Jawetz Chapter 36 - Picornaviruses (Enterovirus and Rhinovirus Groups) PDF

36 C H A P T E R Picornaviruses (Entero...

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