I. Enterobacteriaceae: Facultative anaerobes, ferment glucose, have peritrichous or no flagella, oxidase-negative, urease+.
A. Lactose fermenters
- E. coli
- Klebsiella pneumoniae
B. Nonlactose fermenters
- Salmonella typhi, typhimurium and enteritidis
- Yersinia pestis and enterocolitica, Edwardsiella, Hafnia
II. Others: Facultative anaerobes, ferment sugars, have polar flagella, oxidase positive
- Vibrio cholerae and parahaemolyticus
gram(-), facultative anaerobe
- ferments glucose and lactose, has peritrichous or no flagella, oxidase-negative, urease+. Motile. Member of enterobacteriaceae.
- E. coli are part of normal GI flora. Don't cause infection because lack PAI.
5 major strains of diarrheagenic E. coli:
A. Enterohemorrhagic E. coli (EHEC; inflammatory)
- Can't ferment sorbitol (can be differentiated from other E. coli). Categorized as 0157:H7 and non-0157:H7. Caused by ingesting inadequately cooked meat (hamburgers), contaminated vegetables and milk; also human-to-human. Low infectious dose.
- Clinical presentation:
a. hemorrhagic colitis: Little fever, acute onset cramps and watery diarrhea.
Diarrhea becomes bloody (hemorrhagic colitis) within 24 hours, lasts up to 8 days.
O157:H7 strains more likely to cause large outbreaks, bloody diarrhea, hemolytic uremic syndrome, and ischemic colitis. Hospitalization required in 25-50% of patients.
- Pathogenesis: Produce Shiga-like toxins - clinical symptoms similar to Shigellosis (S. dysenteriae). AB toxin:
i. B subunits bind toxin to it receptor on cells
ii. 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
Locus of Enterocyte Effacement (LEE) on PAI. Type III secretion system delivers E. coli receptor to host cell. Pedestal formation for attachment. Responsible for the diarrhea.
i. Use Sorbitol-MacConkey agar: 0157:H7 strain does not ferment sorbitol (colonies will be white/translucent; Other EHEC and E. coli colonies will be red/pink.)
b. PCR or enzyme linked immunoabsorbant assay (ELISA) used to detect Shiga toxin.
- Rx: Supportive care and monitoring for complications.
- Avoid anti-diarrheals (increase risk of systemic complications).
- Antibiotics are not beneficial and may predispose to HUS by inducing more Shiga toxin release.
B. Enteroinvasive E. coli (EIEC; inflammatory)
- Similar to Shigella (Causes similar disease. No toxins produced)/ Transmitted via food/water or person-to-person contact. Most common in young children* in developing countries.
- Urinary tract, neonatal meningitis, and opportunistic infections, including bacteremia, pneumonia, wounds, meningitis. Infant & traveler' s diarrhea, dysentery, bloody diarrhea and HUS.
- pathogenesis: No toxin produced. Invades intestinal cell, multiplies intracellularly and extends into adjacent intestinal cells.
- Antigenic structures used in serotyping
a. H (flagellar) antigens.
b. O antigens: O-side chain (polysaccharide) of LPS.
C. Enterotoxigenic E. coli (ETEC; non-inflammatory)
- from contaminated water, Most common cause* of traveler's diarrhea.
- presentation: watery diarrhea, ranges from mild to severe. Duration of 1-5 days.
- pathogenesis: Organism produces heat-labile toxin (LT) and heat-stable toxin (ST)
LT similar to Cholera toxin. Stimulates adenylate cyclase and increases intracellular cyclic AMP, resulting in secretion of chloride from intestinal crypt cells and inhibition of absorption of sodium chloride at the villous tips. Secretion of free water into the intestinal lumen follows, manifesting clinically as watery diarrhea
ST activates enterocyte cyclic GMP, also leading to stimulation of chloride secretion and inhibition of sodium chloride absorption. End result again is secretion of free water into the intestinal lumen and watery diarrhea.
D. Enteropathogenic E. coli (EPEC; non-inflammatory)
- Most commonly associated with illness among children <6 months to 2 years of age* in developing countries. Rare in adults.
- features: Profuse, watery diarrhea can be severe with vomiting and dehydration.
- pathogenesis: Organism characterized by ability to produce attaching-effacing lesions and formation of pedestal like structures (LEE). No Shiga toxin produced,
E. Enteraggregative E. coli (EAEC; non-inflammatory)
- Cause of diarrhea in children and adults in both developed and developing countries.
Also can affect HIV patients* in developing countries (and probably developed countries). Can cause traveler's diarrhea.
- Pathogenesis not well understood.
F. Other E. Coli Infections
- Hospital-acquired infections: In many hospital labs, E. coli is the most commonly isolated organism. Common cause of sepsis.
- Neonatal meningitis: Encapsulated strains (K1-antigen).
- UTI: Uropathogenic E. coli (UPEC)
UPEC cause 90% of urinary tract infections (UTI). More common in females than males. Symptoms include frequency, dysuria, pyuria, suprapubic pain, cloudy urine, cramping, afebrile or low-grade fever.
- Diagnosis: bacteria in urine
>10 per ml in females
>10 per ml in males
- Virulence factors include a P fimbriae (also called PAP pili), and a capsule (K antigen).
gram(-) coccobacili with bipolar staining.
- member of enterobacteriaceae [facultative anaerobe, ferments glucose, has peritrichous or no flagella, oxidase-negative, urease+].
- infection more common in europe. Sources are pork, raw milk, f-o contamination.
- Infection preferentially involves ileum, appendix, right colon.
- Organisms multiply in lymphoid tissue resulting in regional lymph node and Peyer patch hyperplasia.
- Clinical presentation: Abdominal pain is the main feature.
a. Acute mesenteric lymphadenitis: Peyer patch and mesenteric lymph node hyperplasia can mimic acute appendicitis in teenagers and young adults.
b. Inflammatory diarrhea: Nausea/vomiting common. Fever/diarrhea can also occur.
c. Extraintestinal symptoms are frequent: pharyngitis, arthralgia, erythema nodosum
- Dx: stool culture
- Rx: most cases do not warrant treatment
gram(-), facultative anaerobe
- ferments glucose not lactose, has peritrichous or no flagella, oxidase-negative, urease+, produces H2. Has peritrichous or no flagella. Member of enterobacteriaceae.
- inflammatory (bloody) diarrhea
A. Enterica (Typhi)
- humans are sole reservoir. F-o contamination. More common in children and young adults than in older patients. Worldwide, most prevalent in impoverished, overcrowded areas with poor access to sanitation. In US, 80% occurring among travelers to countries where typhoid fever is endemic (South-central Asia common). Outbreaks in the U.S. most often foodborne
- Clinical presentation:typhoid fever, does not cause gastroenteritis. Incubation period 5-21 days.
a. 1st week of illness: rising fever/chills develop; patients are bacteremic. Relative bradycardia can be observed.
b. 2nd week of illness: adominal pain and "rose spots" (faint salmon-colored macules on trunk/abdomen) may appear.
c. 3rd week: hepatosplenomegaly, GI bleeding, perforation, secondary bacteremia
Septic shock may develop as well as AMS
d. In the absence of death or severe complications, symptoms resolve over weeks to months.
- Pathogenesis: In small intestine organisms are taken up by and invade M cells. Bacteria are then engulfed by macrophages in the lymphoid tissue.S. typhi proliferate in the submucosa, leading to hypertrophy of the Peyer's patches via recruitment of mononuclear cells and lymphocytes. Hypertrophy and subsequent necrosis of the submucosal tissues are probably responsible for abdominal pain and subsequent ileal perforation, a potentially fatal complication. Then organisms can disseminate to lymph nodes and RES. Subsequent spread to blood. Sepsis can occur.
- Chronic carriage can occur in the biliary tract.
- Dx: blood cultures positive in 50-80% of pts. May requires several days of incubation.
- Rx: Ceftriaxone, Azithromycin, or Ciprofloxacin (unless patient has been in an area with high rates of flouroquinolone resistance such as South Asia). Prevention can be done with vaccine.
B. Enteritidis (Typhimurium)
i. Salmonellosis: food poisoning (diarrhea, cramps, vomiting) from dairy, meat, eggs, pet reptiles, human-human.
- Clinical presentation: Incubation period 1-3 days. Nausea, vomiting, diarrhea (can be bloody), crampy abdominal pain. Fever in 50%. Illness lasts 3-4 days.
ii. 5% will develop invasive disease: bacteremia, endovascular infections, endocarditis, osteomyelitis. Predilection for aortic plaques, bone prostheses. Can also develop reactive arthritis.
- pathogenesis: Organisms attach to the M cells and are endocytosed through a complex pathway. 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. Inflammatory response occurs (S. enteritidis also kills macrophages).
- Dx: Routine stool culture
- Rx: Not required for healthy people between ages of 2 and 50 years.
- Treatment indicated for those at risk of disseminated/invasive disease:
a. Immunocompetent patients with severe infection requiring hospitalization
b. Those with known or suspected atherosclerotic plaques and endovascular/bone prostheses
c. Immunocompromised (HIV, those receive steroids or other immunosuppressants), sickle cell disease.
- Antibiotics: use flouroquinolones. Susceptibility testing should be performed.
- facultative anaerobe, ferments glucose not lactose, has peritrichous or no flagella, oxidase-, urease+. Non-sulfate reducing (does not produce H2S) Nonmotile. Member of enterobacteriaceae.
- More common in daycare centers, migrant workers, travelers to developing countries, nursing homes. Due to f-o transmission.
- features: incubation period 1 wk.
a. inflammatory diarrhea: initially watery diarrhea which progresses to dysentery (bloody) in 50%. Self-limited illness of small volume diarrhea, RBCS and WBCs present, fever, abdominal pain lasting about 1 week.
b. Some adults will have a subacute course that lasts several weeks.
A. Hemolytic uremic syndrome may occur after infection with S. dysenteriae that produces Shiga toxin (AB toxin).
B. reactive arthritis: asymmetric oligoarthritis 1-4wk following infection.
C. urethritis, conjunctivitis
- Reiter's syndrome: "cant see, cant pee, cant bend a knee". characterized by reactive arthritis, conjunctivitis and urethritis.
- Pathogenesis: 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 through formation of membrane-bound protrusions from the surface of the host cell by action on cellular actin polymerization proteins called formins. The bacterium lyses the membranes that surround it, freeing itself into the cytoplasm of the new cell.
- Rx: Antibiotics shorten the course and reduces duration of organism shedding in stools.
- Ceftriaxone, Ciprofloxacin, Azithromycin
gram(-), curved rod ("comma shaped")
- Facultative anaerobe, ferments sugars not lactose, have polar flagella, oxidase(+). Commonly found in salt water; Marked season variation in incidence of infection in most climates due to rapid growth of Vibrio bacteria in warmer temperatures.
A. V. Cholerae
- cholera (severe watery diarrhea)
-Transmitted primarily through fecally contaminated drinking water, less often food.
- Can become rampant in areas devastated by natural/man-made disasters. January 2010 Haiti earthquake led to cholera epidemic; >5% of the population was affected. Other factors predisposing to epidemics: poor sanitation, malnutrition, overcrowding, inadequate medical services. Humans are carriers and environmental reservoirs. Main animal reservoirs: marine shellfish. Ingestion without adequate cooking can transmit the disease.
- Clinical presentation: Incubation period 1-3 days. Watery diarrhea in large volumes (up to 20 L/day). No RBCs or WBCs in stool.
Stool is often termed rice water stools - watery stool with flecks of mucous. Often has a fishy odor. Very large number or organisms in the stool. Vomiting is common. Abdominal pain usually absent. Dehydration common. Loss of fluid and electrolytes leads to cardiac and renal failure. Acidosis and hypokalemia also occur as a result of loss of bicarb and K in the stool.
Mortality rate without treatment 40%
- O1 and O139 serogroups responsible for epidemic and pandemic cholera. O1 serogroup divided into 2 biotypes:
i. E1 Tor
1. Large #s of bacteria must be ingested for colonization to occur (organism is sensitive to stomach acid) - high infectious dose.
Adherence to cells of brush border of the gut is related to secretion of the bacterial enzyme mucinase which dissolves glycoprotein covering over the intestinal cells..
2. Organism then multiplies and secretes cholera toxin - AB toxin:
i. 5 B (binding) subunits: binds to ganglioside receptor on the surface of the enterocyte.
ii. 1 A (active) subunit: inserted into the cytosol and catalyzes addition of ADP-ribose to the Gs (stimulatory G) protein. Causes persistent stimulation of AC. As a result, cAMP is overproduced and activates cAMP-dependent protein kinase which phosphorylates ion transporters in the cell membrane, resulting in the loss of water and ions from the cell. Watery efflux enters the lumen of the gut and massive watery diarrhea ensues.
- Diagnosis: Organism can be isolated from the stool using selective media such as thiosulfate citrate bile sucrose (TCBS) agar, taurocholate tellurite gelatin agar (TTGA), or MacConkey agar (colonies will be colorless)
- Rx: Aggressive volume repletion. Antibiotics adjunctive therapy for patients with cholera and moderate-severe volume depletion: Tetracycline, erythromycin, azithromycin, ciprofloxacin are options.
- Prevention: Clean water supply, appropriate sanitation. About 760 million people still lack access to clean water sources
WHO recommends oral cholera vaccine in cholera control programs in endemic areas.
B. V. parahaemolyticus
- Marine organism transmitted by ingesting raw or undercooked seafood, especially shellfish (oysters). Major cause of diarrhea in Japan (raw fish eaten in large quantities). Relatively rare in the United States. Can be seen in the Gulf and Pacific Coasts in warm months.
- Features: Incubation period about 1 day. Mild to severe watery diarrhea, n/v, abdominal cramps, fever. Self-limited of about 3 days' duration.
- Bacteremia can occur in those with underlying conditions such as liver disease. Also causes wound infections: associated with marine recreational activities and handling of seafood. Generally mild, however in those with liver disease, diabetes, alcoholism, etc., cellulitis can be severe.
- Diagnosis: culture
- Treatment: volume repletion. In severe cases antibiotics are warranted: doxycycline
C. V. vulnificus
- Marine organism
- features: Diarrhea. Can also cause severe skin and soft tissue infections. Shellfish handlers who often sustain hand wounds are at risk. Can cause a rapidly fatal septicemia in immunocompromised people who have eaten raw shellfish containing the organism. Patients most at risk are those with underlying liver disease, alcohol abuse, and some other chronic disease (diabetes, rheumatoid arthritis). 39% mortality rate
Bullous skin lesions are characteristic.
- Diagnosis: Culture
- Treatment: Doxy plus Cefotaxime or Ceftriaxone
gram(-), thin spiral shaped rod
- Facultative anaerobe, ferments sugars not lactose, have polar flagella, oxidase(+). Can only be cultured microaerobically.
- important cause of traveler's diarrhea, Most common enteric pathogen of developed countries*.
- most infections due to consuming raw chicken, unpasteurized milk. Highly transmissible.
- Clinical presentation: Incubation period 1 week. Watery diarrhea (10+ BMs/day) which becomes bloody in 15% of adults and more than half of children. Fever, crampy, periumbilical abdominal pain. Self-limited over 3-7 days.
a. Guillain Barre syndrome: ascending paralysis. 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.
b. Erythema nodosum
c. Reactive arthritis - more common with HLAB27 phenotype (can be part of Reiter's syndrome; also be seen with Salmonella, Shigella and Yersinia)
- Dx: Stool culture. Can only be cultured microaerobically (need to press into the agar).
- Rx: 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.
- Oxidize sugars (i.e., do not ferment aka metabolize anaerobically), have polar flagella, cytochrome c and oxidase-positive. P. aeruginosa often produces a greenish-blue pigment ("blue pus") and has a fruity odor.
The genus contains many species and is widely distributed in nature.
A. P. aeruginosa
- the major human pathogen, can be isolated from soil, water, vegetables, and can be found on skin, ears, upper respiratory tract, GI tract (low numbers).
- major cause of opportunistic infections, including respiratory and urinary tract infections and bacteremia and can cause endocarditis in IV drug users. It is a leading cause of hospital-acquired infections (has been isolated from shower heads, sinks, faucets, respiratory equipment, even contaminated disinfectants). It also is a cause of external ear infections (swimmer's ear) and corneal infections, particularly if eyes are abraded by contacts (P. aeruginosa can grow in lens solution). Perhaps the most important P. aeruginosa infections (along with Staph aureus), are contamination of burn wounds and infection of the lungs of cystic fibrosis patients.
Gram (+), spore-forming rods
- The only anaerobic endospore-forming bacteria. Resistant to high heat and to harsh environment. Found in the colon and soil (spores).
- Organisms are identified through their toxins in fecal material.
- pathogenesis: Exotoxins and secreted hydrolytic enzymes.
I. C. perfringens
- Large, "boxcar" gram+ bacilli. Found in soil and colon.
- foodborne diarrhea and possibly drug-induced enterocolitis. 3rd most common foodborne illness in the U.S. Outbreaks in psych inpatient facilities have been described.
- Clinical syndromes
a. Gas gangrene (discussed previously in septic arthritis/myositis lecture).
b. Food poisoning: 8-16 hour incubation period characterized by watery diarrhea with cramps; minimal vomiting. Resolves in 24 hours.
- Heat-resistant spores survive cooking, then spores can germinate in foods such as meats, poultry or gravy at lower temperatures.
Following ingestion of large quantity of organisms, C. perfringens enterotoxin is produced in the GI tract.
- Alpha toxin: damages cell membranes and produces ischemic necrosis of tissues. Including erythrocytes -> hemolysis. Enzymes produce gas in tissues.
II. C. difficile
- 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.
- Risk factors:
a. Antibiotic usage: Symptoms may begin during antibiotic therapy or 5-10 days following antibiotic administration.
b. Extremes of age
d. Hospitalization or institutionalization
- Clinical presentation: Watery diarrhea is the cardinal symptom. Spectrum of manifestations include carrier state to fulminant disease with toxic megacolon.
i. C diff associated diarrhea (CDAD) with colitis: profuse watery diarrhea (10-15 BM/day), mild lower abdominal pain/cramping, low grade fever, leukocytosis (esp. neutrophils). N/V.
ii. Pseudomembranous colitis: Present similarly; antibiotic-induced. In addition, sigmoidoscopy shows pseudomembranes: adherent layer of inflammatory cells and debris at sites of colonic muscle injury.
iii. Fulminant colitis: severe disease (severe abdominal pain, abdominal distention, fever, hypovolemia)
iv. Toxic megacolon: Colonic dilatation >7 cm with severe systemic toxicity. Hypervirulent strains are emerging: more severe disease, lower clinical cure rates, higher relapse rates (NAP-1/027).
- Pathogenesis: Antibiotics suppress members of the normal flora allowing for C. difficile to multiply and produce exotoxins/cytotoxins A and B.
- Exotoxins A and B cause glucosylation of small GTPases such as Rho which are involved in cytoskeleton structure and signal transduction.
i. Toxin A (enterotoxin) disrupts colonic mucosal cell adherence to colonic basement membrane and damages villous tips; inflammation leads to fluid secretion.
ii. Toxin B (cytotoxin) causes depolymerization of actin, resulting in loss 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.
- Histo: Clostridium difficile toxins kill colonic epithelial cells and elicit a severe acute fibrinopurulent inflammatory reaction; the sloughed mixture of necrotic
epithelial debris and inflammatory exudate forms a pseudomembrane that can resemble a volcano microscopically early in disease. [Be aware, ischemic necrosis can also produce similar pseudomembranes.]
a. Stool assay PCR detecting toxins A and B: highly sensitive and specific
b. EIA for toxins A and B: high false negative rate (sensitivity 75%)
c. 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.
d. pseudomembrane on colonoscopy
a. stop the offending antibiotic (if possible)
b. metronidazole or vancomycin po
c. cholestyramine to bind toxins
- 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.
d. Fecal transplants hot new thing
III. Clostridium botulinum
- not normal flora; infant botulism, an infection; botulism in adults, an intoxication.
a. Foodborne (classic; 25% of all CB cases) botulism (home canned foods like fruits, vegetables; and fish). Spores are resistant to heat, germinate after cooking and release toxin. Subsequent heating will inactivate the toxin (heat-labile).
- Clinical presentation: Symptoms begin within 12-36 hours post-ingestion. Acute, symmetric descending flaccid paralysis. Nausea, dry mouth, dysphagia, diarrhea, blurred vision. Paralysis descends to respiratory muscles, trunk and extremities. Possible death by respiratory failure
b. Infant botulism (72% of all CB cases; inhalation or ingestion of spores in carpet or raw honey). "Floppy baby syndrome."
- Infants 1 week to 12 months of age. Infection first then intoxication. Inhale or ingest spores (environmental dust) or honey.
- Clinical presentation: Presentation and severity variable.Constipation followed by weakness, feeding difficulties, descending global hypotonia, drooling, anorexia, irritability, weak cry.
c. Wound botulism (3%)
d. Inhalational (would be an act of bioterrorism)
- Pathogenesis: AB toxins. 8 (A-H) antigenic types. Most potent bacterial toxin. Cleaves SNARE proteins and prevent release of acetylcholine.
a. Antibiotics are NOT recommended for infant botulism or for adults with suspected gastrointestinal botulism because lysis of intraluminal C. botulinum could increase the amount of toxin available for absorption.Antibiotic therapy unproven but recommended for WOUND botulism only. DOC penicillin, metronidazole possible alternative.
b. Mechanical ventilation
c. Horse anti-toxin for those over 1 year of age. Human-derived botulism immune globulin (BIG-IV) available for infants less than 1 year of age.
IV. Clostridium tetani
- Spores found in soil. Portal of entry usually a wound site (eg. nail penetrates the foot). Also can be introduced during "skin-popping." Neonatal tetanus major problem in developing countries. Organism enters through contaminated umbilicus or circumcision wound.
- Features: Characterized by strong muscle spasms/spastic paralysis. Trismus (lock jaw) first. Characteristic grimace known as risus sardonicus. Exaggerated reflexes. Opisthotonos: pronounced arching of the back due to spasm of the strong extensor muscles of the back. Respiratory failure can occur. High mortality rate.
- Pathogenesis: Tetanus toxin (tetanospasmin) is an AB neurotoxin. Enters at the neuromuscular junction and is transported by motor neurons to ganglia
Toxin binds tightly and irreversibly to ganglioside receptors and blocks release of inhibitory neurotransmitters (glycine and GABA) by its cleaving action on membrane proteines (SNARE) involved in neuroexocytosis. Net effect is disinhibiton of neurons that modulate excitatory impulses from the motor cortex resulting in increased muscle tone, painful spasms, and widespread autonomic instability.
1. Wound debridement to eradicate spores. 2. Human tetanus immune globulin (HTIG) used to neutralize the toxin
3. Antibiotics probably play a minor role but they are universally recommended. DOC metronidazole. Penicillin is an acceptable alternative.
- Tetanus does not confer immunity following recovery from acute illness. All patients with tetanus should receive active immunization with a total of 3 doses of tetanus toxoid spaced at least 2 weeks apart with the 1st dose given immediately at diagnosis.
Rotaviruses are the single most important etiologic agent of severe diarrheal illness of infants and young children worldwide.
• Reo = respiratory, enteric, orphan.
• Non-enveloped, particles consisting of 2-3 concentric icosahedral capsids.
• Segmented, double-stranded RNA genome.
• High antigenic diversity: Divided into 11 G (VP7) and 12 P (VP4) serotypes. Only 4 G-P combinations cause ~90% of disease in humans: G1-P8, G2-P4, G3-P8, G4-P8 (Do not memorize these). Having only four combinations provided the basis for success of the vaccine (THIS IS IMPORTANT).
- NSP4 is a viral protein wiht enterotoxin-like activity: typically heat-stable proteins that target intestine and alter apical membrane permeability resulting in increased release of chloride ions.
- Outbreaks usually start on west coast in november, are mid-US in Jan/Feb and on the east coast in march and april.
1. Virus is taken in by endocytosis and delivered to late endosomes or lysosomes.
a) Capsid proteins are proteolytically processed -> Generates infectious subviral particle
b) Processing can occur either outside cells (during passage through the gut), or following endocytosis in late endosomes or lysosomes.
2. Following penetration, enzymes within the core begin synthesizing mRNAs.
a) Transcription is asymmetric (only individual (+) strand mRNAs (10-12) are made.
b) These are extruded through the vertices of the capsid structure.
3. Some of capped mRNAs are subsequently assembled into "assortment complexes".
a) Capped (+) strand RNAs serve as templates for synthesis of the complementary (-) strands, producing each of the double-stranded RNA genome segments.
4. Assembly of reovirus particles occurs entirely within the cytoplasm in cytoplasmic viroplasms (virus factories).
5. Progeny virus is subsequently released by lysis of host cell.
Most children and adults have neutralizing antibody to the major circulating serotypes of rotavirus and astroviruses
Older children are not significantly at risk for severe disease because of this acquired immunity.
Made development of a vaccine practical and of high importance
1. Rotaviruses cause diarrheal disease primarily in the young.
a) Responsible for 35%-50% of hospitalization for severe diarrhea during the first 2 years of life.
2. Noroviruses are responsible for ~50% of community-based outbreaks of nonbacterial gastroenteritis in older (school-aged) children and adults.
• Known as "winter vomiting disease"
3. Transmission of both rota- and noroviruses is primarily by the fecal-oral route.
a) Both rotaviruses and noroviruses are extremely stable in the environment.
b) Norovirus outbreaks often linked to a single source.
-Contaminated food (raw or steamed shellfish, cake frosting, and salads).
-Contaminated water (Cruise ship outbreaks)
4. The clinical symptoms for both rota- and norovirus infections include nausea, vomiting, diarrhea, fever, and dehydration.
Incubation period is usually very short:
- 1-4 days for rotavirus
- ~1 day for noroviruses, but can be as short as 6-10 hrs.
- Symptoms include: Nausea, vomiting, fever, followed by "watery diarrhea". No blood or leukocytes in stool. Vomiting more prominent with norovirus infections.
5.Both viruses have limited tissue tropism
Primarily infect the villus epithelial cells of the small intestine. Both rota- and noroviruses initially infect villus epithelium of the small intestine.
a) Virus replication and cell lysis causes loss of cells lining the small and large intestine.
b) This results in functional alterations in the small intestinal villous epithelial cells.
c) Glucose-coupled sodium transport is impaired, but adenylate cyclase and cyclic AMP are not stimulated (therefore not like V. cholera mechanism)
Before 2007, approximately 1 million cases of rotavirus diarrhea per year in U.S.
• Less than 100 deaths per year in the U.S. resulting from rotavirus infections.
• Due to availability of effective fluid and electrolytes replacement. *However, world-wide it's estimated that ~600,000 infants and children 1-4 years old die from rotavirus diarrheal illness each year.
1. Local (intestinal) immunity is most important for protection against reinfection by both rota- and noroviruses.
2. Antibody to rotaviruses are obtained relatively early in life, but antibodies to noroviruses are acquired gradually in childhood, and increase steadily over a person's lifetime.
a) There are 4 major serotypes of rotaviruses that cause most disease in humans making development of a vaccine practical even though there is the potential for significant antigenic diversity through antigenic shift and drift.
b) Noroviruses immunity is not long lasting and antigenic diversity is generated via antigenic drift, similar to other single-stranded RNA viruses.
V. Prevention and Control
1. Two new rotavirus vaccines have been developed.
a) RotaTeq® - Approved for sale in U.S. by FDA in February, 2006
-Pentavalent bovine-human reassortant viruses (serotypes G1-G4 and P8)
-Live, attenuated vaccine given orally at 2, 4, and 6 months
b) Rotarix® - Approved in Europe, Mexico, Latin America and now in U.S. as of April, 2008
-Human-derived monovalent (G1, P8), live, attenuated vaccine
-Administered orally in two doses starting at 6-weeks of age
2. There are no approved vaccines currently available for the noroviruses.
3. The most important preventative measures for norovirus infections include:
• Careful hand-washing
• Effective disinfection of contaminated surfaces
• Proper food preparation.
• Small, isosahedral, nonenveloped, (+)-sense RNA viruses.
• Picorna = "pico" + RNA ("small" RNA virus). Spread by oral-fecal route (enteroviruses and coxsackie) or by aerosol contamination of fomites (coxsackie viruses).
1. Human enteroviruses include:
a) Poliovirus --> causes flaccid paralysis (poliomyelitis)
b) Coxsackieviruses --> various illnesses including hand, foot & mouth disease, meningoencephalitis, diarrhea, muscle pain, inflammation of the myocardium and pericardium
c) Echoviruses and "other enteroviruses"--> mild gastroenteritis (echo=enteric cytopathic human orphan). Humans are only known reservoir of Enteroviruses.
**Hepatitis A virus is also an "enterovirus-like" picornavirus.
2. Enteroviruses are differentiated from the rhinoviruses based on:
b) Replication at 37oC
3. Humans are the only known reservoir.
4. Spread by the oral-fecal route.
5. The incubation time is usually short (between 7 - 14 days).
a) Initially replicate in lymphoid tissue of the upper respiratory tract and the gut.
- When a cell is infected with a picornavirus, translation of host-cell proteins stops within a few hours. Why is translation of viral proteins immune to this inhibition? Picornavirus mRNA's do not require cap-binding proteins for their translation.
-Often isolated and cultured for diagnostic purposes from throat-swabs.
b) Viremia results in infection of target organs
• Spinal cord and brain
6. Asymptomatic infection is common.
IV. Prevention and Control
•Besides polio, there are no vaccines for other enteroviruses are available.
»The large number of serotypes, and the fact that many infections are asymptomatic, makes the development of an "enterovirus" vaccine impractical.
I. HVA: enterically-transmitted (ET) hepatitis.
- Nonenveloped icosahedral capsid, ssRNA +. Only one serotype. Human reservoir. Family picornaviridae.
- Early childhood disease is most common and often asymptomatic. HAV accounted for 33% of annual US acute hepatitis cases. One-third of US population has had HAV.
Common source/community outbreaks.
- Transmission: sexual contact, f-o. Higher risk in traveler's to endemic areas, day care workers, gay men, IVDA.
- Features: incubation time is 4 weeks.
II. HBV: parenterally-transmitted (PT) hepatitis
- enveloped, dsDNA virus. Common in Asia and africa. Virus is present in body fluids. Transmission occurs through sexual contact, IVDA, and perinatal delivery.
III. HCV: "nonA, nonB" pareterally transmitted (PT) hepatitis
- enveloped, icosahedral capsid. ssRNA+.
- feature: 7-9 week incubation. Acute infections are milder than HBV. Chronic patients have multiple bouts of reinfection.
IV. HDV: dependent on co-infection with HBV
- enveloped, circular ssRNA virus. Requires HBV surface proteins for infectivity (HBsAG).
V. HEV: "nonA, nonB" ET-hepatitis
- Nonenveloped icosahedral capsid, ssRNA+. Single serotype. Mostly in developing countries. 1/5 fatality rate in pregnant women. Family Calciviridae.
HAV and HEV cause acute hepatitis only
HBV (and HDV) and HCV can cause chronic hepatitis and lead to hepatocellular carcinoma
- Clinical presentations:
1. Acute Hepatitis
- Usually HAV (acquired outside US) or HBV (IVDA, sexual contact)
-Symptoms are malaise, anorexia, nausea and fatigue (all nonspecific) until jaundice appears.
- confirmed by acute phase serum (IgM against viral antigen) generally seen 5-10day before onset of symptoms and usually no longer detectable by 6 months. IgG indicates resolved or active chronic infection; remains detectable for lifetime and if infection resolves, IgG confers protection against infection.
2. Fulminant Hepatic Failure
- Usually HBV, rarely HVA. HEV (animals) can cause FLF in 20% in 20% amoung pregnant women in 3rd trimester.
- features: acute hepatitis with AMS due to hepatic encephalopathy (cerebral edema; usually 1 week to live from onset). High mortality (brain herniation, infection). Liver transplant is only treatment.
- AST/ALT in thousands range. Bilirubin >10.
3. Chronic Hepatitis
- HCV 80%, HBV 5%, rarely HDV
- usually asymptomatic and most cases are found incidentally. Mild elevations in AST and ALT (< 5 times normal) Some patients can have normal LFT.
- Complications of Chronic Hepatitis
a. Cirrhosis: usually seen 10-15 years after infection. Accelerated fibrosis seen in obesity (due to fatty liver), HIV, post liver transplant, alcohol consumption. Patients usually need biopsy to evaluate degree of liver damage.
b. Liver Failure
c. Hepatocellular Carcinoma
Extrahepatic manifestations in viral hepatitis
a. MPGN (membranoproliferative glomerulonephritis
b. porphyria cutanea tarda
c. mixed cryoglobulinemia (vasculitis, neuropathy)
d. lymphoproliferative conditions
e. sjogren syndrome
- extrahepatic manifestations may correlate with viral RNA/DNA levels.
a. Autoimmune disease
b. Ischemic hepatitis (in ICU setting)
c. Alcohol/drug induced, Tylenol over dosage
d. Wilson Disease
a. focal or bridging necrosis. Swollen pale hepatocytes.
b. portal and lobular infiltration by lymphocytes, macrophages (and plasma cells)
c. Kupffer cell hypertrophy and hyperplasia
d. +/- cholestasis
a. High AST/ALT (1000- 5000 IU/L)
b. High bilirubin
c. Prothrombin time (INR) - very high INR may indicate progression fulminant failure.
d. Viral RNA/DNA indicates active infection and does not differentiate between acute or chronic infection (use IgM:IgG).
- Transaminases are elevated (sometimes markedly), usually before the jaundice, and bilirubin and alkaline phosphatase usually do not rise as markedly.
- HCV can be cure because DNA does not incorporate into the nucleus of cells.
- causes of death for HCV: stroke, CVA, MI, kidney failure, hepatic decompensation, HCC.
- HAV/HBV have vaccines that are highly effective. HEV vaccine not sold in the US yet. HCV vaccines are in clinical trial stage.
- HCV leading to liver failure is the leading cause of death in HIV pts.
- HCV leads to HCC due to cirrhosis, HVC can cause HCC even without cirrhosis.