequently used antibiotics:
    • Fluoroquinolones
    • Azithromycin
    • Trimethoprim-sulfamethoxazole (TMP-SMX)
    • 3rd-generation cephalosporins

Complications

• During the infection:
  • Hypovolemic shock
  • Severe dehydration
  • Acute kidney injury 
  • Metabolic acidosis
  • Electrolyte imbalances
  • Death
• Post-diarrheal complications are summarized in the table below:

Campylobacter

Pathogen

• Campylobacter jejuni are curved, gram-negative, oxidase-positive rods with polar flagella.
• Distinguishing features: 
  • Require a CO₂-rich environment
  • Grow at 42.0°C (107.6°F)
  • May appear S-shaped or like seagull wings due to their helical structure
• The most common pathogen responsible for foodborne gastroenteritis in the United States
• Highly contagious

Transmission

• Fecal-oral
• Foodborne (undercooked poultry and unpasteurized milk) and contaminated water
• Direct contact with infected animals (cats, dogs, pigs) or animal products

Pathogenesis

• Invades the mucosa of the intestines → produces endotoxins, enterotoxins, and cytotoxins → destroys mucosal surfaces → blood and pus in stools (inflammatory diarrhea)
• Rarely penetrates to cause septicemia

Clinical presentation

• Acute watery and bloody diarrhea
• Fever
• Severe right lower quadrant abdominal pain resembling appendicitis (“pseudoappendicitis”)
• Headache
• Myalgias

Management

• Most cases will have a spontaneous resolution.
• Macrolides and fluoroquinolones
• A 3rd-generation cephalosporin, imipenem, ampicillin, or gentamicin can be given for extraintestinal infections.

Complications

• Guillain-Barré syndrome (cross-reaction between C. jejuni antibodies and human gangliosides)
• Reactive arthritis (in HLA-B27–positive patients)
• Hemolytic anemia
• Endocarditis and myopericarditis
• Meningitis

Non-typhoidal Salmonella

Pathogen

• S. enteritidis and S. typhimurium are gram-negative, non–lactose fermenting bacteria.
• Produce hydrogen sulfide and are motile (unlike Shigella)
• The 2nd most common pathogen responsible for bacterial foodborne gastroenteritis

Transmission

• Foodborne bacterial infection (poultry, raw eggs, milk)
• Reservoir: enteric tracts of humans and domestic animals (turtles, reptiles, chickens)
• Salmonella is sensitive to stomach acid. Lowered stomach acidity (antacids or gastrectomy) increases the risk for infection.
• Other risk factors: 
  • Hemolytic conditions (sickle cell anemia, malaria)
  • Splenectomy
  • Cirrhosis
  • Leukemia and lymphoma
  • HIV infection

Pathogenesis

• Bacteria invade the mucosa in the ileocecal region and are released into the lamina propria → influx of neutrophils → inflammation → ↑ prostaglandins and cAMP → loose diarrhea and necrosis of the upper mucosa
• Septicemia is not common (< 5%) with S. enteritidis, but may occur with other subtypes.

Clinical presentation

• Incubation period of 8–72 hours, lasts 3–7 days
• Inflammatory watery diarrhea (occasionally bloody) 
• Fever, chills
• Headache
• Myalgias
• Severe vomiting 
• Abdominal cramping

Management

• Supportive care
• Antibiotics:
  • Not required for most uncomplicated cases
  • Prolongs fecal excretion of the pathogen
  • Only indicated for systemic manifestations or severe diarrhea:
    • Fluoroquinolones (ciprofloxacin) 
    • TMP-SMX 
    • Azithromycin
    • 3rd-generation cephalosporins (ceftriaxone)

Complications

• Bacteremia
• Reactive arthritis
• Osteomyelitis (particularly in sickle cell patients)
• Meningitis 
• Myocarditis, endocarditis

Shigella

Shigella causes bacilliary dysentery, also known as shigellosis.

Pathogen

• S. dysenteriae, S. flexneri, S. sonnei, and S. boydii are gram-negative rods.
• Gastric acid resistant
• S. dysenteriae type 1 produces Shiga toxin (enterotoxin).

Transmission

• Fecal-oral
• Humans are the only natural reservoir.
• Flies are vectors.
• Foodborne (unpasteurized milk products and raw, unwashed vegetables)
• Contaminated water
• Highly contagious

Pathogenesis

• Shigella invades M cells through macropinocytosis → taken up by macrophages → escapes its phagosome → reaches epithelial cytoplasm and replicates → induces inflammatory response → epithelial and immune cell death
• Polymerized actin filaments are used to spread cell-to-cell without needing to re-enter the extracellular milieu.
• Shiga toxin release by S. dysenteriae:
  • Has 3 properties: neurotoxic, cytotoxic, enterotoxic
  • Causes intestinal secretion of solutes and water
  • Can induce HUS
• Resulting effects:
  • Watery diarrhea
  • Mucus secretion
  • Leukocyte infiltration 
  • Superficial ulcers 
  • Rarely causes invasion of blood vessels

Clinical presentation

• Incubation period of 0–48 hours, lasts 2–7 days
• Fever
• Abdominal cramping
• Tenesmus (urgency to defecate)
• Inflammatory diarrhea with mucus, pus, and blood

Antibiotics

• Usually resolves spontaneously
• Rehydration and electrolyte replacement may be needed.
• Antibiotics shorten the duration of symptoms and pathogen shedding in the stool:
  • Fluoroquinolones
  • Azithromycin
  • 3rd-generation cephalosporins
• Avoid antimotility medications, because they can worsen symptoms and may lead to toxic megacolon.

Complications

• HUS → due to Shiga toxin, often seen in children
• Acute blood loss → mucosal ulcerations
• Intestinal complications: 
  • Toxic megacolon
  • Colonic perforation
  • Intestinal obstruction 
  • Proctitis
  • Rectal prolapse → due to tenesmus
• Reactive arthritis 
• Though invasive, Shigella only rarely causes septicemia.

Vibrio cholerae

Cholera is a severe form of gastroenteritis caused by Vibrio cholerae (V. cholerae).

Pathogen

• V. cholerae is a gram-negative, oxidase-positive, curved rod with polar flagella.
• Grows on alkaline media
• Distinguishing feature: “shooting star” motility inactivated by specific serum
• Produces the cholera toxin

Transmission

• Inhabitant of coastal estuarine waters
• Fecal-oral spread
• Undercooked seafood or contaminated water
• Sensitive to stomach acid; requires a high dose for infection
• Outbreaks tend to occur during warm months.
• Endemic in areas of Asia, Africa, the Middle East, Central and South America, and the U.S. Gulf Coast
• Susceptibility is increased in:
  • Patients with type O blood
  • Antacid, antihistamine, or proton pump inhibitor use

Pathogenesis

• Motility, mucinase, and toxin-coregulated pili (TCP) aid in attachment to the intestinal mucosa.
• Leads to colonization of the intestinal lining without invasion of the intestinal wall
• Cholera enterotoxin is released: activates adenylate cyclase → ↑ cAMP → efflux of electrolytes and water by the small bowel mucosa in the duodenum and jejunum

Clinical presentation

• Incubation period is 1–3 days.
• Some patients may be asymptomatic or have only mild symptoms.
• Profuse “rice-water” stools 
• Abdominal pain and nausea are less prominent than other forms of gastroenteritis.
• Can quickly lead to severe dehydration and electrolyte depletion within hours:
  • Thirst
  • Oliguria
  • Muscle cramping
  • ↓ skin turgor
• Severe cases can lead to altered mental status, renal tubular necrosis, and circulatory collapse.

Management

• Urgent fluid and electrolyte replacement is the 1st priority.
• Antibiotics are used for severe disease, and can decrease diarrhea and shedding:
  • Doxycycline
  • Azithromycin (erythromycin in children)
  • Ciprofloxacin

Complications

• Severe dehydration
• Renal failure
• Hypovolemic shock

Non-cholera V. cholerae infections

The following table briefly summarizes the milder form of gastroenteritis caused by non-cholera V. cholerae:

Yersinia

Pathogen

• Yersinia enterocolitica are gram-negative, oxidase-negative coccobacilli.
• Facultative anaerobes
• Pleomorphic bacterium that belongs to Enterobacteriaceae
• Obligate pathogen
• Distinguishing features:
  • Motile at 25.0°C (77°F), nonmotile at 37.0°C (98.6°F)
  • Cold growth

Transmission

• Foodborne (raw or undercooked pork, unpasteurized milk)
• Blood products
• Contaminated water
• Direct or indirect contact with an infected animal (livestock, rabbits, rodents)

Pathogenesis

• Adheres to epithelial cells in the ileum → invades the intestinal wall, likely through M cells → colonizes lymphoid tissue (Peyer’s patches)
• Can invade mesenteric lymph nodes and disseminate
• Enterotoxin production similar to ETEC
• Leads to mucosal ulceration in the terminal ileum
• Iron overload states increase the pathogenicity.

Clinical presentation

• Incubation period is around 4–6 days; the duration is 1–2 weeks.
• Inflammatory bloody diarrhea
• Fever
• Nausea and vomiting
• Abdominal pain
• Pharyngitis (approximately 20%)

Management

• Generally only requires supportive care
• Antibiotics may be used based on severity, but there is questionable clinical benefit:
  • Fluoroquinolones 
  • TMP-SMX
  • 3rd-generation cephalosporins

Complications

• Reactive arthritis
• Erythema nodosum
• Systemic infection
• Abdominal (rare): 
  • Mesenteric lymphadenitis (“pseudoappendicitis” with right lower quadrant pain)
  • Mesenteric vein thrombosis (can lead to bowel necrosis)
  • Bowel perforation
  • Toxic megacolon
  • Cholangitis
  • Peritonitis

Clostridium

Clostridium perfringens enterocolitis will be discussed here.

Pathogen

• Clostridium perfringens type A are gram-positive, anaerobic, spore-forming rods.
• Distinguishing features:
  • Non-motile
  • Anaerobic: “stormy fermentation” in milk media
  • Double zone of hemolysis on blood agar

Transmission

• Foodborne (undercooked or poorly refrigerated meat, reheated meat dishes, legumes)
• Spores can survive cooking temperatures.
• Proliferates on foods that are improperly stored

Pathogenesis

• Spores germinate under anaerobic conditions.
• Enterotoxin is produced in the intestines → disrupts ion transport → watery diarrhea, cramps

Clinical presentation

• Incubation period of 6–24 hours, resolves within 24–48 hours (usually < 24 hours)
• Severe abdominal cramping
• Non-inflammatory, watery diarrhea
• Vomiting and fever are uncommon.

Management

• Supportive care 
• Usually a self-limited disease

Other pathologic manifestations

• Gas gangrene
• Cellulitis and fasciitis
• Necrotizing enterocolitis (from type C strains):
  • Beta-toxin produces segmental necrosis of the intestine.
  • Presents with bloody diarrhea, abdominal pain, and vomiting
  • Treatment:
    • Antibiotics (penicillin G, metronidazole)
    • Possible surgery for failure to respond, perforation, or obstruction

Rotavirus

Pathogen

• Rotavirus is a non-enveloped, segmented, double-stranded RNA reovirus.
• The most common cause of severe diarrhea among infants and children worldwide

Transmission

• Fecal-oral route
• Only a small inoculum is required for transmission.
• Common during the winter months

Pathophysiology

• Penetrates cells of the small intestinal villi → cholera toxin–like protein production → destruction and blunting of the microvilli → disrupts electrolyte and water absorption
• ↓ disaccharidase activity → malabsorption of lactose and D-xylose → osmotic influx into the intestine 
• Watery stools develop due to active water secretion and impaired absorption.

Clinical presentation

• Incubation period is < 48 hours, and the duration is 4–5 days.
• Fever
• Malaise
• Abdominal pain
• Vomiting
• Non-inflammatory, non-bloody, watery diarrhea: can be severe and lead to serious dehydration

Management and prevention

• Disease is self-limited.
• Oral rehydration
• IV fluids in patients with severe dehydration
• Live attenuated vaccine: 
  • Given to all children before 8 months of age 
  • Contraindications:
    • Severe combined immunodeficiency disease (SCID)
    • History of intussusception

Complications

• Seizures
• Encephalopathy
• Encephalitis

Norovirus

Pathogen and epidemiology

• Norovirus (also known as Norwalk virus) is a non‑enveloped RNA calicivirus.
• Community outbreaks (nursing homes, hospitals, cruise ships, etc.) are common. 
• Causes the most common type of adult gastroenteritis

Transmission

• The virus is highly virulent.
• Fecal-oral route through contaminated food, water, or contaminated surfaces
• Person‑to‑person contact
• Aerosolized

Pathogenesis

• Mechanism is not entirely understood.
• Delayed gastric emptying leads to nausea and vomiting.
• Jejunal biopsy shows blunting of microvilli, but the mucosa is otherwise intact.
• Cytoplasmic vacuolization is seen along with mononuclear infiltrates of tissue.
• The virus appears to decrease brush border enzymes, causing malabsorption.

Clinical presentation

• Incubation period is 24–60 hours.
• Abrupt onset of nausea and vomiting
• Watery, non-bloody diarrhea
• Abdominal cramps
• Headache
• Myalgias
• Malaise

Diagnosis and management

• Diagnosis is usually based on clinical suspicion.
• Management includes rehydration with oral or IV fluids.