GI Viruses

Question 1

GI Infections

Overview

Answer 1

• Major cause of morbidity and mortality in infants and young children
  
  • Common in the US
• Caused by bacteria, viruses and intestinal parasites
• Transmission:
  
  • Direct contact via fecal-oral route
  • Indirect contact via ingestion of contaminated food and drink
  • May involve an animal reservoir (direct contact)
• Infective dose ∝ ability to overcome innate GI defenses
  
  • Gastric acid
  • Bile and digestive enzymes
  • Mucus layer
  • Normal flora
  • Peristalsis
• Colonize small and/or large intestine
• Damage can be caused by:
  
  • Enterotoxin or cytotoxin production
  • Local invasion of intestinal mucosa
  • More extensive invasion and spread via gut lymphoid tissue

Question 2

GI Infections

Diagnosis

Answer 2

• Patient hx: age, occupation, recent travel, history of food intake
• Presence/absence of fever
• Localization of pain
• Diarrhea characteristics: volume, frequency, ± occult blood, ± fecal leukocytes
  
  • Viruses or enterotoxin producing bacteria ⇒ voluminous, watery diarrhea
  • Invasive bacterial or parasitic organisms ⇒ ↑ inflammation ⇒ lower volume, fecal leukocytes and/or blood
  • Cytotoxin producing organisms ⇒ blood in feces more likely
• Stool specimen
  
  • Culture & isolation routine for bacteria
  • Staining for ova & parasites
  • Ag detection tests for viruses and C. diff

Question 3

GI Infections

Treatment

Answer 3

• Tx typically supportive w/ fluid and electrolyte replacement
  
  • ORT: oral rehydration therapy
  • IV fluids for severe dehydration
• Abx in certain circumstances for non-viral pathogens
  
  • Severe disease
  • Young pt
  • Invasive organisms
  • Shorten duration of disease and/or period of shedding (carrier state)

Question 4

GI Infections

Immunity and Prevention

Answer 4

• Circulating specific IgG develop in systemic infections
  
  • Unclear if sign. immunity persists
• Secretory IgA in GI tract more important
• Vaccines for use in specific at risk populations
  
  • Efficacy variable
• General prevention:
  
  • Proper sanitation and water purification
  • Proper food handling and preparation
  • Personal hygiene

Question 5

GI Tract

Pathogens

Answer 5

Primarily associated w/ GI tract infection and diarrheal disease:

• Viruses: Rotavirus and Norovirus (Norwalk Virus)
• Enterobacteriaceae: E. coli, Salmonella, Shigella and Yersinia
• Related gastrointestinal pathogens: Vibrio, Campylobacter, and Clostridium difficile
• Parasites: Entamoeba histolytica, Giardia lamblia, Cryptosporidium, Cyclospora

~ 70% of infections in US are viral.

International travel predisposes to bacterial etiology.

Question 6

Viral GI Infections

Overview

Answer 6

• Transmission:
  
  • Spread by fecal-oral route
  • Promoted by poor hygiene and contaminated water or food
  • Problematic in day care centers
• Pathogenesis:
  
  • Infect small intestine damaging epithelial lining and absorptive villi
    
    • Malabsorption of water
    • Electrolyte imbalance
• Clinical Disease:
  
  • Ranges from asymptomatic infection to mild diarrhea, to severe diarrhea w/ potentially fatal dehydration
  • ± Vomiting, abdominal cramps, fever
  • Fecal RBCs or leukocytes generally absent
• Diagnosis and Treatment:
  
  • Dx often depends on clinical presentation and exclusion of other known bacterial and parasitic pathogens
  • Lab tests based on viral Ag or nucleic acid detection
  • Tx involves rehydration and restoration of electrolytes

Question 7

Common Diarrheal Viruses

Answer 7

• Infants
  
  • Rotavirus A
  • Adenovirus 40, 41
  • Coxsackie A24 virus
• Infants, Children, Adults
  
  • Norwalk virus
  • Calicivirus
  • Astrovirus
  • Rotavirus B
  • Reovirus

Question 8

Rotavirus

Epidemiology

Answer 8

• Found worldwide w/ 95% of children infected by 3-5 years of age
• Most common cause of infantile diarrhea
  
  • 200-300k deaths in young children per year due to dehydration
• Previously peaked in autumn, winter and spring
  
  • Seasonal pattern less apparent w/ successful vaccines
• Rotavirus type A
  
  • Infants < 24 m/o ⇒ risk for severe disase
  • Older children & adults ⇒ mild diarrhea
• Rotavirus type B
  
  • More common in older children and aults

Question 9

Rotavirus

Characteristics

Answer 9

“Rota” = wheel

• Reovirus family (respiratory, enteric, orphan virus)
  
  • Also Orthoreoviruses, Rotaviruses, Coltiviruses
• Non-enveloped, segmented dsRNA virus
  
  • 11 segments, each encodes one protein
  • Reassortment of gene segments can occur ⇒ hybrid viruses
  • RNA-dependent RNA polymerase
• 7 serotypes based on outer capsid protein & 5 groups based on inner capsid protein
  
  • Serotype A ⇒ infants
  • Serotype B ⇒ older children and adults
• Immunity depends on secretory IgA in GI tract, but is not always protective
• Stable over a wide-range of pH, temperature and conditions (i.e. aerosols)

Question 10

Rotavirus

Pathogenesis and Clinical Disease

Answer 10

• Spread by fecal-oral route
  
  • Acid stability: outer capsid shield, food bolus protection
  • Low infectious dose: 10-100 viral particles
• Incubation 1-3 days
• Passes through to duodenum & proximal jejunum
• Attach to enterocytes via VP4 and VP7 ↔︎ sialic acid receptors (hemagglutinin)
• Activated by GI tract protease w/ cleave of VP4 → infectious/intermediate subvirus particle (ISVP)
• Enters columnar epithelial cells of villi
  
  • NSP4 protein may act in toxin-like manner ⇒ ↑ fluid and electrolyte loss
  • Cytoplasmic inclusions seen within 8 hours, and infected cells die
• Infection results in shortening of microvilli & mononuclear cell infiltrate into lamina propria
  
  • No leukocytes or blood in stool
  • Prevents absorption of water ⇒ loss of electrolytes, watery diarrhea, and ± severe dehydration
• Maximal virus shedding 2-5 days after diarrhea, 10¹⁰ viral particles/gram of stool
• Disease is generally self-limited w/o sequelae
  
  • Infection of enterocytes only on tip of villi
  • Crypt cells repopulate villi follow viral clearance

Question 11

Rotavirus

Diagnosis

Answer 11

Diagnosis usually empiric

Laboratory tests not routinely performed:

• Direct visualization in feces by EM
• Detection of viral Ag in stool
  
  • ELISA, latex agglutination (rapid, inexpensive)
    
    • Good specificity, group A only
• Cell culture – difficult and unreliable
• Serological tests – paired sera; four-fold rise in antiviral titer
  
  • Most children seropositive by age 4-5

Question 12

Rotavirus

Treatment and Immunity

Answer 12

• Immunity:
  
  • Type specific IgA and IgG
  • Neutralizing Ab to VP4 and VP7
• Treatment:
  
  • No specific antiviral therapy recommended
  • Primary treatment involves fluid and electrolyte replacement

Question 13

Rotavirus

Prevention and Control

Answer 13

• Resists drying ⇒ easily spread
  
  • Hygiene important
• Early attenuated vaccine (Rotashield) recalled d/t intussusceptions
• Newer generation vaccines:
  
  • RotaTeq – reassortant bovine/human rotavirus
  • RotaRix – attenuated human rotavirus
• CDC recommends routine immunization of infants

Question 14

Norovirus (Norwalk Virus)

Morphology & Characteristics

Answer 14

Noroviruses or Norwalk-like viruses (NLVs)

• Calicivirus family
  
  • Prototype of the group
• Small, round non-enveloped ⊕-sense ssRNA viruses
  
  • Three open reading frames
    
    • ORF1: RNA-dependent RNA polymerase, helicase
    • ORF2: single, structural capsid protein
    • ORF3: unknown function
• 4 genogroups (GI-GIV), divided into > 20 genetic clusters
  
  • High mutation rate ⇒ large # of strains
• Has not been propagated in cell culture

Question 15

Norovirus

Epidemiology

Answer 15

• Sign. cause of gastroenteritis
• Outbreaks occur year-round
• Most common cause of illness w/ a food origin
• Adults > children
  
  • 60% of non-bacterial adult diarrhea
  • 3% of diarrheas in day-care centers

Question 16

Norovirus

Transmission

Answer 16

• Transmitted by fecal-oral route
  
  • 1° through contaminated water or food
  • Direct person to person spread
• Highly contagious
  
  • Infective dose ~ 10 virions
• Extremely hardy and retain infectivity after exposure to acid, ether and heat (60°C for 30 minutes)

Question 17

Norovirus

Pathogenesis and Clinical Considerations

Answer 17

• Incubation period is 24-48 hrs
• Binds to cells of intestinal brush border in the jejunum ⇒ ⊗ absorption of water and nutrients
  
  • Blunted villi
  • Cytoplasmic vacuolation
  • Infiltration of mononuclear cells
• Acute-onset watery, non-bloody diarrhea and vomiting
  
  • ± Preceding fever
  • Lasts 1-5 days
• Viral shedding in feces for 3-4 days after sx onset but may be prolonged in some
  
  • Infected, asymptomatic individuals can transmit
• Self-limiting w/o long-term sequelae

Question 18

Norovirus

Diagnosis

Answer 18

• Diagnosis is usually empiric
• Lab tests (not routinely performed):
  
  • Radioimmunoassys, ELISA or PCR to detect virus, viral antigen or viral RNA
  • Immunoelectron microscopy to visualize concentrated virus from the stool
    
    • Norwalk: round w/ ragged outline
    • Other calicivirus: six-pointed star shape w/ cup-shaped indentation
  • Serology
    
    • ~70% of kids in US ⊕ by age 7

Question 19

Norovirus

Treatment, Prevention, and Control

Answer 19

• Fluid and electrolyte replacement
• Immunity is strain-specific and short lasting (months)
• Proper food handling
• Maintenance of water supply

Question 20

Enteric Adenoviruses

Answer 20

• Non-enveloped linear dsDNA viruses
• Advenovirus serotypes 40 and 41 (subgenus F) most often ass. w/ gastroenteritis
• 5-15% of viral diarrhea in young children
• Pathogenesis similar to rotavirus
  
  • Infection of enterocytes
  • Villus atrophy
  • Malabsorption and loss of fluids

Question 21

Astroviruses

Answer 21

• Non-enveloped, icosahedral capsid
• Non-segmented ⊕-sense ssRNA
• Virion resembles a 5-6 pointed star by EM
• Symptomatic infection 1° in young children and elderly nursing home residents
• Pathogenesis poorly understood
• Serum Ab titer = protective

Question 22

Enteric Viruses

Comparison

Answer 22