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) - Yersinia (GNR)- Shigella (GNR) - Bacillus (GPR)- Campylobacter (GNR) - Clostridium (GPR)- Vibrio (GNR) - Staphylococcus (GPC)- E.coli (GNR)

• 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– 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 [SENDOUT]• Rotavirus EIA [SENDOUT]

Diagnostic Evaluation

• Algorithm:

Acute Persistent

Community Nosocomial Immuno-competent

Immuno-compromised

Stool cx

+/- Fecal leuks

+/- EHEC assay

+/- C.diff assay

C.diff assayGiardia

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 Typhiserotype Paratyphi

serotype Enteritidisserotype Typhimuriumserotype Choleraesuis

and many, many more…(2000+)

Prolonged systemic infection Self-limited intestinal infection

Human reservoir Animal reservoir

Epidemiology - NT Salmonella

www.cdc.gov/vitalsigns/foodsafety

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)

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– 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 transmissionInfectious 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

CryptosporidiumAcquisition 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)

MerozoiteAsexual 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.

http://www.dpd.cdc.gov/dpdx/Default.htm

Cyclospora oocyst in stool - acid-fast stain

Isospora oocyst in stool - acid-fast stain

Isospora oocyst in enterocyte

Cyclospora oocyst in stool – autofluoresce

under UV microscopy

Clinical Cases51M with low-grade fevers, NS, fatigue x3 wks.No changes in BMs.+ Hepatosplenomegaly

WBC 50 (87%L) ALLALT 500Blood 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