Inflammatory Diarrhea Flashcards
What are some causes of inflammatory Diarrhea?
Causes of inflammatory diarrhea
- EHEC
- EIEC
- Shigella
- Salmonella enterica and enteritidis
- Campylobacter jejuni
- Clostridium difficile
- Yersinia enterocolitica
What are some causes of non inflammatory diarrhea?
Causes of non-inflammatory diarrhea
- ETEC
- EAEC
- EPEC
- Vibrio cholerae, parahemolyticus and vulnificus
- S. aureus
- Bacillus cereus
What is the most common cause of infectious diarrhea?
• what is likely the cause of persistent diarrhea lasting more than 10-14 days?
90% of infectious diarrheas are caused by viruses
Persistent diarrhea (> 10-14 days) is likely from a parasite
What should you consider as a diagnosis when someone has chronic diarrhea that is infectious?
Chronic diarrhea, start considering HIV status
Diarrhea is a big problem with AIDS pts
Mycobacterium avium intracellulare, CMV
Differentiate Acute and Chronic Diarrhea.
Acute diarrhea: 3 or more loose stools per day lasting less than 2 weeks.
Chronic diarrhea: persists greater than 4 weeks
What defines inflammatory diarrhea?
I_nflammatory diarrhea:_bloody diarrhea. Also called dysentery
- WBCs and RBCs seen in stool
- Fever is common
- Small volume diarrhea
- Colon is commonly affected
What defines non-inflammatory diarrhea?
Non-inflammatory diarrhea: watery diarrhea
- No cells in stool
- Usually afebrile
- Large volume diarrhea
- Small intestine is commonly affected
Compare E. coli, Shigella, and Salmonella with regard to:
• Gram Staining
• Aerobic, Anaerobic, Facultative Anaerobe?
• Oxidase
• Nitrate Reduction
• Motility
• Features used for serotyping?
Features common to salmonella, shigella, and E. coli.
• Gram negative, facultative anaerobic rods
• Ferment glucose with acid production
• Oxidase negative
• Reduce nitrates to nitrite (basis for the dipstick test)
• Motile except Shigella
Antigenic structures used in serotyping
• H (flagellar) antigens
• `: O-side chain (polysaccharide) of LPS
What prevents E. coli that is part of the colonic flora from causing disease?
E. coli are part of normal GI flora and most don’t cause infection because lack PAI (pathogenicity associated island)
Shigella
• Gram Staining
• Motility
• Lactose Fermentation
• Production of H2S
Shigella: gram negative, nonmotile, non-lactose fermenting, does not produce H2S
Shigella
• Type that causes epidemics in Central/South America
• Type that is most common in the US
• Type that is most common world wide
S. dysenteriae: Epidemics in Central/South America
S. sonnei: 70% of U.S. cases, mostly children
S. flexneri: 2nd most common in US, most common worldwide
Shigella
• How transmissible is it?
• How is it transmitted?
• Who is most likely to be infected with it?
Highly transmissible (very low infectious dose): fecal-oral or contaminated water/food
1Daycare centers, 2migrant workers, 3travelers to developing countries, 4nursing homes
Where and how does shigella invade tissue?
• what important proteins does it need to do this?
- Resistant to acidic environment of stomach
- Taken up by epithelial cells (M cells) in the intestine.
- They proliferate intracellularly, escape into lamina propria, and are phagocytosed by macrophages where they induce apoptosis.
- Consequent inflammatory response damages epithelia and allow Shigella to gain access to colonic epithelial cells where they can invade.
- Shigella spreads into adjacent cells via bacterium-induced, membrane- bound protrusions from the surface of the host cell. The formation of these protrusions depends on cellular actin polymerization proteins called FORMINS. The bacterium lyses the membranes that surround it, freeing itself into the cytoplasm of the new cell
How does shigellosis present?
• Incubation period
• Self limited?
Incubation period 1 week
Self-limited illness of diarrhea, fever, abdominal pain lasting about 1 week
Initially watery diarrhea which progresses to dysentery (bloody) in 50%.
Some adults will have a subacute course that lasts several weeks
What are some of the complications of Shigella infection?
• Are any of these complications specific to the species of Shigella involved?
Complications:
• reactive arthritis, urethritis, conjunctivitis (formerly known as Reiter’s syndrome)
• Hemolytic uremic syndrome may occur after infection with S. dysenteriae that produces Shiga toxin (AB toxin)
Are antibiotics useful in the treatment of shigellosis?
• if so which ones are used?
Antibiotics shorten the course and reduce duration of organism shedding in stools
Treatment:
Ceftriaxone, Ciprofloxacin, Azithromycin
What 5 types or E. coli are known to cause diarrhea?
• is the diarrhea inflammatory or non-inflammatory?
5 major strains of diarrheagenic E. coli:
Enterohemorrhagic E. coli (inflammatory)
Enteropathogenic E. coli (non-inflammatory)
Enterotoxigenic E. coli (non-inflammatory)
Enteraggregative E. coli (non-inflammatory)
Enteroinvasive E. coli (inflammatory)
Enterohemorrhagic E. coli
• aka?
• What are the 2 different types?
• Source of infection?
• How transmissible is it?
• How often does it cause severe complications requiring hospitalization?
Also called STEC (Shiga toxin producing E. coli)
2 types:
O157:H7 and non-O157:H7
Source:
Caused by ingesting inadequately cooked meat (hamburgers), contaminated vegetables and milk; also human-to-human
Transmissibility:
Low infectious dose
Severity of Infection:
Hospitalization required in 25-50% of patients
What is the pathogenesis of diarrhea in EHEC infections?
Locus of Enterocyte Effacement (LEE)
1. PAI (pathogenicity associated island) - contains genes required to cause LEE
- Type III secretion system (Esp A, B, D) is used to insert receptors (Tir) for the E. coli to latch onto (with Intimin).
- Pedestal formation for attachment - this is called the attaching and effacing lesion
This process causes Diarrhea
What is the clinical presentation of EHEC?
- Little fever, acute onset cramps and watery diarrhea.
- Diarrhea becomes bloody (hemorrhagic colitis) within 24 hours, lasts up to 8 days
Which of the EHEC strains is more likely to cause large outbreaks of hemorrhagic colitis?
O157:H7 strains more likely to cause large outbreaks, bloody diarrhea, hemolytic uremic syndrome, and ischemic colitis
How does Shiga-like toxin work?
• What strain of E. coli has this toxin?
Enterohemorrhagic E. coli has Shiga toxins (or Shiga-like toxins)
Encoded on a lysogenic bacteriophage
AB toxin
• B subunits bind toxin to its receptor on cells
• A subunit then enters the cytosol and cleaves a specific adenine residue from the 28S rRNA of the 60S ribosomal subunit, halting protein synthesis and causing death
T or F: hemolytic uremic syndrome is more associated with Shigella infection than with EHEC infection.
False, EHEC strains are more likely to cause HUS
What is the pathogenesis of Hemolytic Uremic Syndrome in EHEC and Shigella infection?
• how does it get into circulation?
• Explain the pathogenesis of the Anemia, Thrombocytopenia, and Renal Failure.
Shiga toxin is absorbed from the inflamed gastrointestinal mucosa into the circulation, where it alters endothelial cell function in some manner that results in platelet activation and aggregation.
- The hemolytic anemia and renal failure occur because there are receptors for Shiga toxin on the surface of the endothelium of small blood vessels and on the surface of kidney epithelium.
- Death of the endothelial cells of small blood vessels results in a microangiopathic hemolytic anemia - red cells passing through the damaged area become grossly distorted (schistocytes) and then lyse.
- Thrombocytopenia occurs because platelets adhere to the damaged endothelial surface.
- Death of the kidney epithelial cells leads to renal failure.
How common is HUS in EHEC infections?
• how commonly is EHEC the cuprit of HUS?
EHEC accounts for over 90% of HUS in children.
Complicates 6-9% of EHEC infections
What is the Clinical Presentation of HUS?
• how often is this disease fatal?
5-10 days after onset of diarrhea:
Microangiopathic hemolytic anemia and thrombocytopenia
AKI with dialysis required in over half of patients (most regain kidney function)
Neurologic symptoms (seizures, somnolence) in 25%
Mortality rate of about 5%
What is an easy why to differentiate EHEC O157 H7 from other types of EHEC and E. coli?
• what are 2 other methods of diagnosis?
the O157:H7 strain cannot ferment sorbitol when plated on Sorbitol-MacConkey agar and will appear WHITE instead of pink
PCR or enzyme linked immunoabsorbant assay (ELISA) used to detect Shiga toxin.
***How should a case of HUS be treated after diagnosis?
Supportive care and monitoring for complications
- *Important
1. Avoid anti-diarrheals**(increase risk of systemic complications) - *2. Antibiotics are NOT beneficial** and may predispose to HUS by inducing more Shiga toxin release
Enteroinvasive E. Coli
• How is it transmitted?
• Pathogenesis?
• Epidemiology?
• Transmitted via food/water or person-to-person contact
• Invades intestinal cell, multiplies intracellularly and extends into adjacent intestinal cells
• Most common in young children in developing countries
What other bacteria has a pathogenic mechanism similar to Enteroinvasive E. Coli?
EIEC - similar to Shigella in that it invades the intestinal epithelium and spreads from cell to cell to establish infection
***A major difference here is that EIEC does not have any toxins
Salmonella
• Gram Staining
• Lactose Fermentation
• H2S production?
• What are the two subtypes of salmonella?
- Gram negative bacilli, non-lactose fermenting, produces H2S
- Divided into Salmonella enterica serotype Typhimurium (formerly S. typhi) and nontyphoid Salmonella
What types of Salmonella can cause typhiod fever?
• do these also cause gastroenteritis?
S. enterica is the causative agent of typhoid fever, does NOT cause gastroenteritis
S. paratyphi is another species that can cause illness similar to Typhoid fever (also does NOT cause gastroenteritis)
What type of Salmonella is most often associated with Food Poisoning?
Nontyphoid Salmonella, most commonly S. enteritidis, causes salmonellosis- Significant source of gastroenteritis from food poisoning
What is the main source of S. enteritis?
Sources of infection:
• Dairy products
• Meat
• Poultry and eggs
• Pet turtles, lizards, other reptiles
• Human-to-human
How does Salmonella invade the intestinal epithelium?
• where does it live after invasion?
- Organisms attach to the M cells
- Virulence genes encode a type III secretion system capable of transferring bacterial proteins into M cells and enterocytes.
- The bacterial proteins trigger endocytosis and allow bacterial growth within endosomes
- Bacteria cross basal membrane and **enter the lamina propria
- Can take residence inside MACROPHAGES**
What species of salmonella can also kill macrophages?
S. enteritidis also kills macrophages
How does salmonellosis present clinically?
• Incubation period?
• Symptoms
• Duration
Clinical presentation
• Incubation period 1-3 days
• Nausea, vomiting, diarrhea (can be bloody), crampy abdominal pain
• Fever in 50%
• Illness lasts 3-4 days
What are some complications of Salmonellosis?
5% will develop invasive disease:
• bacteremia, endovascular infections, endocarditis, osteomyelitis. Predilection for aortic plaques, bone prostheses
Can also develop reactive arthritis
How is Salmonellosis diagnosed?
• What is the most common way to treat these patients?
Diagnosis:
• Stool Culture
Treatment:
• Not required for healthy people between ages of 2 and 50 years
• For those requiring tx, Flouroquinolones should be used and susceptibility testing should be performed.
In what patients is treatment indicated for Salmonellosis?
Treatment indicated for those at risk of disseminated/invasive disease:
• Immunocompetent patients with severe infection requiring hospitalization
• Those with known or suspected atherosclerotic plaques and endovascular/bone prostheses
• Immunocompromised (HIV, those who receive steroids or other immunosuppressants), sickle cell disease
Typhoid Fever
• Reservior
• Transmission
• Who is it most common in?
• Epidemiology?
Reservior:
Humans are the sole reservoir
Transmission:
Transmission occurs person-to-person (fecal-oral, infected food handler) or via contaminated food/water
Epidemiology:
More common in children and young adults than in older patients
Worldwide, most prevalent in impoverished, overcrowded areas with poor access to sanitation
What should you ask about to determine if someone living in the U.S. may have been exposed to Salmonella eterica or paratyphi?
Ask about travel hx.
This disease is extremely uncommon, but 80% of all U.S. cases are in patients that have traveled to areas where typhoid is endemic
What is the pathogenesis of Typhoid Fever?
- In small intestine organisms are taken up by and invade M cells.
- Bacteria are then engulfed by macrophages in the lymphoid tissue => Organisms proliferate in submucosa and lead to hypertrophy of Peyer’s patches due to influx of inflammatory cells
- Then organisms can disseminate to lymph nodes and RES
- Subsequent spread to blood => Sepsis can occur
What are some potential complications of the Peyer Patch Hypertrophy that occurs in the GI tract in Salmonella enterica or paratyphi infection?
• how can prople become chronic carries of typhoid fever?
Hypertrophy and subsequent necrosis of submucosal tissues can cause GI tract perforation => This can cause a Secondary Bacteremia with a DIFFERENT BACTERIA
Chronic carriage can occur in the biliary tract
What symptom should be a HUGE tip off that someone has a Typhoid Fever?
The patient may have a relative Bradycardia
Describe the Clinical Presentation in the 1st, 2nd, and 3rd weeks of typhoid fever.
• Incubation period
Clinical presentation
• Incubation period 5-21 days
1st week of illness:
• rising fever/chills develop; patients are bacteremic
• Relative bradycardia can be observed
2nd week of illness:
adominal pain and “rose spots” (faint salmon-colored macules on trunk/abdomen) may appear (see picture)
3rd week:
- *hepatosplenomegaly, GI bleeding, perforation, secondary bacteremia**
- *Septic shock may develop as well as AMS**
In the absence of death or severe complications, symptoms resolve over weeks to months
How is typhoid fever diagnosed?
• Treatment?
• Prevention?
Diagnosis
• Blood cultures positive in 50-80% of patients. May require several days of incubation
Treatment
• Ceftriaxone, Azithromycin, or Ciprofloxacin (unless patient has been in an area with high rates of flouroquinolone resistance such as South Asia)
Prevention
• Vaccine
What is the most common bacterial enteric pathogen in developed countries?
• What does it cause?
• Where do people most often contract this pathogen?
• Reserviors?
• Transmission?
Campylobacter jejuni
Important cause of traveler’s diarrhea
Most infections due to eating improperly cooked chicken; other sources include unpasteurized milk or contaminated water.
Reservoirs: sheep, cattle, chickens, wild birds, dogs
Highly transmissible – very low infectious dose
What are the Gram Staining and morphological characteristics of campylobacter jejuni?
Spiral Shaped Gram negative rod
What is the clinical Presentation of Campylobacter Jejuni infection?
• Incubation period?
• Symptoms?
• Resolution?
Incubation period 1 week
Fever, Crampy, periumbilical abdominal pain
Watery diarrhea (10+ BMs/day) which becomes bloody in 15% of adults and more than half of children
Self-limited over 3-7 days
How is Campylobacter Jejuni infection diagnosed?
• Who should get treatment?
• How do you treat?
Diagnosis:
• Stool culture
Treatment:
• Only warranted for those with severe disease or at risk of severe disease (bloody stools, high fever, worsening symptoms)
Azithromycin or Cipro are DOC, however resistance rates to flouroquinolones are rising
What are some possible complications of Campylobacter Jejuni infection?
- *1. Guillian Barre Syndrome
2. Erythema Nodosum
3. Reactive Arthritis**
How does Guillian Barre Syndrome Present?
• How often does this occur with C. jejuni infection?
• Pathogenesis?
• How long after the onset of infection do you start to see symptoms?
Guillain Barre syndrome
• Most common cause of GBS, however it develops in only 0.1% or less of those infected with C. jejuni.
• Molecular mimicry implicated in pathogenesis: serum antibodies to C. jejuni LPS cross-react with peripheral and central nervous system gangliosides
Clinical:
• Ascending paralysis
• Symptoms start one to two weeks after GI infection
What 3 intestinal Bacterial infections are associated with Reactive Arthritis?
• what HLA type is associated with this?
**Salmonella
C. jejuni
Yesernia
- Associated with HLA-B27**
Yersinia enterocolitica
• Staining
• Epidemiology
• Sources of Infection
Gram – coccobacilli with bipolar staining
Infection more common in Europe
Sources: pork, raw milk, contaminated water, pet feces
Yersinia enterocolitica
• Most common location(s) of infection?
• Pathogenesis?
Infection preferentially involves ileum, appendix, right colon. => Except for the Right colon, these are all places associated with lots of lymphoid tissue
Organisms multiply in lymphoid tissue resulting in regional lymph node and Peyer patch hyperplasia
Yersinia enterolitica
• Clinical Presentation
• Extraintestinal Symptoms?
Clinical presentation:
• Abdominal pain is the main feature
• Peyer patch and mesenteric lymph node hyperplasia can mimic acute appendicitis in teenagers and young adults
• Nausea/vomiting common, Fever/diarrhea can also occur
Extraintestinal symptoms are frequent:
• pharyngitis, arthralgia, erythema nodosum
Yersinia enterocolitica
• Diagnosis
• Treatment
Diagnosis: stool culture
Treatment: most cases do not warrant treatment
Clostridium difficile
• Staining
• Metabolism
• Other Key features
C. diff.
Anaerobic, Gram + Rod that can FORM SPORES
Clostridium Difficile
• How common is it for someone to carry it?
• Where/when are infections most common?
• Transmission
- Organism is carried in the GI tract in 3% of the population and 30% of hospitalized patients
- Most common nosocomial cause of diarrhea and most common cause of antibiotic-associated diarrhea
- Fecal-oral transmission => Hands of hospital personnel are important intermediaries
What role do antibiotics play in causes C. diff infections?
Antibiotics suppress members of the normal flora allowing for C diff to multiply and produce exotoxins A and B
Does C. diff have endotoxins or exotoxins?
• How do these work?
• what features are unique to each toxin and which are shared?
Exotoxins A and B cause glucosylation of small GTPases such as Rho which are involved in cytoskeleton structure and signal transduction
_Toxin A (enterotoxin)_ • **disrupts colonic mucosal cell adherence to colonic basement membrane** and **damages villous tips**; *inflammation leads to* **_fluid secretion_**
_Toxin B (cytotoxin)_ • causes **depolymerization of actin**, resulting in l*oss of cytoskeletal integrity, apoptosis and death of enterocytes*
Both toxins (A>B)
• stimulate monocytes and macrophages, which release IL-8 resulting in tissue infiltration with neutrophils; both cause disruption of epithelial tight junctions
Clostridium Difficile
• Clinical Presentation
Clinical presentation
• Watery diarrhea is the cardinal symptom
• Spectrum of manifestations include carrier state to fulminant disease with toxic megacolon
What are the 4 different ways that C. diff can present?
• Clinical Features of each?
C diff associated diarrhea (CDAD) with colitis:
• watery diarrhea (10-15 BM/day), mild lower abdominal pain/cramping, low grade fever, leukocytosis
Pseudomembranous colitis:
• Present similarly. In addition, sigmoidoscopy shows pseudomembranes - adherent layer of inflammatory cells and debris at sites of colonic muscle injury
Fulminant colitis:
• severe disease (severe abdominal pain, abdominal distention, fever, hypovolemia)
Toxic megacolon:
• Colonic dilatation >7 cm with severe systemic toxicity
What is shown here?
Toxic Megacolon that resulted from a C. diff infection
What is shown here?
Pseudomembranes that have formed as a result of C. diff infection
What are the risk factors for C. diff infection?
Risk factors for infection
Advanced age, hospitalization, antibiotic treatment
What are 3 different methods to diagnose a C. Diff infection?
• which is the gold standard?
• Pitfalls of each test?
Diagnosis
PCR detecting toxins A and B: highly sensitive and specific
EIA for toxins A and B: high false negative rate (sensitivity 75%)
Cell culture cytotoxicity assay: “gold standard”. Stool sample is added to a monolayer of cultured cells. If C diff toxin is present, it exerts a cytopathic effect in tissue culture. Labor intensive, takes 2 days.
What are the treatment options for C. diff?
Flagyl 1st line usually. If C. diff is severe, PO Vancomycin is indicated as 1st line.
1st recurrence: Flagyl.2nd recurrence: PO Vancomycin extended course
***Fidaxomycin relatively new, superior clinical response and less recurrences when compared head-to-head with Vanc
***Fecal transplants hot new thing
