Poliomyelitis is an acute infectious disease that in its serious form affects the central nervous system (CNS). The destruction 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.
Poliovirus particles are typical enteroviruses (see earlier). They are inactivated when heated at 55°C for 30 minutes, but Mg2+, 1 mol/L, prevents this inactivation. Whereas purified poliovirus is inactivated by a chlorine concentration of 0.1 ppm, much higher concentrations of chlorine 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.
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 infection is usually asymptomatic and the animals become intestinal 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 infectious 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.
There are three antigenic types of polioviruses based on epitopes 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, there is 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.
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 muscles are secondary to the destruction of nerve cells. Some cells that lose their function may recover completely. Inflammation 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 ulceration of Peyer’s patches.
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.
This is the most common form of disease. The patient has only a minor illness, characterized by fever, malaise, drowsiness, 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 percentage of cases, the disease advances to paralysis.
C. Paralytic Poliomyelitis
The predominating complaint is flaccid paralysis resulting from lower motor neuron damage. However, incoordination secondary to brain stem invasion and painful spasms of nonparalyzed muscles may also occur. The amount of damage 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 postpoliomyelitis 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.
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 recovered from the cerebrospinal fluid—unlike some coxsackieviruses and echoviruses.
Specimens should be submitted immediately to the laboratory, and frozen if testing is delayed. Cultures of human or monkey cells are inoculated, incubated, and observed. Cytopathogenic effects appear in 3–6 days. An isolated virus is identified and typed by neutralization with specific antiserum. 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 infection with poliovirus produces strictly type-specific responses. Subsequent infections with heterotypic polioviruses induce antibodies against a group antigen shared by all three types.
Immunity is permanent to the virus type causing the infection and is predominantly antibody mediated. There may be a low degree of heterotypic resistance induced by infection, especially between type 1 and type 2 polioviruses.
Passive immunity is transferred from mother to offspring. 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.
A major campaign was launched by the World Health Organization 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 certified 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 2014, only three countries—Afghanistan, Nigeria, and Pakistan—remained polio endemic. India was certified as polio-free in March 2014. However, outbreaks of wild poliovirus sometimes occur in previously polio-free countries because of importation of the virus by travel and migration. 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.
Poliomyelitis has had three epidemiologic phases: endemic, epidemic, and the vaccine era. The first two reflect prevaccine patterns. The generally accepted explanation is that improved systems of hygiene and sanitation in cooler climates 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 virus, poliomyelitis is a disease of infancy and early childhood (“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 highest 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 correlation between poor hygiene, sanitation, and crowding and the acquisition of infection and antibodies at an early age.
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 intestinal 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 vaccine 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 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 community. 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 antibodies and protect the CNS from subsequent invasion by wild virus. However, the gut develops a far greater degree of resistance after administration of live-virus vaccine.
A potential limiting factor for oral vaccine is interference. 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 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. However, only extremely rare cases of paralytic poliomyelitis have occurred in recipients 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 disease while maintaining individual and population immunity against polioviruses.
The oral polio vaccine is being used in the global eradication 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 contraindication to required immunization. Live-virus vaccine should not be administered to immunodeficient or immunosuppressed 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 reimported cases is large-scale vaccination.
Coxsackieviruses, a large subgroup of the enteroviruses, were divided into two groups, A and B, having different pathogenic 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 hemorrhagic conjunctivitis are caused by certain coxsackievirus group A serotypes; pleurodynia (epidemic myalgia), myocarditis, 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 produced by nonpolio enteroviruses is incomplete and reversible. Coxsackie B viruses are the most commonly identified 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 enteroviruses exhibit properties similar to the coxsackieviruses.
TABLE 36-3Human Enteroviruses and Parechoviruses and Commonly Associated Clinical Syndromesa ||Download (.pdf) TABLE 36-3 Human Enteroviruses and Parechoviruses and Commonly Associated Clinical Syndromesa
|Syndrome ||Human Enteroviruses A–D ||Parechovirus Types 1–14 |
|Poliovirus Types 1–3 ||Coxsackievirus A Types 1–24 ||Coxsackievirus B Types 1–6 ||Echovirus Types 1–33 ||Enterovirus Types 68–116 |
|Neurologic || || || || || || |
| Aseptic meningitis ||1–3 ||Many ||1–6 ||Many ||71 ||1 |
| Paralysis ||1–3 ||7, 9 ||2–5 ||2, 4, 6, 9, 11, 30 ||70, 71 ||3 |
| Encephalitis || ||2, 5–7, 9 ||1–5 ||2, 6, 9, 19 ||70, 71 || |
|Skin and mucosa |
| Herpangina || ||2–6, 8, 10 || || ||71 || |
| Hand-foot-and- mouth disease || ||5, 10, 16 ||1 || ||71 || |
| Exanthems || ||Many ||5 ||2, 4, 6, 9, 11, 16, 18 || || |
|Cardiac and muscular || || || || || || |
| Pleurodynia (epidemic myalgia) || || ||1–5 ||1, 6, 9 || || |
| Myocarditis, pericarditis || || ||1–5 ||1, 6, 9, 19 || ||1 |
|Ocular || || || || || || |
| Acute hemorrhagic conjunctivitis || ||24 || || ||70 || |
|Respiratory || || || || || || |
| Colds || ||21, 24 ||1, 3, 4, 5 ||4, 9, 11, 20, 25 || ||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 febrile illness ||1–3 || ||1–6 || || || |
| Generalized disease of infants || || ||1–5 ||11 || || |
| Diabetes mellitus || || ||3, 4 || || || |
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 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 paralysis and severe CNS lesions in monkeys. Group A viruses produce 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 determines their susceptibility to coxsackie B viruses.
Pathogenesis and Pathology
Virus has been recovered from the blood in the early stages of natural infection in humans. Virus is also found in the throat for a few days early in the infection and in the stools for up to 5–6 weeks. Virus distribution is similar to that of the other enteroviruses.
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 distinct 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 coxsackieviruses 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 suggestive of paralytic poliomyelitis. Patients almost always recover completely 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 be recovered not only from the stool and pharyngeal secretions but also from vesicular fluid. It is not to be confused with foot-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 usually 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, although relapses are common.
Myocarditis is a serious disease. It is an acute inflammation of the heart or its covering membranes (pericarditis). Coxsackievirus B infections are a cause of primary myocardial disease in adults as well as children. About 5% of all symptomatic coxsackievirus infections induce heart disease. Infections may be fatal in neonates or may cause permanent heart damage at any age. Persistent viral infections of heart muscle may occur, sustaining chronic inflammation.
Enteroviruses are estimated to cause from 15% to 20% of respiratory tract infections, especially in the summer and fall. A number of coxsackieviruses have been associated with common colds and with undifferentiated febrile illnesses.
Generalized disease of infants is an extremely serious disease in which the infant is overwhelmed by simultaneous 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 diarrhea 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 disease there. Certain group A coxsackieviruses have been associated with diarrhea in children, but causality is unproved.
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 conjunctivitis 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 technique, virus isolation in suckling mice is rarely attempted.
B. Nucleic Acid Detection
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 isolates have poor growth characteristics. Real-time PCR assays are comparable in sensitivity to conventional PCR assays but are less labor intensive to perform.
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 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 coxsackieviruses than do children, indicating that multiple experiences with these viruses are common and increasingly so with age.
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 various coxsackieviruses are found in serum collected from persons 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 enterovirus identified in the United States. However, in any given year or area, another type may predominate. Whereas an epidemic 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 children who fail to develop coxsackievirus antibodies.
Familial exposure is important in the acquisition of infections 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.
There are no vaccines or antiviral drugs currently available for prevention or treatment of diseases caused by coxsackieviruses; symptomatic treatment is given.
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. Aseptic meningitis, encephalitis, febrile illnesses with or without rash, common colds, and ocular disease are among the diseases caused by echoviruses and other enteroviruses.
To establish etiologic association of an enterovirus with disease, 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 concurrent infection with such agents. (3) The virus is isolated from body fluids or tissues manifesting lesions (eg, from the cerebrospinal 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.
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 unhygienic conditions.
Enterovirus 71 has been isolated from patients with meningitis, 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 developed countries, the CNS syndromes associated with coxsackieviruses, echoviruses, and other enteroviruses have assumed greater prominence. The latter in children younger than age 1 year may lead to neurologic sequelae and mental impairment. 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.
It is impossible in an individual case to diagnose an echovirus infection on clinical grounds. However, in the following epidemic situations, echoviruses must be considered: (1) summer 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 detection assays, such as PCR, are more rapid than virus isolation for diagnosis. Although the specific virus may not be identified by PCR, it is often not necessary to determine the specific serotype of infecting enterovirus associated with a disease.
Virus isolation may be accomplished from throat swabs, stools, rectal swabs, and, in aseptic meningitis, cerebrospinal fluid. Serologic tests are impractical (because of the many different viral types) except when a virus has been isolated from a patient or during an outbreak of typical clinical illness. Neutralizing and hemagglutination-inhibiting antibodies are type specific and may persist for years.
If an agent is isolated in tissue culture, it can be tested against different pools of antisera against enteroviruses. Determination of the type of virus present is by either immunofluorescence or neutralization test. Infection with two or more enteroviruses may occur simultaneously.
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 in children 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 enteroviruses, dissemination of different serotypes may occur in waves and spread widely.
There appears to be a core group of consistently circulating enteroviruses that determines the bulk of disease 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.
Studies of families into which enteroviruses were introduced 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.
Avoidance of contact with patients exhibiting acute febrile illness is advisable for very young children. There are no antivirals or vaccines (other than polio vaccines) available for the treatment or prevention of any enterovirus diseases.
ENTEROVIRUSES IN THE ENVIRONMENT
Humans are the only known reservoir for members of the human enterovirus group. These viruses are generally shed for longer periods of time in stools than in secretions from the upper alimentary tract. Thus, fecal contamination (hands, utensils, food, water) is the usual avenue of virus spread. Enteroviruses are present in variable amounts in sewage. This may serve as a source of contamination of water supplies used for drinking, bathing, irrigation, or recreation (Figure 36-4). Enteroviruses survive exposure to the sewage treatments and chlorination in common practice, and human wastes in much of the world are discharged into natural waters with little or no treatment. Waterborne outbreaks caused by enteroviruses are difficult to recognize, and it has been shown that the viruses can travel long distances from the source of contamination and remain infectious. Adsorption 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.
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.)
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.
Human rhinovirus isolates are numbered sequentially. More than 150 types are known. Isolates within a type share more 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 intercellular adhesion molecule-1 (ICAM-1) as receptor, and those of the minor group bind members of the low-density lipoprotein receptor (LDLR) family.
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 environmental surfaces.
Nucleotide sequence identity over the entire genome is more than 50% among all rhinoviruses and between enteroviruses 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 pathogenic 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 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.
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 now considered the same serotype 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 illness. 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.
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 symptoms may include headache, mild cough, malaise, and a chilly sensation. There is little or no fever. The nasal and nasopharyngeal mucosa become red and swollen. There are no distinctive clinical findings that permit an etiologic diagnosis of colds caused by rhinoviruses versus colds caused by other viruses. Secondary bacterial infection may produce acute otitis media, sinusitis, bronchitis, or pneumonitis, especially in children.
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 illness 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.
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 communities form highly susceptible groups.
The virus is believed to be transmitted through close contact by means of virus-contaminated respiratory secretions. The fingers of a person with a cold are usually contaminated, 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-inoculation 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 generally 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.
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 vaccine development. Many compounds effective in vitro have failed to be effective clinically.
This genus was defined in the 1990s and contains 16 types, of which types 1 and 2 were originally classified as echoviruses 22 and 23. Parechoviruses are highly divergent from enteroviruses, with no protein sequence having greater than 30% identity with the corresponding protein of other picornaviruses. The capsid contains three proteins because the VP0 precursor protein does not get cleaved.
Parechovirus infections are often acquired in early childhood. The viruses replicate in the respiratory and gastrointestinal tracts. They have been reported to cause diseases similar to other enteroviruses, such as mild gastrointestinal and respiratory 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.
FOOT-AND-MOUTH DISEASE (APHTHOVIRUS OF CATTLE)
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 characterized 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 (particles 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 7 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 vesicles 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. 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 vaccines 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, and the area is not presumed to be safe until susceptible animals fail to develop symptoms within 30 days. Another method is to quarantine the herd and vaccinate all unaffected animals. Other countries have successfully used systematic vaccination schedules. 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.