ACP medicine, 3rd Edition

Infectious Disease

Enteric Viral Infections

Nino Khetsuriani MD, PhD1

Medical Epidemiologist

Umesh D. Parashar MD, MPH2

Medical Epidemiologist

1Respiratory and Enteric Viruses Branch, Centers for Disease Control and Prevention

2Centers for Disease Control and Prevention

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

This chapter was prepared by employees of the federal government as part of their official duty. As such, this chapter is a work of the United States government and is not protected by copyright.

February 2006

Enterovirus Infections

Human enteroviruses belong to the genus Enterovirus, family Picornaviridae. They are divided into five species (human enterovirus A, B, C, and D, and poliovirus) comprising 68 currently recognized serotypes: polioviruses (types 1 to 3); coxsackieviruses A (types 1 to 14, 16, 17, 19 to 22, and 24) and B (types 1 to 6); echoviruses (types 1 to 7, 9, 11 to 21, 24 to 27, and 29 to 33); and numbered enteroviruses (types 68 to 71 and 73 to 78).1 Enteroviruses are small (approximately 30 nm), nonenveloped, single-stranded RNA viruses with an icosahedral capsid composed of 60 subunits consisting of four structural proteins (VP1 to VP4). Enterovirus RNA is approximately 7.5 kb long and codes structural proteins, RNA polymerase, other polypeptides necessary for viral replication, and two untranslated regions at the 5′ and 3′ ends of the RNA molecule. New enteroviruses continue to be identified as molecular techniques of enterovirus typing become increasingly available. In addition, some serotypes have been found to be identical to other enteroviruses (e.g., echovirus 8 is the same as echovirus 1) or have been reclassified as members of other genera (e.g., echoviruses 22 and 23 are now human parechoviruses 1 and 2, respectively).

EPIDEMIOLOGY

Enteroviruses are among the most common viruses worldwide. In temperate climates, the incidence of enterovirus infections peaks during the summer and fall months (June through October in the United States), whereas in the tropics, transmission occurs year-round.

Several enterovirus serotypes commonly cocirculate in the community, and predominant serotypes tend to change over time. The serotypes most commonly reported in the United States included echoviruses 30, 11, 9, 6, and 7 (from 1997 to 19992), echoviruses 13 and 18 (from 2000 to 20013), and echoviruses 9 and 30 (in 2003).4 The appearance of new predominant enterovirus serotypes is often accompanied by large-scale outbreaks. For example, large outbreaks of aseptic meningitis were reported in 2001, when previously rare echoviruses 13 and 18 became the predominant serotypes in the United States.3,5

Illnesses associated with enteroviruses affect predominantly children, but persons of any age may be susceptible. In addition to young age, predisposing factors for enterovirus illness include male sex, lower socioeconomic status, residence in urban areas, poor sanitation, large household size, and crowded living conditions.6

The enteroviruses are universally found in the environment (e.g., in sewage; surface water, such as rivers, lakes, and other reservoirs; and seawater), because they are excreted in large amounts by infected persons. The lack of a lipid envelope and the presence of a dense protein capsid allow enteroviruses to survive in the environment for long periods, especially at low temperatures. Enteroviruses are inactivated by extreme heat, ultraviolet light, drying, and chlorine. A high concentration of organic matter prevents inactivation of enteroviruses by chlorine.7

Enteroviruses are most often transmitted from person to person by the fecal-oral or the respiratory route, but transmission by fomites also occurs. Young children are the most important transmitters of enteroviruses and are often the index case in family or school outbreaks.

PATHOGENESIS

Enteroviruses gain entry into the host cell after binding to specific cellular receptors. Several different receptors with tropism to different serotypes have been identified. Initial virus replication takes place in submucosal lymphatic tissues of the pharynx and the gut (Peyer patches). The virus then spreads to the regional lymph nodes, enters the bloodstream (“minor” viremia), and reaches the reticuloendothelial system (i.e., deep lymph nodes, bone marrow, spleen, and liver). If viral replication is not contained by host defense mechanisms at this stage, symptomatic infection occurs, resulting in “major” viremia and dissemination of the virus to target organs. Certain enteroviruses (e.g., polioviruses) may spread along neural pathways as well. Tissue tropism of the serotype determines target organs for further replication. The histopathologic lesions in target organs consist of inflammation and necrosis of various degrees.

The incubation period for enteroviruses usually is 3 to 7 days (range, 1 to 35 days). Shorter incubation periods are observed in children and for certain specific clinical presentations of enterovirus infections (e.g., upper respiratory illnesses and acute hemorrhagic conjunctivitis).

Excretion of enteroviruses by an infected individual starts at the end of the incubation period, and patients are most infectious shortly before and after onset of illness. Depending on the stage of the infection and the clinical syndrome, enteroviruses are found in oropharyngeal secretions, stool, cerebrospinal fluid, blood, and vesicular fluids. In immunocompetent hosts, viral shedding in oropharyngeal secretions and circulation in the blood or CSF usually lasts up to 1 week, but fecal excretion may persist for up to 2 months after infection, even after clinical symptoms resolve. Long-term persistence of enteroviruses (in some cases, for several years) may occur in individuals with impaired humoral immunity.8,9

IMMUNITY

Immunity to enteroviruses is long lasting and serotype specific and is primarily mediated by humoral mechanisms. Primary infection results in an IgM response and is followed by IgG and IgA production. Secondary infections induce an anamnestic response, resulting in high antibody titers. Circulating IgG and IgM antibodies have a neutralizing effect on enteroviruses during the extracellular phase of replication, and secretory IgA antibodies mediate local mucosal immunity. The importance of antibodies in providing protective immunity against enteroviruses is emphasized by the occurrence of severe chronic enterovirus infections in patients with defective humoral immunity.

CLINICAL SYNDROMES

The vast majority of enterovirus infections are clinically inapparent or result only in a minor febrile illness. A smaller proportion of infected individuals develop more serious diseases, and on relatively rare occasions, conditions with substantial sequelae or death may occur.

Of host factors influencing the clinical outcome of enterovirus infection, age and the degree of immunocompetence are the most important. Agent factors, such as the serotype or intratypic strain of the virus and tissue tropism, are also important. Depending on preferential target organs, enteroviruses can affect several organ systems and tissues, including the respiratory system, central nervous system, heart, skin, muscles, and gastrointestinal tract. Associations between distinctive clinical syndromes and serotypes have been established [see Table 1], but there is considerable overlap.

Table 1 Diseases Associated with Enteroviruses

 

Associated Enteroviruses*

Disease

Polio

Coxs (Group A)

Coxs (Group B)

Echo

Numbered EV

Clinical Features

Febrile illness

+

+

+

+

+

Mild, transient, febrile illness with or without rash or respiratory symptoms; resolves within a few days

Neurologic illnesses

 

 

 

 

 

 

  Aseptic meningitis

+

+

+ (Coxs B5)

+ (Echo 30, 9, 11 6, 4, 7, 13, 18)

+ (EV 71)

Acute onset of fever, severe headache with meningeal irritation; meningeal symptoms in young infants may not be obvious

 

 

 

 

 

CSF findings: mild to moderate pleocytosis (< 1,000 cells/mm3) that is predominantly lymphocytic; rarely, normal cell counts; an initial predominance of polymorphonuclear cells in CSF with a subsequent shift to lymphocytosis may be observed, particularly in young children; CSF glucose level, normal; protein level, normal or elevated; CSF bacterial cultures, negative; enteroviruses often are detected in CSF by culture or PCR; often accompanied by other symptoms of enteroviral infection (respiratory symptoms, rashes, or myalgia)

 

 

 

 

 

Usually resolves with no neurologic deficits in about 1 wk; illness and convalescence in adults may last longer

  Encephalitis

+

+

+ (Coxs B5)

+ (Echo 30, 11, 6, 9, 24)

+ (EV 71)

Clinical presentation of meningoencephalitis; symptoms of aseptic meningitis plus confusion, lethargy, seizures; rarely, coma, cerebellar ataxia, choreiform movements, and paresthesias; diffuse encephalitis more common than focal; CSF profile similar to that of aseptic meningitis

 

 

 

 

 

Outcome usually favorable; residual neurologic deficits uncommon; severe illness and deaths mostly in neonates and with EV 71 infection

  Paralytic illness

+

+ (Coxs A7)

+

+

+ (EV 70, 71)

Usually preceded or accompanied by febrile illness

 

 

 

 

 

Poliomyelitis: acute, usually asymmetrical, rapidly progressive flaccid paralysis; decreased or absent deep tendon reflexes; normal sensory function; respiration and swallowing may be compromised; the extent of paralysis depends on the location of CNS damage (spinal, bulbar, or spinobulbar forms)

 

 

 

 

 

Muscle weakness associated with nonpolio enteroviruses usually milder than polio and transient; other manifestations of enteroviral infection common

 

 

 

 

 

Residual permanent paralysis occurs in paralytic poliomyelitis but is rare after infection with nonpolio enteroviruses

 

 

 

 

 

Death: in fewer than 10% of patients with poliomyelitis, mostly in patients with bulbar involvement; fatal bulbar involvement with nonpolio enteroviruses uncommon

Skin/mucosal syndromes

 

 

 

 

 

 

  Nonspecific rashes

 

+

+

+ (Echo 9, 11, 16)

+

Variety of exanthems and enanthems (e.g., maculopapular, roseolous, vesicular), rarely as a sole manifestation of enteroviral illness; resolve within a few days

  Herpangina

 

+ (Coxs A10, 16, 2, 4, 5, 8)

 

 

 

Acute onset; fever, headache, malaise, sore throat with 10 to 12 vesicular enanthems, usually ulcerating, on soft palate, anterior tonsillar pillars, or posterior pharynx

 

 

 

 

 

Self-limiting illness; complete recovery in a few days

  Hand, foot, and mouth disease

 

+ (Coxs A16)

 

 

+ (EV 71)

Benign illness with acute onset; fever and mild pharyngitis 1 to 2 days before rash onset; lesions initially maculopapular but evolve into whitish-gray tender, flat, often oval vesicles; lesions on oral mucosa, dorsal surface of hands and feet, sometimes buttocks; peripheral distribution of rash on the limbs

 

 

 

 

 

Recovery usually complete in a few days; CNS complications with fatalities observed in outbreaks of hand, foot, and mouth disease caused by EV 71

Muscle diseases

 

 

 

 

 

 

  Myopericarditis

 

+ (Coxs A4, A16)

+ (All serotypes)

+ (Echo 9, 22)

 

Both myocardium and pericardium are affected, but signs of either myocarditis or pericarditis predominate

 

 

 

 

 

Dyspnea, chest pain, fever, malaise; ECG abnormalities (ST segment elevation, nonspecific ST segment and T wave abnormalities, ventricular tachyarrhythmias and heart block); cardiomegaly; serum levels of myocardial enzymes frequently elevated

 

 

 

 

 

Severity varies; permanent myocardial injury possible in approximately 30% of cases; may later lead to chronic dilated cardiomyopathy

 

 

 

 

 

Deaths in acute period rare (< 5%), mostly in patients with severe myocardial involvement; mortality in neonates approximately 50%

  Pleurodynia

 

 

+

 

 

Synonyms: epidemic myalgia, Bornholm disease

 

 

 

 

 

Attacks of spasmodic paroxysmal pain of variable intensity in the chest or upper abdomen with fever, which subsides as the pain recedes; pain usually more intense in adults; affected muscles painful by palpation; may be swollen; chest auscultation and x-ray normal

 

 

 

 

 

Usually resolves within 1 wk; multiple relapses possible

Systemic infections

 

 

 

 

 

 

  Neonatal systemic infection

 

 

+ (All serotypes)

+ (Echo 11)

 

Overwhelming sepsislike illness

 

 

 

 

 

Initial symptoms (fever, poor feeding, irritability, lethargy, hypotonus, and vomiting) are followed by multiple organ involvement; dominant syndromes include encephalomyocarditis (severe myocarditis, often accompanied by heart failure, and meningoencephalitis) and hemorrhage-hepatitis (overwhelming hepatitis with hepatic failure and DIC)

 

 

 

 

 

High mortality (50% to 83%); most deaths within 1 wk of onset; the risk of fatal outcome highest with onset in infants younger than 2 wk

  Chronic EV infection in immunocompromised host

 

 

 

+

 

Occurs in patients with B cell defects; chronic, persistent infection of CNS (meningoencephalitis), skeletal muscles (dermatomyositis-like syndrome), and other organs

 

 

 

 

 

Progressive course; outcome usually fatal

Acute hemorrhagic conjunctivitis

 

+ (Coxs A24 variant)

 

 

+ (EV 70)

Acute eye pain, photophobia, swelling of eyelids, subconjunctival hemorrhages; transient corneal involvement possible

 

 

 

 

 

Complete recovery in less than 10 days; permanent poliolike paralysis with onset after a few weeks of the EV 70 illness has been described

Respiratory illnesses

 

+ (Coxs A21, A24)

+ (Coxs B2)

+ (Echo 11, 9, 4, 18)

+ (EV 71)

Acute febrile illness; both upper (coryza, pharyngitis) and lower (bronchitis, tracheobronchitis, bronchiolitis, pneumonia) respiratory manifestations occur

 

 

 

 

 

Course usually benign with complete recovery, except in neonatal systemic illness; fatal pulmonary edema observed in Southeast Asian outbreaks of EV 71

Diarrhea

 

+

+

+ (Echo 11, 14, 18)

 

Diarrhea usually febrile, accompanying other symptoms of enterovirus infection; recovery complete

*The most commonly associated serotypes are indicated in parentheses. More common serotypes are listed first.
CNS—central nervous system  Coxs—coxsackievirus  CSF—cerebrospinal fluid  DIC—disseminated intravascular coagulation  Echo—echovirus  EV—enterovirus  PCR—polymerase chain reaction  Polio—poliovirus

Minor Febrile Illness

Enteroviruses are a common cause of febrile illness, particularly during the summer and fall months. Fever may be the sole symptom, or infection may be accompanied by rashes or respiratory symptoms (the “summer cold”); in infants, symptoms include irritability, lethargy, anorexia, vomiting, and diarrhea. Because of the need to rule out potentially serious bacterial infections, a high proportion of infants with enteroviral febrile illness require evaluation for bacterial sepsis or meningitis.10

Aseptic Meningitis

Aseptic meningitis is the most common CNS illness associated with enteroviruses; enteroviruses account for more than 90% of cases of aseptic meningitis for which a causative organism is identified.11 Patients experience the acute onset of fever, headache, nuchal rigidity, photophobia, nausea, and vomiting. The fever may be biphasic, subsiding for several days and then recurring; development of meningeal symptoms occurs after recurrence of fever. A variable degree of lethargy, irritability, and drowsiness may be present, but considerable changes in mental status are uncharacteristic. Meningeal signs may not be obvious in young infants. Other manifestations of enterovirus infection, such as respiratory symptoms, exanthems, enanthems, or myalgia, are often present.

Examination of the CSF reveals a mild to moderate pleocytosis, with a predominance of lymphocytes (usually < 1,000 cells/mm3). In some patients—particularly young children—polymorphonuclear cells may predominate initially, with the subsequent development of lymphocytosis. In rare cases, CSF cell counts are normal. CSF glucose levels are normal; protein levels may be normal or elevated.

Symptoms usually resolve in about 1 week, although CSF pleocytosis may persist for some time thereafter. Severe illness and fatal outcome are uncommon except in the immediate neonatal period. Recovery is usually complete, with no significant sequelae.

Encephalitis

Enteroviral encephalitis results from progression of enteroviral meningitis; therefore, most patients with enteroviral encephalitis have symptoms of meningoencephalitis. Meningoencephalitis usually starts as aseptic meningitis, but it is accompanied by changes in mental status or cerebral involvement, characterized by somnolence, lethargy, generalized or focal seizures, and psychiatric symptoms. Coma, cerebellar ataxia, choreiform movements, and paresthesias are rare. Diffuse symptoms are more common than focal symptoms. The outcome is favorable in the majority of cases, but severe residual neurologic damage and death have been reported. In neonates, the disease is part of a systemic illness. In such patients, the disease follows a much more severe course; the prognosis is guarded, and there is a higher risk of neurologic sequelae and death.12 In Southeast Asia, fulminant, rapidly fatal bulbar encephalitis has occurred in young children during outbreaks of enterovirus 71 infection.13

Poliomyelitis and Poliolike Paralytic Illness

Muscle paralysis is primarily associated with poliovirus infection but has also been observed, sometimes in outbreaks, with several nonpolio enteroviruses, such as coxsackievirus A7, enteroviruses 70 and 71, and several echoviruses. Through successful immunization programs, control of poliomyelitis has been achieved in numerous countries worldwide, including the entire Western Hemisphere, but wild polioviruses continue to circulate in some countries of sub-Saharan Africa and Southeast Asia. It is likely that the large-scale Polio Eradication Initiative, led by the World Health Organization since 1988, will result in global polio eradication14; until that occurs, there remains a risk of importation of poliomyelitis into the United States.

Paralysis in poliomyelitis results from the replication of polioviruses in the anterior horn of the spinal cord or in the brain stem, causing the destruction of motor neurons. Depending on the location of the damage, spinal, bulbar, or spinobulbar forms of poliomyelitis may occur. Clinical hallmarks of paralytic poliomyelitis include the acute onset of flaccid, usually asymmetrical, rapidly progressive paralysis that is more severe proximally than distally and that is characterized by decreased or absent deep tendon reflexes without sensory loss. Respiration and swallowing may be compromised if respiratory muscles, cranial nerves, or respiratory centers are affected. Death occurs in fewer than 10% of cases; the majority of deaths involve cases of bulbar poliomyelitis. Recovery of muscle function takes place during the first few months after disease onset, but some degree of permanent paralysis usually remains.

Paralysis associated with nonpolio enterovirus infections results more from inflammatory changes than motor neuron destruction; therefore, it is usually milder and transient, rarely resulting in residual paresis. Fatal bulbar involvement is uncommon.

Myopericarditis

Carditis caused by enteroviruses (predominantly group B coxsackieviruses) occurs mostly in newborns, adolescents, and young adults and usually affects both pericardium and myocardium. Electrocardiographic abnormalities of varying degree are present; these range from ST segment elevation or nonspecific ST segment and T wave abnormalities to ventricular tachyarrhythmias and heart block. Cardiomegaly caused by pericardial effusion or acute cardiac dilatation is common. Serum levels of myocardial enzymes are frequently elevated. Death in the acute period is rare (< 5%) and mostly occurs in patients with severe myocardial involvement. Most patients recover without complications, but permanent myocardial injury occurs in about 30% of cases. Residual damage includes persistent ECG abnormalities, cardiomegaly, and chronic congestive heart failure and may later lead to dilated cardiomyopathy.15,16

Pleurodynia

Pleurodynia is characterized by attacks of spasmodic paroxysmal pain in the chest or upper abdomen accompanied by fever, which subsides as the pain recedes. The intensity of pain varies and is usually greater in adults. Affected muscles are painful on palpation and may be swollen. Normal auscultatory examination and chest x-ray are helpful in the differential diagnosis. The disease resolves within 1 week, but some patients experience multiple relapses.

Exanthems and Enanthems

Skin and mucosal lesions seldom appear as a sole presentation of enterovirus infection. Maculopapular rashes are most commonly associated with echoviruses; they appear simultaneously with fever, and spread from the face to the chest, neck, and extremities. Roseoliform rashes appear on the face and upper chest after defervescence. Of the vesicular rashes, the most distinctive clinical syndrome is hand, foot, and mouth disease. This disease is most often caused by coxsackievirus A16, but it can also be caused by enterovirus 71. Most cases of hand, foot, and mouth disease occur in children, who present with fever, vesicular lesions in the mouth, and macular rash on the limbs and sometimes buttocks; these lesions may later become vesicular. The disease generally resolves in a few days, but CNS complications with fatalities occurred in Southeast Asia during large outbreaks of hand, foot, and mouth disease caused by enterovirus 71.13,17 The most common example of enterovirus enanthems is herpangina, a common illness of young children that is characterized by fever, sore throat, and vesicular enanthems on the soft palate; symptoms resolve within a few days.

Neonatal Systemic Infection

Enterovirus infections in infants usually are benign, self-limited illnesses similar to those observed in older persons. In some neonates, especially during the first 2 weeks of life, enteroviruses may cause an overwhelming sepsislike illness.18,19 In most cases, infection is transmitted from the sick mother (either transplacentally or during delivery), but nosocomial infections, including nursery outbreaks, also occur. The initial symptoms associated with neonatal enteroviral sepsis are nonspecific and include fever, poor feeding, irritability, lethargy, hypotonia, and vomiting. There subsequently occurs involvement of multiple organs, notably the heart, CNS, liver, lungs, pancreas, and adrenal glands. The dominant features of the encephalomyocarditis syndrome, which is associated with group B coxsackieviruses, are severe myocarditis, often accompanied by heart failure, and meningoencephalitis. The leading clinical features of the hemorrhage-hepatitis syndrome, predominantly associated with echovirus 11, are overwhelming hepatitis with hepatic failure and disseminated intravascular coagulation. Neonatal enteroviral sepsis is often fatal (reported case fatality ranges from 50% to 83%), and most deaths occur within 1 week of onset.12,18,19

Chronic Enterovirus Infection in Immunocompromised Hosts

Neutralizing antibodies play a critical role in the immune response to enteroviruses. Thus, enteroviruses often persist in patients with inherited or acquired defects of humoral immunity; this results in chronic infections of the CNS, skeletal muscles, and the GI system. Most commonly, the condition occurs in children with X-linked agammaglobulinemia, but it may also develop in children with severe combined immunodeficiency syndrome and, rarely, in bone marrow transplant recipients.8,9 Chronic progressive meningoencephalitis is the predominant clinical feature. More than half of patients experience a dermatomyositis-like syndrome. Chronic hepatitis is commonly present. The course of illness is progressive; although periodic improvements may occur, the overall prognosis is poor, and the disorder is usually fatal.9

Acute Hemorrhagic Conjunctivitis

Acute hemorrhagic conjunctivitis occurs in explosive outbreaks, mostly in tropical areas, and is caused by coxsackievirus A24 variant and enterovirus 70. The disease is highly contagious; unlike other enteroviruses, the primary mode of transmission is direct introduction of the virus into the eye by fingers or fomites. The symptoms include eye pain, photophobia, swelling of eyelids, and characteristic subconjunctival hemorrhages of various intensity. The symptoms initially affect one eye and then spread to the other. The disease usually resolves in less than 10 days. Corneal involvement may occur but is transient and leaves no permanent scars. A permanent poliolike paralysis has been reported in persons who had recently had acute hemorrhagic conjunctivitis caused by enterovirus 70.

Other Illnesses

The respiratory syndromes in enterovirus infections involve both upper and lower respiratory tracts and range from the so-called “summer cold” to pneumonia. These infections are usually mild, except when associated with systemic illness in neonates. Fatal pulmonary edema, apparently of neurogenic origin, was reported to have occurred in association with the 1998 outbreak of enterovirus 71 infection in Taiwan.17

GI symptoms are often associated with other manifestations of enterovirus infections. In young children, outbreaks of febrile diarrhea associated with some echoviruses have been described, but in general, enteroviruses are not a major cause of gastroenteritis.

Enteroviruses are also known to cause hepatitis and pancreatitis, usually as part of generalized infection. An association of enterovirus infections, particularly group B coxsackievirus infection, with type 1 (insulin-dependent) diabetes mellitus has been suggested, but no conclusive evidence is available.20,21

DIAGNOSIS

Isolation of the virus with subsequent serotyping has traditionally been the gold standard for the laboratory diagnosis of enterovirus infections. Most enteroviruses can be grown in susceptible cell lines and identified by observing a characteristic cytopathic effect, but for almost all group A coxsackieviruses, inoculation of suckling mice is needed. The use of several cell lines and multiple specimen types from the patient increases the diagnostic yield. However, viral culture is relatively insensitive, laborious, and time consuming; these factors limit the utility of viral culture for patient care.22

The most widely accepted method for the identification of individual enterovirus serotypes is neutralization reaction, using intersecting pools of internationally standardized antisera. Immunofluorescence assay with monoclonal antibodies is also available for several common enteroviruses.

Compared with viral culture for enterovirus detection, reverse transcriptase polymerase chain reaction (RT-PCR) assays have been shown to be more sensitive, as specific, and much more rapid. These assays are being used increasingly in clinical practice with demonstrated clinical utility, particularly for the diagnosis of enterovirus meningitis.18,22,23 The primers most often used in enterovirus RT-PCR have broad specificity for enteroviruses in general; this precludes serotype identification, but specific primers for individual serotypes are becoming available.5,24 Molecular typing by sequence analysis, based on the close correlation of the serotype with the nucleotide sequence of the VP1gene, is a new modality for enterovirus identification that has led to identification of several previously unknown serotypes.1,25

Detection of the virus in normally sterile sites (e.g., CSF, blood, pericardial fluid, tissue specimens) is considered diagnostic. Because enteroviruses are ubiquitous and because asymptomatic infections commonly occur, positive results from testing of nonsterile sites (e.g., stool sample, throat swab) should be interpreted with caution.

Serology has a limited role in the diagnosis of enterovirus infections; it is helpful only if paired sera are available for testing. Demonstration of a greater than fourfold increase in titers of antibodies against the implicated serotype is indicative of recent infection. Of various serologic methods, virus neutralization reaction is preferred.

TREATMENT

Most patients with enterovirus infections recover uneventfully after a few days of supportive care, but patients with potentially serious illnesses require intensive support. No antiviral therapy for enterovirus infections is currently available.

Immunoglobulin preparations are used both for treatment and prophylaxis of enterovirus infections in patients with humoral immunodeficiencies.9 The occurrence of chronic enterovirus meningoencephalitis has declined notably since the introduction of regular prophylactic immunoglobulin treatment. The benefit for patients with established chronic enterovirus meningoencephalitis is less clear. Most commonly, immunoglobulin preparations are administered intravenously. Results of intramuscular and intrathecal administration are mixed.9Intravenous immunoglobulin is sometimes used for neonatal enterovirus infections, but the data on the effectiveness of this therapy are limited.18,26

PREVENTION AND CONTROL

Two types of highly effective vaccines—inactivated poliovaccine (IPV) and live, attenuated oral poliovaccine (OPV)—are available for prevention and control of poliovirus infection. Since 2000, IPV has been the recommended vaccine for routine use in the United States.27

In the absence of vaccines, prevention and control of nonpolio enteroviral illnesses are primarily accomplished through adherence to good personal hygiene (e.g., thorough hand washing, especially after diaper changes). To prevent neonatal infections, routine infection-control measures in neonatal nurseries must be strictly enforced, and pregnant women near term should be advised to avoid contact with patients with known or suspected enterovirus infections. Control of enterovirus transmission is complicated by the fact that the majority of infections are asymptomatic and by the relatively long duration of viral shedding. For similar reasons, the effectiveness of isolation of symptomatic persons is questionable.

Viral Gastroenteritis

Viral gastroenteritis occurs in two distinct epidemiologic forms: sporadic disease that commonly affects children, and epidemic disease that afflicts both children and adults. Sporadic childhood viral gastroenteritis is primarily caused by rotaviruses (group A), human caliciviruses (including both noroviruses [previously called Norwalk-like viruses] and sapoviruses [previously called Sapporo-like viruses]), enteric adenoviruses, and astroviruses. Epidemic viral gastroenteritis is caused most often by norovirus.

ROTAVIRUS INFECTIONS

In 1973, Bishop and colleagues visualized by electron microscopy a 70-nm triple-layered virus in the duodenal epithelium of children with diarrhea.28 This virus, designated as rotavirus because of its morphologic appearance (in Latin, rota means wheel), belongs to the family Reoviridae; its genome consists of 11 segments of double-stranded RNA. The segmented genome of rotavirus allows reassortment during coinfection, a property that has been utilized in the development of rotavirus vaccines and is probably important in virus evolution. There are seven major groups of rotavirus (groups A to G); human illness is caused by rotaviruses of groups A, B, and C. Two outer capsid proteins, the glycoprotein (G protein) and the protease-cleaved protein (P protein), determine the serotype specificity and form the basis of the binary classification (G and P types) of rotaviruses. Both G protein and P protein induce neutralizing antibodies.

Epidemiology

Rotaviruses are ubiquitous, infecting 95% of children worldwide by the time they are 3 to 5 years of age.29 Neonatal infections, although common, are often asymptomatic. The incidence of clinical illness peaks in children 4 to 23 months of age. Globally, rotaviruses are the most common agents of severe childhood gastroenteritis; they are estimated to cause about one third of all gastroenteritis hospitalizations and 500,000 deaths a year.30 Rotavirus infections in adults are usually subclinical but occasionally cause illness in parents of children with rotavirus diarrhea and in immunocompromised individuals, the elderly, and travelers.

In temperate climates, rotavirus disease predominantly occurs during the fall and winter months. A study from Japan showed that, unlike in children, rotavirus diarrhea in adults did not show significant winter seasonality.30 In the United States, rotavirus activity peaks in the Southwest in autumn (October through December) and migrates across the continent, peaking in the Northeast during spring (March through May).31 In tropical settings, rotavirus disease occurs year-round.

During episodes of diarrhea, rotaviruses are shed in large amounts in stool; fecal shedding detectable by antigen enzyme immunoassays usually subsides within a week but may persist for more than 30 days in immunocompromised persons. Viral shedding may be detected for longer periods using more sensitive assays, such as PCR. Transmission of rotavirus occurs predominantly through the fecal-oral route. Transmission through respiratory secretions, person-to-person contact, or contaminated environmental surfaces has been postulated.

In humans, most rotavirus diseases, including endemic childhood diarrhea, are caused by group A rotaviruses. Group B rotaviruses have caused large epidemics of severe gastroenteritis in China since 1982 and have also been identified in India.32,33 Group C rotaviruses have been associated with epidemic gastroenteritis worldwide, and some studies indicate a possible association with extrahepatic biliary atresia in infants.34

Rotavirus strains that infect animals differ from those that infect humans. Although some strains of human rotavirus possess a high degree of genetic homology with animal strains, animal-to-human transmission is uncommon.

Pathogenesis

Rotaviruses infect the mature enterocytes in the middle or upper villous epithelium of the small intestine. Ultimately, the epithelium becomes necrotic and sloughs off. The loss of absorptive villous epithelium coupled with proliferation of secretory crypt cells reverses the inherent absorptive state of the epithelium, resulting in secretory diarrhea. Levels of brush-border enzymes characteristic of differentiated cells (e.g., sucrase and lactase) are reduced, leading to the accumulation of unmetabolized disaccharides in the gut lumen, with consequent osmotic diarrhea. The toxinlike effect of a nonstructural rotavirus protein, NSP4, increases intracellular calcium through the opening of a cation channel, causing an efflux of chloride and, thus, sodium and water, contributing to the secretory diarrhea.35 Furthermore, rotavirus appears to evoke the secretion of intestinal fluids through activation of the enteric nervous system.36

Recent data indicate that a transient antigenemia that peaks 1 to 3 days after onset of symptoms is common in children with rotavirus infection. It remains to be proved whether the presence of antigenemia is correlated with increased severity of disease or with extraintestinal manifestations that are sometimes seen in children with rotavirus infection.37,38

Immunity

Protection against rotavirus disease is correlated with the presence of virus-specific secretory IgA antibodies in the feces and serum.39,40Because virus-specific IgA is short-lived at the intestinal surface, complete protection against natural rotavirus disease is only temporary. Memory B and T cells in the lamina propria are believed to be important in reducing the severity of disease resulting from reinfection.41

Diagnosis

Clinical manifestations

The clinical spectrum of rotavirus infection ranges from subclinical illness to severe gastroenteritis associated with life-threatening dehydration. The onset of illness is abrupt; vomiting frequently precedes the development of diarrhea. Up to one third of patients may have a temperature greater than 39° C (102.2° F). GI symptoms generally resolve in 3 to 6 days.

Respiratory symptoms have been observed in children with rotavirus infection, as have symptoms of CNS involvement, but these associations have not been well studied.42 Rotavirus infection has been observed in patients with a variety of other clinical syndromes, including sudden infant death syndrome, Reye syndrome, necrotizing enterocolitis, intussusception, Kawasaki syndrome, disseminated intravascular coagulation, and Crohn disease. A causal relationship has not been confirmed between any of these syndromes and rotavirus infection.

In immunodeficient children, rotavirus can cause a protracted diarrhea with prolonged viral excretion and, in rare instances, can disseminate systemically and cause hepatic infection.43

Laboratory tests

Illness caused by rotavirus is difficult to distinguish clinically from that caused by other enteric viruses. Because a large number of viruses are shed in feces, the diagnosis usually can be confirmed by using one of a wide variety of commercial immunoassays or by techniques for detecting viral RNA, such as gel electrophoresis, probe hybridization, or RT-PCR.

Treatment and Prevention

Treatment relies primarily on replacement of fluids and electrolytes; antibiotics and antimotility agents should be avoided.44 Although oral rehydration therapy is successful in most children, intravenous fluid replacement may be required for children who have severe dehydration or are unable to tolerate oral therapy. A variety of other therapeutic agents have been evaluated, including probiotics,45 bismuth salicylate,46 and enkephalinase inhibitors,47 but their therapeutic roles are not clearly defined.

In 1998, only 25 years after the identification of rotavirus in humans, a live, attenuated rhesus-human reassortant rotavirus vaccine (Rotashield, Wyeth Laboratories, Marietta, Pennsylvania) with 80% efficacy against severe rotavirus disease was licensed in the United States and was recommended for routine immunization of infants. This vaccine was withdrawn, however, in 1999, after it was confirmed that its use was associated with intussusception.48 Efforts are ongoing to develop other rotavirus vaccines. Two large clinical trials that each involved more than 60,000 infants have recently been completed. The trials examined two leading vaccine candidates—one developed by Merck (a multivalent bovine-human reassortant rotavirus vaccine)49 and the other by GlaxoSmithKline (an attenuated single human strain rotavirus vaccine).50 These trials demonstrated the safety of both vaccines with respect to intussusception and other potential adverse events,51,52 and they indicated that the vaccines have an efficacy of more than 90% against severe rotavirus disease.49,50 Data on the Merck vaccine, which is administered orally to infants in three doses at 2, 4, and 6 months of age, were submitted for licensure to the Food and Drug Administration in April 2005; a decision is expected in 2006.

HUMAN CALICIVIRUS INFECTIONS

In 1972, using immune electron microscopy, Kapikian and colleagues identified the 27-nm Norwalk agent in stool filtrates of a volunteer challenged with fecal specimens from patients affected by an outbreak of gastroenteritis.53 Several related but genetically and antigenically diverse single-stranded RNA viruses of positive polarity measuring 27 to 35 nm were subsequently identified; these organisms are currently classified as noroviruses (previously called Norwalk-like viruses), in the family Caliciviridae. The Caliciviridae family also includes the sapoviruses (previously called Sapporo-like viruses), which cause gastroenteritis in children and adults, and Lagovirus and Vesivirus, neither of which is pathogenic for humans.

Epidemiology

Studies indicate that infections with the Norwalk and related caliciviruses are more common than previously believed; a majority of children and nearly all adults demonstrate antibodies to these viruses. Acquisition of antibody occurs at an earlier age in developing countries, as would be expected, given the presumed fecal-oral mode of transmission of these viruses. Although their role in sporadic illness in children and adults is still being defined, noroviruses are clearly recognized as the most common cause of epidemics of gastroenteritis worldwide.54Epidemics occur throughout the year and are often linked to consumption of fecally contaminated water and foods; often, food and water become contaminated by an infectious food handler. Dispersion of virus through direct contact, vomitus, or airborne droplets has been postulated in situations in which an alternative mode of transmission cannot be established.

Pathogenesis

Because no animal model exists for calicivirus gastroenteritis, the data on pathogenesis of disease arise exclusively from studies of human volunteers. After challenge of volunteers with either Norwalk virus or Hawaii virus, which is a related calicivirus, biopsy demonstrates lesions in the proximal small intestine; these lesions are characterized by villus shortening, crypt hyperplasia, and infiltration of the lamina propria by polymorphonuclear cells and lymphocytes.55 The lesions persist for at least 4 days after the person's symptoms disappear and are associated with malabsorption of carbohydrates and fats and a decreased level of brush-border enzymes. No changes are observed in the stomach or colon, but gastric motor function is delayed, which probably contributes to the characteristic nausea and vomiting.56

Immunity

Approximately 50% of persons challenged with Norwalk virus become ill and acquire short-term homologous immunity (i.e., immunity against the same strain) that is correlated with serum antibody levels; immunity does not appear to persist for longer than 2 years.57 Some reports indicate, paradoxically, that persons with higher levels of preexisting antibody to Norwalk virus are more susceptible to illness.58

Diagnosis

Clinical manifestations

Gastroenteritis caused by Norwalk virus and related enteric caliciviruses occurs with sudden onset after a viral incubation period of 12 to 48 hours. The illness generally lasts 12 to 60 hours and is characterized by nausea, vomiting, abdominal cramps, and diarrhea. In children, vomiting is more prevalent than diarrhea, whereas in adults, diarrhea is more prevalent. Constitutional symptoms, such as headache, fever, chills, and myalgias, are frequently reported. Death is rare and usually occurs from severe dehydration in vulnerable persons, such as the elderly with debilitating health conditions.

Laboratory tests

Cloning and sequencing of the genome of Norwalk virus and a few other human caliciviruses has allowed the development of sensitive detection methods based on PCR amplification and Southern blot analysis; strains can be further characterized by sequencing of nucleotide products. Expression of capsid proteins in a recombinant baculovirus vector produces viruslike particles that have been used to develop immunoassays. Diagnostic assays, however, are not widely available.

Treatment and Prevention

Treatment is generally not required, because the disease is self-limited.44 Rehydration may be required for patients with volume depletion.

Epidemic prevention relies on situation-specific measures, such as control of contamination of food and water, prevention of the handling of food by persons who are ill, and reduction of person-to-person spread through good personal hygiene. Calicivirus vaccines are being developed and may be particularly useful for groups for whom the impact of short-term morbidity from gastroenteritis is great (e.g., military troops) or those who are at high risk for severe disease (e.g., the elderly in nursing homes).

GASTROENTERITIS CAUSED BY OTHER VIRAL AGENTS

Enteric adenoviruses have double-stranded DNA and measure 70 to 80 nm; they belong to the family Adenoviridae. Serotypes 31, 40, and 41 cause approximately 10% of diarrheal illness in young children. Unlike their counterparts that cause respiratory illness, enteric adenoviruses are difficult to cultivate in cell lines. Their detection requires the use of immunoassays to the adenovirus hexon antigen and subsequent serotyping using monoclonal antibodies.

Astroviruses have positive-sense, single-stranded RNA and measure 28 to 30 nm; they belong to the family Astroviridae. Although at least seven different serotypes have been identified, strains of serotype 1 are most common. Preliminary epidemiologic studies indicate that astroviruses may be important causes of mild to moderate diarrhea in children, causing half as many illnesses as rotavirus.59 The availability of simple immunoassays to detect virus in fecal specimens and of molecular methods to confirm and further characterize strains will allow for a more comprehensive assessment of the etiologic role of these agents in endemic childhood diarrhea.

Other viruses, including toroviruses, picobirnaviruses, coronaviruses, pestiviruses, and parvoviruses, have been identified in the feces of patients with diarrhea, but their etiologic role has not been well studied. It appears from preliminary studies that some of these agents, such as picobirnaviruses, may be important causes of diarrhea in HIV-infected persons.60,61

References

  1. Stanway G, Brown F, Christian P, et al: Picornaviridae: virus taxonomy: classification and nomenclature of viruses. 8th report of the International Committee on the Taxonomy of Viruses. Fauquet CM, Mayo MA, Maniloff J, et al, Eds. Elsevier Academic Press, Amsterdam, 2005, p 757
  2. Enterovirus surveillance—United States, 1997–1999. MMWR Morb Mortal Wkly Rep 49:913, 2000
  3. Enterovirus Surveillance—United States, 2000–2001. MMWR Morb Mortal Wkly Rep 51:1047, 2002
  4. Outbreaks of Aseptic Meningitis Associated with Echoviruses 9 and 30 and Preliminary Surveillance Reports on Enterovirus Activity—United States, 2003. MMWR Morb Mortal Wkly Rep 52:761, 2003
  5. Mullins JA, Khetsuriani N, Nix WA, et al: Emergence of echovirus 13 as a prominent enterovirus. Clin Infect Dis 38:70, 2004.
  6. Morens MM, Pallansch MA: Epidemiology. Human Enterovirus Infections. Rotbart HA, Ed. ASM Press, Washington, DC, 1995, p 3
  7. Feachem R, Garelick H, Slade J: Enteroviruses in the environment. Trop Dis Bull 78:185, 1981.
  8. Galama JM, de Leeuw N, Wittebol S, et al: Prolonged enteroviral infection in a patient who developed pericarditis and heart failure after bone marrow transplantation. Clin Infect Dis 22:1004, 1996.
  9. McKinney RE Jr, Katz SL, Wilfert CM: Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 9:334, 1987.
  10. Rittichier KR, Bryan PA, Bassett KE, et al: Diagnosis and outcomes of enterovirus infections in young infants. Pediatr Infect Dis J 24:546, 2005.
  11. Rotbart HA: Viral meningitis. Semin Neurol 20:277, 2000.
  12. Modlin JF: Update on enterovirus infections in infants and children. Adv Pediatr Infect Dis 12:155, 1996.
  13. Chan LG, Parashar UD, Lye MS, et al: Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis 31:678, 2000.
  14. Progress Toward Interruption of Wild Poliovirus Transmission—Worldwide January 2004–March 2005. MMWR Morb Mortal Wkly Rep 54:408, 2005
  15. Smith WG: Coxsackie B myopericarditis in adults. Am Heart J 89:34, 1970
  16. Helin M, Savola J, Lapinleimu K: Cardiac manifestations during a coxsackie B5 epidemic. BMJ 3:97, 1968.
  17. Chang LY, Lin TY, Hsu KH, et al: Clinical features and risk factors of pulmonary oedema after enterovirus-71—related hand, foot, and mouth disease. Lancet 354:1862, 1999
  18. Lin TY, Kao HT, Hsieh SH, et al: Neonatal enterovirus infections: emphasis on risk factors of severe and fatal infections. Pediatr Infect Dis J 22:889, 2003.
  19. Abzug MJ: Presentation, diagnosis, and management of enterovirus infections in neonates. Paediatric Drugs 6:1, 2004.
  20. Hyoty H, Taylor KW: The role of viruses in human diabetes. Diabetologia 45:1353, 2002.
  21. Haverkos HW, Battula N, Drotman DP, et al: Enteroviruses and type 1 diabetes mellitus. Biomedicine & Pharmacotherapy 57:379, 2003
  22. Tanel RE, Kao SY, Niemiec TM, et al: Prospective comparison of culture vs genome detection for diagnosis of enteroviral meningitis in childhood. Arch Pediatr Adolesc Med 150:919, 1996.
  23. Ramers C, Hartin M, Ho S, et al: Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 283:2680, 2000.
  24. Kilpatrick DR, Quay J, Pallansch MA, et al: Type-specific detection of echovirus 30 isolates using degenerate reverse transcriptase PCR primers. J Clin Microbiol 39:1299, 2001.
  25. Oberste MS, Maher K, Kilpatrick DR, et al: Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol 37:1288, 1999.
  26. Abzug MJ, Keyserling HL, Lee ML, et al: Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis 20:1201, 1995.
  27. Poliomyelitis prevention in the United States: updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 49[RR-5]:1, 2000
  28. Bishop RF, Davidson GP, Holmes IH, et al: Virus particles in epithelial cells of duodenal mucosa from children with viral gastroenteritis. Lancet 2:1281, 1973.
  29. Parashar UD, Bresee JS, Gentsch JR, et al: Rotavirus. Emerg Infect Dis 4:561, 1998.
  30. Nakajima H, Nakagomi T, Kamisawa T, et al: Winter seasonality and rotavirus in adults. Lancet 357:1950, 2001.
  31. Torok TJ, Kilgore PE, Clarke MJ, et al: Visualizing geographic and temporal trends in rotavirus activity in the United States, 1991 to 1996. National Respiratory and Enteric Virus Surveillance System Collaborating Laboratories. Pediatr Infect Dis J 16:941, 1997.
  32. Fang ZY, Ye Q, Ho MS, et al: Investigation of an outbreak of adult diarrhea rotavirus in China. J Infect Dis 160:948, 1989.
  33. Kang G, Kelkar SD, Chitambar SD, et al: Epidemiological profile of rotaviral infection in India: challenges for the 21st century. J Infect Dis 192(suppl 1):S120, 2005.
  34. Riepenhoff-Talty M, Gouvea V, Evans MJ, et al: Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 174:8, 1996.
  35. Ball JM, Tian P, Zeng CQ, et al: Age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein. Science 272:101, 1996.
  36. Lundgren O, Peregrin AT, Persson K, et al: Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea. Science 287:491, 2000.
  37. Blutt SE, Kirkwood CD, Parreno V, et al: Rotavirus antigenaemia and viraemia: a common event? Lancet 362:1445, 2003.
  38. Fischer TK, Ashley D, Kerin T, et al: Rotavirus antigenemia in patients with acute gastroenteritis. J Infect Dis 192:913, 2005.
  39. Coulson BS, Grimwood K, Hudson IL, et al: Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol 30:1678, 1992.
  40. Matson DO, O'Ryan ML, Herrera I, et al: Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis 167:577, 1993.
  41. Offit PA: Host factors associated with protection against rotavirus disease: the skies are clearing. J Infect Dis 174(suppl 1):S59, 1996.
  42. Lynch M, Lee B, Azimi P, et al: Rotavirus and central nervous system symptoms: cause or contaminant? Case reports and review. Clin Infect Dis 33:932, 2001.
  43. Gilger MA, Matson DO, Conner ME, et al: Extraintestinal rotavirus infections in children with immunodeficiency. J Pediatr 120:912, 1992.
  44. Farthing MJ: Treatment of gastrointestinal viruses. Novartis Found Symp 238:289, 2001.
  45. Szajewska H, Mrukowicz JZ: Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr 33(suppl 2):S17, 2001.
  46. Figueroa-Quintanilla D, Salazar-Lindo E, Sack RB, et al: A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N Engl J Med 328:1653, 1993.
  47. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, et al: Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med 343:463, 2000.
  48. Murphy TV, Gargiullo PM, Massoudi MS, et al: Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 344:564, 2001.
  49. Salinas B, Schael IP, Linhares AC, et al: Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX 4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J 24:807, 2005.
  50. Velasquez FR, Abate H, Clemens SA: The human monovalent G1P[8] rotavirus vaccine, Rotarix, is highly efficacious and provides cross protection against G1 and non-G1 serotypes. Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Valencia, Spain, May 18–20, 2005
  51. Vesikari T, Matson D, Van Damme P, et al: Incidence of intussusception with the pentavalent (human-bovine) reassortant rotavirus vaccine (PRV) is similar to placebo. Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Valencia, Spain, May 18–20, 2005
  52. Vesikari T, Matson D, Dennehy P, et al: Protection against rotavirus gastroenteritis of multiple serotypes by a pentavalent (human-bovine) reassortant rotavirus vaccine (PRV). Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Valencia, Spain, May 18–20, 2005
  53. Kapikian AZ, Wyatt RG, Dolin R, et al: Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol 10:1075, 1972.
  54. Parashar UD, Monroe SS: “Norwalk-like viruses” as a cause of foodborne disease outbreaks. Rev Med Virol 11:243, 2001
  55. Schreiber DS, Blacklow NR, Trier JS: The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. N Engl J Med 288:1318, 1973.
  56. Meeroff JC, Schreiber DS, Trier JS, et al: Abnormal gastric motor function in viral gastroenteritis. Ann Intern Med 92:370, 1980.
  57. Graham DY, Jiang X, Tanaka T, et al: Norwalk virus infection of volunteers: new insights based on improved assays. J Infect Dis 170:34, 1994.
  58. Johnson PC, Mathewson JJ, DuPont HL, et al: Multiple-challenge study of host susceptibility to Norwalk gatroenteritis in US adults. J Infect Dis 161:18, 1990.
  59. Clark B, McKendrick J: A review of viral gastroenteritis. Curr Opin Infect Dis 17:461, 2004.
  60. Grohmann GS, Glass RI, Pereira HG, et al: Enteric viruses and diarrhea in HIV-infected patients. Enteric Opportunistic Infections Working Group. N Engl J Med 329:14, 1993.
  61. Giordano MO, Martinez LC, Rinaldi D, et al: Diarrhea and enteric emerging viruses in HIV-infected patients. AIDS Res Hum Retroviruses 15:1427, 1999.

Editors: Dale, David C.; Federman, Daniel D.