A. Overview

1. Classified by causative agent and by timing of illness after ingestion of food
2. Causative Agents
   1. Virus
   2. Bacteria - Toxin Production and/or Direct pathogenesis
   3. Protozoal
3. Timing of illness after food ingestion and associated symptoms
   1. Preformed toxins cause symptoms very rapidly (<6 hours)
   2. Enterotoxins may cause delayed diarrhea (8-16 hours)
   3. Majority of manifestations are gastrointestinal (GI), usually 24-72 hours
   4. Mushrooms cause a variety of often serious problems
   5. Variable extrainstestinal manifestations can occur
4. Diseases are best classified by timing and type of symptoms

B. Clinical Syndromes [1]

1. Nausea and Vomiting (<1-6 hour)
   1. Ham, poultry, cream-filled pastries, potato and egg salads - S. aureus preformed toxins
   2. Fried rice, pork - Bacillus cereus (emetic toxin)
   3. Acidic beverages - heavy metals (copper, tin, cadmium, zinc)
2. Scromboid Poisoning (<1 hour) [31]
   1. Urticarial and GI symptoms lasting <6-8 hours
   2. Fish - usually tuna and mackeral
   3. Shellfish
   4. Histamine reaction develops 20-30 minutes after ingestion
   5. Flushing, nausea, vomiting, diarrhea, abdominal cramps, headache, palpitations
   6. Dizziness, dry mouth, urticaria, conjunctival injection
   7. Diphenhydramine (25-50mg) po, IM, or IV or other H1-antihistamine
   8. Add H2-histamine blockade (famotidine, ranitidine) in severe cases
3. Neurologic (Paresthesias) and GI Symptoms (<1-6 hours)
   1. Puffer Fish - tetrodotoxin (may cause paralysis)
   2. Ciguatera toxin - from scavenging (see below)
   3. Shellfish - paralytic toxins
   4. Mussels - domoic acid
   5. Chinese Food - monosodium glutamate (chinese restaurant syndrome)
4. Ciguatera Poisoning [31]
   1. Usually Amberjack, Barracuda, Grouper, Snapper, King Mackerel, Moray Eel (most toxic)
   2. Due to high levels of dinoflagellate Gambierdiscus toxicus
   3. Symptoms usually begin 6-12 hours after ingestion, but may start within 1-24 hours
   4. GI: nausea, vomiting, abdominal pain, profuse watery diarrhea
   5. Neurologic: numbness, paresthesias, vertigo, ataxia, weakness, lethargy, myalgia
   6. Decreased vibration and pain sensation, cold sensation reversal, diffuse pain, coma
   7. Cardiac: bradycardia, hypotension may occur
   8. No current way to detect or destroy toxin
   9. Treatment: intravenous fluid and other supportive measures as needed
   10. Atropine for bradycardia; pressors for hypotension
   11. Amitriptyline (Elavil®) for pruritus or dysesthesias 25mg po bid
   12. Supportive care and monitoring are critical in severe cases
5. Abdominal Cramps and Watery Diarrhea (8-16 hours)
   1. Beef, pork, chicken, vanilla sauce - B. cereus (enterotoxin)
   2. Beef, poultry, gravy - C. perfringens (enterotoxin)
6. Abdominal Cramps and Watery Diarrhea (16-48 hours)
   1. Shellfish, salads, ice - caliciviruses
   2. Fruits, vegetables - enterotoxigenic E. coli
   3. Shellfish - Vibrio cholerae O1 and O139, non-O1
7. Diarrhea, Fever, Abdominal Cramps, Bloody Stools (16-72 hours) [6]
   1. Poultry, pork, eggs, dairy products, vegetables, fruit, sprouts [3] - Salmonella
   2. Egg salad, vegetalbes - Shigella
   3. Poultry, raw milk - Campylobacter jejuni
   4. Vegetables and sprouts - invasive E. coli [4]
   5. Pork, tofu, raw milk - Yersinia enterocolitica
   6. Fish, shellfish - Vibrio parahaemolyticus
8. Bloody Diarrhea and Abdominal Cramps (72-120 hours)
   1. Beef - enterohemorrhagic E. coli (for example, strain 0157:H7)
9. Cystitis (urinary tract infections): Sprouts - E. coli [3]
10. Neurotoxins - Botulism (see below)

C. Viruses

1. Norovirus (Norwalk Agent, Small Round Structured Viruses, SRSV) [5,6]
   1. Family Calciviridae
   2. Common cause of infectious diarrhea, mainly in adults
   3. Diarrheal syndrome after drinking contaminated water or eating undercooked shellfish
2. Hepatitis A Virus [7]
   1. Mainly from raw oysters and other raw seafood, produce
   2. Vaccination available for at risk >2 weeks from initial vaccine
   3. Immune globulin prophylaxis for risk <2 weeks

D. Parasites

1. Cryptosporidium parvum: contaminated produce, water; gastroenteritis
2. Cyclospora: contaminated produce, water; gastroenteritis
3. Toxoplasmosa gondii: food contaminated with cat feces, undercooked meat; influenza-like
4. Giardia lamblia: contaminated water; gastroenteritis
5. Taenia solium: raw pork; asymptomatic, cysticercosis

E. Bacterial

1. Living organisms
   1. Salmonella (see below) [8,9]
   2. Campylobacter jejuni (see below)
   3. Vibrio vulnificus (see below) [10]
   4. Hemorrhagic E. coli (mainly O157:H7) [11,12]
   5. Enterotoxogenic E. coli
   6. Shigella [13]
   7. Listeria monocytogenes
   8. Yersinia enterocolitica
2. Toxins
   1. Staphylococcus aureus
   2. Baccilus cereus
   3. Clostridium botulinum
3. Vibrio vulnificus [10,14]
   1. Most virulent of non-cholera vibrios
   2. Sepsis may also present in normal hosts
   3. Raw oysters are most common vehicle in these cases
   4. Handling fresh fish can also transmit infection
   5. All susceptible persons should avoid raw oysters and care in handling fish
   6. Most severe syndrome in persons with liver disease or or immunosuppression
   7. Particularly common in alcoholics who eat raw oysters
   8. In these patients, bacteria can cross gut and cause systemic sepsis syndrome
   9. May cause severe cellulitis and skin ulceration after infection of wounds
   10. Skin lesiosn are common and look like boils or bullous lesions
   11. Hypotension is quite common
4. Vibrio parahaemolyticus [30]
   1. Usually associated with eating raw or undercooked shellfish
   2. Most commonly oysters
   3. Leading cause of Vibrio associated gastroenteritis in USA

F. Campylobacter jejuni [6]

1. May be most common form of acute infectious gastroenteritis in USA
2. 2-5 day incubation, 2-10 duration of gastroenteritis
3. Organism does not replicate in food so massive outbreaks are not seen
4. Fewer than 1000 colony forming units (CFU) can cause infection

G. Salmonella [2,6,8,9]

1. Bacterium
   1. Gram Negative organisms
   2. Facultative anaerobes
   3. Widely distributed in nature
   4. Cause gastrointestinal (GI) disturbances in humans
   5. Cause typhoid fever
2. GI Disease
   1. Epithelial cell invasion in gut
   2. Likely produce both a cytotoxin and enterotoxin, but not similar to Shiga toxin
   3. Bacteremia is common, particularly in sickle cell and AIDS patients
   4. Highly susceptible to stomach acid; increased risk in persons with achlorhydria
   5. About 20,000 confirmed cases of salmonella enterocolitis reported in USA each year
   6. Estimated ~2 million Salmonella infections annually in USA [2]
3. Serogroups
   1. S. paratyphi (serogroup A) and S. typhi (causes of Typhoid Fever)
   2. S. typhimurium (serotype B, Salmonella enterica subtype typhimurium)
   3. S. choleraesuis (serotype C)
   4. S. enterica subtype typhi
   5. S. durban (serotype D)
4. Transmission
   1. Poultry products or eggs
   2. Unpasteurized milk and/or cheese [15,16]
   3. Occasionally water
   4. Fecal-oral spread can occur, particularly in children
   5. Transmission from pigs (Serotype B) [17]
5. Symptoms of Food Poisoning
   1. 1-3 day incubation with 4-7 day gastroenteritis
   2. Nausea, vomiting and diarrhea begin 6-48 (average ~24) hours after ingestion
   3. Myalgia, headache and fever are common
   4. Diarrhea is moderately voluminous, crampy, with mildly bloodiness in most cases
   5. Pus and frank blood in stool are less common than with shigella
   6. Usually caused by non-typhi strains and occasionally S. choleraesuis
6. Salmonella Bacteremia
   1. ~5% of salmonella food poisoning leads to bacteremia
   2. Increased risk in immunocompromised hosts and sickle cell anemia
   3. Osteomyelitis, absces formation, meningitis, endarteritis, endocarditis can occur
   4. Cardiovascular infections develop in ~25% of salmonella bacteremia
   5. Infected aneurysms including aortitis can occur
   6. Aortitis presents with fever, back pain, abdominal pain, leukocytosis occur
   7. Full body CT scans or similar assessment in any patient with salmonella bacteremia
7. Drug Resistance [17,18]
   1. Increasing antibacterial drug resistance in USA and in Denmark
   2. Mainly due to increased use of antibiotics for farm animals
   3. Multidrug resistant S. typhimurium DT104 isolated
   4. Resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline
   5. These resistant strains from USA are sensitive to ciprofloxacin
   6. Increasing number of strains from Denmark resistant to ciprofloxacin [17]
   7. AmpC expressing, ceftriaxone resistant Salmonella has been reported in USA [19]
   8. Essentially all strains respond to second generation fluoroquinolones
   9. Levofloxacin (Levoquin®) 500mg po qd is effective
8. Typhoid and Enteric Fever [20,21,22]
   1. Salmonella enterica serotype typhi (formerly Serotype D)
   2. Less commonly Salmonella paratyphi A
   3. Less than 500 cases per year in USA
   4. Over 200,000 deaths globally in 2000, mainly in developing world
   5. Usually associated with travel to endemic areas, especially Indian subcontinant
   6. Does not cause early inflammatory response, do disease disseminates rapidly
   7. Bacteremia with reticuloentothelial invasion, full septic picture possible
   8. Severe fever, malaise, headache, anorexia occur, some sore throat
   9. Abdominal pain due to inflammation of Peyer's patches in distal ileum
   10. Diarrhea is not prominant, and splenomegaly is unusual in antibiotic era
   11. Rose spots on abdomen are now very uncommon, usually after 1-2 weeks
   12. Complications involving brain, bone, joints and heart valves may occur
   13. Diagnosis with culture confirmation, agglutinating antibodies (Widal Test) or serology
   14. Untreated mortality is ~15%; treated with antibiotics <1%
   15. Quinolones or 3rd generation cephalosporins are recommended empiric treatment
   16. Most patients can be treated at home with oral antibiotics, fluids
   17. Severe cases receive parenteral antibiotics and intravenous fluids, electrolyte monitoring
9. Salmonella Typhi Vi Conjugate Vaccine [23]
   1. Typhoid fever is common in developing countries
   2. Older vaccine effective ~70% overall; little efficacy in young children
   3. New capsular polysaccharide vaccine bound to nontoxigenic pseudomonas exotoxin A
   4. This vaccine has enhanced immunogenecity
   5. Requires two injections 6 weeks apart
   6. Vaccine efficacy 91%

H. Shigella [6,13]

1. Gram negative organisms closely related to E. coli
2. Four Species based on O angitens
   1. S. dysenteriae (group A) - produces tropical bacillary dysentery (inflammatory diarrhea)
   2. S. flexneri (group B)
   3. S. boydii (group C)
   4. S. sonnei (group D)
3. Transmission
   1. Contaminated food
   2. Contaminated water
   3. Fecal-oral - may be associated with swimming pool transmissions
4. Pathogenesis
   1. Produce cytotoxins and are directly invasive to enterocytes
   2. Organism invades both small and large intestine
   3. S. dysenteriae Types 1 and 2 produce classic cytotoxic and neurotoxic Shiga Toxin
   4. The other strains produce Shigalike toxins
   5. These toxins have one active (A) subunit and five binding (B) subunits
   6. Many enteropathogenic and enterohemorrhagic E. coli produce similar toxins (see above)
5. Clinical Syndrome
   1. Called shigellosis - acute bloody diarrheal illness with cramping (dysentery)
   2. 1-2 day incubation and 4-7 days of symptoms
   3. Initially, stools may be watery, but quickly become mucoid and bloody (colonic disease)
   4. Usually self limiting, except for Type 1 S. dysenteriae (~15% mortality without drugs)
   5. Fevers occur
   6. Diagnosis with stool culture
6. Treatment
   1. Sulfa-agents or doxycycline were generally used
   2. Quinolones are now the agents of choice

I. Escherichia coli O157:H7 [6,11,24]

1. Enterohemorrhagic E. coli due mainly to strain E. coli O157:H7
   1. Somatic antigen (O) #157
   2. Flagellar antigen (H) #7
   3. Related to E coli O55 H7 which produces a diarrheal illness in infants
2. Transmission
   1. Mainly from undercooked meats, particularly hamburger
   2. Healthy cattle appear to be the major reservoir
   3. Visiting a dairy farm and petting contaminating animals clearly a risk factor [12]
   4. Other foods including fruits and vegetables
   5. Organism can also live in unchlorinated drinking water and in juices
   6. Transmission also with swimming in a lake though this is very uncommon
   7. May be shed from human stool for several weeks following symptoms resolution
   8. Hand-washing greatly reduces risk of infection and complications
3. Virulence Factors [24]
   1. Produces high titers of one or more Shiga Toxins (verocytotoxins, Shiga-like toxins)
   2. Type 1 Shiga Toxin is identical to that produced by Shigella dysenteriae type 1
   3. Type 2 Shiga Toxin has 56% homology with Shiga Toxin 1
   4. Both toxins are composed of 5 B subunits (binding) and 1 A subunit (active)
   5. The genes for the toxins are carried on bacteriophages integrated into the chromosome
   6. The B subunit binds to globotrialosylceramide (Gb3)
   7. The A subunit enzymatically inactivates the 60S eukaryotic ribosomal subunit
   8. MDa plasmid is also required for virulence, encodes a hemolysin
   9. The locus of enterocyte effacement gene (LEE) is also required for virulence
   10. LEE codes for the intimin adhesion molecule and other factors for cell effacement
   11. Post-diarrheal hemolytic uremic syndrome (HUS) due to activation of toxin in kidney [25]
4. Clinical Presentation
   1. Watery and (usually) bloody diarrhea, may be voluminous
   2. Sporadic and epidemic cases described
   3. Major complication is HUS and related conditions
   4. About 70% of children with HUS had this infection
   5. 10-30% of persons with E. coli O157:H7 infection will develop HUS [25]
   6. HUS develops 3-7 days following initial bloody diarrheal illness
   7. Thrombotic thrombocytopenic purpura (TTP) much less commonly seen
   8. Gastrectomy is a risk factor for HUS/TTP development
5. Diagnosis
   1. High clinical suspicion in any patients with acute blood diarrhea or visibly bloody stool
   2. High suspicion for all cases of HUS
   3. Stool specimens must be tested specifically for the organism
   4. Detection rate in stool is ~90% within 6 days of illness
   5. This detection rate drops to ~33% for stolls collected >6 days of illness
   6. Convalescent phase serum samples can be assayed for Abs to O157 LPS (research phase)
6. Treatment [25]
   1. Antibiotics may prolong duration of illness and could worsen course of disease
   2. Antibiotics probably do not increase risk of developing HUS [26]
   3. Sulfa agents had no effect on the course of disease or HUS in prospective study [24]
   4. Use of antimotility drugs increases HUS/TTP risk
   5. No therapy against the organism which decreases likelihood of HUS/TTP occurrance
   6. HUS management requires highly specialized and intensive care to improve outcomes
   7. Therefore, supportive care is the mainstay of therapy at this time

J. Staphylococcus aureus

1. Due to production of enterotoxin by bacteria
   1. Toxin appears to be a superantigen, causing polyclonal lymphocyte activation
   2. Toxin is heat resistant
2. Disease is due to an intoxication, not to live, infectious organisms
3. Usually found in meats, potato and egg salads, cream pastries
4. Clinical Syndrome
   1. Acute vomiting and diarrhea within 1-6 hours of toxin ingestion
   2. Duration 1-2 days usually with marked nausea
   3. Dehydration is common, without fever
   4. Generally limited
5. Supportive care may be required for high-risk groups (very elderly, chronic disease)

K. Baccilus cereus [27]

1. Foodborne pathogen that usually causes self-limiting gastroenteritis
2. Incubation 1-6 hours after ingestion, <24 hour severe vomiting, gastroenteritis
3. Diarrheal toxin (enterotoxin) and emetic toxin (cereulide) are produced
4. The diarrheal toxin is similar to cholera toxin
5. Some liver complications can occur, unusual cases of fulminant failure
6. Increased risk of severe infection in immunosuppressed persons

L. Botulism [18,29]

1. Neuroparalytic illness
2. Caused by Clostridium botulinum
   1. Anaerobic, spore forming bacillus
   2. Species consists of at least 3 genetically diverse types of organisms
   3. Seven different neurotoxins, A through G, have been described
   4. Commonly found in soils throughout the world
   5. C. baratii (toxin F) and C. butyricum (toxin E) can also produce botulinum
3. Neurotoxins
   1. Human illness usually caused by toxins A, B, or E
   2. Toxin F (C. barabii) can also cause botulism
   3. Types C or D toxins cause botulism primarily in nonhuman species
   4. All toxins consist of 100K heavy chain and 50K light chain joined by a disulfide bond
   5. Toxin binds irreversibly to presynaptic nerve endings of peripheral and cranial nerves
   6. Inhibits the release of acetylcholine
   7. Heavy chain apparently binds to nerve membrane and light chain is active chain
   8. Light chain cleaves protein components of neuroexocytosis within neuron
4. Clinical Symptoms
   1. 12-72 hour incubation; duration days to months
   2. GI symptoms initially - nausea, vomiting, diarrhea (early), constipation (late)
   3. Blurred vision, dry mouth then occur
   4. Dysarthria
   5. Diplopia
   6. Descending paralysis
   7. Dyspnea
   8. Physical Findings: ptosis, other cranial nerve abnormalities, extremity weakness
   9. Pupils fixed or dilated, nystagmus, hypoactive deep tendon reflexes
   10. Respiratory failure may develop rapidly
5. Uncommon illness due to improperly sterilized foods
   1. Canned vegetables and fruits (usually home canned, pH >4.6)
   2. Canned fish
   3. Some salted fish
   4. Bottled garlic in oil
   5. Baked potatoes in aluminum foil
   6. Cheese sauce
   7. Sauteed onions under butter sauce
6. Differential Diagnosis
   1. Stroke
   2. Guillain-Barre Syndrome
   3. Myasthenia Gravis
7. Laboratory confirmation of suspected diagnosis (through CDC)
   1. Mouse inoculation test for toxin - stool, serum or food
   2. Stool culture for C. botulinum
8. Management
   1. Mechanical ventilation is mainstay of therapy
   2. Monitor all patients for potential respiratory arrest, which may be rapid
   3. Gastric lavage is attempted if potential food exposure was recent
   4. Penicillin (or metronidazole) antimicrobial treatment should be given
   5. Antitoxin specific for toxins A, B, or E are available through Centers for Disease Control
   6. Human botulism immune globulin is available in USA only for treatment of infants [32]
   7. Human botulism immune globulin reduces duration of hospitalization and illness severity in infants with Types A or B botulism [32]
   8. Rapidly effective vaccines are not currently available
   9. All cases must be reported to the CDC
9. With supportive care, outcome can be good
10. Vaccine (ABCDE toxoid) is in development but is not effective post-exposure

M. Mushrooms

1. Nausea and Vomiting - 1-6 hours
2. Neurologic and GI Symptoms can occur within 2 hours due to early onset toxins
3. Methemoglobin poisoning - usually 6-12 hours (late onset)
4. Hepatic and hepatorenal Failure - usually 6-24 hours (late onset)

N. Extraintestinal Manifestations

1. Cheese, raw milk - Brucella (cowborne)
2. Egg and potato salads - Group A Streptococcus (including toxigenic strains)
3. Cheese, raw milk, hot dogs, cole slaw, cold cuts - Listeria
4. Pork - Trichinella spiralis
5. Shellfish - Vibrio vulnificus, Hepatitis A virus

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