Jeffrey W. Almond
Most infections are inapparent. Some picornaviruses cause mild illnesses; a few serotypes give rise to serious conditions of the central nervous system, heart, skeletal muscles, and liver. These varied manifestations are presented under each of the five genera.
The picornavirus virion is an icosahedral, nonenveloped, small (22 to 30 nm) particle. The capsid proteins encase a sense RNA strand consisting of approximately 7,500 nucleotides. The RNA carries a covalently bound noncapsid viral protein (VPg) at its 5' end and a polyadenylated tail at its 3' end.
Classification is based on morphology, physicochemical and biologic properties, antigenic structures, genomic sequence and mode of replication. The family PICORNAVIRIDAE comprises five genera, namely, enteroviruses, rhinoviruses, hepatoviruses, cardioviruses, and aphthoviruses.
The enteroviruses are subdivided into human polioviruses (1-3); human coxsackieviruses A1-22, 24 (CA1-22 and CA24, CA23 = echovirus 9); human coxsackieviruses (B1-6 (CB1-6); human echoviruses 1-7, 9, 11-27, 29-33 (E1-7, 9, 11-27, 29-33; E8=E1; E10 = Reovirus; E28 = Rhinovirus 1A and E34 = CA24 prime strain); human enterovirus 68-71 (EV68-71); vilyuish virus; simian enteroviruses 1-18 (SEV1-18); porcine enteroviruses 1-11 (PEV1-11); bovine enteroviruses 1-2 (BEV1-2).
Picornaviruses multiply in the cytoplasm, and their RNA acts as a messenger to synthesize viral macromolecules. Viral RNA replicates in complexes associated with cytoplasmic membranes via two distinct, partially double-stranded RNAs - the "replicative intermediates." One complex uses the sense RNA strand, and the other uses the antisense RNA strand as template.
Enterovirus can replicate in epithelium of the nasopharynx and regional lymphoid tissue, conjunctiva, intestines, mesenteric nodes, and the reticuloendothelial system. Viremia may cause virus transfer to the spinal cord, brain, meninges, heart, liver, and skin. Some chronic enterovirus infections result in postviral fatigue syndrome. Rhinoviruses infect and replicate mainly in nasopharyngeal epithelium and regional lymph nodes. Hepatitis A virus replicates in the intestinal epithelium, viremia transports the virus to the liver where secondary virus multiplication in the hepatocytes and Kupffer cells results in infectious hepatitis A.
Interferon and virus-specific IgA, IgM, and IgG antibodies are important in host defense. Neutralizing antibody confers serotype-specific immunity.
Picornaviruses are widely prevalent. Enteroviruses are transmitted by the fecal-oral route, via salivary and respiratory droplets, and in some cases via conjunctival secretions and skin lesion exudates. Cockroaches and flies may be vectors. Rhinoviruses are transmitted by saliva, respiratory discharge, and contaminated inanimate objects. Immunity is serotype specific.
Viruses must be isolated and identified in the clinical laboratory. Serology is used to confirm the virus as the cause of infection and for the assessment of immune status.
Poliomyelitis can be prevented by Salk-type (inactivated) and Sabin-type (live) attenuated poliovirus vaccines. Hepatitis A can be prevented by inactivated hepatitis A vaccine (Havrix). Control can be achieved via public education on transmission modes and personal hygiene. Adequate sewage disposal and uncontaminated water supplies are critical for prevention of enteroviral infections. There is no specific therapy.
Poliovirus has tropism for epithelial cells of the alimentary tract and cells of the central nervous system. Infection is asymptomatic or causes a mild, undifferentiated febrile illness. Spinal and bulbar poliomyelitis occasionally occurs. Paralytic poliomyelitis is not always preceded by minor illness. Paralysis is usually irreversible, and there is residual paralysis for life. All three poliovirus serotypes (1 to 3) can give rise to paralytic poliomyelitis.
Most infections are inapparent or mild. Rashes and vesicular lesions are most commonly caused by group A coxsackieviruses and pleurodynia and viral pericarditis/myocarditis by group B coxsackieviruses. The coxsackievirus A24 variant causes epidemic and pandemic outbreaks of acute hemorrhagic conjunctivitis. Occasionally, coxsackieviruses are associated with paralytic and encephalitic diseases. Coxsackieviruses are characterized by their pathogenicity for suckling mice. They are classified by antibody neutralization tests as coxsackievirus group A (A1 to A24) and coxsackievirus group B (B1 to B6).
Echoviruses have been associated with febrile and respiratory illnesses, aseptic meningitis, rash, occasional conjunctivitis, and paralytic diseases.
Enterovirus types 68 and 69 cause respiratory illnesses; type 70 causes acute hemorrhagic conjunctivitis and occasionally polio-like radiculomyelitis; type 71 can cause meningitis, encephalitis and outbreaks of hand-foot-mouth disease with or without encephalitis.
Rhinoviruses cause mainly respiratory infections including the common cold. There are to date 115 serotypes. Immunity is type specific.
There is only one serotype of Hepatitis A virus. This virus causes gastroenteritis infections and hepatitis A.
The picornaviruses are small (22 to 30 nm) nonenveloped, single-stranded RNA viruses with cubic symmetry. The virus capsid is composed of 60 protein subunits, each consisting of four poly-peptides VP1-VP4. Because they contain no essential lipids, they are ether resistant. They replicate in the cytoplasm. The picornaviruses that affect humans are the enteroviruses, found primarily in the gut; the rhinoviruses, found in the upper respiratory tract and hepatovirus (Hepatitis A virus) in the intestine and liver. Subclinical infections with the picornaviruses are common. The hepatitis A virus is discussed in Chapter 70, "Hepatitis Viruses."
FIGURE 53-1 Pathogenesis of enterovirus infections
FIGURE 53-2 Pathogenesis of rhinovirus infections
Enteroviruses are implicated in many diseases, including undifferentiated febrile illnesses, upper and lower respiratory tract infections, gastrointestinal disturbances, conjunctivitis, skin and mucous membrane lesions, and diseases of the central nervous system, muscles, heart, and liver. Less commonly, enteroviruses are associated with generalized neonatal infections, diabetes mellitus, pancreatitis, orchitis, and occasionally hemolytic-uremic syndrome and intrauterine infections. A new disease called wandering myoclonus was discovered in China (see below). Rhinoviruses cause mainly upper (e.g. coryza) and lower respiratory tract illnesses (Table 53-1).
Laboratory tests are needed to establish the etiology of a suspected picornavirus infection because a particular serotype can give rise to more than one clinical syndrome and different serotypes can produce the same syndrome. Some illnesses caused by enteroviruses are clinically indistinguishable from those caused by other viruses.
The picornaviruses are nonenveloped (naked), small (22 to 30 nm) icosahedral virions resistant to lipid solvents. The virus capsid is composed of 60 copies each of four viral proteins VP1-4, which form a quasi T = 3 icosahedral shell. The structures of several picornaviruses have been determined to near atomic resolution. All show a similar structural pattern in which VP1-3 have an 8-stranded, B-barrel type structure which forms the matrix of the shell. Random coil structures which connect the b strands may contribute to the antigenicity of the viruses and show high variability. The genome is a single sense-strand RNA (molecular weight, approximately 2 x 106 to 3 x 106) (Fig. 53-3). The RNA strand consists of approximately 7,500 nucleotides and is covalently bonded to a noncapsid viral protein (VPg) at its 5' end and to a polyadenylated tail at its 3' end. This genome RNA serves as an mRNA and initiates the synthesis of virus macromolecules.
FIGURE 53-3 Electron micrograph of a poliovirus showing the characteristic nonenveloped, small (20 to 30) icosahedral particles of a picornavirus.
Replication begins with attachment to a specific cellular receptor, the identity of which is known for poliovirus, some enteroviruses and the majority of the rhinoviruses. Replication and assembly take place in the cytoplasm of infected cells. The viral RNA replicates via two distinct, partially double-stranded RNAs called the replicative intermediates (RIs). One complex uses the sense RNA strand and the other uses the antisense RNA strand as template. Functional proteins are produced from a single large polyprotein (Molecular weight, 2.4 x 105 to 2.5 x 105) followed by post-translational cleavage. The coat protein is encoded by the 5' one third (PI region); VPg, two proteases, and polymerases or polymerase factors are encoded downstream in the P2-P3 regions. The major neutralizing antigens that distinguishes picornavirus species and induces serotype-specific immunity is formed by parts of one VP1, VP2 and VP3 proteins. The viral capsid gives the picornaviruses their characteristic shape and size (Fig. 53-3) and protects the infectious viral RNA from hostile environments and host ribonucleases. Enteroviruses can survive for long periods in organic matter and are resistant to the low pH in the stomach (pH 3.0 to 5.0). By contrast, rhinoviruses are labile at this pH range. Picornaviruses are inactivated by pasteurization, boiling, Formalin, and chlorine. Enteroviruses and rhinoviruses are distinguished by density gradient centrifugation. The buoyant density of enteroviruses is approximately 1.33 to 1.34 g/ml in CsCl, and that of human rhinoviruses is about 1.38 to 1.42 g/ml. Enteroviruses are stabilized against thermal inactivation by molar MgCl2.
Picornaviruses may undergo antigenic variation during replication and may give rise to strains with altered virulence and disease patterns.
The family Picornaviridae comprises five genera: Enterovirus, Hepatovirus and Rhinovirus, which infect humans: Apthovirus (foot-and-mouth disease virus), which infects cloven-hoofed animals and occasionally humans; and Cardiovirus, which infects rodents. At the time of writing, 67 human enterovirus serotypes and 115 rhinovirus serotypes are known.
Picornaviruses do not have a common group-specific antigen. However, antigenic sharing is observed between a few serotypes. Each serotype has a type-specific antigen, which is identifiable by neutralization tests.
When the portal of entry for a picornavirus is the mouth or nose, the virus infects and replicates in the nasopharyngeal epithelium and regional lymphoid tissues to give rise to asymptomatic infections or respiratory illnesses. Because enteroviruses can resist stomach acid and bile, they can penetrate to the lower intestine, where they infect and multiply in the intestinal epithelium and mesenteric lymph nodes. Viremia may result; this leads to further multiplication of virus in the reticuloendothelial system. From there, the virus can be carried by the bloodstream to target organs such as the spinal cord, brain meninges, heart, liver and skin. From the central nervous system the virus can travel via neural pathways to skeletal and heart muscles. It can be transferred by fingers and inanimate objects, such as handkerchiefs and towels, to the eye, where it may replicate in the conjunctival epithelium and cornea.
Shortly after infection of the respiratory or alimentary tract, increasing amounts of interferon and subsequently virus-specific IgA-antibody are detected in the saliva and the respiratory and gut secretions. Interferon inhibits virus multiplication, and IgA complexes with extracellular virus. The complexing of virus by IgA not only inhibits the spread of virus to susceptible epithelial cells but also reduces the oral and fecal shedding of infectious virus.
The earliest serum antibody to appear in response to picornavirus infection is IgM. By about 2 weeks, IgM is overtaken by IgG. The IgG response peaks at about 2 to 3 weeks and remains at a plateau for a few weeks, before it begins to fall. The IgG elicited by some enterovirus infections remains detectable for several years. This neutralizing IgG confers serotype-specific immunity. Both IgG and IgM can complex with invading virus and prevent the spread of virus via the bloodstream to target organs. Virus-antibody complexes are eliminated by phagocytosis, digestion, and excretion.
Picornaviruses are found worldwide, the enteroviruses primarily in alimentary tracts of humans and animals but can be in nerve and muscle cells. Rhinoviruses are found in the respiratory tract. Although enteroviruses are transmitted mostly by the fecal-oral route, they can also be transmitted by salivary and respiratory droplets. Some serotypes are spread by conjunctival secretions and exudates from skin lesions.
In temperate countries, outbreaks of enterovirus illnesses occur most frequently in summer and autumn, whereas rhinovirus infections appear more often in autumn and spring. In the tropics, there is no apparent seasonal occurrence. Enteroviruses in excreta that contaminate the soil are carried by surface waters to lakes, beaches, vegetation, and community water supplies. These sources may serve as foci of infection. Shellfish that feed in freshwater or seawater beds contaminated by excreta harbor enteroviruses. Cockroaches in sewage pipelines and flies that settle on excreta may act as transient vectors.
Enteroviruses and rhinoviruses may be isolated from feces pharyngeal swabs, saliva, and nasal aspirates, and some enteroviruses may be isolated from skin lesions, conjunctiva cerebrospinal fluid, spinal cord, brain, heart, and blood. Virus is present in respiratory and conjunctival secretions from a few days before onset of illness to about 1 week after. Virus excretion in feces may continue for several weeks or longer. However, the chance of virus isolation is greatest if appropriate specimens are sent to the laboratory at the onset of illness. Table 53-2 lists the virus isolation systems that are used. The most specific of the conventional laboratory tests used to identify picornavirus serotypes is the neutralization test. Serodiagnosis for the whole range of picornaviruses is impractical because of the multiplicity of serotypes. A serologic test is performed primarily to confirm the causative role of virus isolated from clinical specimens (i.e., to exclude the coincidental presence of a passenger virus that does not contribute to the disease process). A fourfold or greater rise in the titer of neutralizing antibody to the isolate between sera collected during the acute and convalescent phases of the illness is regarded as diagnostic of a current or recent infection. The neutralization test is also used to determine the immune status of a person.
Control of picornavirus diseases depends largely on mass education of the public on the mode of virus transmission, stressing the importance of good personal hygiene, and on provision of a good sewage disposal system and uncontaminated water supply. Fecal and pharyngeal discharges are infectious; hence, they must be handled with care and disposed of safely. Vaccine is commercially available for poliomyelitis and hepatitis A.
There is no established specific therapy. Treatment is symptomatic and supportive. Clinical studies show that ribavirin shortens respiratory illnesses and interferon nasal sprays have prophylactic value for common colds.
Paralytic poliomyelitis can occur without antecedent minor illnesses. A patient may suffer aseptic meningitis with pains in the back and neck muscles for several days without progressing to paralytic poliomyelitis. The incubation period is about 3 to 5 days for minor illness and 1 to 2 weeks for central nervous system involvement, with a range of 3 to 35 days between ingestion of virus and onset of symptoms. Virus is present in the throat before onset of illness. It disappears from the throat in about 1 week but persists in the feces for weeks. Examination of cerebrospinal fluid in the early phase of central nervous system involvement reveals increased numbers of leukocytes. In confirming a poliovirus etiology, a patient's poliomyelitis immunization record, if available, is reviewed together with the history, clinical and laboratory findings.
The outcome of poliovirus infection is influenced by the virulence of the infecting strain, the size of the infecting dose, and the immune status of the host. The predisposing factors of inflammation and trauma include recent or previous tonsillectomy, which not only removes the immunologically active tonsils but also exposes nerve endings to the virus. There have been reports of unimmunized persons who developed paralysis in the limb inoculated with alum-precipitated diphtheria-pertussis-tetanus (DPT) vaccines during outbreaks of poliomyelitis. Also pregnant, immunodeficient, and immunocompromised persons are predisposed to more severe illness.
Humans are the only natural host of poliovirus. Polioviruses have a tropism for the epithelial cells lining the alimentary tract and for cells of the central nervous system. They attach to a specific receptor on these cells, which in humans is encoded by a gene on chromosome 19. Poliovirus infection is quite common in nonimmunized individuals, but only about 1 percent of these cases progress to the paralytic form of the disease. The histocompatibility antigens HLA-3 and HLA-7 are believed to be highly associated with an increased risk of paralysis. Primary replication of poliovirus takes place in the oropharyngeal and intestinal mucosa (the alimentary phase). From here, the virus spreads to the tonsils and Peyer's patches of the ileum and to deep cervical and mesenteric nodes, where it multiplies abundantly (the lymphatic phase). Subsequently, the virus is carried by the bloodstream to various internal organs and regional lymph nodes (the viremic phase). In most cases, no further virus spread occurs, and there is asymptomatic or mild febrile undifferentiated illness, such as fever, malaise, headache, nausea, gastrointestinal disturbances, and sore throat, or combinations of these.
In rare cases in which disease progresses to the neurologic phase, the virus spreads hematogenously to the spinal cord or brain stem or to both. If only scattered nerve cells are destroyed, the patient may develop no visible sign of muscle weakness. More concentrated damage results in flaccid paralysis of the muscles innervated by the affected motor nerves. Muscle involvement peaks a few days after the paralytic phase begins. Paralysis is usually irreversible, and residual paralysis remains for life. Paralytic disease is called spinal poliomyelitis if the weakness is limited to muscles innervated by the motor neurons in the spinal cord and bulbar poliomyelitis if the cranial nerve nuclei or medullary centers are involved. The areas most affected are the anterior horn cells of the spinal cord, the motor area of the cerebral cortex, and the motor nuclei of the medulla. The lesions feature neuronal necrosis, necrophagia, and loss of nerve cells. Areas of neuronal damage show leukocytic infiltration and perivascular cuffing. Round-cell infiltration is usually present in leptomeninges. Bulbar poliomyelitis is serious because it may result in swallowing dysfunction and in cardiac or respiratory failure. Comparative clinical aspects of poliomyelitis, Guillain-Barre syndrome, and transverse myelitis are presented in Table 53-3.
Poliomyelitis affects all age groups. In areas with poor hygiene and poor sanitation, most infants are infected relatively early in life and acquire active immunity while still protected by maternal antibodies. Infants who escape early contact with poliovirus become susceptible to infection as maternal antibodies wane. With improving sanitation, infants may escape early contact with polioviruses and become susceptible for an outbreak of poliomyelitis when wild poliovirus is introduced into the community. The most susceptible are children less than 2 years old. In countries which have high poliomyelitis immunization coverage in their childhood vaccination programs there is a shift to an older age group.
The Salk-type inactivated poliovirus vaccine (IPV) consists of a mixture of three poliovirus serotypes grown in monkey kidney cell cultures and made noninfectious by Formalin treatment. It is given in two intramuscular injections spaced a month apart and requires periodic boosters to maintain an adequate serum neutralizing-antibody level. Its effectiveness depends on stimulation of serum neutralizing antibodies that block the spread of poliovirus to the central nervous system. It has some suppressive effect on replication of wild poliovirus in the highly vascularized oropharyngeal region, but it has no effect on replication in the gut or on viral transmission in the excreta.
The Sabin-type live attenuated oral poliovirus vaccine (OPV) that is commercially available is also trivalent, but monovalent vaccine can be obtained if requested. The viruses were attenuated by multiple passages in monkey kidney or human diploid cell cultures, and the vaccine potency was stabilized with molar magnesium chloride or sucrose. This vaccine mimics wild poliovirus infections by inducing serum -neutralizing antibody, as well as interferon and virus-specific IgA antibody in the pharynx and gut. Hence, the vaccine virus not only prevents paralytic poliomyelitis, but also, when given in sufficient doses, can abort a threatening epidemic and has the potential of eradicating poliomyelitis. During an outbreak trivalent OPV is recommended, but as soon as the causative poliovirus serotype is known, monovalent OPV containing the responsible serotype should be administered without delay to susceptible individuals in the community to prevent an epidemic. The chief disadvantage of this vaccine is the occurrence of vaccine-associated paralysis. The risk of paralytic poliomyelitis associated with reversion to neurovirulence is exceedingly small, estimated at one case of paralysis for every 2 to 4 million doses of trivalent OPV distributed. Recently, a combination of IPV and OPV vaccination strategy used in the control and eradication of poliomyelitis in the West Bank and Gaza from 1978-1993 attracted international interest. This combined IPV/OPV approach deserves consideration as an additional tool for the control and eradication of poliomyelitis in countries where polio is endemic and where there is a danger of importation of poliovirus. In 1988, the World Health Assembly, the governing body of the World Health Organization, set the goal of global eradication of poliomyelitis by the year 2000.
Coxsackieviruses are differentiated from other groups of picornaviruses by their pathogenicity for suckling mice and by classification of their antigenicity. They are classified as coxsackievirus group A (A1 to A, A24) and coxsackievirus group B (B1 to B6) (Table 53-2).
Subcutaneous and intracerebral inoculation of suckling mice with group A coxsackieviruses produces myositis in skeletal muscles and generalized paralysis. Group B coxsackieviruses produce focal muscle lesions, necrosis of fat pads between the shoulders, focal lesions in the brain, and spinal cord and spastic paralysis.
Little is known about the pathology of human coxsackievirus infections because very few patients die of them. Autopsies of neonates with generalized coxsackievirus B infection show focal myocarditis and inflammation. Fatal myocarditis in adults is also associated with focal necrosis. Findings in order of decreasing incidence include meningoencephalitis, hepatitis, and pancreatitis. Fatal cases of encephalomyelitis show involvement of the motor neurons in the brain stem and spinal cord. Coxsackievirus B affects both white and gray matter.
Humans are the only natural host for these agents. Disorders caused by coxsackieviruses are shown in Table 53-1. Most infection is inapparent or mild. Illnesses include acute nonspecific febrile disease and common cold-like or influenza like-respiratory diseases, pharyngitis, croup, and pneumonia.
Rashes and vesicular lesions are most commonly caused by group A viruses. Herpangina presents as small, scattered oral vesicles with red areolae in the posterior oropharynx, tonsils, tongue, and palate, which progress to shallow ulcers and heal within a week. Coxsackievirus A10 causes acute lymphonodular pharyngitis with solid white to yellow papules. Coxsackievirus A16, A10 and A5 give rise to sporadic cases and outbreaks of hand-foot-mouth diseases characterized by fever, an oral vesicular exanthema, and sparse symmetric maculopapular eruptions that involve the hands, feet, mouth, buttocks, and occasionally other sites.
Coxsackieviruses also cause exanthematous diseases that may be mistaken for rubella and an aseptic meningitis that is clinically indistinguishable from meningitis caused by polioviruses and a list of other viruses. Occasionally, they cause paralytic and encephalitic diseases or other cerebral dysfunction.
Pleurodynia, also known as epidemic myalgia, devil's grip and Bornholm disease, is caused primarily by group B coxsackieviruses. Onset is usually abrupt, with fever, headache, and stabbing pain in muscles of the chest and/or upper abdomen. The pain is intensified by respiration and movement and may persist for a few weeks. The disease is self-limiting, but relapses, with recurrences of fever and other symptoms, are common. Occasional complications include pleuritis and orchitis.
The most important cause of viral pericarditis and myocarditis in children and adults is coxsackievirus B. Patients develop fever, tachycardia, dyspnea, precordial pain, and occasionally pericardial friction rub. Electrocardiography and radiography are helpful in confirming the diagnosis. The prognosis for uncomplicated pericarditis is good, but when myocarditis is also present the situation is serious.
Neonatal myocarditis in the first month of life may result in severe and frequently fatal disease. The myocarditis is accompanied by involvement of various organs, especially the central nervous system and liver. Onset may be abrupt, with lethargy, feeding difficulties, fever and often signs of cardiac or respiratory distress. The infant may die within days or may recover over the next few weeks. These infections are generally acquired from infected mothers or during a nursery outbreak.
Coxsackievirus A24 (Ca24V) variant is the first human enterovirus known to cause a disease which has the eyes as the primary site of clinical manifestations. Since its discovery in Singapore in 1970, CA24V continues to give rise to sporadic and extensive epidemics of acute hemorrhagic conjunctivitis (AHC) world over. The conjunctivitis is characterized by a short incubation period and high secondary attack rate. Lacrimation, chemosis, edema and hyperemia of the conjunctiva, and preauricular gland enlargement also occur. Follicular hypertrophy of the conjunctiva is more prominent in the upper than lower fornix. Small petechiae to large blotches of subconjunctival hemorrhage, although striking, are seen in only a few cases. Anterior uveitis is common. Corneal lesions cause pain and blurring of vision. Recovery occurs within 1 to 2 weeks without sequelae. Clinically, it is not possible to distinguish conjunctivitis caused by CA24V from conjunctivitis caused by Enterovirus 70. Headaches, respiratory and gastrointestinal complaints may accompany conjunctivitis.
Virus isolation is often used for diagnosis. Serodiagnosis is used to confirm a suspected case of coxsackievirus B myocarditis, because by the time the cardiac involvement is recognized, virus excretion has usually ceased. The diagnostic four-fold or greater rise in neutralizing antibody titer between paired sera or high antibody titers to a single serotype is commonly registered in children. In adults, antibody to more than one serotype is frequently observed. It is recommended that in the absence of a fourfold or greater rise in antibody titer, unchanging titers of 512 and above be regarded as suggestive of recent infection. Some patients maintain high antibody titers for years, which suggests that chronic infections do occur.
Recently, a molecular approach using oligo-primers designed for PCR amplification of viral cDNA and analysis of amplified products by gel electrophoresis has been shown to provide a rapid diagnostic tool for AHC and allows differentiation between CA24V and EV70.
The echoviruses (enteric, cytopathic, human, and orphan viruses) are grouped together because they produce cytopathogenic effects in cell cultures but generally are not pathogenic for mice, and they differ antigenically from the polioviruses. They were first named "orphan viruses" because their relationship with disease was obscure. Echoviruses are identified by neutralization tests as serotypes 1 to 9, 11 to 27, and 29 to 33 (Table 53-2). Echovirus 1 and 8 show antigenic sharing. Echovirus 22 is distinctive in its genomic sequence, which shows little or no identity to other picornavirus. Nevertheless, its biophysical properties, disease manifestations, epidemiology and pathogenesis support its remaining as a member of Enterovirus.
Echoviruses, like coxsackieviruses, are associated with various disorders including respiratory illnesses, febrile illnesses with or without rash, Boston exanthema, aseptic meningitis, paralytic diseases, and occasional conjunctivitis (Table 53-1). Echovirus type 3 was responsible for epidemics of wandering myoclonus in China that most commonly affected young adults.
The prominent features are migratory pains and tenderness in the trunk and musculatures of the limbs and severe sweating. Mortality is high (12 to 33 percent).
Enterovirus types 68 and 69 cause respiratory illnesses in infants and children. Enterovirus type 70 gives rise to epidemic and pandemic outbreaks of acute hemorrhagic conjunctivitis that is clinically similar to that caused by coxsackievirus A24 variant. Enterovirus type 71 causes meningitis, encephalitis and hand-foot-mouth disease with or without encephalitis.
The natural hosts of rhinoviruses are humans and chimpanzees. Rhinoviruses are present in the nose and pharynx, and, unlike enteroviruses, which are acid resistant and have an optimum growth temperature of 36 to 37°C, they are inactivated at pH 3.0 and have an optimum growth temperature of 33°C, the temperature of the nasal epithelium. Furthermore, not all strains are stabilized by molar magnesium chloride.
Rhinovirus infections are among the most prevalent of acute respiratory illnesses in humans. More than 90 percent of susceptible individuals infected with rhinoviruses succumb to the infection. Although most rhinovirus infections manifest as mild common colds with rhinorrhea, nasal obstruction, fever, sore throat, coughs, and hoarseness lasting for a few days, serious lower respiratory tract illnesses in infants are common. Secondary bacterial infections with Streptococcus pneumoniae and Haemophilus influenzae may result in sinusitis and otitis media. The incubation period is a few days. Viral shedding begins several days after infection peaks shortly after the onset of symptoms, and may persist for a few weeks. In the adult population, rhinovirus disorders create significant economic losses in terms of lost working hours.
Pathologic findings in the common cold consist of inflammatory changes with hyperemia, edema, and inflammation of the columnar epithelial cells lining the nasopharynx. Desquamation of these infected cells coincides with the peak of virus spread. Regeneration is completed within a few weeks.
Volunteer experiments indicate that spread from nasal secretions by contaminated hands to nasal and conjunctival mucosa is a more important mode of virus transmission than are respiratory droplets and aerosols.
Immunity to infection is type specific, as it is with the enteroviruses. Therefore, because of the multiple rhinovirus serotypes, control of rhinovirus infections and development of an effective vaccine are difficult. Furthermore, the localized nature of infections results in a poor humoral antibody response, and the secretory antibody that is vital in conferring protection is not long lasting.
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