A. True Enteroviruses [10]

1. Genus within the family Picornaviridae (RNA viruses)
   1. Small RNA viruses
   2. Other members include rhinoviruses and hepatitis A virus
2. Broad Range of Diseases
   1. Exanthems
   2. Hemorrhagic conjunctivitis
   3. Myocarditis
   4. Pericarditis
   5. Asepetic meningitis
   6. Hand-Foot-and-Mouth disease
   7. Febrile illnesses with or without respiratory symptoms
3. Most infections are mild or asymptomatic and self limited
4. Subgroups of Enteroviruses
   1. Polioviruses
   2. Group A Coxsackieviruses
   3. Group B Coxsackieviruses
   4. Echoviruses
   5. Enteroviruses 68, 69, 70, and 71
   6. Hepatitis A Virus
5. Other Viruses Affecting the Gut (see below)
   1. Norwalk Agent
   2. Adenovirus
   3. Rotavirus
   4. Cytomegalovirus (CMV)

B. Poliovirus [2]

1. Picornavirus, three serotypes
2. Causes acute diarrhea and later paralytic illness
3. Central nervous system Disease
   1. Tropism is mainly in motor centers of anterior horn
   2. Hallmark of paralytic poliomyelitis is asymmetric flaccid paralysis
   3. Little sensory loss
   4. Bulbar polio includes paralysis of all limbs, cranial nerves, muscles of respiration
4. Clinical Disease
   1. ~90% of infections are subclinical
   2. Incubation period is typically 4-14 days
   3. Abortive poliomyelitis - nonspecific febrile illness of 2-3 days, no residua
   4. Aseptic meningitis - nonparalytic poliomyelitis, signs of meningitis, no paralysis
   5. Paralytic poliomyelitis - usually follows 2-3 days after minor polio illness
   6. Postpolio Syndrome - occurs 10-30 years after recover from acute poliomyelitis
5. Postpolio Syndrome [2]
   1. Decompensation of chronic denervation and reinnervation
   2. Eventually, denervation exceeds regenerative capacity of motor neurons
   3. Occurs 10-30 years after "full" recover from acute neurologic poliomyelitis
   4. Initial symptoms include fatigue, weakness, pain, cold intolerance, muscle atrophy
   5. Diagnosis requires exclusion of other diseases including multiple sclrosis, neuropathies
   6. Persons must have a history and electromyography tests consistent with polio infection
   7. EMG findings demonstrate horn cell disease
   8. Etiology of syndrome is unclear, and no specific therapies alter the slow disease course
6. Vaccination
   1. Inactivated polio vaccine (IPV) - Salk Vaccine, killed vaccine, no risk of infection
   2. Oral polio vaccine (OPV) - paralysis risk ~1 per 3.7 million doses; withdrawn from market
   3. IPV supplemental (4th) dose is beneficial in developing countries after 3 doses of OPV [15]

C. Coxsackieviruses

1. Serotypes
   1. Group A - 23 serotypes
   2. Group B - 6 serotypes
2. Common Syndromes
   1. Aseptic meningitis - most common clinical illness associated with Cocksackie Virus
   2. Muscle weakness and paralysis - uncommon, poliovirus-like disease
   3. Exanthema - similar to other childhood illness
   4. Myocarditis [9]
   5. Pericarditis - unclear associations with these viruses
   6. Orchitis
   7. Conjunctivitis
   8. Respiratory Disease
3. Hand-Foot-and-Mouth Disease
   1. Vesicular eruptions extremities, oral cavity in children
   2. Self limited in most cases over 5-10 days
   3. Caused by coxsackievirus A16
4. No current specific treatment; supportive therapy generally provided

D. Enterovirus 71 [10,11,12]

1. Associated with sporadic cases and outbreaks worldwide
2. Large outbreaks have occurred in 1998-99
3. Causes a variety of conditions which were seen in the recent outbreaks
   1. Hand-Foot-and-Mouth Disease
   2. Herpangina
   3. Aseptic meningitis
   4. Encephalomyelitis
   5. Flaccid paralysis
   6. Myocarditis
4. Severe and fatal outbreak most prominant in Taiwan (1998) [11,12,13]
   1. Patients who died often had pulmonary edema and/or pulmonary hemorrhage
   2. Most of the patients who died in the epidemic were young
   3. Rhombencephalitis also occurred and was most frequent neurologic complication
   4. Unclear if this strain was particularly neurovirulent
   5. Molecular and biochemical analyses of virus is ongoing
5. Outbreak in Taiwan in February 2001 - August 2002 [18]
   1. High household transmission rates with children
   2. Age <3 years associated with very severe disease
   3. In children, ~20% had severe disease, ~6% died within 6 months
   4. Neurologic sequelae in ~7%
6. Enterovirus 71 and Pulmonary Edema [13]
   1. Early onset of severe disease in children associated with pulmonary edema
   2. Tachycardia, tachypnea, and cyanosis within 1-3 days of onset
   3. Significant association between central nervous system symptoms and pulmonary edema
   4. Early hyperglycemia heralded development of pulmonary edema
7. Severe enterovirus 71 infection in children associated with neurologic sequellae, delayed neurological development, and cognitive impairment [22]

E. Echovirus

1. Series of related small RNA viruses (picornavirus)
2. Common cause of mild to severe gastrointestinal upset, primarily in neonates
3. Up to 60% of infections are subclinical
4. Often associated with aseptic meningitis as well
5. Generally self limited infections

F. Noroviruses (Calciviruses) [4,5,20]

1. Also called Small Round-Structured Viruses (SRSV), formerly Norwalk Agent
2. Single stranded RNA virus family, 23-34 nm particles member of family Caliciviridae
3. Most common cause of gastroenteritis in adults including epidemic spreads
4. Incubation period of 1-2 days, with vomiting and diarrhea for 3-8 days
5. Mainly occur in older children and adults and peak in winter
6. Self limited infections, respond to oral rehydration therapy

G. Adenovirus [20]

1. Very common cause (~15%) of diarrhea in adults
2. Types 40 and 41 are most common cause
3. Self limited illness
4. Large number of serotypes, but types cause either repiratory or GI symptoms, not both
5. Presence of adenovirus DNA in cardiac grafts associated with 4.7X risk for graft loss [17]
6. Thus, adenovirus infection may stimulate immunologic rejection of cardiac graft [17]

H. Rotavirus [20]

1. Most common cause of viral gastroenteritis in children
   1. ~50% of cases of of acute gastroenteritis in age <2 years
   2. Often very severe in infants
   3. In USA: 500,000 cases annually, with 50,000 hospitalizations and 20 deaths
   4. Worldwide: 870,000 deaths worldwide annually
   5. Most commonly occurs in cooler months
2. Double stranded, 11-segment RNA virus
3. Symptoms
   1. Major problem is diarrhea (5-8 days) with severe dehydration
   2. Vomiting may occur (1-2 days)
   3. May be recurrent, over months, with each bout of reduced severity [1]
4. Laboratory Diagnosis
   1. Not routinely performed in USA
   2. Virus culture from fecal material
   3. Serological: anti-rotaviral IgM and IgG
   4. Natural immunity does build up over years
5. Oral rehydration therapy effective
6. Nitazoxanide (Alinia®) [21]
   1. Thiazolide anti-infective agent
   2. Approved for Cryptosporidium and Giardia
   3. Effective for Entamoeba, Blastocystis, Clostridium difficile
   4. Dose 7.5mg/kg oral bid x 3 days in children with severe rotavirus significantly reduced disease duration from 75 hours (placebo) to 31 hours [21]
7. Ondansetron (Zofran®) oral disintegrating tablets also reduce emesis and improve oral rehydration in children 6 months - 10 years old treated for gastroenteritis [3]
8. Enkephalinase Inhibitor [14]
   1. Racecadotril is an oral enkephalinase inhibitor that prevents breakdown of endogenous gut opiates
   2. Decreases intestinal hypersecretion but not motility
   3. Effective and safe in children and adults with acute watery diarrhea
   4. Excellent synergy with oral rehydration therapy
   5. Effective in bacterial and rotaviral acute water diarrhea
9. Human-Derived Vaccine (Rotarix®) [23,24,25,26]
   1. Attenuated live human rotavirus vaccine RIX4414 G1P(8), Rotarix®
   2. Derived from an attenuated G1 (P8) human isolate called 89-12
   3. Two oral doses of vaccine given
   4. Vaccine reduced incidence of rotavirus 80-90%, hospitalizations >85%
   5. Severe diarrhea reduced 80-100%
   6. Effective in infants age up to 2 years as well [26]
   7. Mild fever in 20% of vaccinated subjects after first dose only
   8. No increased risk of intussusception compared with placebo
10. Rhesus-Derived Vaccine (Rotashield®) [8,19]
    1. Quadravalent recombinant rhesus-human reassortment vaccine
    2. Reduced sever diarrhea in clinical trials in Venezuala [6] and Finland [7]
    3. Efficacy was lower in Peru and Brazil [19]
    4. Withdrawn from US market due to increased cases of intussusception [16]

I. Astrovirus [20]

1. Cause outbreaks of acute gastrointestinal illness
2. Usually person-to-person spread
3. Common cause of outbreaks in children, military recruits, hospital wards
4. High rate of contagion: 50-90% of children, 25% of adults in exposed areas

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