Infectious Diarrhea

1. Infectious Diarrhea

2. 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

3. 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

4. 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 Intestinal Infections - Uncommon

5. 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

6. 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

7. 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: • Vibriocholerae • EnterotoxigenicE.coli (Traveller’s diarrhea)

8. 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: • EnterohemorrhagicE.coli (O157:H7) • Shigella • Clostridium difficile

9. 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)

10. 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

11. Case • 30 F presents with 3 day history of watery diarrhea with intermittent abdominal cramps. • Previously healthy. • Further questions?

12. 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?

13. 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

14. 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

15. 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

16. 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]

17. Diagnostic Evaluation • Algorithm: Acute Persistent Community Nosocomial Immuno-competent Immuno-compromised Stool cx +/- Fecal leuks +/- EHEC assay +/- C.diff assay C.diff assay Giardia Cryptosporidia O&P Fecal leuks Extensive

18. Foodborne Infections www.cdc.gov/vitalsigns/foodsafety

19. 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

20. 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.

21. E.coli O104:H4 10.1056/NEJMoa1106483

22. STEC Lancet 2010; 376:1428

23. 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

24. 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

25. Epidemiology - Typhoid Clin Infect Dis 2005; 41:1467-1472

26. 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 Salmonella

27. 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

28. 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.

29. 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

30. 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. Giardia intestinalis (G.lamblia) http://www.dpd.cdc.gov/dpdx/Default.htm

31. 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 Entamoeba histolytica http://www.dpd.cdc.gov/dpdx/Default.htm

32. 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

33. 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.

34. 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.

35. 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

36. 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

37. 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)

38. 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

39. Blood Cx Gram Stain