Infectious Diarrhea
Learning Objectives
• Microbiology
– Recognize common and atypical pathogens
• Pathogenesis
– Understand general mechanisms of infection / categories
• Clinical approach
– Identify important elements in the clinical history
– Diagnostic algorithm
• Review of selected organisms
• Management of acute infectious diarrhea
• Common causes of persistent infectious diarrhea
Intestinal Infections - Common
• Viral
- Norovirus
- Rotovirus
• Bacterial
-
Salmonella (GNR)
Shigella (GNR)
Campylobacter (GNR)
Vibrio (GNR)
E.coli (GNR)
- Yersinia (GNR)
- Bacillus (GPR)
- Clostridium (GPR)
- Staphylococcus (GPC)
• Protozoal
- Giardia
- Entamoeba
Intestinal Infections - Uncommon
• Viral
– CMV
• Bacterial
– Mycobacteria
• M. tuberculosis
• M. avium complex
• M. bovis
– Tropheryma whipplei
– Listeria monocytogenes
– Brucella species
• Fungal
– Histoplasma
– Candida
• Parasites
– Protozoa
• Cryptosporidia
• Isospora/Cyclospora
– Worms
• Tapeworms
• Roundworms
Bacterial GI Infections
• Noninflammatory
– Clinical manifestation
• Diarrhea - watery to loose, ± nausea/vomiting/abd pain
– Mechanism:
• Preformed toxin, enterotoxin
• Inflammatory
– Clinical manifestation
• Diarrhea – mucoid or bloody, fever, tenesmus, ± abd pain
– Mechanism:
• Cytotoxin, cellular invasion
• Invasive (mononuclear inflammation)
– Clinical manifestation
• Fever & abd pain, ± diarrhea
– Mechanism:
• Cellular invasion
Mechanism - Toxin Production
• Preformed toxin
– Food poisoning
– Symptoms: nausea, vomiting, abdominal cramps,
diarrhea
– Onset: within 6 hours after consumption
– Heat stable, mechanism not well-described
– Examples:
• Bacillus cereus – GPR, can form spores
– Classically reheated rice
• Staphylococcus aureus – GPC
– Classically ham
Mechanism - Toxin Production
• Enterotoxin
– Cause intestinal mucosa to secrete fluid
– Symptoms: abdominal cramps, watery diarrhea which
can be voluminous (V.cholerae  rice-water diarrhea)
– Onset: >16 (up to 72) hours after consumption
– Attachment, local elaboration & delivery of toxin
• Enterocytes – ↓ Na absorption and ↑ Cl secretion
– Examples:
• Vibrio cholerae
• Enterotoxigenic E.coli (Traveller’s diarrhea)
Mechanism - Toxin Production
• Cytotoxin
– Cause direct mucosal damage
– Symptoms: abdominal cramps, bloody or mucoid
diarrhea, tenesmus
– Onset: >24 hours after consumption
– Attachment, local elaboration & delivery of toxin
• Multiple mechanims of action  inflammation of GI mucosa
– Examples:
• Enterohemorrhagic E.coli (O157:H7)
• Shigella
• Clostridium difficile
Mechanism – Cellular Invasion
• Enterocyte invasion
– Intracellular replication
– Can be complicated with extraintestinal infection
– Characterized by neutrophilic inflammation:
• Incubation period 1-3 days
• Shigella, Campylobacter, Salmonella (non-typhoid)
• Listeria
– Characterized by mononuclear inflammation:
• Incubation period 1-3 weeks
• Salmonella (typhoid)
Summary
• Non-inflammatory
– Preformed toxin: Bacillus cereus, Staph aureus
– Enterotoxin: Vibrio, ETEC
– Non-bacterial causes:
• Viruses: Noroviruses, Rotoviruses
• Protozoa: Giardia, Cryptosporidium
• Inflammatory
– Cytotoxin: C.diff, EHEC, Shigella
– Invasive:
• Salmonella, Shigella, Campylobacter, Yersinia, Listeria
• Amebiasis
• Invasive (Mononuclear inflammation)
– Classic: Salmonella, Brucella
– Atypical: Mycobacteria, Histoplasma
Case
• 30 F presents with 3 day history of watery diarrhea with
intermittent abdominal cramps.
• Previously healthy.
• Further questions?
Case
• 30 F presents with 3 day history of watery diarrhea with
intermittent abdominal cramps.
–
–
–
–
–
–
–
Feels a little warm - ? subjective fever
No tenesmus, mucus, blood
No recent travel, sick contacts, pets
Ate a hamburger for lunch today, maybe a little pink in the center
Ate some left-over fried rice 10 days ago
Otherwise nothing undercooked/raw. No shellfish.
Notes almost 10 BMs/day, not getting better
• Does she need further evaluation?
Clinical Terminology
• Bacterial food poisoning
– Preformed toxin
• Gastroenteritis
– Noninflammatory versus inflammatory
• Enterocolitis
– Inflammatory
• Dysentery
– Inflammatory – invasive mechanism (neutrophilic)
• Enteric fever
– Salmonella serotype Typhi or Paratyphi
• Mesenteric adenitis
– Infection of mesenteric lymph nodes – typically due to Yersinia
Approach to Infectious Diarrhea
• Definition of diarrhea:
– Increase in water content, volume, or frequency
– Acute: ≤14d duration (viral, bacterial)
– Persistent: >14d duration (protozoal, non-infectious)
• What do you need to know from patients:
– Duration  acute or persistent
• Immunocompromised state renders duration unreliable
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–
–
–
Symptoms  noninflammatory vs inflammatory
Exposures/travel  affects differential diagnosis
Sick contacts  attack rate
Recent antibiotic use  Clostridium difficile
Diagnostic Evaluation
• Indications:
–
–
–
–
Dehydration with signs of hypovolemia
Inflammatory diarrhea (mucus, blood, tenesmus)
Fever ≥ 38.50C
Severe diarrhea (episodes ≥ 6/d or duration > 2d)
• Requiring hospitalization
–
–
–
–
Severe abdominal pain
Elderly or immunocompromised
Recent antibiotic use
Systemic symptoms
Stool Studies
– Fecal Leukocytes
• Sensitivity highly variable
– Stool culture
• Detects: Salmonella, Shigella, Campylobacter
• Special media: Vibrio, Yersinia
– EHEC/STEC immunoassay
– Protozoa
• Giardia/Cryptosporidium immunoassay
• Entamoeba histolytica antigen
[SENDOUT]
– O&P
• Special stains required for Cyclospora/Isospora
– Virus
• Norovirus PCR or EIA
• Rotavirus EIA
[SENDOUT]
[SENDOUT]
Diagnostic Evaluation
• Algorithm:
Acute
Community
Stool cx
+/- Fecal leuks
+/- EHEC assay
+/- C.diff assay
Persistent
Nosocomial
Immunocompetent
Immunocompromised
C.diff assay
Giardia
Cryptosporidia
O&P
Fecal leuks
Extensive
Foodborne Infections
www.cdc.gov/vitalsigns/foodsafety
Pathogenic Escherichia
ETEC - Enterotoxigenic
– Enterotoxin (similar to cholera toxin), elaborated locally
– Non-inflammatory: watery diarrhea
EAEC - Enteroaggregative
– Adhere to intestinal mucosa and damage microvilli, ± enterotoxin
– Variable from noninflammatory to inflammatory
EHEC - Enterohemorrhagic / STEC
– Cytotoxin (Shiga toxin), can cause hemolytic-uremic syndrome
– Inflammatory: bloody diarrhea without fever
EIEC - Enteroinvasive
– Invasion  phagosome escape  multiply  actin driven spread
– Dysentery: fever, abdominal pain, tenesmus, bloody or mucoid stool
STEC
• Shiga toxin-producing E.coli
– O157:H7 most common serotype in U.S.
– O104:H4 responsible for recent epidemic in Europe
• Shiga toxin
– Receptor-mediated endocytosis  cytosol
– Toxin interferes ribosome function  cell death
– Enters bloodstream  damages endothelial cells  HUS
• Clinical disease
–
–
–
–
Only 5-15% develop HUS
Abd pain, diarrhea  bloody diarrhea after 1-4 days
HUS develops 5-13 days after diarrhea starts
Supportive therapy. Avoid/discontinue antibiotics.
E.coli O104:H4
10.1056/NEJMoa1106483
STEC
Lancet 2010; 376:1428
Salmonella - Disease Entities
Salmonella enterica
Typhoidal
Non-typhoidal
Typhoid Fever / Enteric Fever
Inflammatory gastroenteritis
serotype Typhi
serotype Paratyphi
serotype Enteritidis
serotype Typhimurium
serotype Choleraesuis
and many, many more…
(2000+)
Prolonged systemic infection
Self-limited intestinal infection
Human reservoir
Animal reservoir
Epidemiology - NT Salmonella
OUTBREAKS
2007
Frozen Pot Pies n=272
2008
Jalapeno peppers n=1442
2009
Peanut butter n=714
2010
Eggs n=1939
2011
African frogs n=241
Ground turkey n=78 (8/4/11)
www.cdc.gov/vitalsigns/foodsafety
Epidemiology - Typhoid
Clin Infect Dis 2005; 41:1467-1472
Salmonella
Typhoid / Enteric Fever
• Incubation = 1-3 weeks
• Clinical characteristics:
Fever & abd pain
Diarrhea or constipation
Hepatosplenomegaly
Rose spots
Relative bradycardia
• Laboratory:
Leukopenia, hepatitis
Dx – blood, BM & stool cxs
• Complications:
Intestinal perforation
Neurologic disease
Relapsing disease
Gastroenteritis
• Incubation = 1-2 days
• Clinical characteristics:
Diarrhea watery to dysentery-like
lasting 3-7 days
Variable fever lasting 2-3 days
Abx not useful in uncomplicated dz
• Laboratory:
Dx – stool cx
Blood cx in immunocompromised
• Complications:
Particularly in immunocompromised
Bacteremia (5%)
Metastatic infection
Recurrent bacteremia
Shigella & Campylobacter
• Shigella
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–
–
–
Human reservoir. Person-to-person spread.
Shiga toxin (cytotoxin)  E.coli O157:H7 (HUS)
Classic cause of “Bacillary dysentery”
Complications:
• Bacteremia, HUS, post-infectious reactive arthritis, acute GN
• Campylobacter
– Animal (wild/domestic) reservoir. Commercial poultry.
– Undercooked poultry most common culprit.
– Complications:
• Bacteremia, post-infectious reactive arthritis, GBS
Vibrio
• Vibrio cholerae
– Toxigenic (O1 & O139) – contaminated water / food
• Voluminous watery diarrhea, without fevers / abd pain
– Non-toxigenic – shellfish, wounds
• Vibrio parahemolyticus
– Consumption of raw/undercooked shellfish
• Diarrhea can range from watery to dysentery-like
– Diarrhea > wound infection / septicemia
• Vibrio vulnificus
– Consumption of raw/undercooked shellfish.
• Septicemia with secondary cellulitis in cirrhotics / iron overload
– Wound infection with severe cellulitis / necrosis in healthy patients.
Acute Infectious Diarrhea
Management
• Rehydration
• Symptomatic therapy
– Anti-motility agent: NO/low-grade fevers, non-bloody stool
– Bismuth subsalicylate
• Antibiotics indicated for:
– Immunocompromised host
– Severe diarrhea requiring hospitalization
– Traveler’s diarrhea – severe (4+ BM/day) or inflammatory symptoms
• Decreased duration also seen in treatment of mild disease
– Isolation of Shigella in stool culture
• Antibiotics not useful:
– EHEC/STEC
– Uncomplicated NT Salmonella in healthy host
Giardia intestinalis (G.lamblia)
Surface water contaminated by
human or animal source.
Cysts survive well in cold water.
Person-to-person transmission
Infectious dose 10-102 cysts
Daycare centers
MSM
After treatment, can develop
continued diarrhea due to
lactose intolerance.
http://www.dpd.cdc.gov/dpdx/Default.htm
Entamoeba histolytica
Cysts viable for weeks-months
Worldwide distribution, in U.S.
Recent immigrants
International travel
Intestinal disease:
Asymptomatic – fulminant colitis
Chronic disease confused w/ IBD
Extraintestinal disease:
Amebic liver abscess
Pleuropulmonary amebiasis
http://www.dpd.cdc.gov/dpdx/Default.htm
Cryptosporidium
Acquisition of Infection:
Ingestion of oocysts
Oocysts resistant to chlorination
Infective when shed (person  person)
Low infectious dose (10 oocysts)
Microbiology:
Sporozoite
Binds to intestinal epithelium and induces
cell membrane to surround the sporozoite.
Trophozoite  Merozoite (motile)
Merozoite
Asexual reproduction
Sexual cycle  Gametocytes  Oocysts
Cryptosporidium hominis – humans
Cryptosporidium parvum
Animals (cattle, sheep, pig, pets) & humans
http://www.dpd.cdc.gov/dpdx/Default.htm
Cyclospora
•
Microbiology:
– Life-cycle similar to Cryptosporidium:
• Ingestion of oocyst. Oocyst requires maturation period in warm environment.
• Invades small intestinal enterocytes – within cytoplasm.
•
Epidemiology:
– Distributed worldwide: Nepal, Latin America, Caribbean.
– U.S. foodborne outbreaks: imported raspberries, basil, snowpeas, salad greens.
•
Clinical Disease:
– Watery diarrhea – cyclic / relapsing.
• Can last 2-7 weeks or longer.
• More persistent / severe in immunocompromised patients.
•
Diagnosis:
Oocysts require special staining (acid-fast) for detection in stool.
•
Treatment:
Trimethoprim-Sulfamethoxazole, Ciprofloxacin.
Isospora / Cystoisospora
•
Microbiology:
– Life-cycle similar to Cryptosporidium:
• Ingestion of oocyst. Oocyst infective when passed (person  person).
• Invades small intestinal enterocytes – within cytoplasm.
•
Epidemiology:
– Distributed in tropical / sub-tropical regions: Africa, South America, SE Asia
– U.S. – immunocompromised, daycare centers, psychiatric institutions
•
Clinical Disease:
– Watery diarrhea. May have peripheral blood eosinophilia.
• Can last 2-3 weeks or longer.
• More persistent / severe in immunocompromised patients.
•
Diagnosis:
Oocysts require special staining (acid-fast) for detection in stool.
•
Treatment:
Trimethoprim-Sulfamethoxazole, Ciprofloxacin.
Cyclospora oocyst in
stool - acid-fast stain
Isospora oocyst in
stool - acid-fast stain
Cyclospora oocyst in
stool – autofluoresce
under UV microscopy
Isospora oocyst in
enterocyte
http://www.dpd.cdc.gov/dpdx/Default.htm
Clinical Cases
51M with low-grade fevers,
NS, fatigue x3 wks.
No changes in BMs.
+ Hepatosplenomegaly
WBC 50 (87%L)  ALL
ALT 500
Blood cultures on admit:
Salmonella
Reports recent travel to
NYC, never outside U.S.
No sick contacts, no pet
reptiles, no unusual dietary
habits or exposures.
IV Ceftriaxone x2wks 
splenic abscesses 
aspirated  Salmonella
54 M presents with diarrhea x3
months. No fevers or abd pain.
Admitted to OSH 6 weeks ago for
chronic diarrhea, weight loss,
nausea & vomiting.
Found to have HIV / AIDS CD4
count of 70, candidal esophagitis.
Cause of diarrhea not determined.
Subsequently admitted to BGSMC
x3 for chronic diarrhea over 1
month period. Watery, non-bloody.
CBC: WBC 4.9 (50%N, 25%L, 15%E)
• 50 F with EtOH cirrhosis presents with acute onset of
chills, abdominal pain, N/V/D for 1 day.
• Recently attended a party, where she consumed shrimp
cocktail, pizza, and chips.
• 24h later developed chills, abdominal cramps, and
diarrhea - loose, non-bloody, low volume.
• Next morning was found to be lethargic, confused, and
with slurred speech by her husband.
• Brought to OSH  septic shock. She was intubated, and
started on vasopressors and empiric abx. Transferred to
BGSMC for higher level of care.
• SH: pet python, parakeet, fish, dog.
• LABS: WBC 6.5 29% B, ascites 1399 WBC 70%N
Blood Cx Gram Stain