Jawetz Chapter 36.pdf

Picornaviruses (Enterovirus and Rhinovirus Groups) Picornaviruses represent a very large virus family with respect to the number of members but one of the smallest in terms of virion size and genetic complexity. They include two major groups of human pathogens: enteroviruses and rhino- viruses. Enteroviruses are transient inhabitants of the human alimentary tract and may be isolated from the throat or lower intestine. Rhinoviruses are associated with the respiratory tract and isolated chiefly from the nose and throat. Less com- mon picornaviruses associated with human illness include hepatitis A virus, parechovirus, cardiovirus, and Aichi virus. Several genera of picornaviruses are also associated with ani- mal, plant, and insect disease. Many picornaviruses cause diseases in humans rang- ing from severe paralysis to aseptic meningitis, pleurodynia, myocarditis, vesicular and exanthematous skin lesions, mucocutaneous lesions, respiratory illnesses, undifferenti- ated febrile illness, conjunctivitis, and severe generalized disease of infants. However, subclinical infection is far more common than clinically manifest disease. Etiology is difficult to establish because different viruses may produce the same syndrome, the same picornavirus may cause more than a sin- gle syndrome, and some clinical symptoms cannot be distin- guished from those caused by other types of viruses. The most serious disease caused by any enterovirus is poliomyelitis. A worldwide effort is making progress toward the goal of total eradication of poliomyelitis. PROPERTIES OF PICORNAVIRUSES Important properties of picornaviruses are shown Structure and Composition The virion of enteroviruses and rhinoviruses consists of a capsid shell of 60 subunits, each of four proteins (VP1–VP4) arranged with icosahedral symmetry around a genome made up of a single strand of positive-sense RNA (Figure 36-1). Parechoviruses are similar except that their capsids contain only three proteins because VP0 does not get cleaved into VP2 and VP4. By means of x-ray diffraction studies, the molecular structures of poliovirus and rhinovirus have been determined. Riedel_CH36_p531-p546.indd 531 532 SECTION IV Virology TABLE 36-1 Important Properties of Picornaviruses Virion: Icosahedral, 28–30 nm in diameter, contains Composition: RNA (30%), protein (70%) Genome: Single-stranded RNA, linear, positive sense, 7.2–8.4 kb in size, molecular weight 2.5 million, infectious, contains genome- linked protein (VPg) Proteins: Four major polypeptides cleaved from a large precursor polyprotein. Surface capsid proteins VP1 and VP3 are major antibody-binding sites. VP4 is an internal protein. Envelope: None Replication: Cytoplasm Outstanding characteristic: Family is made up of many enterovirus and rhinovirus types that infect humans and lower causing various illnesses ranging from poliomyelitis meningitis to the common cold. these viruses included the following: (1) polioviruses, types 1–3; (2) coxsackieviruses of group A, types 1–24 (there is no type 15, 18, or 23); (3) coxsackieviruses of group B, types 1–6; (4) echoviruses, types 1–33 (no type 8, 10, 22, 23, 28, or 34); and (5) enteroviruses, types 68–116 (no type 72) (Table 36-2). Since 1969, new enterovirus types have been assigned entero- virus type numbers rather than being subclassified as cox- sackieviruses or echoviruses. The vernacular names of the previously identified enteroviruses have been retained. The coxsackie A viruses fall into human enterovirus species HEV-A and HEV-C and coxsackie B viruses and echoviruses into HEV-B. Human rhinoviruses include more than 100 anti- genic types and fall into human rhinovirus (HRV) species A, B, and C. Rhinoviruses of other host species include those of horses and cattle. Hepatitis A virus was originally classified as enterovirus type 72 but is now assigned to a separate genus. It is described in Chapter 35. Parechoviruses, previously classified as echoviruses 22 and 23, were found to differ significantly from the enterovi- ruses in both biologic properties and molecular characteris- tics and were placed into a new genus, Parechovirus. Other picornaviruses are foot-and-mouth disease virus of cattle (Aphthovirus) and encephalomyocarditis virus of rodents (Cardiovirus). The host range of picornaviruses varies greatly from one type to the next and even among strains of the same type. Many enteroviruses (polioviruses, echoviruses, some cox- sackieviruses) can be grown at 37°C in human and mon- key cells; most rhinovirus strains can be recovered only in human cells at 33°C. Coxsackieviruses are pathogenic for newborn mice. Picornavirus Replication The picornavirus replication cycle occurs in the cytoplasm of cells (Figure 36-3). First, the virion attaches to a specific Riedel_CH36_p531-p546.indd 532 A COOH NH2 B ICAM-1 THR 216 LEU H 106 CYS 199 ASN TYR LEU 198 197 112 C FIGURE 36-1 Structure of a typical picornavirus. capsid composed of pentamers of proteins VP1, B: Binding of cellular receptor to the floor diameter roughly half that of an immunoglobulin antiviral drug shown, WIN 52084, prevents viral Rueckert RR: Picornaviridae: The viruses and Lippincott-Raven, 1996.) Properties of the Virus A. General Properties Poliovirus particles are typical enteroviruses (see earlier). They are inactivated when heated at 55°C for 30 minutes, but Mg 2+, 1 mol/L, prevents this inactivation. Whereas Riedel_CH36_p531-p546.indd 533 534 SECTION IV Virology 5 UTR AUG VPg L 1ABCD 1ABC VP0 VP4 VP2 FIGURE 36-2 Organization and expression of the picornavirus end and is polyadenylated at the 3′ terminus. L specifies human rhinoviruses, or human hepatitis virus A. The domain (red) encodes capsid proteins, and the P2 (green) replication. Cleavage of the polyprotein is accomplished polyprotein, and all other cleavages are performed by Novel roles of the picornaviral 3D polymerase in viral TABLE 36-2 Characteristics of Human Picornaviruses Property Polio Serotypes 1–3 Acid pH (pH 3.0) Stable Density (g/mL) 1.34 1.34 Optimal temperature for 37 37 growth (°C) Common sites of isolation from humans Nose 0 0 Throat + + Lower intestine + + Infect newborn mice e 0 + a Because of reclassifications, there are no coxsackievirus b Since 1969, new enteroviruses have been assigned a inclusion in the International Committee on Taxonomy c Rhinovirus 87 was reclassified as enterovirus 68. d Parechoviruses 1 and 2 were previously classified e Some variability exists in this property. Riedel_CH36_p531-p546.indd 534 Nucleus Cell lysis VPg VPg VPg VPg VPg VPg FIGURE 36-3 Overview of the picornavirus replication The structure–function relationship of the B. Animal Susceptibility and Growth of Virus Polioviruses have a very restricted host range. Most strains will infect monkeys when inoculated directly into the brain or spinal cord. Chimpanzees and cynomolgus monkeys can also be infected by the oral route; in chimpanzees, the infec- tion is usually asymptomatic and the animals become intesti- nal carriers of the virus. Most strains can be grown in primary or continuous cell line cultures derived from a variety of human tissues or from monkey kidney, testis, or muscle but not from tissues of lower animals. Poliovirus requires a primate-specific membrane receptor for infection, and the absence of this receptor on the surface of nonprimate cells makes them virus resistant. This restriction can be overcome by transfection of infec- tious poliovirus RNA into resistant cells. Introduction of the viral receptor gene converts resistant cells to susceptible cells. Transgenic mice harboring the primate receptor gene have been developed; they are susceptible to human polioviruses. C. Antigenic Properties There are three antigenic types of polioviruses based on epit- opes found in the VP1, VP2, and VP3 proteins. Pathogenesis and Pathology The mouth is the portal of entry of the virus, and primary multiplication takes place in the oropharynx or intestine. The virus is regularly present in the throat and in the stools before the onset of illness. One week after infection, little virus in the throat, but virus continues to be excreted in the stools for several weeks even though high antibody levels are present in the blood. Riedel_CH36_p531-p546.indd 535 536 SECTION IV Virology headache, nausea, vomiting, constipation, and sore throat in various combinations. Recovery occurs in a few days. B. Nonparalytic Poliomyelitis (Aseptic Meningitis) In addition to the symptoms and signs listed in the preceding paragraph, the patient with the nonparalytic form has stiffness and pain in the back and neck. The disease lasts 2–10 days, and recovery is rapid and complete. Poliovirus is only one of many viruses that produce aseptic meningitis. In a small per- centage of cases, the disease advances to paralysis. C. Paralytic Poliomyelitis The predominating complaint is flaccid paralysis resulting from lower motor neuron damage. However, incoordina- tion secondary to brain stem invasion and painful spasms of nonparalyzed muscles may also occur. The amount of dam- age varies greatly. Maximal recovery usually occurs within 6 months, with residual paralysis lasting much longer. D. Progressive Postpoliomyelitis Muscle Atrophy A recrudescence of paralysis and muscle wasting has been observed in individuals decades after their experience with paralytic poliomyelitis. Although progressive postpoliomyeli- tis muscle atrophy is rare, it is a specific syndrome. It does not appear to be a consequence of persistent infection but rather a result of physiologic and aging changes in paralytic patients already burdened by loss of neuromuscular functions. Laboratory Diagnosis The virus may be recovered from throat swabs taken soon after onset of illness and from rectal swabs or stool samples collected over long periods. No permanent carriers have been identified among immunocompetent individuals, but long-term excretion of poliovirus has been observed in some immunodeficient persons. Poliovirus is uncommonly recov- ered from the cerebrospinal fluid—unlike some coxsackievi- ruses and echoviruses. Specimens should be submitted immediately to the labo- ratory, and frozen if testing is delayed. Cultures of monkey cells are inoculated, incubated, and observed. Cyto- pathogenic effects appear in 3–6 days. An isolated virus is identified and typed by neutralization with specific antise- rum. Virus can also be identified more rapidly by polymerase chain reaction (PCR) assays. Paired serum specimens are required to show a rise in antibody titer during the course of the disease. Only first infec- tion with poliovirus produces strictly type-specific responses. Subsequent infections with heterotypic polioviruses induce antibodies against a group antigen shared by all three types. Immunity Immunity is permanent to the virus type causing the infec- tion and is predominantly antibody mediated. There may be Riedel_CH36_p531-p546.indd 536 CHAPTER 36 virus, poliomyelitis is a disease of infancy and early child- hood (“infantile paralysis”). In developed countries, before the advent of vaccination, the age distribution shifted so that most patients were older than age 5 years, and 25% were older than age 15 years. The case fatality rate is variable. It is high- est in the oldest patients and may reach from 5% to 10%. Before the beginning of vaccination campaigns in the United States, there were about 21,000 cases of paralytic poliomyelitis per year. Humans are the only known reservoir of infection. Under crowded conditions of poor hygiene and sanitation in warm areas, where almost all children become immune early in life, polioviruses maintain themselves by continuously infecting a small part of the population. In temperate zones with high levels of hygiene, epidemics have been followed by periods of little spread of virus until sufficient numbers of susceptible children have grown up to provide a pool for transmission in the area. Virus can be recovered from pharynx and intestine of patients and healthy carriers. The prevalence of infection is highest among household contacts. In temperate climates, infection with enteroviruses, including poliovirus, occurs mainly during the summer. Virus is present in sewage during periods of high prevalence and can serve as a source of contamination of water used for drinking, bathing, or irrigation. There is a direct correla- tion between poor hygiene, sanitation, and crowding and the acquisition of infection and antibodies at an early age. Prevention and Control Both live-virus and killed-virus vaccines are available. Formalin-inactivated vaccine (Salk) is prepared from virus grown in monkey kidney cultures. Killed-virus vaccine induces humoral antibodies but does not induce local intesti- nal immunity so that virus is still able to multiply in the gut. Live attenuated vaccine (Sabin) is grown in primary monkey or human diploid cell cultures and delivered orally. The vac- cine can be stabilized by magnesium chloride kept without losing potency for a year at 4°C moderate room temperature (∼25°C). Nonstabilized vaccine must be kept frozen until used. The live polio vaccine infects, multiplies, and immunizes the host against virulent strains. In the process, infectious progeny of the vaccine virus are disseminated in the com- munity. The vaccine produces not only immunoglobulin M (IgM) and IgG antibodies in the blood but also secretory IgA antibodies in the intestine, enabling mucosal immunity (see Figure 30-10). Both killed-virus and live-virus vaccines induce anti- bodies and protect the CNS from subsequent invasion by wild virus. However, the gut develops a far greater degree of resis- tance after administration of live-virus vaccine. A potential limiting factor for oral vaccine is interfer- ence. If the alimentary tract of a child is infected with another enterovirus at the time the vaccine is given, the establishment of polio infection and immunity may be blocked. This may Riedel_CH36_p531-p546.indd 537 538 SECTION IV Virology causative agents of viral heart disease in humans (Table 36-3). The coxsackieviruses tend to be more pathogenic than the echoviruses. Some of the more recent isolates of enterovi- ruses exhibit properties similar to the coxsackieviruses. Properties of the Virus Coxsackieviruses are highly infective for newborn mice, in contrast to most other human enteroviruses. Certain strains (B1–6, A7, 9, 16, and 24) also grow in monkey kidney cell TABLE 36-3 Human Enteroviruses and Parechoviruses and Poliovirus Syndrome Types 1–3 Neurologic Aseptic meningitis 1–3 Paralysis 1–3 Encephalitis Skin and mucosa Herpangina Hand-foot-and- mouth disease Exanthems Many Cardiac and muscular Pleurodynia (epidemic myalgia) Myocarditis, pericarditis Ocular Acute hemorrhagic 24 conjunctivitis Respiratory Colds Pneumonia Pneumonitis of infants 9, 16 Pulmonary edema Gastrointestinal Diarrhea Hepatitis 4, 9 Other Undifferentiated 1–3 febrile illness Generalized disease of infants Diabetes mellitus a Examples are not all inclusive. Other enterovirus b Causality not established. Riedel_CH36_p531-p546.indd 538 CHAPTER 36 Pathogenesis and Pathology Virus has been recovered from the blood in the natural infection in humans. Virus is also found for a few days early in the infection and in 5–6 weeks. Virus distribution is similar to enteroviruses. Clinical Findings The incubation period of coxsackievirus infection ranges from 2 to 9 days. The clinical manifestations of infection with various coxsackieviruses are diverse and may present as dis- tinct disease entities (see Table 36-3). They range from mild febrile illness to CNS, skin, cardiac, and respiratory diseases. The examples shown are not all-inclusive; different serotypes may be associated with a particular outbreak. Aseptic meningitis is caused by all types of group B cox- sackieviruses and by many group A coxsackieviruses, most commonly A7 and A9. Fever, malaise, headache, nausea, and abdominal pain are common early symptoms. The disease sometimes progresses to mild muscle weakness paralytic poliomyelitis. Patients almost always pletely from nonpoliovirus paresis. Herpangina is a severe febrile pharyngitis that is caused by certain group A viruses. Despite its name, it has nothing to do with herpesviruses. There is an abrupt onset of fever and sore throat with discrete vesicles on the posterior half of the palate, pharynx, tonsils, or tongue. The illness is self-limited and most frequent in small children. Hand-foot-and-mouth disease is characterized by oral and pharyngeal ulcerations and a vesicular rash of the palms and soles that may spread to the arms and legs. Vesicles heal without crusting, which clinically differentiates them from the vesicles of herpesviruses and poxviruses. This disease has been associated particularly with coxsackievirus A16 but also with B1 (and enterovirus 71). Coxsackievirus A6 has also emerged as a cause of severe hand-foot-and-mouth disease, sometimes followed by nail shedding. Virus may ered not only from the stool and pharyngeal secretions also from vesicular fluid. It is not to be confused and-mouth disease of cattle, which is caused by an unrelated picornavirus that does not normally infect humans. Pleurodynia (also known as epidemic myalgia) is caused by group B viruses. Fever and stabbing chest pain are usu- ally abrupt in onset but are sometimes preceded by malaise, headache, and anorexia. The chest pain may last from 2 days to 2 weeks. Abdominal pain occurs in approximately half of cases, and in children, this may be the chief complaint. The illness is self-limited and recovery is complete, relapses are common. Myocarditis is a serious disease. It is an acute inflam- mation of the heart or its covering membranes (pericarditis). Coxsackievirus B infections are a cause of primary myo- cardial disease in adults as well as children. About 5% of all symptomatic coxsackievirus infections induce heart disease. Riedel_CH36_p531-p546.indd 539 540 SECTION IV Virology types) unless the antigen used in the test has been isolated from a specific patient or during an epidemic outbreak. Adults have antibodies against more types of coxsackie- viruses than do children, indicating that multiple experience with these viruses are common and increasingly so with age. Epidemiology Viruses of the coxsackie group have been encountered around the globe. Isolations have been made mainly from human feces, pharyngeal swabbings, and sewage. Antibodies to vari- ous coxsackieviruses are found in serum collected from per- sons all over the world and in pooled immune globulin. The most frequent types of coxsackieviruses recovered worldwide over an 8-year period (1967–1974) were types A9 and B2–B5. In the United States from 1970 to 2005, the most common coxsackievirus detections were types A9, B2, and B4 in endemic patterns and type B5 in an epidemic pattern. During 2006–2008, type B1 became the predominant entero- virus identified in the United States. However, in any given year or area, another type may predominate. Whereas an epi- demic pattern is characterized by fluctuations in circulation levels, an endemic pattern shows stable, low-level circulation with few peaks. Coxsackieviruses are recovered much more frequently in the summer and early fall. Children develop antibodies in the summer, indicating infection by coxsackieviruses during this period. Such children have much higher incidence rates for acute, febrile minor illnesses during the summer than chil- dren who fail to develop coxsackievirus antibodies. Familial exposure is important in the acquisition of infec- tions with coxsackieviruses. After the virus is introduced into a household, all susceptible persons usually become infected, although all do not develop clinically apparent disease. The coxsackieviruses share many properties with other enteroviruses. Because of their epidemiologic similarities, various enteroviruses may occur together in nature even in the same human host or the same specimens of sewage. Control There are no vaccines or antiviral drugs currently available for prevention or treatment of diseases caused by coxsacki- eviruses; symptomatic treatment is given. OTHER ENTEROVIRUSES Echoviruses (enteric cytopathogenic human orphan viruses), based on historical terminology, were grouped together because they infect the human enteric tract and because they can be recovered from humans only by inoculation of certain tissue cultures. More than 30 serotypes are known but not all have been associated with human illness. More recent isolates are designated as numbered enteroviruses. Group D entero- viruses consist of five serotypes (68, 70, 94, 111, and 120). Riedel_CH36_p531-p546.indd 540 CHAPTER 36 1 year may lead to neurologic sequelae and mental impair- ment. Enteroviruses recovered from fecal samples of patients with acute flaccid paralysis in Australia between 1996 and 2004 included coxsackieviruses A24 and B5; echoviruses 9, 11, and 18; and enteroviruses 71 and 75. Enterovirus 71 was most common. Laboratory Diagnosis It is impossible in an individual case to diagnose an echovirus infection on clinical grounds. However, in the following epi- demic situations, echoviruses must be considered: (1) summer outbreaks of aseptic meningitis and (2) summer especially in young children, of a febrile illness The diagnosis depends on laboratory tests. Nucleic acid detection assays, such as PCR, are more rapid and sensitive than virus isolation for diagnosis. Although may not be identified by PCR, it is often not determine the specific serotype of infecting ciated with a disease. Virus isolation may be accomplished from stools, rectal swabs, and, in aseptic meningitis, nal fluid. Serologic tests are impractical (because different viral types) except when a virus has from a patient or during an outbreak of typical ness. Neutralizing and hemagglutination-inhibiting ies are type specific and may persist for years. If an agent is isolated in tissue culture, against different pools of antisera against enteroviru Determination of the type of virus present is nofluorescence or neutralization test. Infection more enteroviruses may occur simultaneously. Epidemiology The epidemiology of echoviruses is similar to that of other enteroviruses. They occur in all parts of the globe and are more apt to be found in younger than in older individuals. In the temperate zone, infections occur chiefly in the summer and autumn and are about five times more prevalent dren of lower-income families than in those living in more favorable circumstances. The most commonly recovered echoviruses worldwide in the period from 1967 to 1974 were types 4, 6, 9, 11, and 30. In the United States from 1970 to 2005, the most commonly detected echoviruses were types 6, 9, 11, 13, and 30 along with coxsackieviruses A9, B2, B4, and B5 and enterovirus 71, and the diseases most often seen in those patients were aseptic meningitis and encephalitis. However, as with all entero- viruses, dissemination of different serotypes may occur in waves and spread widely. There appears to be a core group of consistently culating enteroviruses that determines the bulk burden. Fifteen serotypes accounted for 83% of reports in the United States from 1970 to 2005. Children younger than 1 year of age accounted for 44% of reports of disease. Riedel_CH36_p531-p546.indd 541 542 SECTION IV Virology Excreta from humans Land runoff Sewage Oceans and estuaries Rivers and lakes Shellfish Recreation HUMANS FIGURE 36-4 Routes of potential enteric virus transmission Wallis C: Viruses in water. Bull World Health Org 1978;56:499 than 70% sequence identity within certain protein-coding regions. Human rhinoviruses can be divided into major and minor receptor groups. Viruses of the major group use inter- cellular adhesion molecule-1 (ICAM-1) as receptor, and those of the minor group bind members of the low-density lipopro- tein receptor (LDLR) family. Properties of the Virus A. General Properties Rhinoviruses share many properties with other enteroviruses but differ from HEV A–D in having a buoyant density in cesium chloride of 1.40 g/mL and in being acid labile. Virions are unstable below a pH of 5.0–6.0, and complete inactivation occurs at a pH of 3.0. Rhinoviruses are more thermostable than other enteroviruses and may survive for hours on envi- ronmental surfaces. Nucleotide sequence identity over the entire genome is more than 50% among all rhinoviruses and between entero- viruses and rhinoviruses. There is greater or less identity for particular genomic regions. In 2009, the genomes of all known strains of rhinovirus were sequenced, defining conserved and divergent regions. This information will facilitate new understanding of patho- genic potential and the design of antiviral drugs and vaccines. B. Animal Susceptibility and Growth of Virus These viruses are infectious only for humans, gibbons, and chimpanzees. They can be grown in a number of human cell lines, including the WI-38 and MRC-5 lines. Organ cultures of Riedel_CH36_p531-p546.indd 542 CHAPTER 36 Clinical Findings The incubation period is brief—from 2 to 4 days—and the acute illness usually lasts for 7 days, although a nonproductive cough may persist for 2–3 weeks. The average adult has one or two attacks each year. Usual symptoms in adults include sneezing, nasal obstruction, nasal discharge, and sore throat; other symp- toms may include headache, mild cough, malaise, and a chilly sensation. There is little or no fever. The nasal and nasopha- ryngeal mucosa become red and swollen. There are no distinc- tive clinical findings that permit an etiologic diagnosis of colds caused by rhinoviruses versus colds caused by Secondary bacterial infection may produce acute otitis media, sinusitis, bronchitis, or pneumonitis, especially Immunity Neutralizing antibody to the infecting virus develops in serum and secretions of most persons. Depending on the test used, estimates of the frequency of response have ranged from 37% to greater than 90%. Antibody develops 7–21 days after infection; the time of appearance of neutralizing antibody in nasal secretions parallels that of serum antibodies. Because recovery from ill- ness usually precedes appearance of antibody, it seems that recovery is not dependent on antibody. However, antibody may accomplish final clearance of infection. Serum antibody persists for years but decreases in titer. Epidemiology The disease occurs throughout the world. In the zones, the attack rates are highest in early Prevalence rates are lowest in summer. Members of isolated communities form highly susceptible groups. The virus is believed to be transmitted contact by means of virus-contaminated respiratory secre- tions. The fingers of a person with a cold are usually contam- inated, and transmission to susceptible persons then occurs by hand-to-hand, hand-to-eye, or hand-to-object-to-hand (eg, doorknob) contamination. Rhinoviruses can survive for hours on contaminated environmental surfaces. Self-inocu- lation after hand contamination may be a more important mode of spread than that by airborne particles. Infection rates are highest among infants and children and decrease with increasing age. The family unit is a major site of spread of rhinoviruses. Introduction of virus is gener- ally attributable to preschool-aged and school-aged children. Secondary attack rates in a family vary from 30% to 70%. Infections in young children are symptomatic, but infections in adults are often asymptomatic. In a single community, multiple rhinovirus serotypes cause outbreaks of disease in a single season, and different serotypes predominate during different respiratory disease seasons. There are usually a limited number of serotypes causing disease at any given time. Riedel_CH36_p531-p546.indd 543 544 SECTION IV Virology The typical disease can be reproduced by inoculating the virus into the pads of the foot. Formalin-treated vaccines have been prepared from virus grown in tissue cultures, but such vac- cines do not produce long-lasting immunity. New vaccines are being developed based on recombinant DNA techniques. The methods of control of the disease are dictated by its high degree of contagiousness and the resistance of the virus to inactivation. Should a focus of infection occur in the United States, all exposed animals are slaughtered and their carcasses destroyed. Strict quarantine is established, area is not presumed to be safe until susceptible animals fail to develop symptoms within 30 days. Another method is to quar- antine the herd and vaccinate all unaffected animals. Other countries have successfully used systematic vaccination sched- ules. Some nations (eg, the United States and Australia) forbid the importation of potentially infective materials such as fresh meat, and the disease has been eliminated in these areas. CHAPTER SUMMARY The Picornaviridae family is large with many members. Picornaviruses are small, nonenveloped, single-stranded RNA-containing viruses that replicate in the cytoplasm. About 100 serotypes of enteroviruses and an additional 150 serotypes of rhinoviruses are recognized. Major human pathogens included in this virus family are polioviruses, coxsackieviruses, rhinoviruses, and other enteroviruses. Diseases caused by these viruses include paralysis, asep- tic meningitis, pleurodynia, myocarditis, hepatitis, skin lesions, respiratory illnesses, diarrhea, fevers, common colds, conjunctivitis, and severe disease of infants. Rhinoviruses cause the common cold. Fecal contamination is the usual means of enterovirus spread; sources can involve water, food, hands, and utensils. Rhinoviruses are transmitted by virus-contaminated respiratory secretions, with hand contamination an impor- tant mode of spread. Subclinical infection with enteroviruses is far more com- mon than clinical disease. No animal reservoirs are known for the human enteroviruses. Both killed-virus and live-virus polio vaccines are available. A global effort is underway to eradicate poliovirus from the world. Foot-and-mouth disease, a serious and highly contagious disease of animals, is caused by an unrelated picornavirus classified in the Aphthovirus genus. REVIEW QUESTIONS 1. Which of the following statements about rhinoviruses is correct? (A) There are three antigenic types. (B) Amantadine protects against infection. (C) They do not survive on environmental surfaces. Riedel_CH36_p531-p546.indd 544 CHAPTER 36 7. A person with asthma has an acute exacerbation with increased lower respiratory illness. A virus is recovered. most l 36 C H A P T E R The three largest viral proteins—VP1, VP2, and VP3—have a very similar core structure in which the peptide backbone of the protein loops back on itself to form a barrel of eight strands held together by hydrogen bonds (the β barrel). The amino acid chain between the β barrel and the amino and carboxyl terminal portions of the protein contains a series of loops. These loops include the main antigenic sites that are found on the surface of the virion and are involved in the neutralization of viral infection. There is a prominent cleft or canyon around each pen- tameric vertex on the surface of the virus particle. The receptor-binding site used to attach the virion to a host cell is thought to be located near the floor of the canyon. This loca- tion would presumably protect the crucial cell attachment site from structural variation influenced by antibody selec- tion in hosts because the canyon is too narrow to permit deep penetration of antibody molecules (Figure 36-1). The genome RNA ranges in size from 7.2 kb (human rhinovirus) to 7.4 kb (poliovirus, hepatitis A virus) to 8.4 kb (aphthovirus). The organization of the genome is similar for all (Figure 36-2). The genome is polyadenylated at the 3′ end and has a small viral-coded protein (VPg) covalently bound to the 5′ end. The positive-sense genomic RNA is infectious. Whereas enteroviruses are stable at acid pH (3.0–5.0) for 1–3 hours, rhinoviruses are acid labile. Enteroviruses and some rhinoviruses are stabilized by magnesium chloride against thermal inactivation. Enteroviruses have a buoyant density in cesium chloride of about 1.34 g/mL; human rhino- viruses, about 1.4 g/mL. in Table 36-1. Classification The Picornaviridae family contains 12 genera, including Enterovirus (enteroviruses and rhinoviruses), Hepatovirus (hepatitis A virus), Kobuvirus (Aichi virus), Parechovirus (parechoviruses), Cardiovirus (cardioviruses), and Aphtho- virus (foot-and-mouth disease viruses). The first five groups contain important human pathogens. Rhinoviruses histori- cally were placed in a separate genus but are now considered to be members of the Enterovirus genus. Enteroviruses of human origin are subdivided into seven species (human enterovirus A–D and human rhinovirus A–C) based mainly on sequence analyses. The former taxonomy for 531 04/04/19 5:05 PM receptor in the plasma membrane. The receptors for polio- virus and human rhinovirus are members of the immuno- 60 subunits globulin gene superfamily, which includes antibodies and some cell surface adhesion molecules. In contrast, echovi- ruses recognize a member of the integrin adhesion super- family. Not all rhinoviruses or echoviruses use the same cellular receptor. The viruses that cause hand-foot-and- mouth disease (enterovirus 71 and coxsackievirus A16) can both use two receptors, SCARB2 and PSGL1. Recep- tor binding triggers a conformational change in the virion that results in release of the viral RNA into the cell cyto- sol. VPg is removed from the viral RNA as it associates with ribosomes. Translation occurs via a cap-independent mechanism, using the internal ribosome entry site (IRES) animals, to aseptic downstream from the 5′ end of the viral genome. This bypasses the need for intact cellular initiation factor com- plex (eIF4F), which is required by many capped cellular mRNAs. eIF4 is often cleaved by a viral protease, leading to shut-off of host protein synthesis and preferential trans- lation of viral RNAs. The infecting viral RNA is translated into a polyprot- ein that contains both coat proteins and essential replication proteins. This polyprotein is rapidly cleaved into fragments by proteinases encoded in the polyprotein (see Figure 36-2). Synthesis of new viral RNA cannot begin until the virus- coded replication proteins, including an RNA-dependent RNA polymerase, are produced. The infecting viral RNA strand is copied, and that complementary strand serves as template for the synthesis of new plus strands. Many plus strands are generated from each minus-strand template. Some new plus strands are recycled as templates to amplify the pool of progeny RNA; many plus strands get packaged into virions. Maturation involves several cleavage events. Coat precursor protein P1 (see Figure 36-2) is cleaved to form aggregates of VP0, VP3, and VP1. When an adequate con- centration is reached, these “protomers” assemble into pentamers that package plus-stranded VPg-RNA to form “provirions.” The provirions are not infectious until a final cleavage changes VP0 to VP4 and VP2. The mature virus particles are released when the host cell disinte- grates. The multiplication cycle for most picornaviruses takes 5–10 hours. ENTEROVIRUS GROUP POLIOVIRUSES Poliomyelitis is an acute infectious disease that in its serious form affects the central nervous system (CNS). The destruc- tion of motor neurons in the spinal cord results in flaccid paralysis. However, most poliovirus infections are subclinical. Poliovirus has served as a model enterovirus in many laboratory studies of the molecular biology of picornavirus replication. 04/04/19 5:05 PM CHAPTER 36 Picornaviruses (Enterovirus and Rhinovirus Groups) 533 Pentamer Shell Myristate (VP1) Canyon Pore (VP2) (VP4) RNA core (VP3) Protomer VPg Antibody Cellular COOH receptor Fab Fab NH2 Five-fold vertex IgG Canyon floor “Pore” MET HIS SER 224 220 223 ASN TYR 219 ASN MET 152 PRO CH3 105 221 174 N N O VAL O CH 3 176 O ALA 24 (VP3) TYR PHE VAL VAL 128 186 VP1 191 188 RNA Interior A: Exploded diagram showing internal location of the RNA genome surrounded by VP2, VP3, and VP4. Note the “canyon” depression surrounding the vertex of the pentamer. of the canyon. The major rhinovirus receptor (intercellular adhesion molecule-1 [ICAM-1]) has a G (IgG) antibody molecule. C: Location of a drug-binding site in VP1 of a rhinovirus. The attachment by deforming part of the canyon floor. (Reproduced with permission from their replication. In Fields BN, Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 3rd ed. purified poliovirus is inactivated by a chlorine concen- tration of 0.1 ppm, much higher concentrations of chlo- rine are required to disinfect sewage containing virus in fecal suspensions and in the presence of other organic matter. Polioviruses are not affected by ether or sodium deoxycholate. 04/04/19 5:05 PM Capsid Replication P1 P2 P3 UAG 3′ UTR L VP4 VP2 VP3 VP1 2A 2B 2C 3A VPg 3C 3D pA Translation Cleavage 2 ABC 3 ABCD VP1 2A 2BC 3AB 3CD VP3 2B 2C 3A VPg 3C 3D genome. The viral genomic RNA has genome-linked VPg protein at the 5′ a leader protein found in cardioviruses and aphthoviruses but not in enteroviruses, plus-sense single-stranded RNA genome is translated into a single polyprotein. The P1 and P3 (blue) domains encode noncapsid proteins used for protein processing and by virus-coded proteinases 2A and 3C. Protein 2A performs early cleavages of the proteinase 3C. (Reproduced with permission from Kerkvliet J, Edukulla R, Rodriguez M: pathogenesis. Adv Virol 2010;368068. Copyright © 2010 Jason Kerkvliet et al.) Human Enteroviruses A–D Human Rhinoviruses Human Coxsackie Aa Coxsackie B Echoa Enterob A–Cc Parechovirusesd 1–24 1–6 1–33 68–116 >150 1–19 Stable Stable Stable Stable Labile Stable 1.34 1.34 1.34 1.4 37 37 37 33 37 0 0 0 + 0 + + + + + + + 0 + + 0 0 A15, A18, or A23; echovirus types 8, 10, 22, 23, 28, or 34; or enterovirus type 72. number rather than being subclassified as coxsackieviruses or echoviruses. Enteroviruses 103, 108, 112, and 115 await of Viruses classification. as echovirus types 22 and 23. 04/04/19 5:05 PM CHAPTER 36 Picornaviruses (Enterovirus and Rhinovirus Groups) 535 AAA(+) VPg Uptake RNA Translation release NH2 Polyprotein COOH Proteolytic processing 2BC 2C 3D 3CD VP1 Encapsidation VP3 VP0 2A 2B 3A 3B 3C Capsids Nonstructural proteins AAA(+) (–) RNA AAA(+) synthesis AAA(+) AAA(+) VPg AAA(+) AAA(+) (+) RNA UUU(–) AAA(+) synthesis cycle. (Reproduced with permission from Zoll J, Heus HA, van Kuppeveld FJ, et al: enterovirus 3′-UTR. Virus Res 2009;139:209–216. Copyright Elsevier.) The virus may be found in the blood of patients with nonparalytic poliomyelitis. Antibodies to the virus appear early in the disease, usually before paralysis occurs. It is believed that the virus first multiplies in the tonsils, the lymph nodes of the neck, Peyer’s patches, and the small intestine. The CNS may then be invaded by way of the circulating blood. Poliovirus can spread along axons of peripheral nerves to the CNS, where it continues to progress along the fibers of the lower motor neurons to increasingly involve the spinal cord or the brain. Poliovirus invades certain types of nerve cells, and in the process of its intracellular multiplication, it may damage or completely destroy these cells. Poliovirus does not multiply in muscle in vivo. The changes that occur in peripheral nerves and voluntary mus- cles are secondary to the destruction of nerve cells. Some cells that lose their function may recover completely. Inflamma- tion occurs secondary to the attack on the nerve cells. In addition to pathologic changes in the nervous system, there may be myocarditis, lymphatic hyperplasia, and ulcer- ation of Peyer’s patches. Clinical Findings When an individual susceptible to infection is exposed to the virus, the response ranges from inapparent infection without symptoms to a mild febrile illness to severe and permanent paralysis. Most infections are subclinical; only about 1% of infections result in clinical illness. The incubation period is usually 7–14 days, but it may range from 3 to 35 days. there is A. Mild Disease This is the most common form of disease. The patient has only a minor illness, characterized by fever, malaise, drowsiness, 04/04/19 5:05 PM a low degree of heterotypic resistance induced by infection, especially between type 1 and type 2 polioviruses. Passive immunity is transferred from mother to off- spring. The maternal antibodies gradually disappear during the first 6 months of life. Passively administered antibody lasts only 3–5 weeks. Virus-neutralizing antibody forms soon after exposure to the virus, often before the onset of illness, and apparently persists for life. Its formation early in the disease reflects the fact that viral multiplication occurs in the body before the invasion of the nervous system. Because the virus in the brain and spinal cord is not influenced by high titers of antibodies in the blood, immunization is of value only if it precedes the onset of symptoms referable to the nervous system. The VP1 surface protein of poliovirus contains several virus-neutralizing epitopes, each of which may contain fewer than 10 amino acids. Each epitope is capable of inducing virus-neutralizing antibodies. Global Eradication A major campaign was launched by the World Health Orga- nization in 1988 to eradicate poliovirus from the world as was done for smallpox virus. There were an estimated 350,000 cases of polio worldwide in 1988. The Americas were certi- fied as free from wild poliovirus in 1994, the Western Pacific Region in 2000, and Europe in 2002. Progress is being made globally; fewer than 2000 cases of polio still occur each year, principally in Africa and the Indian subcontinent. No cases of wild poliovirus type 2 have been seen since 1999. In 2016, only three countries—Afghanistan, Nigeria, and Pakistan—remained polio endemic. India was certi- fied as polio-free in March 2014. However, outbreaks of wild poliovirus sometimes occur in previously polio-free coun- tries because of importation of the virus by travel and migra- tion. Surveillance of cases of acute flaccid paralysis, testing of sewage for polioviruses, and vaccination coverage of infants with oral polio vaccine is the strategy followed to identify and interrupt poliovirus transmission. human or Epidemiology Poliomyelitis has had three epidemiologic phases: endemic, epidemic, and the vaccine era. The first two reflect prevac- cine patterns. The generally accepted explanation is that improved systems of hygiene and sanitation in cooler cli- mates promoted the transition from endemic to epidemic paralytic disease in those societies. Before global eradication efforts began, poliomyelitis occurred worldwide—year-round in the tropics and during summer and fall in the temperate zones. Winter outbreaks were rare. The disease occurs in all age groups, but children are usually more susceptible than adults because of the acquired immunity of the adult population. In developing areas, where living conditions favor the wide dissemination of 04/04/19 5:05 PM Picornaviruses (Enterovirus and Rhinovirus Groups) 537 be an important problem in areas—particularly in tropical regions—where enterovirus infections are common. The vaccine viruses—particularly types 2 and 3—may mutate in the course of their multiplication in vaccinated children to a more virulent form. However, only extremely rare cases of paralytic poliomyelitis have occurred in recip- ients of oral polio vaccine or their close contacts (no more than one vaccine-associated case for every 2 million persons vaccinated). Trivalent oral polio vaccine was generally used in the United States. However, in 2000, the Advisory Committee on Immunization Practices recommended a switch to the use of only inactivated polio vaccine (four doses) for children in the United States. The change was made because of the reduced risk for wild virus-associated disease resulting from continuing progress in global eradication of poliovirus. This schedule will reduce the incidence of vaccine-associated dis- ease while maintaining individual and population immunity against polioviruses. The oral polio vaccine is being used in the global eradica- tion program. After global eradication is achieved, the use of oral polio vaccine will cease. Continuation of its use could lead to the reemergence of polio caused by mutation and increased transmissibility and neurovirulence of vaccine virus. Pregnancy is neither an indication for nor a contraindi- cation to required immunization. Live-virus vaccine should not be administered to immunodeficient or immunosup- pressed individuals or their household contacts. Only killed- virus vaccine is to be used in those cases. There are no antiviral drugs for treatment of poliovirus infection, and treatment is symptomatic. Immune globulin can provide protection for a few weeks against the paralytic disease but does not prevent subclinical infection. Immune globulin is effective only if given shortly before infection; it is of no value after clinical symptoms develop. The primary public health response to interrupt transmission of reim- ported cases is large-scale vaccination. so that it can be and for weeks at COXSACKIEVIRUSES Coxsackieviruses, a large subgroup of the enteroviruses, were divided into two groups, A and B, having different patho- genic potentials for mice. They are now classified into HEV groups A, B, and C. They produce a variety of illnesses in humans, including aseptic meningitis and respiratory and undifferentiated febrile illnesses. Herpangina (vesicular pharyngitis), hand-foot-and-mouth disease, and acute hem- orrhagic conjunctivitis are caused by certain coxsackievirus group A serotypes; pleurodynia (epidemic myalgia), myocar- ditis, pericarditis, and severe generalized disease of infants are caused by some group B coxsackieviruses. In addition to these, a number of group A and B serotypes can give rise to meningoencephalitis and paralysis. Generally, paralysis pro- duced by nonpolio enteroviruses is incomplete and revers- ible. Coxsackie B viruses are the most commonly identified 04/04/19 5:05 PM culture. Some group A strains grow in human amnion and human embryonic lung fibroblast cells. Type A14 produces poliomyelitis-like lesions in adult mice and in monkeys but only myositis in suckling mice. Type A7 strains produce paral- ysis and severe CNS lesions in monkeys. Group A viruses pro- duce widespread myositis in the skeletal muscles of newborn mice, resulting in flaccid paralysis without other observable lesions. The genetic makeup of inbred strains of mice deter- mines their susceptibility to coxsackie B viruses. Commonly Associated Clinical Syndromesa Human Enteroviruses A–D Coxsackievirus Coxsackievirus Echovirus Enterovirus Parechovirus A Types 1–24 B Types 1–6 Types 1–33 Types 68–116 Types 1–19 Many 1–6 Many 68, 71 1 7, 9 2–5 2, 4, 6, 9, 11, 30 68, 70, 71 3 2, 5–7, 9 1–5 2, 6, 9, 19 68, 70, 71 2–6, 8, 10 71 5, 10, 16 1 71 5 2, 4, 6, 9, 11, 16, 18 1–5 1, 6, 9 1–5 1, 6, 9, 19 1 70 21, 24 1, 3, 4, 5 4, 9, 11, 20, 25 68 1 4, 5 68 1 71 18, 20–22, 24b Manyb 1 5 4, 9 1–6 1–5 11 3, 4 types may be associated with a given disease. 04/04/19 5:05 PM Picornaviruses (Enterovirus and Rhinovirus Groups) 539 Infections may be fatal in neonates or may cause permanent heart damage at any age. Persistent viral infections of heart early stages of muscle may occur, sustaining chronic inflammation. in the throat Enteroviruses are estimated to cause from 15% to 20% the stools for up to of respiratory tract infections, especially in the summer and that of the other fall. A number of coxsackieviruses have been associated with common colds and with undifferentiated febrile illnesses. Generalized disease of infants is an extremely seri- ous disease in which the infant is overwhelmed by simul- taneous viral infections of multiple organs, including the heart, liver, and brain. The clinical course may be rapidly fatal, or the patient may recover completely. The disease is typically caused by group B coxsackieviruses. In severe cases, myocarditis or pericarditis can occur within the first 8 days of life; it may be preceded by a brief episode of diar- rhea and anorexia. The disease may sometimes be acquired transplacentally. Although the gastrointestinal tract is the primary site of replication for enteroviruses, they do not cause marked dis- ease there. Certain group A coxsackieviruses have been asso- ciated with diarrhea in children, but causality is unproved. suggestive of recover com- Laboratory Diagnosis A. Recovery of Virus Virus can be isolated from throat washings during the first few days of illness and from stools during the first few weeks. In coxsackievirus A21 infections, the largest amount of virus is found in nasal secretions. In cases of aseptic meningitis, strains have been recovered from the cerebrospinal fluid as well as from the alimentary tract. In hemorrhagic conjunc- tivitis cases, A24 virus is isolated from conjunctival swabs, throat swabs, and feces. Specimens can be inoculated into tissue cultures and suckling mice. In tissue culture, a cytopathic effect appears within 5–14 days. In suckling mice, signs of illness appear usually within 1–2 weeks. Because of the difficulty of the tech- nique, virus isolation in suckling mice is rarely attempted. be recov- but B. Nucleic Acid Detection with foot- Methods for the direct detection of enteroviruses provide rapid and sensitive assays useful for clinical samples. Reverse transcription PCR tests can be broadly reactive (detect many serotypes) or more specific. Such assays have advantages over cell culture methods because many enterovirus clinical iso- lates have poor growth characteristics. Real-time PCR assays are comparable in sensitivity to conventional PCR assays but are less labor intensive to perform. although C. Serology Neutralizing antibodies appear early during the course of infection, tend to be specific for the infecting virus, and persist for years. Serum antibodies can also be detected by other methods such as immunofluorescence. Serologic tests are difficult to evaluate (because of the multiplicity of virus 04/04/19 5:05 PM Aseptic meningitis, encephalitis, febrile illnesses with or without rash, common colds, and ocular disease are among the diseases caused by echoviruses and other enteroviruses. s Clinical Findings To establish etiologic association of an enterovirus with dis- ease, the following criteria are used: (1) There is a much higher rate of recovery of virus from patients with the disease than from healthy individuals of the same age and socioeconomic level living in the same area at the same time. (2) Antibodies against the virus develop during the course of the disease. If the clinical syndrome can be caused by other known agents, virologic or serologic evidence must be negative for concur- rent infection with such agents. (3) The virus is isolated from body fluids or tissues manifesting lesions (eg, from the cere- brospinal fluid in cases of aseptic meningitis). Many echoviruses have been associated with aseptic meningitis. Rashes are most common in young children. Infantile diarrhea may be associated with some types, but causality has not been established. For many echoviruses, no disease entities have been defined. A large outbreak of enterovirus 68 was recognized in 2014 in the United States, causing severe respiratory illness in >1000 individuals nationwide, mostly among children with previous asthma or wheezing. While most patients recovered, a small fraction of these cases were associated with acute flac- cid paralysis, making it a substantial public health concern. Enterovirus 68 shares several characteristics with rhinovi- ruses, including acid lability and lower optimum growth tem- perature, and had been previous classified as rhinovirus 87. Retrospective review demonstrated cases as early as 2012, and subsequent sequence analysis showed that the acute flac- cid myelitis-associated viruses grouped into a clade B1 strain that emerged in 2010. Enterovirus 70 is the chief cause of acute hemorrhagic conjunctivitis. It was isolated from the conjunctiva of patients with this striking eye disease, which occurred in pandemic form from 1969 to 1971 in Africa and Southeast Asia. Acute hemorrhagic conjunctivitis has a sudden onset of subconjunctival hemorrhage. The disease is most common in adults, with an incubation period of 1 day and a duration of 8–10 days. Complete recovery is the rule. The virus is highly communicable and spreads rapidly under crowded or unhy- gienic conditions. Enterovirus 71 has been isolated from patients with men- ingitis, encephalitis, and paralysis resembling poliomyelitis. It is one of the main causes of CNS disease, sometimes fatal, around the world. An outbreak of hand-foot-and-mouth disease caused by enterovirus 71 occurred in China in 2008 and involved about 4500 cases and 22 deaths in infants and young children. With the virtual elimination of poliomyelitis in devel- oped countries, the CNS syndromes associated with coxsacki- eviruses, echoviruses, and other enteroviruses have assumed greater prominence. The latter in children younger than age 04/04/19 5:05 PM Picornaviruses (Enterovirus and Rhinovirus Groups) 541 Studies of families into which enteroviruses were intro- duced demonstrated the ease with which these agents spread and the high frequency of infection in persons who had formed no antibodies from earlier exposures. This is true for all enteroviruses. Control Avoidance of contact with patients exhibiting acute febrile ill- ness is advisable for very young children. There are no anti- virals or vaccines (other than polio vaccines) available for the treatment or prevention of any enterovirus diseases. epidemics, with rash. ENTEROVIRUSES IN THE ENVIRONMENT the specific virus Humans are the only known reservoir for members of the necessary to human enterovirus group. These viruses are generally shed enterovirus asso- for longer periods of time in stools than in secretions from the upper alimentary tract. Thus, fecal contamination throat swabs, (hands, utensils, food, water) is the usual avenue of virus cerebrospi- spread. Enteroviruses are present in variable amounts in of the many sewage. This may serve as a source of contamination of water been isolated supplies used for drinking, bathing, irrigation, or recreation clinical ill- (Figure 36-4). Enteroviruses survive exposure to the sewage antibod- treatments and chlorination in common practice, and human wastes in much of the world are discharged into natural it can be tested waters with little or no treatment. Waterborne outbreaks ses. caused by enteroviruses are difficult to recognize, and it has by either immu- been shown that the viruses can travel long distances from with two or the source of contamination and remain infectious. Adsorp- tion to organics and sediment material protects viruses from inactivation and helps in transport. Filter-feeding shellfish (oysters, clams, mussels) have been found to concentrate viruses from water and, if inadequately cooked, may transmit disease. Bacteriologic standards using fecal coliform indices as a monitor of water quality probably are not an adequate reflection of a potential for transmission of viral disease. in chil- RHINOVIRUSES Rhinoviruses are the common cold viruses. They are the most commonly recovered agents from people with mild upper respiratory illnesses. They are usually isolated from nasopharyngeal secretions but may also be found in throat and oral secretions. These viruses—as well as coronaviruses, adenoviruses, enteroviruses, parainfluenza viruses, and influenza viruses—cause upper respiratory tract infections, including the common cold syndrome. Rhinoviruses are also responsible for about half of asthma exacerbations. cir- of disease Classification Human rhinovirus isolates are numbered sequentially. More than 150 types are known. Isolates within a type share more 04/04/19 5:05 PM Solid waste landfills Groundwater Irrigation Water supply Crops Aerosols in the environment. (Reproduced with permission from Melnick JL, Gerba CP, .) ferret and human tracheal epithelium may be necessary for some fastidious strains. Most grow better at 33°C, which is similar to the temperature of the nasopharynx in humans, than at 37°C. C. Antigenic Properties More than 150 serotypes are known. New serotypes are based on the absence of cross-reactivity in neutralization tests using polyclonal antisera. Human rhinovirus 87 is reclassified as human enterovirus 68. Pathogenesis and Pathology The virus enters via the upper respiratory tract. High titers of virus in nasal secretions—which can be found as early as 2–4 days after exposure—are associated with maximal ill- ness. Thereafter, viral titers fall, although illness persists. In some instances, virus may remain detectable for 3 weeks. There is a direct correlation between the amount of virus in secretions and the severity of illness. Replication is limited to the surface epithelium of the nasal mucosa. Biopsies have shown that histopathologic changes are limited to the submucosa and surface epithelium. These include edema and mild cellular infiltration. Nasal secretion increases in quantity and in protein concentration. Rhinoviruses rarely cause lower respiratory tract disease in healthy individuals, although they are associated with the majority of acute asthma exacerbations. Experiments under controlled conditions have shown that chilling, including the wearing of wet clothes, does not produce a cold or increase susceptibility to the virus. Chilliness is an early symptom of the common cold. 04/04/19 5:05 PM Picornaviruses (Enterovirus and Rhinovirus Groups) 543 Treatment and Control No specific prevention method or treatment is available. The development of a potent rhinovirus vaccine is unlikely because of the difficulty in growing rhinoviruses to high titer in culture, the fleeting immunity, and the multiplicity of serotypes causing colds. Antiviral drugs are thought to be a more likely control measure for rhinoviruses because of the problems with vac- cine development. Many compounds effective in vitro have failed to be effective clinically. other viruses. PARECHOVIRUS GROUP in children. This genus was defined in the 1990s and contains 19 types, of which types 1 and 2 were originally classified as echoviruses 22 and 23. Parechoviruses are highly divergent from entero- viruses, with no protein sequence having greater than 30% identity with the corresponding protein of other picornavi- ruses. The capsid contains three proteins because the VP0 precursor protein does not get cleaved. Parechovirus infections are often acquired in early child- hood. The viruses replicate in the respiratory and gastrointes- tinal tracts. They have been reported to cause diseases similar to other enteroviruses, such as mild gastrointestinal and respi- ratory illness, meningitis, and neonatal sepsis. Human parechovirus 1 was one of the 15 most common enterovirus detections from 2006 to 2008. However, human parechovirus cannot be detected by enterovirus-specific nucleic acid typing assays commonly used, so it may be underreported. Specific PCR methods are available to detect parechovirus in patient samples. temperate fall and late spring. FOOT-AND-MOUTH DISEASE (APHTHOVIRUS OF CATTLE) through close This highly infectious disease of cloven-hoofed animals such as cattle, sheep, pigs, and goats is rare in the United States but endemic in other countries. It may be transmitted to humans by contact or ingestion. In humans, the disease is charac- terized by fever, salivation, and vesiculation of the mucous membranes of the oropharynx and of the skin of the feet. The virus is a typical picornavirus and is acid labile (par- ticles are unstable below a pH of 6.8). It has a buoyant density in cesium chloride of 1.43 g/mL. There are at least seven types with more than 50 subtypes. The disease in animals is highly contagious in the early stages of infection when viremia is present and when vesi- cles in the mouth and on the feet rupture and liberate large amounts of virus. Excreted material remains infectious for long periods. The mortality rate in animals is usually low but may reach 70%. Infected animals become poor producers of milk and meat. Many cattle serve as foci of infection for up to 8 months. Immunity after infection is of short duration. A variety of animals are susceptible to infection, and the virus has been recovered from at least 70 species of mammals. 04/04/19 5:05 PM (D) They are the most frequent causative agent of the common cold. (E) They share physicochemical similarities with coronaviruses. 2. A 26-year-old man develops myopericarditis with mild conges- tive heart failure that increases over several weeks. Coxsackie- virus B5 infection is diagnosed. Which of the following clinical syndromes is not associated with coxsackievirus infections? (A) Herpangina (B) Myocarditis or pericarditis (C) Aseptic meningitis and the (D) Acute hemorrhagic conjunctivitis (E) Progressive postpolio muscle atrophy 3. A 3-month-old child develops fever, restlessness, and unusual crying. These are followed by apparent lethargy. Physi- cal examination shows a normal-appearing infant who is minimally responsive to stimuli. A lumbar puncture yields cerebrospinal fluid with 200 white blood cells per microliter, predominantly lymphocytes. Acute aseptic meningitis is diag- nosed, probably caused by an enterovirus. Enteroviruses are characterized by (A) Latency in sensory ganglia and reactivation primarily in immunocompromised patients (B) Transmission primarily by the fecal–oral route (C) The presence of a DNA polymerase enzyme (D) The entry of cells following binding to the intercellular adhesion molecule-1 (ICAM-1) receptor (E) Undergoing antigenic shift and drift 4. Picornavirus vaccines have been used for several decades in the prevention of human disease. Which of the following state- ments is correct? (A) The live, attenuated poliovirus vaccine produces gastroin- testinal tract resistance. (B) There is an effective killed vaccine against the three major types of rhinoviruses. (C) The live, attenuated poliovirus vaccine induces protective immunity against the closely related coxsackie B viruses. (D) None of the available echovirus vaccines should be given to immunocompromised patients. (E) Only the live attenuated poliovirus vaccine is currently recommended for use in the United States. 5. One month after school has been let out for the summer, a 16-year-old girl develops fever, myalgia, and headache. An outbreak of an illness with similar symptoms caused by an echovirus is known to be occurring in the community. The primary anatomic site of echovirus multiplication in the human host is (A) The muscular system (B) The central nervous system (C) The alimentary tract (D) The blood and lymph system (E) The respiratory system 6. Which of the following properties of enteroviruses is not shared by rhinoviruses? (A) Single-stranded RNA genome (B) Production by cleavage of viral proteins from a polyprotein precursor (C) Resistance to lipid solvents (D) Stability at acid pH (pH 3.0) (E) Icosahedral symmetry 04/04/19 5:05 PM Picornaviruses (Enterovirus and Rhinovirus Groups) 545 13. Which of the following statements about enteroviral meningitis The isolate is is true?

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