20-21 Infectious Disease Lecture 1 and 2

Question 1

Definitions

• Gastroenteritis
  
  • ?
  • characterized by/
• Diarrhea
  
  • ?
  • defined as/
  • In bacterial gastroenteritis, diarrhea often results from/
• Dysentery usually involves/

Answer 1

• Gastroenteritis:
  
  • a syndrome involving inflammation of the stomach and intestines
  • characterized by gastrointestinal symptoms such as vomiting, diarrhea, abdominal cramps and nausea.
• Diarrhea
  
  • the most common consequence of these infections
  • defined as a frequent, and usually profuse, watery discharge.
  • In bacterial gastroenteritis, diarrhea often results from toxins and usually involves the small intestine.
• Dysentery usually involves
  
  • frequent, low volume stools containing blood and pus.
  • inflammation (often from pathogen invasion into the intestines)
  • the colon.

Question 2

Gastroenteritis

• Frequency of gastroenteritis
  
  • frequency
  • occurs in/
  • high risk populations
  • worldwide, diarrheal illnesses/
• Transmission
• Outcome of Exposure depend upon/
• Virulence of Some GI Pathogens
• Agents
  
  • viruses
  • bacteria

Answer 2

• Frequency of gastroenteritis
  
  • Gastroenteritis is extremely common
  • Occurs in both children and adults, but is a particular problem with young children <2 years
  • high risk populations: e.g., children in day care centers, patients receiving antibiotics, the immunocompromised, travelers to underdeveloped countries.
  • Worldwide, diarrheal illnesses are the second leading cause of death
• Transmission
  
  • usually acquired by ingestion;
  • often (but not always) involves fecal-oral transmission.
• Outcome of Exposure depend upon
  
  • the virulence of the pathogen and host GI tract defenses.
• Virulence of Some GI Pathogens
  
  • Shigella spp. > Campylobacter jejuni > Nontyphoid Salmonella > Vibrio cholerae > Giardia spp.
  • Viruses like norovirus are also often exceptionally virulent (low ID50)
• Agents
  
  • viruses cause most gastroenteritis in the USA.
  • bacteria cause most of the severe cases.

Question 3

Defenses Present in the Human GI Tract

Answer 3

• normal flora-compete out microorganisms (including some pathogens)
• gastric acid-kills many ingested microorganisms
• motility-helps remove many ingested microorganisms
• mucus-forms a protective layer that microorganisms (or their toxins) must penetrate
• bile
• shedding and replacement of the epithelium
• IgA- inhibits microbial adherence to intestines and neutralizes toxins
• local lymphoid tissue-besides producing IgA, also helps to fight invasive microorganisms (cellular immunity)

Question 4

Mechanisms of Infectious Diarrhea/Gastroenteritis (p.12-17)

• Increased Secretion
• Decreased Absorption from Intestinal Damage
• Inflammation
• Changed GI motility

Answer 4

• Increased Secretion:
  
  • from enterotoxins (e.g., cholera, ETEC)
• Decreased Absorption from Intestinal Damage
  
  • high osmotic pressure in lumen then causes diarrhea
  • viral (e.g., rotaviruses, noroviruses)
  • enterotoxin-mediated (e.g., C. perfringens type A food poisoning)
• Inflammation:
  
  • usually results from invasion (e.g., Salmonella, Shigella)
  • can also result from an enterotoxin with proinflammatory properties (e.g., Clostridium difficile).
  • Inflammatory diarrheas often result in increased fecal leukocytes
• Changed GI motility:
  
  • e.g., during viral gastroenteritis, viruses may impede gastric emptying, which triggers vomiting.

Question 5

Epidemiology of Gastroenteritis:
Endemic Infections

• Definition
• Examples in USA
• Who’s affected

Answer 5

• Definition: diseases that occur in the usual living conditions of the patient and their family.
• Examples in USA:
  
  • rotaviruses and other viruses (e.g., enteric adenoviruses) causing viral gastroenteritis.
  • involve brief incubation periods, vomiting and diarrhea (sometimes fever), and fecal-oral spread.
• Who’s affected: particularly common and severe in infants and young children because of their lower immune function and the spread of these viruses by the fecal-oral route.

Question 6

Rotaviruses (p.28)

• organism
• transmission
• clinical
• pathogenesis
• diagnosis
• treatment
• vaccine

Answer 6

• organism: Reovirus with segmented ds RNA genome.
• transmission: fecal-oral route, most common in winter.
• clinical:
  
  • prevaccination was the most common cause of diarrhea in young children (also affect the elderly);
  • Often a severe diarrhea, with vomiting and fever; 1-2 day incubation, illness lasts up to 1 week.
  • Can be fatal.
• pathogenesis: kills intestinal cells, resulting in malabsorption;
  
  • may make an enterotoxin?
• diagnosis: antigen detection in stool; EM.
• treatment: rehydration.
• vaccine:
  
  • now given universally at 2,4 and 6 months (RotaTeq) or 2 and 4 months (RotaRix);
  • >85% effective in preventing severe illness.

Question 7

Epidemiology of Gastroenteritis:
Epidemic Infections

• Definition
• Who’s affected
• Where
• Agents

Answer 7

• Definition: diseases that occur in large clusters beyond the family unit.
• Who’s affected: usually result from breakdown in public health sanitary measures.
• Where: very common in developing countries (e.g., cholera).
• Agents:
  
  • Worldwide, these include many agents (most notably, Vibrio cholerae, see below).
  • uncommon in USA, but do occur, e.g., outbreak of cryptosporidiosis in Milwaukee in the early 1990’s was due to breakdown in water treatment; recent cruise ship outbreaks due to Noroviruses.
  • Among leading cause of waterborne diseases in USA are Cryptosporidium parvum and Giardia spp.

Question 8

Vibrio cholerae (p.14-15+34+37+41-42)

• organism
• transmission
• clinical
• pathogenesis
• diagnosis
• treatment
• control

Answer 8

• organism: Gram-negative bacterial rod (oxidase-positive).
• transmission: fecally-contaminated water (also food).
• clinical: Severe dehydration due to fluid/electrolyte loss (some vomiting) that can lead to cardiac, kidney, etc. malfunction.
• pathogenesis:
  
  • mediated by an enterotoxin that increases intestinal cyclic AMP, activating chloride secretion.
  • Watery diarrhea-no inflammation.
• diagnosis: Culture.
• treatment: Fluid/electrolyte replacement and antibiotics.
• control: Water sanitation, vaccines?

Question 9

Noroviruses (p.44)

• organism
• transmission
• clinical picture
• pathogenesis
• diagnosis
• treatment
• control

Answer 9

• organism: Group of caliciviruses (ss RNA virus), e.g., Norwalk virus
• transmission:
  
  • Fecal-oral, often from ingestion of fecally-contaminated food or water
  • can also involve direct ingestion.
  • Easily spread
  • Often occurs in epidemics;
  • Persistent shedding?
• clinical picture:
  
  • More common cause of gastroenteritis in adults and older children than rotavirus.
  • Typical symptoms of viral gastroenteritis (like rotavirus), i.e.,vomiting and diarrhea.
  • Sudden onset.
  • Incubation period is 1/2 day to 2 days; lasts for 1-2 days.
• pathogenesis: Causes damage to the intestinal mucosa, resulting in malabsorption
• diagnosis: EM or serologic tests for antigens in feces; PCR
• treatment: Fluid and electrolyte replacement.
• control: Handwashing, careful food/water preparation, disinfect contaminated surfaces (fairly difficult- use 10% bleach).

Question 10

Epidemiology of Gastroenteritis:
Food Poisoning

• Definition
• Agents
• Contributing factors
• Bacterial foodborne diseases can be either intoxications or infections:
  
  • Intoxications
    
    • Foodborne botulism
    • Staphylococcal food poisoning and Bacillus cereus emetic food poisoning (emetic form)

Answer 10

• Definition: food is the transmission vehicle.
• Agents: ~40% from bacteria, ~60% from viruses (e.g., noroviruses), 1% from parasites (e.g., Cyclospora) and 2-3% from chemicals.
• Contributing factors: improper cooking or storage of foods.
• Bacterial foodborne diseases can be either intoxications or infections:
  
  • Intoxications-no viable pathogen need be ingested, only a microbial toxin.
    
    • Foodborne botulism (Clostridium botulinum makes an incredibly powerful neurotoxin with a neuron-specific proteolytic activity).
      
      • Causes flaccid paralysis.
      • Can be fatal.
    • Staphylococcal food poisoning and Bacillus cereus emetic food poisoning (emetic form); both involve vomiting and some diarrhea.
      
      • Onset is very fast (<6 hours).
      • Caused by heat-stable enterotoxins (probably have a neurotoxic action).
      • Not usually fecal-oral spread.
      • Treatment is symptomatic.

Question 11

Epidemiology of Gastroenteritis:
Food Poisoning (p.61)

• Bacterial foodborne diseases can be either intoxications or infections:
  
  • Infections
    
    • In vivo toxin production examples
    • Invasion

Answer 11

• Bacterial foodborne diseases can be either intoxications or infections:
  
  • Infections-viable pathogen must be ingested. Can involve either in vivo toxin production or invasion.
    
    • In vivo toxin production examples: Clostridium perfringens, B. cereus diarrheal form of food poisoning and EHEC (e.g., E. coli O157).
      
      • Diarrheal symptoms vary in development from 8-16 hours (C. perfringens, B. cereus diarrheal form) to ~4 days (E. coli O157:H7).
      • Treatment is symptomatic (no antibiotics).
    • Invasion-symptoms often include fever (from inflammation) as well as diarrhea.
      
      • Can be limited invasion involving pathogens such as Shigella spp., Campylobacter jejuni, or nontyphoid Salmonella.
      • Alternatively, can involve systemic invasion, notably Salmonella typhi, which causes typhoid fever.
      • Invasives cause disease with relatively slow onset (>16 hours to several days).
      • Fecal leucocytes are often elevated.
      • Treatment may include antimicrobials.

Question 12

EHEC (Enterohaemorrhagic E. coli) (p.56)

• organism
• transmission
• clinical picture
• pathogenesis
• diagnosis
• treatment

Answer 12

• organism: Gram-negative bacterial rod, these E. coli include O157:H7.
• transmission: ingestion of contaminated foods (e.g., hamburgers, apple cider). Also petting zoos!
• clinical picture: Causes two illnesses;
  
  • Hemorhhagic colitis,
    
    • shiga toxin primarily affects the colon.
    • Causes bloody diarrhea but no bacterial invasion (so usually few or no fecal leukocytes or substantial fever).
    • Children and elderly most often become ill.
    • Disease develops about 4 days after ingestion of contaminated food and lasts about a week.
  • Hemolytic uremic syndrome:
    
    • mostly in children
    • ~10% of HC cases, sufficient amounts of shiga toxin are absorbed from the gut to enter the circulation and damage the kidneys.
    • This causes acute renal failure.
    • Life-threatening.
• pathogenesis:
  
  • Symptoms result primarily from production of shiga toxin in the colon.
  • Shiga toxin kills mammalian cells by inhibiting protein synthesis.
• diagnosis: Isolation by culturing and DNA hybridization tests for shiga toxin genes or serologic tests for shiga toxin production.
• treatment:
  
  • For HUS, may require dialysis.
  • For HC, fluid replacement.
  • Antimicrobials generally considered ineffective and may be harmful.

Question 13

Salmonella spp. (p.18-19)

• organism
• transmission
• clinical picture
• pathogenesis
• diagnosis
• treatment
• vaccine

Answer 13

• organism:
  
  • Gram-negative bacterial rod, belong to Enterobacteriaceae
  • S. typhi (causes typhoid fever)
  • nontyphoid Salmonella (cause gastroenteritis and, less commonly, septicemia).
• transmission: Fecal-oral route;
  
  • nontyphoid Salmonella are the #1 cause of bacterial food borne disease in the USA (millions of cases/year);
  • typhoid fever still important in developing countries. Can be carriers.
• clinical picture:
  
  • For typhoid fever, multiorgan disease with fever, diarrhea (late), can lead to intestinal perforation. Slow developing.
  • For nontypoid Salmonella gastroenteritis, nausea, vomiting, cramps and diarrhea, with fever in >50% of patients. Develops about 1-2 days after ingestion of contaminated food.
• pathogenesis:
  
  • Both S. typhi and nontyphoid Salmonella invade through M cells into the Peyer’s Patches.
  • Nontyphoid Salmonella remain localized at the intestines,
  • S. typhi can survive in macrophages and is transported in these cells to reticuloendothelial tissue throughout the body (particularly to the liver).
  • Symptoms result from invasion-induced inflammation (at least in part, caused by endotoxin).
• diagnosis: Culture and serotyping.
• treatment:
  
  • Antimicrobials may be used for gastroenteritis, along with fluid and electrolyte replacement.
  • They are routinely used for typhoid fever.
• vaccine: available for typhoid fevers (travelers to developing countries)

Question 14

Epidemiology of Gastroenteritis:
Hospital-Acquired Gastroenteritis

• Who’s affected
• Agents
• Cause
• Treatment
• Relapse

Answer 14

• Who’s affected:
  
  • institutionalized patients, particularly those receiving antimicrobial therapy, are at increased risk for developing diarrheal disease.
  • Risk increases with age.
• Agents:
  
  • range in severity
  • mild diarrhea (a mild infection with C. difficile or an infection with enterotoxigenic C. perfringens)
  • life-threatening (a severe case of C. difficile-mediated pseudomembranous colitis and/or toxic megacolon).
• Cause: antimicrobials disturb normal GI flora, opening opportunities for pathogens to grow in GI tract.
• Treatment: first step in treatment is usually to discontinue current antimicrobial, then treat with an effective antimicrobial against offending pathogen.
• Relapse: even with effective antimicrobial therapy, can have relapses (often due to spores).

Question 15

Clostridium difficile (p.72-75)

• organism
• transmission
• clinical picture
• pathogenesis
• diagnosis
• treatment
• Prevention

Answer 15

• organism: Gram-positive, anaerobic, spore-forming rod.
• transmission:
  
  • Incidence of C. difficile GI disease has doubled since 2000.
  • Infections also becoming more severe/fatal.
  • Classical nosocomial infection involves hospital/nursing home environment with environmental person-to-person transmission.
  • New epidemic strain: makes more toxins A and B, another toxin named CDT, more antibiotic resistant. First noted in Quebec (and Pittsburgh).
• clinical picture: Disease ranges from
  
  • antibiotic-associated diarrhea ( a mild diarrhea)
  • pseudomembranous colitis (can involve systemic symptoms, such as high fever, along with severe dehydration).
  • 1-3% develop toxic megacolon-rapidly fatal due to colonic perforation.
• pathogenesis:
  
  • Mediated by toxins (A and B) that damage the colonic mucosa by glucosylating Rho proteins.
  • These toxins induce a severe inflammation.
• diagnosis: Perform fecal toxin tests for toxins A and B.
• treatment:
  
  • Fluid/electrolyte replacement and antimicrobials (e.g., metronidazole or vancomycin).
  • Fidaxomicin
  • Fecal transplants?
• Prevention: gloves, handwashing, restrict equipment, disinfection (10% bleach)

Question 16

Epidemiology of Gastroenteritis:
Gastroenteritis in Immunocompromised People

• Agents
  
  • Immunocompromised are more sensitive to/
  • Immunocompromised are also affected by/
• Who’s affected

Answer 16

• Agents:
  
  • Immunocompromised are more sensitive to “true GI pathogens” (such as Salmonella and Shigella)
    
    • i.e., lower doses are needed to cause an infection and disease is often more severe and long-lasting.
  • Immunocompromised are also affected by unusual opportunists that don’t normally cause GI disease.
• Who’s affected:
  
  • transplant recipients
    
    • often viruses are responsible (most commonly cytomegalovirus or Epstein-Barr virus)
  • AIDS patients
    
    • 50-60% of AIDS patients in the US develop a diarrhea disease-these can become prolonged, life threatening illnesses.
    • These can be difficult to manage.

Question 17

Some Common Causes of Diarrhea in AIDS Patients

Answer 17

Entamoeba histolytica (a parasite)
Cryptosporidium parvum
Giardia spp.
Isospora (a parasite)
Salmonella spp.
Shigella spp.
Campylobacter jejuni
Mycobacterium avium intracellulare
Cytomegalovirus
Herpes simplex virus

Question 18

Cryptosporidium parvum

• organism
• transmission
• clinical
• pathogenesis
• diagnosis
• treatment

Answer 18

• organism: Parasite that forms resistant cyst.
• transmission: Fecal-oral contamination, e.g., drinking contaminated water. Animal reservoir.
• clinical: Ranges
  
  • moderate diarrhea lasting up to several weeks (in immunocompetent)
  • serious diarrhea that becomes chronic in immunodeficient (may contribute to death).
• pathogenesis: Not well understood.
• diagnosis: Staining of concentrated feces with a modified acid-fast stain to show cysts.
• treatment:
  
  • No really effective antimicrobial treatment for immunocompromised adults at present (paromomycin sometimes used for AIDS patients).
  • Improvement of immune status due to antiretroviral therapy can lessen cryptosporidiosis in AIDS patients.
  • Nitazoxanide is FDA-approved for treatment of people with healthy immune systems.

Question 19

Epidemiology of Gastroenteritis:
Traveler’s Diarrhe

• Frequency
• Agents
• Prophylaxis
• Treatment

Answer 19

• Frequency: with increased business, military, and vacation travel, these are becoming a more common problem.
• Agents: most common cause is ETEC, but many other microorganisms (including viruses) can also cause this illness-can involve more exotic organisms than found domestically.
• Prophylaxis: efficacy unclear, may promote antibiotic resistance.
• Treatment:
  
  • adult overseas traveler might take thermometer, loperamide (an anti-intestinal motility agent) and broad-spectrum antimicrobial with them.
  • If they become sick, they should take their temperature.
    
    • If no fever, use loperamide.
    • If fever, take antimicrobial (good chance caused by invasive bacterium).

Question 20

Enterotoxigenic E. coli (ETEC)

• organism
• transmission
• clinical picture
• pathogenesis
• diagnosis
• treatment

Answer 20

• organism: Gram-negative bacterial rod. Belongs to Enterobacteriacae.
• transmission: Fecal-oral; usually through contaminated foods or water.
• clinical picture: Watery diarrhea (no fever).
• pathogenesis: Involves enterotoxins, heat-labile enterotoxin (which acts like cholera toxin and increases intestinal cAMP) and/or heat-stable enterotoxin (which increases intestinal cGMP).
• diagnosis: Isolate by culture and do DNA tests for presence of toxin genes.
• treatment: Fluid/electrolyte replacement and symptomatic.

Question 21

Diagnosis of Gastroenteritis

• First step is to obtain a good history:
• If mild, watery diarrhea with no fever
• If fever or bloody diarrhea (or patient is immunocompromised or taking antibiotics):

Answer 21

• First step is to obtain a good history:
  
  • Recent travels?
  • Does the patient know anyone else who is also sick (identifying a common source)?
  • What are the symptoms? Diarrhea? Vomiting? Fever?
  • When did symptoms start?
  • Frequency of bowel movements? Is the stool bloody?
  • Recent antibiotic use?
  • Remember: not all diarrhea, etc. is from infectious agents.
• If mild, watery diarrhea with no fever: Usually just treat symptomatically (no further diagnostic tests unless illness does not go away).
• If fever or bloody diarrhea (or patient is immunocompromised or taking antibiotics):
  
  • Do a microscopic exam for fecal leukocytes (may also show parasites).
  • Culture for routine GI pathogens (e.g., Salmonella, Shigella); if patient is sufficiently immunosuppressed may need to consider more exotics if the patient doesn’t respond but don’t try initially to culture all these -too expensive.
  • C. difficile toxin test, if appropriate.

Question 22

Management of Gastroenteritis (p.92)

• In the immunocompetent:
  
  • Always address…
    
    • For mild diarrhea
    • for moderate diarrhea
    • for serious diarrhea
  • If noninflammatory diarrhea
  • Symptomatic therapy for noninflammatory diarrhea:
  • If inflammatory diarrhea (blood, fever, fecal leukocytes):
• In AIDS / immunocompromised patients
  
  • If routine cultures show a typical GI pathogen (Salmonella, Giardia),
  • If routine cultures are negative,

Answer 22

• In the immunocompetent:
  
  • Always address fluid/electrolyte loss, particularly in children.
    
    • For mild diarrhea can use pedialyte or mineral water plus saltine crackers;
    • for moderate diarrhea can use Oral Rehydration Solution (ORS);
    • for serious diarrhea may need i.v., fluids
  • If noninflammatory diarrhea
    
    • e.g., due to rotavirus, noroviruses, ETEC, C. perfringens, S. aureus):
    • also give symptomatic therapy, unless there is no resolution (then might consider parasites).
  • Symptomatic therapy for noninflammatory diarrhea:
    
    • Absorbants (Attapulgite, e.g., Kaopectate in Canada)
    • Anti-intestinal motility agents (loperamide, i.e., Immodium A-D; diphenoxlate-atropine, i.e., Lomotil)
      
      • Do not use for inflammatory diarrheas! Prolongs contact of invasive bacteria with intestines.
    • Anti-secretory agents (bismuth salts, e.g., Peptobismol)
  • If inflammatory diarrhea (blood, fever, fecal leukocytes):
    
    • also give antimicrobials to adults, e.g., quinolones.
    • Be cautious with children - could be EHEC.
• In AIDS / immunocompromised patients
  
  • If routine cultures show a typical GI pathogen (Salmonella, Giardia),
    
    • treat this first with appropriate antimicrobials.
  • If routine cultures are negative,
    
    • then treat symptomatically, e.g., with loperamide-
    • if no response, then order more extensive cultures.

Question 23

Summary

• Gastroenteritis caused by infectious agents/
• Infectious gastroenteritis requires/
• A number of infectious agents are able to cause gastroenteritis; typically, each infectious agent causing gastroenteritis is associated with/
• Infectious agents use several mechanisms/
• diagnosing which specific pathogen is responsible for a particular case of gastroenteritis is often/
• Treatment of gastroenteritis varies according to disease severity;
  
  • milder cases
  • more serious cases
  • all cases of gastroenteritis

Answer 23

• Gastroenteritis caused by infectious agents is one of the most common illnesses seen by physicians; this illness can be life-threatening in certain situations.
• Infectious gastroenteritis requires that the infectious agent overcome the defenses naturally present in the GI tract; the likelihood of this happening depends upon both the virulence of the pathogen and the status of the host.
• A number of infectious agents are able to cause gastroenteritis; typically, each infectious agent causing gastroenteritis is associated with a specific epidemiologic scenario.
• Infectious agents use several mechanisms (including enterotoxin-mediated secretion, malabsorption, inflammation, and altered motility) to induce the diarrheal symptoms of gastroenteritis.
• diagnosing which specific pathogen is responsible for a particular case of gastroenteritis is often difficult; this is usually attempted only for serious or chronic cases.
• Treatment of gastroenteritis varies according to disease severity;
  
  • milder cases often can be treated symptomatically,
  • antimicrobials should be considered in more serious cases.
  • Fluid/electrolyte replacement is critical for all cases of gastroenteritis.