Infectious Diarrhea

Charles S. Bryan, M.D.

November 27, 2007

Overview
Worldwide

the greatest single cause of morbidity and mortality Decisive role in world history Third most common syndrome seen in general practice in the United States

Enteric host defenses

Age

Personal

hygiene, physical barriers Gastric acidity Intestinal mobility Enteric microflora Specific immunity: phagocytes, B-cell, T-cell Intestinal receptors

Infectious doses of enteric pathogens

Shigella: 101-2 Giardia lamblia: 101-2 Entamoeba histolytica: 101-2 Campylobacter jejuni:102-6 Salmonella: 105 E. coli: 108 Vibrio cholerae: 108

Old and new pathogens: bacteria

Old: Salmonella, Shigella, invasive E. coli, Vibrio cholerae, Clostridium perfringens, S. aureus New: Toxigenic E. coli, enterohemorrhagic E. coli, E. coli 0157:H7, Yersinia, Vibrio parahemolyticus, Vibrio vulnificus, Campylobacter, Clostridium difficile, Aeromonas, Plesiomonas shigeloides

Old and new pathogens: viruses

Old:

viral diarrhea New: Reovirus, parvovirus, Norwalk agent, rotavirus, calcivirus, adenovirus, astrovirus, coronavirus

Old and new pathogens: parasites

Old:

Entamoeba histolytica, Giardia lamblia New: Cryptosporidium parvum, Isospora belli, Blastocystis hominis, Microsporidium

Low-versus high-volume diarrhea

Low volume (low water): colonic High volume (high water): small bowel OSMOTIC DIARRHEA: high-volume diarrhea in which the measured fecal osmolality is less than 2 [Na + K] SECRETORY DIARRHEA: high-volume diarrhea in which the measured fecal osmolality equals 2 [Na + K]

Small- versus large-bowel diarrhea

Small bowel (the runs): large, watery, less frequent, painless stools. Blood and WBCs are rare. Proctoscopy is normal. Pain is mid-abdominal. Large bowel (the squirts): small, often mucoid, more frequent, painful stools. Blood and WBCs are common. Proctoscopy is abnormal. Pain is lower-abdominal (left lower quadrant)

Fecal leukocytes
Shigellosis Enteroinvasive E. coli Clostridium difficile Salmonella enteritidis Vibrio parahemolyticus Ulcerative colitis Ischemic colitis

Pathophysiologic mechanisms of infectious diarrhea

Toxin

production Enteroadherence Mucosal invasion Systemic infection

Toxin production (examples)

Preformed toxin: Bacillus cereus, Clostridium perfringens, Staphylococcus aureus Enterotoxin: Aeromonas species, enterotoxigenic E. coli, Vibrio cholerae Cytotoxin: Clostridium difficile, E. coli 0157:H7

Enteroadherence (examples)
Cryptosporidiosis

(Cryptosporidium parvum) Cyclospora species (?) Enteroadherent and enteropathogenic E. coli Helminths Giardiasis (Giardia lamblia)

Mucosal invasion
Minimal

invasion: Norwalk virus, Rotavirus, other viruses Variable invasion: Aeromonas sp., Campylobacter sp., Salmonella sp., Vibrio parahemolyticus Severe invasion: Entamoeba histolytica, enteroinvasive E. coli, Shigella species

Systemic infection
Legionellosis Listeriosis Measles Psittacosis Rocky Mountain spotted fever Toxic shock syndrome Septicemia Viral hepatitis

Enteric infection
Noninflammatory

(enterotoxin): proximal small bowel, watery diarrhea, no fecal leukocytes Inflammatory (invasion, ? cytotoxin): colon, dysentery, fecal polymorphonuclear leukocytes Penetrating: distal small bowel, enteric fever syndrome, fecal mononuclear leukocytes

Noninflammatory (enterotoxin) diarrhea

Cholera Toxigenic E. coli Food poisoning syndromes; Clostridium perfringens, Bacillus cereus, Staphylococcus aureus Viral: rotavirus, Norwalk agent Parasitic: giardiasis, Cryptosporidium ? Salmonella, ? Vibrio parahemolyticus

Noninflammatory diarrhea
Neonates: enteropathogenic E. coli; rotaviruses; many other agents Healthy adults in temperate climates: viruses, food poisoning, parasites Travelers: enterotoxigenic E. coli; others Adults in areas of poor sanitation: cholera, entertoxigenic E. coli Hospitals: Cl. difficile; viruses; Salmonella Chronic cases: giardia, sprue, other

Enteric bacterial toxins

Neurotoxins: Usually ingested preformed (examples: Cl. botulinum, S. aureus, B. cereus) True enterotoxins: Direct effect on intestinal mucosa to elicit fluid secretion (examples: E. coli, V. cholerae; Salmonella; others) Cytotoxins: Mucosal destruction causing inflammatory colitis (examples: Shigella, E. coli 0157:H7; Clostridium difficile)

Inflammatory diarrhea
Colon

Dysentery
Fecal

polymorphonuclear leukocytes Examples: Shigella; invasive E. coli; Salmonella enteritidis; Clostridium difficile; Vibrio parahemolyticus; ? Campylobacter jejuni

Penetrating bowel infection (enteric fever)

A systemic febrile illness originating from the distal small bowel with some combination of sustained fever, headache, rash, splenomegaly, positive blood cultures, and fecal mononuclear leukocytes, and mimicked by many diseases Examples: Salmonella typhi; Yersinia enterocolitica (yersinosis); ? Campylobacter fetus

Syndromes of salmonellosis
Gastroenteritis Enteric

fever Bacteremia with or without metastatic disease Asymptomatic carrier state

Nontyphoidal Salmonella
Widely

disseminated in nature, intimately associated with animals Contaminate 1/2 of chickens in U.S.; also eggs; unpasteurized milk; fruits and vegetables; marijuana; reptiles (e.g., turtles, rattlesnakes)

Salmonella: required inoculum

> 105 needed to cause disease Recent outbreaks: as few as 103 Volunteer study: placement of as few as 25 organisms in the nose caused disease Required inoculum is reduced by raising gastric pH (atrophic gastritis; antacids; H2 blockers
Dogma:

Bacteremia in salmonellosis
Usually

transient and inconsequential Sickle cell disease: osteomyelitis Atherosclerosis: mycotic aneurysm Underlying heart disease: endocarditis Young children: ? meningitis

Salmonella carrier state

3%

of cases of typhoid fever (recall Typhoid Mary 0.2% to 0.6% of symptomatic nontyphoidal infections (relevant especially to foodhandlers) High association with biliary tract disease and gallstones

Shigellosis
Highly

communicable; 10% to 40% of cases of diarrhea worldwide, especially small children Virulent strains involve colonic mucosa; S. dysenteriae type 1 (Shiga bacillus) is the worst Often biphasic (large stools, then dysentery) Complications: DIC, hemolytic-uremic syndrome

E. coli diarrhea
Enterotoxigenic:

watery diarrhea Enteropathogenic: diarrhea with mucus Enteroinvasive: dysentery with blood and mucus Enterohemorrhagic (E coli 0157:H7): copious bloody diarrhea sometimes with the hemolyticuremic syndrome Toxigenic: ? mild diarrhea

Shiga-toxin E. coli (0157:H7 and other serotypes)

Usually transmitted by beef, but many other foods

transmit Low infectious dose (as few as 100 bacteria) Crampy abdominal pain, often disproportionate to physical findings Complications include hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura

Clostridium difficile
1970s: Found to be the cause of enterocolitis related to the antibiotic clindamycin Pseudomembranous colitis with yellow-white plaques; can progress to toxic megacolon At least two toxins (A and B) cause necrosis of epithelium Nosocomial transmission

Clostridium difficile
Colonization rate is 2% to 3% in healthy adults; 20% to 40% in hospitalized patients Widespread contamination of hospital environments Infection control measures including handwashing and gloves have been shown to reduce infection rates

New epidemic strain of C. difficile

(Bartlett, Ann Intern Med 2006; 145:758-764)

First recognized in Quebec; now recognized as causing outbreaks in U.S. More serious and more refractory to therapy Increased rates of toxic megacolon, disease requiring colectomy, shock, and death Attributable mortality 17% (versus <1%! For other strains with therapy) Designated B1/NAP1

Five features of C. difficile B1/NAP1

Produces much larger quantities of toxins A and B Toxinotype III (based on analysis of a portion of the genome responsible for toxins A and B Shows deletion from its genome of tcdC, an 18 base-pair sequence in the pathogenicity locus responsible for downregulation of toxin production Produces a binary toxin (unclear significance) Resistance to quinolone antibiotics

Campylobacter infection
Campylobacter

fetus ssp. jejuni causes 5% to 7% of cases of gastroenteritis; contaminated food products are the most common source Symptoms: diarrhea, cramps, anorexia, weight loss, nausea, dehydration Stool exam: blood in 60%, PMNs in 78% Usually self-limited

Yersinia enterocolitica
Enterocolitis

(2/3rds of cases): especially young children; fever, diarrhea, abdominal pain Mesenteric adenitis/terminal ileitis: fever, RLQ pain, leukocytosis Reactive polyarthritis, often with erythema nodosum (10% to 30% of adults in Scandinavia) Septicemia especially in children

Yersinia pseudotuberculosis
Mesenteric

lymphadenitis resembling acute appendicitis Septicemia

Vibrio parahemolyticus
Seafood or raw shellfish Often in epidemics Diarrhea, abdominal cramps, nausea, fever, headache (42%); may have fecal leukocytes Produces both an enterotoxin and an inflammatory reaction A halophilic (salt-requiring) vibrio readily isolated on TCBS agar

Vibrio vulnificus
Usually

an extra-intestinal pathogen Septicemia, especially in persons with cirrhosis (ingestion of raw oysters is the classic vector history) Cellulitis after exposure of wounds to salt water

Vibrio cholerae
01

serotype: watery diarrhea, dehydration; associated with residence in endemic areas non-01-serotypes: diarrhea, fever, nausea, vomiting, blood in stool; often associated with travelers diarrhea

Aeromonas hydrophila
Summer

months Diarrhea and abdominal cra+mps Possibly both an enterotoxin and a cytotoxin Also causes severe cellulitis in wounds exposed to fresh water

Entamoeba histolytica (amebiasis)

Affects

10% of worlds population In the United States, affects up to 4% Order of involvement: cecum, ascending colon, rectum, sigmoid Flask-shaped ulcers Liver abscesses in up to 10%

Giardia lamblia (giardiasis)

Waterborne

Rocky

Mountains; Leningrad; but also widespread Can cause diarrhea by several mechanisms Weight loss (62%), cramps (61%), steatorrhea (57%), flatulence (35%), vomiting (29%), belching (26%), fever (17%)

Cryptosporidium parvum
Formerly

best known as an animal pathogen infecting numerous species Severity and duration of human infection vary directly with immunocompetence Healthy adults: self-limited diarrhea, usually lasting 10 to 14 days AIDS patients: severe intractable diarrhea

Rotavirus diarrhea
Usually

sporadic but can cause epidemics in institutions, including nursing homes Winter months in temperate climates: usually infants and young children fecal-oral transmissions DNA virus with at least 2 sterotypes; can be demonstrated with ELISA

Norovirus diarrhea
Typically

epidemic, often traced to a common

source Throughout the year Usually adults and school-aged children Often traced to contaminated food or water At least 3 serotypes; can be demonstrated by immune electron microscopy or radioimmunoassay

Travelers diarrhea
E.

coli the most common cause However, consider Salmonella, Shigella, Campylobacter, Amebiasis, Cholera, Vibrio parahemolyticus, Norwalk virus, others Many persons are infected by multiple pathogens