Jawetz Chapter 40: Paramyxoviruses and Rubella Virus PDF

40 C H A P T E R Paramyxoviruses and...

40 C H A P T E R Paramyxoviruses and Rubella Virus The paramyxoviruses include the most important agents of which are involved in the viral polymerase activity that func- respiratory infections of infants and young children (respi- tions in transcription and RNA replication. ratory syncytial virus [RSV] and the parainfluenza viruses) Three proteins participate in the formation of the viral as well as the causative agents of two of the most common envelope. Matrix (M) protein underlies the viral envelope; contagious diseases of childhood (mumps and measles). it has an affinity for both the N and the viral surface glyco- The World Health Organization estimates that acute respi- proteins and is important in virion assembly. The nucleo- ratory infections and pneumonia are responsible every year capsid is surrounded by a lipid envelope that is studded worldwide for the deaths of 4 million children younger than with 8- to 12-nm spikes of two different transmembrane 5 years. Paramyxoviruses are the major respiratory patho- glycoproteins. The activities of these surface glycoproteins gens in this age group. help differentiate the various genera of the Paramyxoviri- All members of the Paramyxoviridae family initiate dae family (Table 40-2). The larger glycoprotein (HN or G) infection via the respiratory tract. Whereas replication of the may or may not possess hemagglutination and neuramini- respiratory pathogens is limited to the respiratory epithelia, dase activities and is responsible for attachment to the host measles and mumps become disseminated throughout the cell. It is assembled as a tetramer in the mature virion. body and produce generalized disease. The other glycoprotein (F) mediates membrane fusion and Rubella virus, although classified as a togavirus because hemolysin activities. The pneumoviruses and metapneu- of its chemical and physical properties (see Chapter 29), can moviruses contain two additional small envelope proteins be considered with the paramyxoviruses on an epidemiologic (M2-1 and SH). basis. A diagram of a paramyxovirus particle is shown in Figure 40-3. PROPERTIES OF PARAMYXOVIRUSES Classification Major properties of paramyxoviruses are listed in Table 40-1. 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 Structure and Composition consist of a single serotype); all are antigenically stable. The morphology of Paramyxoviridae is pleomorphic, with The genus Respirovirus contains two serotypes of human particles 150 nm or more in diameter, occasionally ranging parainfluenza viruses, and the genus Rubulavirus contains up to 700 nm. A typical particle is shown in Figure 40-1. The two other parainfluenza viruses as well as mumps virus. envelope of paramyxoviruses seems to be fragile, making Some animal viruses are related to the human strains. Sendai virus particles labile to storage conditions and prone to dis- virus of mice, which was the first parainfluenza virus iso- tortion in electron micrographs. lated and is now recognized as a common infection in mouse The viral genome is linear, negative-sense, single-stranded, colonies, is a subtype of human type 1 virus. Simian parain- nonsegmented RNA, about 15 kb in size (Figure 40-2). fluenza virus 5 (PIV5), a common contaminant of primary Because the genome is not segmented, this negates any monkey cells, is the same as canine parainfluenza virus type 2; opportunity for frequent genetic reassortment, resulting in shipping fever virus of cattle and sheep is a subtype of type 3. antigenic stability. Newcastle disease virus, the prototype avian parainfluenza Most paramyxoviruses contain six structural proteins. virus of genus Avulavirus, is also related to the human Three proteins are complexed with the viral RNA—the viruses. nucleocapsid (N) protein that forms the helical nucleocapsid Members within a genus share common antigenic deter- (13 or 18 nm in diameter) and represents the major internal minants. Although the viruses can be distinguished anti- protein and two other large proteins (designated P and L), genically using well-defined reagents, hyperimmunization 595 Riedel_CH40_p595-p616.indd 595 04/04/19 5:09 PM  596   SECTION IV  Virology TABLE 40-1 Important Properties of Paramyxoviruses Virion: Spherical, pleomorphic, 150 nm or more in diameter (helical nucleocapsid, 13 or 18 nm) Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate (6%) Genome: Single-stranded RNA, linear, nonsegmented, negative sense, ∼15 kb Proteins: Six to eight structural proteins Envelope: Contains viral glycoprotein (G, H, or HN) (which sometimes carries hemagglutinin or neuraminidase activity) and fusion (F) glycoprotein; very fragile Replication: Cytoplasm; particles bud from plasma membrane Outstanding characteristics: Antigenically stable Particles are labile yet highly infectious 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 FIGURE 40-1 Ultrastructure of parainfluenza virus type 1. The of the virus, are commonly observed in older people. This virion is partially disrupted, showing the nucleocapsid. Surface projections are visible along the edge of the particle. (Courtesy of FA phenomenon makes it difficult to determine by serodiagno- Murphy and EL Palmer.) sis the most likely infecting type. All members of the genera Leader Trailer N P/V/C M F HN L 3′ 5′ Respiroviruses – Sendai virus N V/P M F SH HN L 3′ 5′ Rubulaviruses – Parainfluenza virus 5 N P/V/C M F HN L 3′ 5′ Morbilliviruses – Measles virus N P/V/C M F G L 3′ 5′ Henipaviruses – Nipah virus NS1 NS2 N P M SH G F M2 L 3′ 5′ Pneumoviruses – Respiratory syncytial virus SH N P M F M2 G L 3′ 5′ Metapneumoviruses – Human metapneumovirus FIGURE 40-2 Genetic maps of representative members of the genera of the family Paramyxoviridae. Gene sizes (boxes) are drawn approximately to scale. (Copyright GD Parks and RA Lamb, 2006.) Riedel_CH40_p595-p616.indd 596 04/04/19 5:09 PM  CHAPTER 40 Paramyxoviruses and Rubella Virus   597 TABLE 40-2 Characteristics of Genera in the Subfamilies of the Family Paramyxoviridae Paramyxovirinae Pneumovirinae Property Respirovirus Rubulavirus Morbillivirus Henipavirus a Pneumovirus Metapneumovirus Human viruses Parainfluenza Mumps, Measles Hendra, Respiratory Human metapneumovirus 1, 3 parainfluenza 2, Nipah syncytial 4a, 4b virus Serotypes 1 each 1 each 1 Unknown 2 Several Diameter of 18 18 18 18 13 13 nucleocapsid (nm) Membrane + + + + + + fusion (F protein) Hemolysinb + + + Unknown 0 0 Hemagglutininc + + + 0 0 0 Hemadsorption + + + 0 0 0 Neuraminidasec + + 0 0 0 0 Inclusions C C N,C C C C C, cytoplasm; N, nucleus. a Zoonotic paramyxoviruses. b Hemolysin activity carried by F glycoprotein. c Hemagglutination and neuraminidase activities carried by HN glycoprotein of respiroviruses and rubulaviruses; H glycoprotein of morbilliviruses lacks neuraminidase activity; G glycoprotein of other paramyxoviruses lacks both activities. Respirovirus and Rubulavirus possess hemagglutinating and The Morbillivirus genus contains measles virus (rube- neuraminidase activities, both carried by the HN glycopro- ola) of humans as well as canine distemper virus, rinderpest tein, as well as membrane fusion and hemolysin properties, virus of cattle, and aquatic morbilliviruses that infect marine both functions of the F protein. 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 L Large polymerase HN/G proteins display more variability. Measles virus has N Nucleocapsid RNP a hemagglutinin but lacks neuraminidase activity. Measles SH Small P Phosphoprotein hydrophobic virus induces formation of intranuclear inclusions, but other protein paramyxoviruses do not. The Henipavirus genus contains zoonotic paramyxo- M Matrix protein viruses 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. FIGURE 40-3 Schematic diagram of a paramyxovirus showing major components (not drawn to scale). The viral matrix protein (M) underlies the lipid bilayer. Inserted through the viral membrane are the hemagglutinin–neuraminidase (HN) attachment glycoprotein and the fusion (F) glycoprotein. Only some paramyxoviruses contain the SH protein. Inside the virus is the negative-strand virion RNA, Lipid bilayer which is encased in the nucleocapsid protein (N). Associated with the nucleocapsid are the L and P proteins, and together this complex F Fusion protein has RNA-dependent RNA transcriptase activity. The V protein is only HN Hemagglutinin- V Multifunctional found in rubulavirus virions. (Copyright GD Parks and RA Lamb, neuraminidase zinc-binding protein 2006.) Riedel_CH40_p595-p616.indd 597 04/04/19 5:09 PM  598   SECTION IV  Virology Respiratory syncytial viruses of humans and cattle and Paramyxovirus Replication pneumonia virus of mice constitute the genus Pneumovi- The typical paramyxovirus replication cycle is illustrated in rus. There are two antigenically distinct strains of RSV of Figure 40-4. humans, subgroups A and B. The larger surface glycoprotein of pneumoviruses lacks hemagglutinating and neuramini- dase activities characteristic of respiroviruses and rubulavi- A. Virus Attachment, Penetration, and Uncoating ruses, so it is designated the G protein. The F protein of RSV Paramyxoviruses attach to host cells via the hemagglutinin exhibits membrane fusion activity but no hemolysin activity. glycoprotein (HN, H, or G protein). In the case of measles Human metapneumoviruses are respiratory pathogens of virus, the receptor is the membrane CD46 or CD150 mole- humans classified in the genus Metapneumovirus. cule. Next, the virion envelope fuses with the cell membrane (–) (+) Genome replication N-P-L Primary Nucleus N-P-L Secondary transcription transcription P-L P-L (–) An An An An An An An ER N P C L M F HN SH V Golgi M M M M M M M M M M M M M M M M M M M M M M M FIGURE 40-4 Paramyxovirus life cycle. The infecting virus particle fuses with the plasma membrane and releases the viral nucleocapsid into the cytoplasm. Solid lines represent transcription and genome replication. Dotted lines indicate transport of newly synthesized viral proteins to plasma membrane. Progeny virions are released from the cell by a budding process. The entire paramyxovirus replication cycle takes place in the cell cytoplasm. ER, endoplasmic reticulum. (Copyright GD Parks and RA Lamb, 2006.) Riedel_CH40_p595-p616.indd 598 04/04/19 5:09 PM  CHAPTER 40 Paramyxoviruses and Rubella Virus   599 by the action of the fusion glycoprotein F1 cleavage product. During budding, most host proteins are excluded from the The F1 protein undergoes complex refolding during the pro- membrane. cess of viral and cellular membrane fusion. If the F0 precur- The neuraminidase activity of the HN protein of para- sor is not cleaved, it has no fusion activity; virion penetration influenza viruses and mumps virus presumably functions to does not occur; and the virus particle is unable to initiate prevent self-aggregation of virus particles. Other paramyxovi- infection. Fusion by F1 occurs at the neutral pH of the extra- ruses do not possess neuraminidase activity (see Table 40-2). cellular environment, allowing release of the viral nucleocap- If appropriate host cell proteases are present, F0 pro- sid directly into the cell. Thus, paramyxoviruses are able to teins in the plasma membrane will be activated by cleavage. bypass internalization through endosomes. Activated fusion protein will then cause fusion of adjacent cell membranes, resulting in formation of large syncytia B. Transcription, Translation, and RNA Replication (Figure 40-5). Syncytium formation is a common response to paramyxovirus infection. Acidophilic cytoplasmic inclusions Paramyxoviruses contain a nonsegmented, negative-strand are regularly formed (see Figure 40-5). Inclusions are believed RNA genome. Messenger RNA transcripts are made in the to reflect sites of viral synthesis and have been found to con- cell cytoplasm by the viral RNA polymerase. There is no tain recognizable nucleocapsids and viral proteins. Measles need for exogenous primers and therefore no dependence on virus also produces intranuclear inclusions (see Figure 40-5). cell nuclear functions. The mRNAs are much smaller than genomic size; each represents a single gene. Transcriptional regulatory sequences at gene boundaries signal transcrip- PARAINFLUENZA VIRUS INFECTIONS tional start and termination. The position of a gene relative to the 3′ end of the genome correlates with transcription effi- Parainfluenza viruses are ubiquitous and cause common ciency. Whereas the most abundant class of transcripts pro- respiratory illnesses in persons of all ages. They are major duced by an infected cell is from the N gene, located nearest pathogens of severe respiratory tract disease in infants and the 3′ end of the genome, the least abundant is from the L young children. Reinfections with parainfluenza viruses are gene, located at the 5′ end (see Figure 40-2). common. Viral proteins are synthesized in the cytoplasm, and the quantity of each gene product corresponds to the level Pathogenesis and Pathology of mRNA transcripts from that gene. Viral glycoproteins are Parainfluenza virus replication in the immunocompetent synthesized and glycosylated in the secretory pathway. host appears to be limited to respiratory epithelia. Viremia, if The viral polymerase protein complex (P and L proteins) it occurs at all, is uncommon. The infection may involve only is also responsible for viral genome replication. For successful the nose and throat, resulting in a “common cold” syndrome. synthesis of a positive-strand antigenome intermediate tem- However, infection may be more extensive and, especially plate, the polymerase complex must disregard the termination with types 1 and 2, may involve the larynx and upper tra- signals interspersed at gene boundaries. Full-length progeny chea, resulting in croup (laryngotracheobronchitis). Croup genomes are then copied from the antigenome template. is characterized by respiratory obstruction caused by swell- The nonsegmented genome of paramyxoviruses negates ing of the larynx and related structures. The infection may the possibility of gene segment reshuffling (ie, genetic reas- spread deeper to the lower trachea and bronchi, culminating sortment) so important to the natural history of influenza in pneumonia or bronchiolitis, especially with type 3, but at a viruses. The HN/H/G and F surface proteins of paramyxo- much lower frequency than that observed with RSV. viruses exhibit minimal antigenic variation over long periods The duration of parainfluenza virus shedding is about 1 of time. It is surprising that they do not undergo antigenic week after onset of illness; some children may excrete virus drift as a result of mutations introduced during replication, several days prior to symptoms. Type 3 may be excreted for because RNA polymerases tend to be error-prone. One pos- up to 4 weeks after onset of primary illness. This persistent sible explanation is that nearly all the amino acids in the shedding from young children facilitates spread of infection. primary structures of paramyxovirus glycoproteins may be Prolonged viral shedding may occur in children with com- involved in structural or functional roles, leaving little oppor- promised immune function and in adults with chronic lung tunity for substitutions that would not markedly diminish disease. the viability of the virus. Factors that determine the severity of parainfluenza virus disease are unclear but include both viral and host properties, C. Maturation such as susceptibility of the protein to cleavage by different The virus matures by budding from the cell surface. Prog- proteases, production of an appropriate protease by host cells, eny nucleocapsids form in the cytoplasm and migrate to immune status of the patient, and airway hyperreactivity. the cell surface. They are attracted to sites on the plasma The production of virus-specific IgE antibodies during membrane that are studded with viral HN/H/G and F0 gly- primary infections has been associated with disease severity. coprotein spikes. The M protein is essential for particle for- The mechanism may involve release of mediators of inflam- mation, serving to link the viral envelope to the nucleocapsid. mation that alter airway function. Riedel_CH40_p595-p616.indd 599 04/04/19 5:09 PM  600   SECTION IV  Virology A B C D FIGURE 40-5 Syncytial formation induced by paramyxoviruses. A: Respiratory syncytial virus in MA104 cells (unstained, 100×). Syncytia (arrows) result from fusion of plasma membranes; nuclei are accumulated in the center. B: Respiratory syncytial virus in HEp-2 cells (hematoxylin and eosin [H&E] stain, 400×). Syncytium contains many nuclei and acidophilic cytoplasmic inclusions (arrow). C: Measles virus in human kidney cells (H&E stain, 30×). Huge syncytium contains hundreds of nuclei. D: Measles virus in human kidney cells (H&E stain, 400×). Multinucleated giant cell contains acidophilic nuclear inclusions (vertical arrow) and cytoplasmic inclusions (horizontal arrow). (Used with permission from I Jack.) Clinical Findings The most common complication of parainfluenza virus infection is otitis media. The relative importance of parainfluenza viruses as a cause Immunocompromised children and adults are suscep- of respiratory diseases in different age groups is indicated in tible to severe infections. Mortality rates after parainfluenza Table 30-5. Their presence in lower respiratory tract infections infection in bone marrow transplant recipients range from in young children shows seasonal variation seen in Figure 40-6. 10% to 20%. Primary infections in young children usually result in Newcastle disease virus is an avian paramyxovirus that rhinitis and pharyngitis, often with fever and some bron- produces pneumoencephalitis in young chickens and respi- chitis. However, children with primary infections caused by ratory disease in older birds. In humans, it may produce parainfluenza virus type 1, 2, or 3 may have serious illness, inflammation of the conjunctiva. Recovery is complete in ranging from laryngotracheitis and croup (particularly with 10–14 days. Infection in humans is an occupational disease types 1 and 2) to bronchiolitis and pneumonia (particularly limited to workers handling infected birds. 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 Immunity half of initial infections with parainfluenza virus type 1, 2, Parainfluenza virus types 1, 2, and 3 are distinct serotypes or 3 result in febrile illness. It is estimated that only 2–3% that lack significant cross-neutralization (see Table 40-2). develop into croup. Parainfluenza virus type 4 does not usu- Virtually all infants have maternal antibodies to the viruses ally cause serious disease, even on first infection. in serum, yet these antibodies do not prevent infection or Riedel_CH40_p595-p616.indd 600 04/04/19 5:10 PM  CHAPTER 40 Paramyxoviruses and Rubella Virus   601 Parainfluenza virus paramyxovirus associated with a given infection using sero- 15 logic assays. 10 5 0 Laboratory Diagnosis Respiratory syncytial virus Nucleic acid amplification tests are the preferred diagnostic 30 methods because of their sensitivity and specificity, their 25 ability to detect a broad range of viruses, and the rapidity of 20 results. No. of lower respiratory tract illnesses per month 15 Antigen detection methods are also useful for rapid 10 diagnosis. The immune response to the initial parainfluenza 5 virus infection in life is type specific. However, with repeated infections, the response becomes less specific, and cross- 0 reactions extend even to mumps virus. Definitive diagnosis 15 Human metapneumovirus relies on viral isolation from appropriate specimens. 10 5 A. Nucleic Acid Detection 0 Reverse transcription polymerase chain reaction (RT-PCR) assays can be used to detect viral RNA in nasopharyngeal Influenzavirus swabs, washes or aspirates, or lower respiratory tract speci- 15 10 mens such as bronchoalveolar lavage fluid. Sequence analyses 5 are useful in molecular epidemiology studies of parainflu- 0 enza virus infections. Adenovirus 15 B. Antigen Detection 10 Detection of viral antigens can be done in exfoliated nasopha- 5 ryngeal cells by direct or indirect immunofluorescence tests. 0 These methods are fairly rapid and simple to perform but are July Aug Sept Oct Nov Dec Jan Feb Mar Apr May June limited by low sensitivity and the range of viruses detected. FIGURE 40-6 Patterns of lower respiratory tract infections in infants and young children with paramyxoviruses and other C. Isolation and Identification of Virus viruses. Data from 25 years of surveillance (1976–2001) involving Rapid cell culture methods can detect a number of respira- 2009 children from birth to age 5 years. (Reproduced with tory viruses able to be cultured in vitro but are slower to pro- permission from Williams JV, Harris PA, Tollefson SJ, et al: Human vide results than nucleic acid or antigen detection methods metapneumovirus and lower respiratory tract disease in otherwise and are not able to easily detect mixed infections. A continu- healthy infants and children. N Engl J Med 2004;350:443–450. Copyright © 2004 Massachusetts Medical Society.) ous monkey kidney cell line, LLC-MK2, is suitable for isola- tion of parainfluenza viruses. Prompt inoculation of samples into cell cultures is important for successful viral isolation disease. Reinfection of older children and adults also occurs because viral infectivity drops rapidly. For rapid diagnosis, in the presence of antibodies elicited by an earlier infection. samples are inoculated onto cells growing on coverslips in However, those antibodies modify the course of disease; such shell vials and are incubated. One to 3 days later, the cells reinfections usually present simply as nonfebrile upper respi- are fixed and tested by immunofluorescence. Another way ratory infections (colds). to detect the presence of virus is to perform hemadsorption Natural infection stimulates appearance of immuno- using guinea pig erythrocytes. Depending on the amount of globulin A (IgA) antibody in nasal secretions and concomi- virus, 10 days or more of incubation may be necessary before tant resistance to reinfection. The secretory IgA antibodies the cultures become hemadsorption positive. Virus culture are most important for providing protection against reinfec- is necessary if a viral isolate is desired for research purposes. tion but disappear within a few months. Reinfections are thus common even in adults. D. Serology Serum antibodies are made to both HN and F viral sur- Serodiagnosis should be based on paired sera. Anti- face proteins, but their relative roles in determining resis- body responses can be measured using neutralization, tance are unknown. As successive reinfections occur, the hemagglutination-inhibition (HI), or enzyme-linked immu- antibody response becomes less specific because of shared nosorbent assay (ELISA) tests. A fourfold rise in titer is antigenic determinants among parainfluenza viruses and indicative of infection with a parainfluenza virus, as is the mumps virus. This makes it difficult to diagnose the specific appearance of specific IgM antibody. However, because of the Riedel_CH40_p595-p616.indd 601 04/04/19 5:10 PM  602   SECTION IV  Virology problem of shared antigens, it is impossible to be confident of account for approximately 25% of pediatric hospitalizations the specific virus type involved. caused by respiratory disease in the United States. Epidemiology Pathogenesis and Pathology Parainfluenza viruses are a major cause of lower respiratory RSV replication occurs initially in epithelial cells of the naso- tract disease in young children (see Figure 40-6). Parainflu- pharynx. Virus may spread into the lower respiratory tract enza viruses are widely distributed geographically. Type 3 and cause bronchiolitis and pneumonia. Viral antigens can is most prevalent, with about two-thirds of infants infected be detected in the upper respiratory tract and in shed epithe- during the first year of life; virtually all have antibodies to lial cells. Viremia occurs rarely if at all. type 3 by age 2 years. Infections with types 1 and 2 occur The incubation period between exposure and onset of at a lower rate, reaching prevalences of about 75% and 60%, illness is 3–5 days. Viral shedding may persist for 1–3 weeks respectively, by 5 years of age. from infants and young children, but adults shed virus for Type 3 is endemic, with some increase during the spring; only 1–2 days. High viral titers are present in respiratory tract types 1 and 2 tend to cause epidemics during the fall or win- secretions from young children. Inoculum size is an impor- ter, frequently on a 2-year cycle. tant determinant of successful infection in adults (and pos- Reinfections are common throughout childhood and sibly in children as well). in adults and result in mild upper respiratory tract illnesses. An intact immune system seems to be important in Reportedly, 67% of children are reinfected with parainflu- resolving an infection because patients with impaired cell- enza type 3 during the second year of life. Reinfections may mediated immunity may become persistently infected with necessitate hospitalization of adults with chronic lung dis- RSV and shed virus for months. eases (eg, asthma). Although the airways of very young infants are narrow Parainfluenza viruses are transmitted by direct person- and more readily obstructed by inflammation and edema, to-person contact or by large-droplet aerosols. Type 1 has only a subset of young babies develops severe RSV disease. It been recovered from air samples collected in the vicinity of has been reported that susceptibility to bronchiolitis is genet- infected patients. Infections can occur through both the nose ically linked to polymorphisms in innate immunity genes. and the eyes. Parainfluenza viruses are usually introduced into a group by preschool children and then spread readily from person to Clinical Findings person. The incubation period appears to be from 5 to 6 days. The spectrum of respiratory illness caused by RSV in infants Type 3 virus especially will generally infect all susceptible includes inapparent infection, the common cold, bronchiol- individuals in a semiclosed population, such as a family or a itis, and pneumonia. Bronchiolitis is the distinct clinical syn- nursery, within a short time. Parainfluenza viruses are trou- drome associated with this virus. About one-third of primary blesome causes of nosocomial infection in pediatric wards in RSV infections involve the lower respiratory tract severely hospitals. Other high-risk situations include day-care centers enough to require medical attention. Almost 2% infected and schools. 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 Treatment and Prevention been reported that higher viral loads in respiratory secretions Contact isolation precautions are necessary to manage nos- is a predictor of longer hospitalizations. ocomial outbreaks of parainfluenza virus. These include Progression of symptoms may be very rapid, culminating restriction of visitors, isolation of infected patients, and in death. With the availability of modern pediatric intensive gowning and handwashing by medical personnel. care, the mortality rate in normal infants is low (∼1% of hos- The antiviral drug ribavirin has been used with some pitalized patients). But if an RSV infection is superimposed benefit in treatment of immunocompromised patients with on preexisting disease, such as congenital heart disease, the lower respiratory tract disease. mortality rate may be high. No vaccine is available. 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 RESPIRATORY SYNCYTIAL cold, in healthy individuals. VIRUS INFECTIONS RSV infections account for about one-third of respira- tory infections in bone marrow transplant patients. Pneumo- RSV is the most important cause of lower respiratory tract nia develops in about half of infected immunocompromised illness in infants and young children, usually outranking all children and adults, especially if infection occurs in the early other microbial pathogens as the cause of bronchiolitis and posttransplant period. Reported mortality rates range from pneumonia in infants younger than 1 year. It is estimated to 20% to 80%. Riedel_CH40_p595-p616.indd 602 04/04/19 5:10 PM  CHAPTER 40 Paramyxoviruses and Rubella Virus   603 Infections in elderly adults may cause symptoms simi- preferred method and is especially useful for adult specimens lar to influenza virus disease. Pneumonia may develop. Esti- in which only small amounts of virus are often present. Such mates of RSV prevalence in long-term care facilities include assays also are useful for subtyping RSV isolates and for the infection rates of 5–10%, pneumonia in 10–20% of those analysis of genetic variation in outbreaks. Antigen detection infected, and mortality rates of 2–5%. is much less sensitive than nucleic acid detection. Children who have had RSV bronchiolitis and pneumo- RSV can be isolated from nasal secretions. The virus is nia as infants often exhibit recurrent episodes of wheezing extremely labile and samples should be inoculated into cell illness for many years. However, no causal relationship has cultures immediately; freezing of clinical specimens may been shown between RSV infections and long-term abnor- result in complete loss of infectivity. Human heteroploid cell malities. It may be that certain individuals have underlying lines HeLa and HEp-2 are the most sensitive for viral isola- physiologic traits that predispose them both to severe RSV tion. The presence of RSV can usually be recognized by devel- infections and to reactive airway disease. opment of giant cells and syncytia in inoculated cultures (see RSV is an important cause of otitis media. It is estimated Figure 40-5). It may take as long as 10 days for cytopathic that 30–50% of wintertime episodes in infants may be caused effects to appear. More rapid isolation of RSV can be achieved by RSV infection. by inoculation of shell vials containing tissue cultures grow- ing on coverslips. Cells can be tested 24–48 hours later by immunofluorescence or RT-PCR. RSV differs from other Immunity paramyxoviruses in that it does not have a hemagglutinin; High levels of neutralizing antibody that is maternally trans- therefore, diagnostic methods cannot use hemagglutination mitted and present during the first several months of life are or hemadsorption assays. believed to be critical in protective immunity against lower Serum antibodies can be assayed in a variety of ways. respiratory tract illness. Severe respiratory syncytial disease Although measurements of serum antibody are important for begins to occur in infants at 2–4 months of age when mater- epidemiologic studies, they typically are not used in clinical nal antibody levels are falling. However, primary infection decision making. and reinfection can occur in the presence of viral antibodies. Serum neutralizing antibody appears to be strongly corre- lated with immunity against disease of the lower respiratory Epidemiology tract but not of the upper respiratory tract. RSV is distributed worldwide and is recognized as the major RSV is not an effective inducer of interferon—in contrast pediatric respiratory tract pathogen (see Figure 40-6). About to influenza and parainfluenza virus infections, in which 70% of infants are infected by age 1 and almost all by age interferon levels are high and correlate with disappearance 2 years. Serious bronchiolitis or pneumonia is most apt to of virus. occur in infants between the ages of 6 weeks and 6 months, Both serum and secretory antibodies are made in response with peak incidence at 2 months. The virus can be isolated to RSV infection. Primary infection with one subgroup induces from most infants younger than age 6 months with bron- cross-reactive antibodies to virus of the other subgroup (see chiolitis, but it is almost never isolated from healthy infants. Table 40-2). Younger infants have lower IgG and IgA secre- Subgroup A infections appear to cause more severe illness tory antibody responses to RSV than do older infants. Cellular than subgroup B infections. RSV is the most common cause immunity is important in recovery from infection. of viral pneumonia in children younger than age 5 years but An association has been noted between virus-specific may also cause pneumonia in elderly adults or in immuno- IgE antibody and severity of disease. Viral secretory IgE anti- compromised persons. RSV infection of older infants and bodies have been correlated with occurrence of bronchiolitis. children typically results in milder respiratory tract infection It is apparent that immunity is only partially effective than in those younger than age 6 months. and is often overcome under natural conditions; reinfections RSV is spread by large droplets and direct contact. are common, but the severity of ensuing disease is lessened. Although the virus is very labile, it can survive on environ- mental surfaces for up to 6 hours. The main portal of entry into the host is through the nose and eyes. Laboratory Diagnosis Reinfection occurs frequently (despite the presence of Methods described for diagnosis of parainfluenza viruses are specific antibodies), but resulting symptoms are those of a applicable to RSV. Detection of RSV is strong evidence that mild upper respiratory infection (a cold). In families with an the virus is involved in a current illness because it is rarely identified case of RSV infection, virus spread to siblings and found in healthy people. Detection of viral RNA or viral anti- adults is common. gen in respiratory secretions is the test of choice. RSV spreads extensively in children every year during Large amounts of virus are present in nasopharyngeal the winter season. Although the virus persists throughout swabs and washes from young children (103–108 plaque-forming the summer months, outbreaks tend to peak in January or units/mL), but much less is present in specimens from adults February in the Northern Hemisphere. In tropical areas, RSV (35%) among Treatment, Prevention, and Control more than 250 cases; a few survivors had persistent neuro- Vitamin A treatment in developing countries has decreased logic deficits. It appeared that the infections were caused by mortality and morbidity. Measles virus is susceptible in vitro direct viral transmission from pigs to humans. Some patients to inhibition by ribavirin, but clinical benefits have not been (