Chapter 40: Paramyxoviruses and Rubella Virus

The paramyxoviruses include the most important agents of respiratory infections of infants and young children ­(respiratory syncytial virus [RSV] and the parainfluenza viruses) as well as the causative agents of two of the most ­common contagious diseases of childhood (mumps and ­measles). The World Health Organization estimates that acute respiratory infections and pneumonia are responsible every year worldwide for the deaths of 4 million children younger than 5 years. Paramyxoviruses are the major ­respiratory pathogens in this age group.

All members of the Paramyxoviridae family initiate infection via the respiratory tract. Whereas replication of the respiratory pathogens is limited to the respiratory epithelia, measles and mumps become disseminated throughout the body and produce generalized disease.

Rubella virus, although classified as a togavirus because of its chemical and physical properties (see Chapter 29), can be considered with the paramyxoviruses on an epidemiologic basis.

Major properties of paramyxoviruses are listed in Table 40-1.

Structure and Composition

The morphology of Paramyxoviridae is pleomorphic, with particles 150 nm or more in diameter, occasionally ranging up to 700 nm. A typical particle is shown in Figure 40-1. The envelope of paramyxoviruses seems to be fragile, making virus particles labile to storage conditions and prone to ­distortion in electron micrographs.

The viral genome is linear, negative-sense, single-stranded, nonsegmented RNA, about 15 kb in size (Figure 40-2). Because the genome is not segmented, this negates any opportunity for frequent genetic reassortment, resulting in antigenic stability.

Most paramyxoviruses contain six structural proteins. Three proteins are complexed with the viral RNA—the nucleocapsid (N) protein that forms the helical nucleocapsid (13 or 18 nm in diameter) and represents the major internal protein and two other large proteins (designated P and L), which are involved in the viral polymerase activity that functions in transcription and RNA replication.

Three proteins participate in the formation of the viral envelope. Matrix (M) protein underlies the viral envelope; it has an affinity for both the N and the viral surface glycoproteins and is important in virion assembly. The nucleocapsid is surrounded by a lipid envelope that is studded with 8- to 12-nm spikes of two different transmembrane glycoproteins. The activities of these surface glycoproteins help ­differentiate the various genera of the Paramyxoviridae family (Table 40-2). The larger glycoprotein (HN or G) may or may not possess hemagglutination and neuraminidase activities and is responsible for attachment to the host cell. It is assembled as a tetramer in the mature virion. The other glycoprotein (F) mediates membrane fusion and hemolysin activities. The pneumoviruses and metapneumoviruses contain two additional small envelope proteins (M2-1 and SH).

A diagram of a paramyxovirus particle is shown in Figure 40-3.

Classification

The Paramyxoviridae family is divided into two subfamilies and seven genera, six of which contain human pathogens (see Table 40-2). Most of the members are monotypic (ie, they consist of a single serotype); all are antigenically stable.

The genus Respirovirus contains two serotypes of human parainfluenza viruses, and the genus Rubulavirus contains two other parainfluenza viruses as well as mumps virus. Some animal viruses are related to the human strains. Sendai virus of mice, which was the first parainfluenza virus isolated and is now recognized as a common infection in mouse colonies, is a subtype of human type 1 virus. Simian parainfluenza virus 5 (PIV5), a common contaminant of primary monkey cells, is the same as canine parainfluenza virus type 2; shipping fever virus of cattle and sheep is a subtype of type 3. Newcastle disease virus, the prototype avian parainfluenza virus of genus Avulavirus, is also related to the human viruses.

Members within a genus share common antigenic determinants. Although the viruses can be distinguished antigenically using well-defined reagents, hyperimmunization stimulates cross-reactive antibodies that react with all four parainfluenza viruses, mumps virus, and Newcastle disease virus. Such heterotypic antibody responses, which include antibodies directed against both internal and surface proteins of the virus, are commonly observed in older people. This phenomenon makes it difficult to determine by serodiagnosis the most likely infecting type. All members of the genera Respirovirus and Rubulavirus possess hemagglutinating and neuraminidase activities, both carried by the HN glycoprotein, as well as membrane fusion and hemolysin properties, both functions of the F protein.

The Morbillivirus genus contains measles virus (rubeola) of humans as well as canine distemper virus, rinderpest virus of cattle, and aquatic morbilliviruses that infect marine mammals. These viruses are antigenically related to each other but not to members of the other genera. Whereas the F protein is highly conserved among the morbilliviruses, the HN/G proteins display more variability. Measles virus has a hemagglutinin but lacks neuraminidase activity. Measles virus induces formation of intranuclear inclusions, but other paramyxoviruses do not.

The Henipavirus genus contains zoonotic paramyxoviruses that are able to infect and cause disease in humans. Hendra and Nipah viruses, both indigenous to fruit bats, are members of the genus. These viruses lack neuraminidase activity.

Respiratory syncytial viruses of humans and cattle and pneumonia virus of mice constitute the genus Pneumovirus. There are two antigenically distinct strains of RSV of humans, subgroups A and B. The larger surface ­glycoprotein of pneumoviruses lacks hemagglutinating and neuraminidase activities characteristic of ­respiroviruses and rubulaviruses, so it is designated the G protein. The F protein of RSV exhibits membrane fusion activity but no hemolysin activity. Human metapneumoviruses are respiratory pathogens of humans classified in the genus Metapneumovirus.

Paramyxovirus Replication

The typical paramyxovirus replication cycle is illustrated in Figure 40-4.

A. Virus Attachment, Penetration, and Uncoating

Paramyxoviruses attach to host cells via the hemagglutinin glycoprotein (HN, H, or G protein). In the case of measles virus, the receptor is the membrane CD46 or the CD150 ­molecule. Next, the virion envelope fuses with the cell membrane by the action of the fusion glycoprotein F₁ cleavage product. The F₁ protein undergoes complex refolding during the process of viral and cellular membrane fusion. If the F₀ precursor is not cleaved, it has no fusion activity; virion penetration does not occur; and the virus particle is unable to initiate infection. Fusion by F₁ occurs at the neutral pH of the extracellular environment, allowing release of the viral nucleocapsid directly into the cell. Thus, paramyxoviruses are able to bypass internalization through endosomes.

B. Transcription, Translation, and RNA Replication

Paramyxoviruses contain a nonsegmented, negative-strand RNA genome. Messenger RNA transcripts are made in the cell cytoplasm by the viral RNA polymerase. There is no need for exogenous primers and therefore no dependence on cell nuclear functions. The mRNAs are much smaller than genomic size; each represents a single gene. Transcriptional regulatory sequences at gene boundaries signal transcriptional start and termination. The position of a gene relative to the 3′ end of the genome correlates with transcription efficiency. Whereas the most abundant class of transcripts produced by an infected cell is from the N gene, located nearest the 3′ end of the genome, the least abundant is from the L gene, located at the 5′ end (see Figure 40-2).

Viral proteins are synthesized in the cytoplasm, and the quantity of each gene product corresponds to the level of mRNA transcripts from that gene. Viral glycoproteins are synthesized and glycosylated in the secretory pathway.

The viral polymerase protein complex (P and L proteins) is also responsible for viral genome replication. For successful synthesis of a positive-strand antigenome intermediate template, the polymerase complex must disregard the termination signals interspersed at gene boundaries. Full-length progeny genomes are then copied from the antigenome template.

The nonsegmented genome of paramyxoviruses negates the possibility of gene segment reshuffling (ie, genetic reassortment) so important to the natural history of influenza viruses. The HN/H/G and F surface proteins of paramyxoviruses exhibit minimal antigenic variation over long periods of time. It is surprising that they do not undergo antigenic drift as a result of mutations introduced during replication, because RNA polymerases tend to be error-prone. One possible explanation is that nearly all the amino acids in the primary structures of paramyxovirus glycoproteins may be involved in structural or functional roles, leaving little opportunity for substitutions that would not markedly diminish the viability of the virus.

C. Maturation

The virus matures by budding from the cell surface. Progeny nucleocapsids form in the cytoplasm and migrate to the cell surface. They are attracted to sites on the plasma membrane that are studded with viral HN/H/G and F₀ ­glycoprotein spikes. The M protein is essential for particle formation, ­serving to link the viral envelope to the nucleocapsid. ­During budding, most host proteins are excluded from the membrane.

The neuraminidase activity of the HN protein of parainfluenza viruses and mumps virus presumably functions to prevent self-aggregation of virus particles. Other paramyxoviruses do not possess neuraminidase activity (see Table 40-2).

If appropriate host cell proteases are present, F₀ ­proteins in the plasma membrane will be activated by cleavage. Activated fusion protein will then cause fusion of adjacent cell membranes, resulting in formation of large syncytia (Figure 40-5). Syncytium formation is a common response to paramyxovirus infection. Acidophilic cytoplasmic inclusions are regularly formed (see Figure 40-5). Inclusions are believed to reflect sites of viral synthesis and have been found to contain recognizable nucleocapsids and viral proteins. Measles virus also produces intranuclear inclusions (see Figure 40-5).

Parainfluenza viruses are ubiquitous and cause common respiratory illnesses in persons of all ages. They are major pathogens of severe respiratory tract disease in infants and young children. Reinfections with parainfluenza viruses are common.

Pathogenesis and Pathology

Parainfluenza virus replication in the immunocompetent host appears to be limited to respiratory epithelia. Viremia, if it occurs at all, is uncommon. The infection may involve only the nose and throat, resulting in a “common cold” ­syndrome. However, infection may be more extensive and, especially with types 1 and 2, may involve the larynx and upper ­trachea, resulting in croup (laryngotracheobronchitis). Croup is ­characterized by respiratory obstruction caused by ­swelling of the larynx and related structures. The infection may spread deeper to the lower trachea and bronchi, ­culminating in pneumonia or bronchiolitis, especially with type 3, but at a much lower frequency than that observed with RSV.

The duration of parainfluenza virus shedding is about 1 week after onset of illness; some children may excrete virus several days prior to symptoms. Type 3 may be excreted for up to 4 weeks after onset of primary illness. This persistent shedding from young children facilitates spread of ­infection. Prolonged viral shedding may occur in children with ­compromised immune function and in adults with chronic lung disease.

Factors that determine the severity of parainfluenza virus disease are unclear but include both viral and host properties, such as susceptibility of the protein to cleavage by different proteases, production of an appropriate protease by host cells, immune status of the patient, and airway hyperreactivity.

The production of virus-specific IgE antibodies during primary infections has been associated with disease severity. The mechanism may involve release of mediators of inflammation that alter airway function.

Clinical Findings

The relative importance of parainfluenza viruses as a cause of respiratory diseases in different age groups is indicated in Table 30-5. Their presence in lower respiratory tract infections in young children shows seasonal variation seen in Figure 40-6.

Primary infections in young children usually result in rhinitis and pharyngitis, often with fever and some bronchitis. However, children with primary infections caused by parainfluenza virus type 1, 2, or 3 may have serious illness, ranging from laryngotracheitis and croup (particularly with types 1 and 2) to bronchiolitis and pneumonia (particularly with type 3). The severe illness associated with type 3 occurs mainly in infants younger than the age of 6 months; croup or laryngotracheobronchitis is more likely to occur in older children between ages 6 months and 18 months. More than half of initial infections with parainfluenza virus type 1, 2, or 3 result in febrile illness. It is estimated that only 2–3% develop into croup. Parainfluenza virus type 4 does not usually cause serious disease, even on first infection.

The most common complication of parainfluenza virus infection is otitis media.

Immunocompromised children and adults are susceptible to severe infections. Mortality rates after parainfluenza infection in bone marrow transplant recipients range from 10% to 20%.

Newcastle disease virus is an avian paramyxovirus that produces pneumoencephalitis in young chickens and respiratory disease in older birds. In humans, it may produce inflammation of the conjunctiva. Recovery is complete in 10–14 days. Infection in humans is an occupational disease limited to workers handling infected birds.

Immunity

Parainfluenza virus types 1, 2, and 3 are distinct serotypes that lack significant cross-neutralization (see Table 40-2). Virtually all infants have maternal antibodies to the viruses in serum, yet these antibodies do not prevent infection or disease. Reinfection of older children and adults also occurs in the presence of antibodies elicited by an earlier infection. However, those antibodies modify the course of disease; such reinfections usually present simply as nonfebrile upper respiratory infections (colds).

Natural infection stimulates appearance of immunoglobulin A (IgA) antibody in nasal secretions and concomitant resistance to reinfection. The secretory IgA antibodies are most important for providing protection against reinfection but disappear within a few months. Reinfections are thus common even in adults.

Serum antibodies are made to both HN and F viral ­surface proteins, but their relative roles in determining ­resistance are unknown. As successive reinfections occur, the antibody response becomes less specific because of shared antigenic determinants among parainfluenza viruses and mumps virus. This makes it difficult to diagnose the specific paramyxovirus associated with a given infection using serologic assays.

Laboratory Diagnosis

Nucleic acid amplification tests are the preferred diagnostic methods because of their sensitivity and specificity, their ability to detect a broad range of viruses, and the rapidity of results.

Antigen detection methods are also useful for rapid diagnosis. The immune response to the initial parainfluenza virus infection in life is type specific. However, with repeated infections, the response becomes less specific, and cross-reactions extend even to mumps virus. Definitive diagnosis relies on viral isolation from appropriate specimens.

A. Nucleic Acid Detection

Reverse transcription polymerase chain reaction (RT-PCR) assays can be used to detect viral RNA in nasopharyngeal swabs, washes or aspirates, or lower respiratory tract specimens such as bronchoalveolar lavage fluid. Sequence analyses are useful in molecular epidemiology studies of parainfluenza virus infections.

B. Antigen Detection

Detection of viral antigens can be done in exfoliated nasopharyngeal cells by direct or indirect immunofluorescence tests. These methods are fairly rapid and simple to perform but are limited by low sensitivity and the range of viruses detected.

C. Isolation and Identification of Virus

Rapid cell culture methods can detect a number of respiratory viruses able to be cultured in vitro but are slower to provide results than nucleic acid or antigen detection methods and are not able to easily detect mixed infections. A continuous monkey kidney cell line, LLC-MK2, is suitable for isolation of parainfluenza viruses. Prompt inoculation of samples into cell cultures is important for successful viral isolation because viral infectivity drops rapidly. For rapid diagnosis, samples are inoculated onto cells growing on coverslips in shell vials and are incubated. One to 3 days later, the cells are fixed and tested by immunofluorescence. Another way to detect the presence of virus is to perform hemadsorption using guinea pig erythrocytes. Depending on the amount of virus, 10 days or more of incubation may be necessary before the cultures become hemadsorption positive. Virus culture is necessary if a viral isolate is desired for research purposes.

D. Serology

Serodiagnosis should be based on paired sera. Antibody responses can be measured using neutralization, hemagglutination-inhibition (HI), or enzyme-linked immunosorbent assay (ELISA) tests. A fourfold rise in titer is indicative of infection with a parainfluenza virus, as is the appearance of specific IgM antibody. However, because of the problem of shared antigens, it is impossible to be confident of the specific virus type involved.

Epidemiology

Parainfluenza viruses are a major cause of lower respiratory tract disease in young children (see Figure 40-6). Parainfluenza viruses are widely distributed geographically. Type 3 is most prevalent, with about two-thirds of infants infected during the first year of life; virtually all have antibodies to type 3 by age 2 years. Infections with types 1 and 2 occur at a lower rate, reaching prevalences of about 75% and 60%, respectively, by 5 years of age.

Type 3 is endemic, with some increase during the spring; types 1 and 2 tend to cause epidemics during the fall or winter, frequently on a 2-year cycle.

Reinfections are common throughout childhood and in adults and result in mild upper respiratory tract illnesses. Reportedly, 67% of children are reinfected with parainfluenza type 3 during the second year of life. Reinfections may necessitate hospitalization of adults with chronic lung diseases (eg, asthma).

Parainfluenza viruses are transmitted by direct person-to-person contact or by large-droplet aerosols. Type 1 has been recovered from air samples collected in the vicinity of infected patients. Infections can occur through both the nose and the eyes.

Parainfluenza viruses are usually introduced into a group by preschool children and then spread readily from person to person. The incubation period appears to be from 5 to 6 days. Type 3 virus especially will generally infect all susceptible ­individuals in a semiclosed population, such as a family or a nursery, within a short time. Parainfluenza viruses are ­troublesome causes of nosocomial infection in pediatric wards in hospitals. Other high-risk situations include day care centers and schools.

Treatment and Prevention

Contact isolation precautions are necessary to manage nosocomial outbreaks of parainfluenza virus. These include restriction of visitors, isolation of infected patients, and gowning and handwashing by medical personnel.

The antiviral drug ribavirin has been used with some benefit in treatment of immunocompromised patients with lower respiratory tract disease.

No vaccine is available.

RSV is the most important cause of lower respiratory tract illness in infants and young children, usually outranking all other microbial pathogens as the cause of bronchiolitis and pneumonia in infants younger than 1 year. It is estimated to account for approximately 25% of pediatric hospitalizations caused by respiratory disease in the United States.

Pathogenesis and Pathology

RSV replication occurs initially in epithelial cells of the nasopharynx. Virus may spread into the lower respiratory tract and cause bronchiolitis and pneumonia. Viral antigens can be detected in the upper respiratory tract and in shed ­epithelial cells. Viremia occurs rarely if at all.

The incubation period between exposure and onset of illness is 3–5 days. Viral shedding may persist for 1–3 weeks from infants and young children, but adults shed virus for only 1–2 days. High viral titers are present in respiratory tract secretions from young children. Inoculum size is an important determinant of successful infection in adults (and ­possibly in children as well).

An intact immune system seems to be important in resolving an infection because patients with impaired cell-mediated immunity may become persistently infected with RSV and shed virus for months.

Although the airways of very young infants are narrow and more readily obstructed by inflammation and edema, only a subset of young babies develops severe RSV disease. It has been reported that susceptibility to bronchiolitis is genetically linked to polymorphisms in innate immunity genes.

Clinical Findings

The spectrum of respiratory illness caused by RSV ranges from inapparent infection or the common cold through pneumonia in infants to bronchiolitis in very young babies. Bronchiolitis is the distinct clinical syndrome associated with this virus. About one-third of primary RSV infections involve the lower respiratory tract severely enough to require medical attention. Almost 2% infected babies require ­hospitalization, resulting in an estimated 75,000–125,000 hospitalizations annually in the United States, with the peak occurrence at 2–3 months of age. It has been reported that higher viral loads in respiratory secretions is a predictor of longer hospitalizations.

Progression of symptoms may be very rapid, culminating in death. With the availability of modern pediatric intensive care, the mortality rate in normal infants is low (~1% of hospitalized patients). But if an RSV infection is superimposed on preexisting disease, such as congenital heart disease, the mortality rate may be high.

Reinfection is common in both children and adults. Although reinfections tend to be symptomatic, the illness is usually limited to the upper respiratory tract, resembling a cold, in healthy individuals.

RSV infections account for about one-third of respiratory infections in bone marrow transplant patients. Pneumonia develops in about half of infected immunocompromised children and adults, especially if infection occurs in the early posttransplant period. Reported mortality rates range from 20% to 80%.

Infections in elderly adults may cause symptoms ­similar to influenza virus disease. Pneumonia may develop. ­Estimates of RSV prevalence in long-term care facilities include ­infection rates of 5–10%, pneumonia in 10–20% of those infected, and mortality rates of 2–5%.

Children who have had RSV bronchiolitis and ­pneumonia as infants often exhibit recurrent episodes of wheezing illness for many years. However, no causal relationship has been shown between RSV infections and long-term abnormalities. It may be that certain individuals have underlying physiologic traits that predispose them both to severe RSV infections and to reactive airway disease.

RSV is an important cause of otitis media. It is estimated that 30–50% of wintertime episodes in infants may be caused by RSV infection.

Immunity

High levels of neutralizing antibody that is maternally transmitted and present during the first several months of life are believed to be critical in protective immunity against lower respiratory tract illness. Severe respiratory syncytial disease begins to occur in infants at 2–4 months of age when maternal antibody levels are falling. However, primary infection and reinfection can occur in the presence of viral antibodies. Serum neutralizing antibody appears to be strongly correlated with immunity against disease of the lower respiratory tract but not of the upper respiratory tract.

RSV is not an effective inducer of interferon—in contrast to influenza and parainfluenza virus infections, in which interferon levels are high and correlate with disappearance of virus.

Both serum and secretory antibodies are made in response to RSV infection. Primary infection with one subgroup induces cross-reactive antibodies to virus of the other subgroup (see Table 40-2). Younger infants have lower IgG and IgA secretory antibody responses to RSV than do older infants. Cellular immunity is important in recovery from infection.

An association has been noted between virus-specific IgE antibody and severity of disease. Viral secretory IgE antibodies have been correlated with occurrence of bronchiolitis.

It is apparent that immunity is only partially effective and is often overcome under natural conditions; reinfections are common, but the severity of ensuing disease is lessened.

Laboratory Diagnosis

Methods described for diagnosis of parainfluenza viruses are applicable to RSV. Detection of RSV is strong evidence that the virus is involved in a current illness because it is rarely found in healthy people. Detection of viral RNA or viral antigen in respiratory secretions is the test of choice.

Large amounts of virus are present in nasopharyngeal swabs and washes from young children (10³–10⁸ plaque-forming units/mL), but much less is present in specimens from adults (<100 plaque-forming units/mL). Nucleic acid testing is the preferred method and is especially useful for adult specimens in which only small amounts of virus are often present. Such assays also are useful for subtyping RSV isolates and for the analysis of genetic variation in outbreaks. Antigen detection is much less sensitive than nucleic acid detection.

RSV can be isolated from nasal secretions. The virus is extremely labile and samples should be inoculated into cell cultures immediately; freezing of clinical specimens may result in complete loss of infectivity. Human heteroploid cell lines HeLa and HEp-2 are the most sensitive for viral isolation. The presence of RSV can usually be recognized by development of giant cells and syncytia in inoculated cultures (see Figure 40-5). It may take as long as 10 days for cytopathic effects to appear. More rapid isolation of RSV can be achieved by inoculation of shell vials containing tissue cultures growing on coverslips. Cells can be tested 24–48 hours later by immunofluorescence or RT-PCR. RSV differs from other paramyxoviruses in that it does not have a hemagglutinin; therefore, diagnostic methods cannot use hemagglutination or hemadsorption assays.

Serum antibodies can be assayed in a variety of ways. Although measurements of serum antibody are important for epidemiologic studies, they typically are not used in clinical decision making.

Epidemiology

RSV is distributed worldwide and is recognized as the major pediatric respiratory tract pathogen (see Figure 40-6). About 70% of infants are infected by age 1 and almost all by age 2 years. Serious bronchiolitis or pneumonia is most apt to occur in infants between the ages of 6 weeks and 6 months, with peak incidence at 2 months. The virus can be isolated from most infants younger than age 6 months with bronchiolitis, but it is almost never isolated from healthy infants. Subgroup A infections appear to cause more severe illness than subgroup B infections. RSV is the most common cause of viral pneumonia in children younger than age 5 years but may also cause pneumonia in elderly adults or in immunocompromised persons. RSV infection of older infants and children typically results in milder respiratory tract infection than in those younger than age 6 months.

RSV is spread by large droplets and direct contact. Although the virus is very labile, it can survive on environmental surfaces for up to 6 hours. The main portal of entry into the host is through the nose and eyes.

Reinfection occurs frequently (despite the presence of specific antibodies) but resulting symptoms are those of a mild upper respiratory infection (a cold). In families with an identified case of RSV infection, virus spread to siblings and adults is common.

RSV spreads extensively in children every year during the winter season. Although the virus persists throughout the summer months, outbreaks tend to peak in January or February in the Northern Hemisphere. In tropical areas, RSV epidemics may coincide with rainy seasons.

RSV causes nosocomial infections in nurseries and on pediatric hospital wards. Transmission occurs primarily via hospital staff members.

RSV can also cause symptomatic disease in healthy young adults in crowded conditions (eg, military recruits in basic training). In a study in 2000, RSV was identified in 11% of recruits with respiratory symptoms. This compared with identification of adenoviruses (48%), influenza viruses (11%), and parainfluenza virus 3 (3%) in the symptomatic recruits.

Treatment and Prevention

Treatment of serious RSV infections depends primarily on supportive care (eg, removal of secretions, administration of oxygen). The antiviral drug ribavirin is approved for treatment of lower respiratory tract disease caused by RSV, especially in infants at high risk for severe disease. The drug is administered in an aerosol for 3–6 days. Oral ribavirin is not useful.

Immune globulin with high-titer antibodies against RSV is of marginal benefit. Humanized antiviral monoclonal antibodies are available.

Much research effort has been expended in an attempt to develop an RSV vaccine. In the late 1960s, an experimental formalin-inactivated RSV vaccine was tested. Recipients developed high titers of nonneutralizing serum antibodies, but when immunized children encountered a subsequent infection with wild-type RSV, they had significantly more severe lower respiratory tract illness than did children from the control group. It has been suggested that the formalin treatment destroyed protective epitopes on the virus or that because of lack of stimulation of Toll-like receptors, the vaccine induced only low-avidity antibodies that were not protective. No vaccine is available today.

RSV poses special problems for vaccine development. The target group, newborns, would have to be immunized soon after birth to afford protection at the time of greatest risk of serious RSV infection, and eliciting a protective immune response at this early age is difficult in the presence of maternal antibody. A strategy being tested is maternal immunization with a vaccine. The aim is to ensure transfer of protective levels of virus-specific neutralizing antibody to infants that would persist for 3–5 months, the period of greatest vulnerability of newborns to severe RSV disease.

Control measures necessary when nosocomial outbreaks occur are the same as described above for parainfluenza viruses (contact isolation, handwashing, and restriction of visitors).

Human metapneumovirus is a respiratory pathogen first described in 2001. It was detected using a molecular approach on clinical samples from children with respiratory illnesses but with negative test results for known respiratory viruses. Human metapneumovirus is able to cause a wide range of respiratory illnesses from mild upper respiratory symptoms to severe lower respiratory tract disease in all age groups. In general, symptoms are similar to those caused by RSV.

Pathogenesis and Pathology

Human metapneumovirus infects only humans and is related to avian metapneumovirus that causes rhinotracheitis in chickens. It consists of two subgroups and at least four genetic lineages. These viral lineages are distributed worldwide; ­multiple lineages can be circulating at the same time in the same location. It appears that the predominant strain in circulation may vary by geographic location and from year to year.

The incubation period for metapneumovirus is estimated to be from 4 to 9 days. The duration of shedding is about 5 days in children and several weeks in immunocompromised hosts.

Replication is limited to respiratory epithelial cells in infected hosts. The cell surface receptor for human ­metapneumovirus appears to be αvβ1-integrin. Cytopathic effects induced by human metapneumovirus in cultured cells, such as LLC-MK2 monkey kidney cells, are similar to those of RSV.

Clinical Findings

Human metapneumoviruses are associated with a variety of symptoms of the respiratory tract. These symptoms cannot be distinguished from those induced by RSV. Children usually display rhinorrhea, cough, and fever and may develop acute otitis media. Lower respiratory tract illnesses may occur, including bronchiolitis, pneumonia, croup, and exacerbation of asthma. Bronchiolitis in children seems to be less frequently associated with metapneumovirus than with RSV.

Populations at risk besides children include elderly adults and immunocompromised individuals. Many children hospitalized because of metapneumovirus have underlying chronic conditions. Severe infections may occur in immunocompromised individuals, such as children or adults with cancer or bone marrow transplants, and in institutionalized elderly persons.

Healthy adults tend to develop cold and flu-like symptoms in response to metapneumovirus infection. Asymptomatic infections are more common than for influenza virus or RSV in this population.

Immunity

The prevalence of antibodies to human metapneumovirus increases in children from the age of 6 months and reaches nearly 100% by 5–10 years of age. Despite high rates of antibody in adults, reinfections are common. It has been suggested there may be limited cross-protective immunity among different strains of metapneumovirus and that antibody-mediated protection may not be adequate to prevent disease.

Laboratory Diagnosis

The best specimens for detection of human metapneumovirus are nasopharyngeal aspirates or swabs. RT-PCR assays are the methods of choice. Detection of viral antigens in respiratory specimens by direct immunofluorescence staining is sensitive for children due to higher viral loads but poorer for adults. Detection of antibodies in patient sera is useful primarily for research studies.

Epidemiology

Human metapneumoviruses are ubiquitous and distributed worldwide. Infections occur in all age groups, but especially in pediatric patients. It appears that infections with human metapneumovirus in young children are less common than with RSV but more common than with the parainfluenza viruses (see Figure 40-6). The majority of infections occur in late winter to early spring in the United States. The median age of metapneumovirus-positive hospitalized children is 6–12 months, older than seen with RSV (2–3 months).

Different strains of human metapneumovirus are in circulation simultaneously, with predominant strains varying by location and over time.

Treatment and Prevention

There is no specific therapy for human metapneumovirus infections, and no vaccine is available.

Mumps is an acute contagious disease characterized by nonsuppurative enlargement of one or both salivary glands. Mumps virus mostly causes a mild childhood disease, but in adults complications including meningitis and orchitis are fairly common. More than one-third of all mumps infections are asymptomatic.

Pathogenesis and Pathology

Humans are the only natural hosts for mumps virus. Primary replication occurs in nasal or upper respiratory tract epithelial cells. Viremia then disseminates the virus to the salivary glands and other major organ systems. Involvement of the parotid gland is not an obligatory step in the infectious process.

The incubation period may range from 2 to 4 weeks but is typically about 14–18 days. Virus is shed in the saliva from about 3 days before to 9 days after the onset of salivary gland swelling. About one-third of infected individuals do not exhibit obvious symptoms (inapparent infections) but are equally capable of transmitting infection. It is difficult to control transmission of mumps because of the variable incubation periods, the presence of virus in saliva before clinical symptoms develop, and the large number of asymptomatic but infectious cases.

Mumps is a systemic viral disease with a propensity to replicate in epithelial cells in various visceral organs. Virus frequently infects the kidneys and can be detected in the urine of most patients. Viruria may persist for up to 14 days after the onset of clinical symptoms. The central nervous system is also commonly infected and may be involved in the absence of parotitis.

Clinical Findings

The clinical features of mumps reflect the pathogenesis of the infection. At least one-third of all mumps infections are subclinical, including the majority of infections in children younger than 2 years. The most characteristic feature of symptomatic cases is swelling of the salivary glands, which occurs in about 50% of patients.

A prodromal period of malaise and anorexia is ­followed by rapid enlargement of parotid glands as well as other ­salivary glands. Swelling may be confined to one parotid gland, or one gland may enlarge several days before the other. Gland enlargement is associated with pain.

Central nervous system involvement is common (10–30% of cases). Mumps causes aseptic meningitis and is more common among males than females. Meningoencephalitis usually occurs 5–7 days after inflammation of the salivary glands, but up to half of patients will not have clinical evidence of parotitis. Meningitis is reported in up to 15% of cases and encephalitis in fewer than 0.3%. Cases of mumps meningitis and meningoencephalitis usually resolve without sequelae, although unilateral deafness occurs in about five in 100,000 cases. The mortality rate from mumps encephalitis is about 1%.

The testes and ovaries may be affected, especially after puberty. Around 20–50% of men who are infected with mumps virus develop orchitis (often unilateral). Because of the lack of elasticity of the tunica albuginea, which does not allow the inflamed testis to swell, the complication is extremely painful. Atrophy of the testis may occur as a result of pressure necrosis but only rarely does sterility result. Mumps oophoritis occurs in about 5% of women. Pancreatitis is reported in about 4% of cases.

Immunity

Immunity is permanent after a single infection. There is only one antigenic type of mumps virus, and it does not exhibit significant antigenic variation (see Table 40-2).

Antibodies to the HN glycoprotein, the F glycoprotein, and the nucleocapsid protein (NP) develop in serum after natural infection. Antibodies to the NP protein appear earliest (3–7 days after the onset of clinical symptoms) but are transient and are usually gone within 6 months. Antibodies to HN antigen develop more slowly (~4 weeks after onset) but persist for years.

Antibodies against the HN antigen correlate well with immunity. Even subclinical infections are thought to generate lifelong immunity. A cell-mediated immune response also develops. Interferon is induced early in mumps infection. In immune individuals, IgA antibodies secreted in the nasopharynx exhibit neutralizing activity.

Passive immunity is transferred from mother to offspring; thus, it is rare to see mumps in infants younger than 6 months.

Laboratory Diagnosis

The diagnosis of typical cases usually can be made on the basis of clinical findings. However, other infectious agents, drugs, and conditions can cause similar symptoms. In cases without parotitis, the laboratory can be helpful in establishing the diagnosis. Tests include detection of viral nucleic acid by RT-PCR, isolation of infectious virus, and serology.

A. Nucleic Acid Detection

RT-PCR is a very sensitive method that can detect mumps genome sequences in clinical samples. It can detect the virus in many clinical samples that have negative results in virus isolation attempts. RT-PCR assays can identify virus strains and provide useful information in epidemiologic studies.

B. Isolation and Identification of Virus

The most appropriate clinical samples for viral isolation are saliva, cerebrospinal fluid, and urine collected within a few days after onset of illness. Virus can be recovered from the urine for up to 2 weeks. Monkey kidney cells are preferred for viral isolation. Samples should be inoculated shortly after collection because mumps virus is thermolabile. For rapid diagnosis, immunofluorescence using mumps-specific antiserum can detect mumps virus antigens as early as 2–3 days after the inoculation of cell cultures in shell vials.

In traditional culture systems, cytopathic effects typical of mumps virus consist of cell rounding and giant cell formation. Because not all primary isolates show characteristic syncytial formation, the hemadsorption test may be used to demonstrate the presence of a hemadsorbing agent 1 and 2 weeks after inoculation.

C. Serology

Simple detection of mumps antibody is not adequate to diagnose an infection. Rather, an antibody rise can be demonstrated using paired sera: a fourfold or greater rise in antibody titer is evidence of mumps infection. The ELISA or HI test is commonly used. Antibodies against the HN protein are neutralizing.

ELISA can be designed to detect either mumps-specific IgM antibody or mumps-specific IgG antibody. Mumps IgM is uniformly present early in the illness and seldom persists longer than 60 days. Therefore, demonstration of mumps-specific IgM in serum drawn early in illness strongly suggests recent infection. Heterotypic antibodies induced by parainfluenza virus infections do not cross-react in the mumps IgM ELISA.

Epidemiology

Mumps occurs endemically worldwide. Cases appear throughout the year in hot climates and peak in the winter and spring in temperate climates. Mumps is primarily an infection of children, with the highest incidence in children ages 5–9 years. Outbreaks occur where crowding favors dissemination of the virus. In children younger than 5 years, mumps may commonly cause upper respiratory tract infection without parotitis.

Mumps is quite contagious; most susceptible individuals in a household will acquire infection from an infected member. The virus is transmitted by direct contact, airborne droplets, or fomites contaminated with saliva or urine. Closer contact is necessary for transmission of mumps than for transmission of measles or varicella.

About one-third of infections with mumps virus are inapparent. During the course of inapparent infection, the patient can transmit the virus to others. Individuals with subclinical mumps acquire immunity.

The overall mortality rate for mumps is low (one death per 10,000 cases in the United States), mostly caused by encephalitis.

The incidence of mumps and associated complications has declined markedly since introduction of the live-virus vaccine. In 1967, the year mumps vaccine was licensed, there were about 200,000 mumps cases (and 900 patients with encephalitis) in the United States. From 2001 to 2003, there were fewer than 300 mumps cases each year.

In 2006, there was an outbreak of mumps in the United States that resulted in more than 5700 cases. Six states in the Midwest reported 84% of the cases. The outbreak started on a college campus among young adults and spread to all age groups. In 2009, a mumps outbreak occurred in the states of New York and New Jersey in which 88% of those affected had been vaccinated. The SH gene of mumps virus is variable and has allowed classification of known virus strains into 12 genotypes. The viruses that caused the 2006 and 2009 outbreaks in the United States were both identified as belonging in genotype G. A massive mumps epidemic occurred in 2004 in the United Kingdom that caused more than 56,000 cases. It also involved closely related genotype G viruses.

Treatment, Prevention, and Control

There is no specific therapy.

Immunization with attenuated live mumps virus vaccine is the best approach to reducing mumps-associated morbidity and mortality rates. Attempts to minimize viral spread during an outbreak by using isolation procedures are not effective because of the high incidence of asymptomatic cases and the degree of viral shedding before clinical symptoms appear; however, students and health care workers who acquire mumps illness should be excluded from school and work until 5 days after the onset of parotitis.

An effective attenuated live-virus vaccine made in chick embryo cell culture was licensed in the United States in 1967. It produces a subclinical, noncommunicable infection. Mumps vaccine is available in combination with measles and rubella (MMR) live-virus vaccines. Combination live-virus vaccines produce antibodies to each of the viruses in about 78–95% of vaccines. There is no increased risk of aseptic meningitis after MMR vaccination. Other live attenuated mumps virus ­vaccines have been developed in Japan, Russia, and Switzerland.

Two doses of MMR vaccine are recommended for school entry. Because of the 2006 outbreak of mumps, updated ­vaccination recommendations for prevention of mumps transmission in settings with high risk for spread of infection were released. Two doses of vaccine should be given to health care workers born before 1957 without evidence of mumps immunity, and a second dose of vaccine should be considered for those who had received only a single dose.

MEASLES (RUBEOLA) VIRUS INFECTIONS

Measles is an acute, highly infectious disease characterized by fever, respiratory symptoms, and a maculopapular rash. Complications are common and may be quite serious. The introduction of an effective live-virus vaccine has dramatically reduced the incidence of this disease in the United States, but measles is still a leading cause of death of young children in many developing countries.

Pathogenesis and Pathology

Humans are the only natural hosts for measles virus, although numerous other species, including monkeys, dogs, and mice, can be experimentally infected. The natural history of measles infection is shown in Figure 40-7.

The virus gains access to the human body via the respiratory tract, where it multiplies locally; the infection then spreads to the regional lymphoid tissue, where further multiplication occurs. Primary viremia disseminates the virus, which then replicates in the reticuloendothelial system. Finally, a secondary viremia seeds the epithelial surfaces of the body, including the skin, respiratory tract, and conjunctiva, where focal replication occurs. Measles can replicate in certain lymphocytes, which aids in dissemination throughout the body. Multinucleated giant cells with intranuclear inclusions are seen in lymphoid tissues throughout the body (lymph nodes, tonsils, appendix). The described events occur during the incubation period, which typically lasts 8–15 days but may last up to 3 weeks in adults.

Patients are contagious during the prodromal phase (2–4 days) and the first 2–5 days of rash, when virus is ­present in tears, nasal and throat secretions, urine, and blood. The characteristic maculopapular rash appears about day 14 just as circulating antibodies become detectable, the viremia ­disappears, and the fever falls. The rash develops as a result of interaction of immune T cells with virus-infected cells in the small blood vessels and lasts about 1 week. (In patients with defective cell-mediated immunity, no rash develops.)

Involvement of the central nervous system is common in measles (Figure 40-8). Symptomatic encephalitis develops in about one in 1000 cases. Because infectious virus is rarely recovered from the brain, it has been suggested that an autoimmune reaction is the mechanism responsible for this complication. In contrast, progressive measles inclusion body encephalitis may develop in patients with defective cell-mediated immunity. Actively replicating virus is present in the brain in this usually fatal form of disease.

A rare late complication of measles is subacute sclerosing panencephalitis (SSPE). This fatal disease develops years after the initial measles infection and is caused by virus that remains in the body after acute measles infection. Large amounts of measles antigens are present within inclusion bodies in infected brain cells, but only a few virus particles mature. Viral replication is defective owing to lack of production of one or more viral gene products, often the matrix protein.

Clinical Findings

Infections in nonimmune hosts are almost always symptomatic. Measles has an incubation period of 8–15 days from exposure to the onset of rash.

The prodromal phase is characterized by fever, sneezing, coughing, running nose, redness of the eyes, Koplik spots, and lymphopenia. The cough and coryza reflect an intense inflammatory reaction involving the mucosa of the respiratory tract. The conjunctivitis is commonly associated with photophobia. Koplik spots—pathognomonic for measles—are small, bluish white ulcerations on the buccal mucosa opposite the lower molars. These spots contain giant cells and viral antigens and appear slightly before the rash. The fever and cough persist until the rash appears and then subside within 1–2 days. The rash, which starts on the head and then spreads progressively to the chest, the trunk, and down the limbs, appears as light pink, discrete maculopapules that coalesce to form blotches, becoming brownish in 5–10 days. The fading rash resolves with desquamation. Symptoms are most marked when the rash is at its peak but subside rapidly thereafter.

Modified measles occurs in partially immune persons, such as infants with residual maternal antibody. The incubation period is prolonged, prodromal symptoms are diminished, Koplik spots are usually absent, and the rash is mild.

The most common complication of measles is otitis media (5–9% of cases).

Pneumonia caused by secondary bacterial infection is the most common life-threatening complication of measles. This occurs in fewer than 10% of cases in developed countries but is much more frequent (20–80%) in developing countries. Pulmonary complications account for more than 90% of measles-related deaths. Viral pneumonia develops in 3–15% of adults with measles, but fatalities in this instance are rare.

Giant cell pneumonia is a serious complication in children and adults with deficiencies in cell-mediated immunity. It is believed to be caused by unrestrained viral replication and has a high fatality rate.

Complications involving the central nervous system are the most serious. About 50% of children with regular measles register electroencephalographic changes. Acute encephalitis occurs in about one in 1000 cases. There is no apparent correlation between the severity of the measles and the appearance of neurologic complications. Postinfectious encephalomyelitis (acute disseminated encephalomyelitis) is an autoimmune disease associated with an immune response to myelin basic protein. The mortality rate in encephalitis associated with measles is about 10–20%. The majority of survivors have neurologic sequelae.

SSPE, the rare late complication of measles infection, occurs with an incidence of about one in 10,000 to one in 100,000 cases. The disease begins insidiously 5–15 years after a case of measles; it is characterized by progressive mental deterioration, involuntary movements, muscular rigidity, and coma. It is usually fatal within 1–3 years after onset. Patients with SSPE exhibit high titers of measles antibody in cerebrospinal fluid and serum and defective measles virus in brain cells. With the widespread use of measles vaccine, SSPE has become less common.

Immunity

There is only one antigenic type of measles virus (see Table 40-2). Infection confers lifelong immunity. Most ­so-called second attacks represent errors in diagnosis of either the initial or the second illness.

The presence of humoral antibodies indicates ­immunity. Protective immunity is attributed to neutralizing ­antibodies against the H protein. However, cellular immunity appears to be essential for clearing the virus and for long-lasting ­protection. Patients with immunoglobulin deficiencies recover from measles and resist reinfection, but patients with cellular immune deficiencies do very poorly when they acquire ­measles infections. The role of mucosal immunity in resistance to infections is unclear.

Measles immune responses are involved in disease pathogenesis. Local inflammation causes the prodromal symptoms, and specific cell-mediated immunity plays a role in development of the rash.

Measles infection causes immune suppression—most importantly in the cell-mediated arm of the immune system—but is observed to affect all components. This is related to the serious secondary infections and may persist for months after measles infection.

Laboratory Diagnosis

Typical measles is reliably diagnosed on clinical grounds; laboratory diagnosis may be necessary in cases of modified or atypical measles.

A. Antigen and Nucleic Acid Detection

Measles antigens can be detected directly in epithelial cells from respiratory secretions, the nasopharynx, conjunctiva, and urine. Antibodies to the nucleoprotein are useful because that is the most abundant viral protein in infected cells.

Detection of viral RNA by RT-PCR is a sensitive method that can be applied to a variety of clinical samples for measles diagnosis.

B. Isolation and Identification of Virus

Nasopharyngeal and conjunctival swabs, blood samples, respiratory secretions, and urine collected from a patient during the febrile period are appropriate sources for viral isolation. Monkey or human kidney cells or a lymphoblastoid cell line (B95-a) are optimal for isolation attempts. Measles virus grows slowly; typical cytopathic effects (multinucleated giant cells containing both intranuclear and intracytoplasmic inclusion bodies) take 7–10 days to develop (see Figure 40-5). Shell vial culture tests can be completed in 2–3 days using fluorescent antibody staining to detect measles antigens in the inoculated cultures. However, virus isolation is technically difficult.

C. Serology

Serologic confirmation of measles infection depends on a fourfold rise in antibody titer between acute-phase and ­convalescent-phase sera or on demonstration of measles-specific IgM antibody in a single serum specimen drawn between 1 and 2 weeks after the onset of rash. ELISA, HI, and neutralization tests all may be used to measure measles antibodies, although ELISA is the most practical method.

Dried blood spots and oral fluids appear to be useful alternatives to serum for detection of measles antibody in areas where serum samples are difficult to collect and handle.

The major part of the immune response is directed against the viral nucleoprotein. Patients with SSPE display an exaggerated antibody response, with titers 10- to 100-fold higher than those seen in typical convalescent sera.

Epidemiology

The key epidemiologic features of measles are as follows: The virus is highly contagious, there is a single serotype, there is no animal reservoir, inapparent infections are rare, and ­infection confers lifelong immunity. Prevalence and age ­incidence of measles are related to population density, ­economic and environmental factors, and the use of an ­effective live-virus vaccine.

Transmission occurs predominantly via the respiratory route (by inhalation of large droplets of infected secretions). Fomites do not appear to play a significant role in transmission. Hematogenous transplacental transmission can occur when measles occurs during pregnancy.

A continuous supply of susceptible individuals is required for the virus to persist in a community. A population size approaching 500,000 is necessary to sustain measles as an endemic disease; in smaller communities, the virus disappears until it is reintroduced from the outside after a critical number of nonimmune persons accumulates.

Measles is endemic throughout the world. In general, ­epidemics recur regularly every 2–3 years. A population’s state of immunity is the determining factor; the disease will flare up when there is an accumulation of susceptible ­children. The severity of an epidemic is a function of the number of susceptible individuals. When the disease is introduced into isolated communities where it has not been endemic, an ­epidemic builds rapidly and attack rates are almost 100%. All age groups develop clinical measles, and the mortality rate may be as high as 25%.

In industrialized countries, measles occurs in 5- to 10-year-old children; in developing countries, it commonly infects children younger than 5 years. Measles rarely causes death in healthy people in developed countries. However, in malnourished children in developing countries where adequate medical care is unavailable, measles is a leading cause of infant mortality. Those with immunologic disorders, such as advanced human immunodeficiency virus infections, are at risk of severe or fatal measles. The World Health Organization estimated in 2005 that there were 30–40 million measles cases and 530,000 deaths annually worldwide. Measles is a major global cause of mortality among children younger than 5 years, and measles deaths occur disproportionately in Africa and Southeast Asia.

The World Health Organization and the United Nations International Children’s Emergency Fund established a plan in 2005 to reduce measles mortality through immunization activities and better clinical care of cases. Between 2000 and 2008, the numbers of measles cases and of measles deaths were estimated to be reduced by more than 75%.

Measles cases occur throughout the year in temperate climates. Epidemics tend to occur in late winter and early spring.

There were 540 measles cases in the United States from 1997 to 2001, 67% of which were linked to imports (persons infected outside the United States). Over an 8-year period (1996–2004), 117 passengers with imported measles cases were considered infectious while traveling by aircraft. Despite the highly infectious nature of the virus, only four secondary-spread cases were identified.

Measles was declared eliminated from the United States in 2000. However, imported cases have caused multiple outbreaks, particularly in communities declining measles vaccination. Typically measles causes about 50–100 cases annually, but over 600 cases were reported in 2014, with 23 outbreaks. To sustain elimination of measles transmission, vaccine coverage rates need to exceed 90%. Since the first dose of vaccine is given at 12–15 months, infants less than 1 year are at particular risk for severe complications in communities with low measles vaccine coverage.

Treatment, Prevention, and Control

Vitamin A treatment in developing countries has decreased mortality and morbidity. Measles virus is susceptible in vitro to inhibition by ribavirin, but clinical benefits have not been proved.

A highly effective and safe attenuated live measles virus vaccine has been available since 1963. Measles vaccine is available in monovalent form and in combination with live attenuated rubella vaccine (MR), live attenuated rubella and mumps vaccines (MMR), and live attenuated varicella vaccine (MMRV). Measles vaccines are derived from the Edmonston strain of measles virus and protect against all wild measles viruses. However, because of failure to vaccinate children and because of infrequent cases of vaccine failure, measles has not been eliminated from the world, but it has been eliminated from the United States.

Mild clinical reactions (fever or mild rash) occur in 2–5% of vaccines, but there is little or no virus excretion and no transmission. Immunosuppression occurs as with measles, but it is transient and clinically insignificant. Antibody titers tend to be lower than after natural infection, but studies have shown that vaccine-induced antibodies persist for up to 33 years, indicating that immunity is probably lifelong.

It is recommended that all children, health care workers, and international travelers be vaccinated. Contraindications to vaccination include pregnancy, allergy to eggs or neomycin, immune compromise (except that caused by infection with human immunodeficiency virus), and recent administration of immunoglobulin.

The use of killed measles virus vaccine was discontinued by 1970; certain vaccines became sensitized and developed severe atypical measles when infected with wild virus.

Quarantine is not effective as a control measure because transmission of measles occurs during the prodromal phase.

Rinderpest

Rinderpest, the world’s most devastating disease of cattle, was caused by rinderpest virus, a relative of measles virus. In 2010, rinderpest was declared to be eradicated from the earth after a successful global effort launched in 1994. This represented the first animal disease (and the second disease in human history after smallpox) to be eradicated worldwide. It was accomplished by widespread vaccination programs and long-term monitoring of cattle and wildlife.

Two zoonotic paramyxoviruses that represent a new genus (Henipavirus) were recognized in the late 1990s in disease outbreaks in Australasia (see Table 40-2). An outbreak of severe encephalitis in Malaysia in 1998 and 1999 was caused by Nipah virus. There was a high mortality rate (>35%) among more than 250 cases; a few survivors had persistent neurologic deficits. It appeared that the infections were caused by direct viral transmission from pigs to humans. Some patients (<10%) may develop late onset encephalitis months to several years after the initial Nipah virus infection.

Hendra virus—an equine virus—has caused many horse fatalities and a few human fatalities in Australia. An equine outbreak in 2008 resulted in two human cases of Hendra virus encephalitis, one of which was fatal. The attack rate among veterinary clinic staff exposed to infected horses was 10%.

Fruit bats (flying foxes) are the natural host for both Nipah and Hendra viruses. Ecologic changes, including land use and animal husbandry practices, are probably the reason for the emergence of these two infectious diseases.

Both viruses are of public health concern because of their high mortality rate, wide host range, and ability to jump ­species barriers. They are classified as Biosafety Level 4 pathogens. No vaccines or proven therapies are available.

Rubella (German measles; 3-day measles) is an acute febrile illness characterized by a rash and lymphadenopathy that affects children and young adults. It is the mildest of common viral exanthems. However, infection during early pregnancy may result in serious abnormalities of the fetus, including congenital malformations and mental retardation. The consequences of rubella in utero are referred to as the congenital rubella syndrome.

Classification

Rubella virus, a member of the Togaviridae family, is the sole member of the genus Rubivirus. Although its morphologic features and physicochemical properties place it in the togavirus group, rubella is not transmitted by arthropods. Togavirus structure and replication are described in Chapter 38.

There is significant sequence diversity among rubella virus isolates. They are currently classified into two distantly related groups (clades) and nine genotypes.

For clarity in presentation, postnatal rubella and ­congenital rubella infections are described separately.

POSTNATAL RUBELLA

Pathogenesis and Pathology

Neonatal, childhood, and adult infections occur through the mucosa of the upper respiratory tract. Rubella has an ­incubation period of about 12 days or longer. Initial viral ­replication probably occurs in the respiratory tract ­followed by multiplication in the cervical lymph nodes. Viremia ­develops after 7–9 days and lasts until the appearance of antibody on about day 13–15. The development of antibody coincides with the appearance of the rash, suggesting an immunologic basis for the rash. After the rash appears, the virus remains ­detectable only in the nasopharynx, where it may persist for several weeks (Figure 40-9). In 20–50% of cases, the primary ­infection is subclinical.

Clinical Findings

Rubella usually begins with malaise, low-grade fever, and a morbilliform rash appearing on the same day. The rash starts on the face, extends over the trunk and extremities, and rarely lasts more than 3 days. No feature of the rash is pathognomonic for rubella. Unless an epidemic occurs, the disease is difficult to diagnose clinically because the rash caused by other viruses (eg, enteroviruses) is similar.

Transient arthralgia and arthritis are commonly seen in adults, especially women. Despite certain similarities, rubella arthritis is not etiologically related to rheumatoid arthritis. Rare complications include thrombocytopenic purpura and encephalitis.

Immunity

Rubella antibodies appear in the serum of patients as the rash fades and the antibody titer rises rapidly over the next 1–3 weeks. Much of the initial antibody consists of IgM antibodies, which generally do not persist beyond 6 weeks after the illness. IgM rubella antibodies found in a single serum sample obtained 2 weeks after the rash give evidence of recent rubella infection. IgG rubella antibodies usually persist for life.

One attack of the disease confers lifelong immunity because only one antigenic type of the virus exists. Because of the nondescript nature of the rash, a history of “rubella” is not a reliable index of immunity. Immune mothers transfer antibodies to their offspring, who are then protected for 4–6 months.

Laboratory Diagnosis

Clinical diagnosis of rubella is unreliable because many viral infections produce symptoms similar to those of rubella. Certain diagnosis rests on specific laboratory studies (isolation of virus, detection of viral RNA, or evidence of seroconversion).

A. Nucleic Acid Detection

RT-PCR can be used to detect rubella virus nucleic acid directly in clinical samples or in cell cultures used for virus isolation. Molecular typing can identify virus subtypes and genotypes and is useful in surveillance studies. Throat swabs are appropriate samples for molecular typing.

B. Isolation and Identification of Virus

Nasopharyngeal or throat swabs taken 6 days before and after onset of rash are a good source of rubella virus. Various cell lines of monkey or rabbit origin may be used. Rubella produces a rather inconspicuous cytopathic effect in most of the cell lines. Using cells cultured in shell vials, viral antigens can be detected by immunofluorescence 3–4 days postinoculation.

C. Serology

The HI test is a standard serologic test for rubella. However, serum must be pretreated to remove nonspecific inhibitors before testing. ELISA tests are preferred because serum pretreatment is not required and they can be adapted to detect specific IgM.

Detection of IgG is evidence of immunity because there is only one serotype of rubella virus. To accurately confirm a recent rubella infection (critically important in the case of a pregnant woman), either a rise in antibody titer must be demonstrated between two serum samples taken at least 10 days apart or rubella-specific IgM must be detected in a single specimen.

Epidemiology

Rubella is worldwide in distribution. Infection occurs throughout the year with a peak incidence in the spring. Epidemics occur every 6–10 years, with explosive pandemics every 20–25 years. Infection is transmitted by the respiratory route, but rubella is not as contagious as measles.

A worldwide rubella epidemic occurred from 1962 to 1965. There were more than 12 million cases in the United States, resulting in 2000 cases of encephalitis, more than 11,000 fetal deaths, 2000 neonatal deaths, and 20,000 infants born with congenital rubella syndrome. The economic impact of this epidemic in the United States was estimated at $1.5 billion. The use of rubella vaccine eliminated both epidemic and endemic rubella in the United States by 2005. A program is underway to also eliminate rubella and rubella congenital syndrome from Central and South America.

Treatment, Prevention, and Control

Rubella is a mild, self-limited illness, and no specific treatment is indicated.

Laboratory-proved rubella in the first 3–4 months of pregnancy is almost uniformly associated with fetal ­infection. Intravenous immune globulin injected into the mother does not protect the fetus against rubella infection because it is usually not given early enough to prevent viremia.

Attenuated live rubella vaccines have been available since 1969. The vaccine is available as a single antigen or combined with measles and mumps vaccine. The primary ­purpose of rubella vaccination is to prevent congenital rubella infections. The vaccine virus multiplies in the body and is shed in small amounts, but it does not spread to contacts. Vaccinated children pose no threat to mothers who are susceptible and pregnant. In contrast, nonimmunized children can bring home wild virus and spread it to susceptible family contacts. The vaccine induces lifelong immunity in at least 95% of recipients.

The vaccine is safe and causes few side effects in children. In adults, the only significant side effects are transient arthralgia and arthritis in about one-fourth of vaccinated women.

Vaccination in the United States decreased the incidence of rubella from about 70,000 cases in 1969 to fewer than 10 in 2004, cases that occurred predominantly among persons born outside the United States. The virus was subsequently declared eliminated from the United States. Cost–benefit studies in both developed and developing countries have shown that the benefits of rubella vaccination outweigh the costs.

CONGENITAL RUBELLA SYNDROME

Pathogenesis and Pathology

Maternal viremia associated with rubella infection during pregnancy may result in infection of the placenta and fetus. Only a limited number of fetal cells become infected. The growth rate of infected cells is reduced, resulting in fewer numbers of cells in affected organs at birth. The infection may lead to deranged and hypoplastic organ development, resulting in structural anomalies in the newborn.

The timing of the fetal infection determines the extent of teratogenic effect. In general, the earlier in pregnancy infection occurs, the greater the damage to the fetus. Infection during the first trimester of pregnancy results in abnormalities in the infant in about 85% of cases, but detectable defects are found in about 16% of infants who acquired infection during the second trimester. Birth defects are uncommon if maternal infection occurs after the 20th week of gestation.

Inapparent maternal infections can produce these anomalies as well. Rubella infection can also result in fetal death and spontaneous abortion.

Intrauterine infection with rubella is associated with chronic persistence of the virus in the newborn. At birth, virus is easily detectable in pharyngeal secretions, multiple organs, cerebrospinal fluid, urine, and rectal swabs. Viral excretion may last for 12–18 months after birth, but the level of shedding gradually decreases with age.

Clinical Findings

Rubella virus has been isolated from many different organs and cell types from infants infected in utero, and rubella-induced damage is similarly widespread.

Clinical features of congenital rubella syndrome may be grouped into three broad categories: (1) transient effects in infants, (2) permanent manifestations that may be ­apparent at birth or become recognized during the first year, and (3) developmental abnormalities that appear and progress during childhood and adolescence.

The classic triad of congenital rubella consists of ­cataracts, cardiac abnormalities, and deafness. Infants may also display transient symptoms of growth retardation, rash, hepatosplenomegaly, jaundice, and meningoencephalitis.

Central nervous system involvement is more global. The most common developmental manifestation of ­congenital rubella is moderate to profound mental ­retardation. Problems with balance and motor skills develop in ­preschool children. Severely affected infants may require institutionalization.

Progressive rubella panencephalitis, a rare complication that develops in the second decade of life in children with congenital rubella, is a severe neurologic deterioration that inevitably progresses to death.

Immunity

Normally, maternal rubella antibody in the form of IgG is transferred to infants and is gradually lost over a period of 6 months. Demonstration of rubella antibodies of the IgM class in infants is diagnostic of congenital rubella. Because IgM antibodies do not cross the placenta, their presence indicates that they must have been synthesized by the infant in utero. Children with congenital rubella exhibit impaired cell-mediated immunity specific for rubella virus.

Treatment, Prevention, and Control

There is no specific treatment for congenital rubella. It can be prevented by childhood immunization with rubella vaccine to ensure that women of childbearing age are immune.

• Paramyxoviruses are a large family; six genera contain human pathogens. These include parainfluenza viruses, respiratory syncytial virus, and human metapneumovirus (respiratory diseases); measles virus, mumps virus, and Hendra and Nipah viruses (zoonotic encephalitides).

• Paramyxoviruses are enveloped RNA viruses with a ­negative-sense, nonsegmented genome. All are antigenically stable.

• Paramyxoviruses are transmitted by contact or large droplets and initiate infections through the respiratory tract.

• The entire viral replication cycle for paramyxoviruses occurs in the cytoplasm of cells.

• Respiratory syncytial virus is the most important cause of lower respiratory tract illness in infants and young children. Serious bronchiolitis or pneumonia occurs most often in infants ages 6 weeks to 6 months. Elderly adults are also susceptible.

• Human metapneumoviruses are respiratory pathogens for young children, immunocompromised individuals, and elderly adults. Disease resembles that of respiratory syncytial virus.

• Parainfluenza viruses cause respiratory illnesses in all ages; most serious disease occurs in infants and young children.

• Detection of viral RNA or viral antigens is a preferred method for diagnosis of respiratory virus infections.

• Ribavirin is approved for treatment of respiratory syncytial virus disease in infants.

• Reinfections are common with the respiratory viruses.

• Mumps is a systemic disease, with about half of infections causing swelling of the salivary glands. Many infections are asymptomatic.

• Measles (rubeola) is a highly infectious, disseminated infection characterized by a rash. Serious complications, including pneumonia and encephalitis, can occur. Inapparent infections are rare.

• There are single serotypes of measles virus and mumps virus. Infection confers lifelong immunity.

• No vaccines are available for parainfluenza viruses, respiratory syncytial virus, or human metapneumoviruses. Effective vaccines exist for both measles and mumps.

• Hendra and Nipah viruses are animal paramyxoviruses able to infect humans; they cause encephalitis with a high mortality rate. There is no treatment.

• Rubella (German measles) is classified as a togavirus but is not transmitted by arthropods. It is the mildest of the common viral exanthems.

• Rubella infection during early pregnancy can result in serious harm to the fetus, including fetal death. Children born with congenital rubella may have a variety of physical problems and developmental abnormalities.

• A rubella vaccine is available. Congenital rubella can be prevented by childhood vaccination so that women of childbearing age are immune.