Respiratory Syncytial Virus

Etiology

RSV is an enveloped RNA virus with a single-stranded negative-sense genome that replicates entirely in the cytoplasm of infected cells and matures by budding from the apical surface of the cell membrane. Because this virus has a nonsegmented genome, it cannot undergo antigenic shift by reassortment like the influenza viruses do. The virus belongs to the family Pneumoviridae, which comprises large enveloped, negative-sense RNA viruses. This taxon was formerly a subfamily within the Paramyxoviridae but was reclassified in 2016 as a family with two genera, Orthopneumovirus (which includes RSV) and Metapneumovirus (which includes human metapneumovirus; see Chapter 288 ). There are two antigenic subgroups of RSV (subgroups A and B), distinguished based primarily on sequence and antigenic variation in one of the two surface proteins, the G glycoprotein that is responsible for attachment to host cells. This antigenic variation, which is caused by point mutations from infidelity of the viral RNA polymerase, may contribute to some degree to the frequency with which RSV reinfects children and adults. However, adult human challenge experiments have shown that the same RSV strain can reinfect in the upper respiratory tract repetitively, suggesting that mucosal immunity in that site is incomplete or short-lived.

RSV replicates in a wide variety of cell line monolayer cultures in the laboratory. In HeLa and HEp-2 cell monolayers, the virus causes cell-to-cell fusion that produces characteristic cytopathology called syncytia (multinucleate enlarged cells), from which the virus derives its name. Identification of syncytia in diagnostic cultures of respiratory secretions is helpful in identifying RSV, but it is not clear whether syncytium formation occurs to any significant degree in the airway epithelium in patients.

Epidemiology

RSV is distributed worldwide and appears in yearly epidemics. In temperate climates, these epidemics occur each winter over a 4- to 5-mo period. During the remainder of the year, infections are sporadic and much less common. In the Northern hemisphere, epidemics usually peak in January, February, or March, but peaks have been recognized as early as December and as late as June. Some areas in the United States, such as Florida, report a moderate incidence year-round. In the Southern hemisphere, outbreaks also occur during the winter months in that hemisphere. RSV outbreaks often overlap with outbreaks of influenza virus or human metapneumovirus but are generally more consistent from year to year and result in more disease overall, especially among infants younger than 6 mo of age. In the tropics, the epidemic pattern is less clear. The pattern of widespread annual outbreaks and the high incidence of infection during the first 3-4 mo of life are unique among human viruses.

Transplacentally acquired anti-RSV maternal immunoglobulin G (IgG) serum antibodies, if present in high concentration, appear to provide partial protection for the neonate. The age of peak incidence of severe lower respiratory tract disease and hospitalization is about 6 wk. Maternal IgGs may account for the lower severity and incidence of RSV infections during the first 4-6 wk of life, except among infants born prematurely, who receive less maternal immunoglobulin. Breastfeeding provides some protection against severe disease, an effect that may pertain only to female and not male infants. RSV is one of the most contagious viruses that affect humans. Infection is nearly universal among children by their second birthday. Reinfection occurs at a rate of at least 10–20% per epidemic throughout childhood, with a lower frequency among adults. In situations of high exposure, such as daycare centers, attack rates are nearly 100% among previously uninfected infants and 60–80% for second and subsequent infections.

Reinfection may occur as early as a few weeks after recovery but usually takes place during subsequent annual outbreaks. Antigenic variation is not required for reinfection, as shown by the fact that a proportion of adults inoculated repeatedly with the same experimental preparation of wild-type virus could be reinfected multiple times. The immune response of infants is poor in quality, magnitude, and durability. The severity of illness during reinfection in childhood is usually lower than that in first infection and appears to be a function of partial acquired immunity, more robust airway physiology, and increased age.

Asymptomatic RSV infection is unusual in young children. Most infants experience coryza and pharyngitis, often with fever and frequently with otitis media caused by virus in the middle ear or bacterial superinfection following eustachian tube dysfunction. The lower respiratory tract is involved to a varying degree, with bronchiolitis and bronchopneumonia in about a third of children. The hospitalization rate for RSV infection in otherwise healthy infants is typically 0.5–4%, depending on region, gender, socioeconomic status, exposure to cigarette smoke, gestational age, and family history of atopy. The admitting diagnosis is usually bronchiolitis with hypoxia, although this condition is often indistinguishable from RSV pneumonia in infants, and, indeed, the two processes frequently coexist. All RSV diseases of the lower respiratory tract (excluding croup) have their highest incidence at 6 wk to 7 mo of age and decrease in frequency thereafter. The syndrome of bronchiolitis is much less common after the 1st birthday. The terminology used for the diagnosis of virus-associated wheezing illnesses in toddlers can be confusing, because these illnesses are variably termed wheezing-associated respiratory infection, wheezy bronchitis, exacerbation of reactive airways disease, or asthma attack. Because many toddlers wheeze during RSV infection but do not go on to have lifelong asthma, it is best to use the diagnostic term asthma only later in life. Acute viral pneumonia is a recurring problem throughout childhood, although RSV becomes less prominent as the etiologic agent after the first year. RSV plays a causative role in an estimated 40–75% of cases of hospitalized bronchiolitis, 15–40% of cases of childhood pneumonia, and 6–15% of cases of croup.

Bronchiolitis and pneumonia resulting from RSV are more common in males than in females by a ratio of approximately 1.5 : 1. Other risk factors with a similar impact in the United States include one or more siblings in the home, white race, rural residence, maternal smoking, and maternal education < 12 yr. The medical factors in infants associated with the highest risk are chronic lung disease of prematurity, congenital heart disease, immunodeficiency, and prematurity. Still, most infants admitted to the hospital because of RSV infection do not have strong, easily identifiable risk factors. Therefore, any strategy for prophylaxis focused only on individuals with strong risk factors probably could prevent only approximately 10% of hospitalizations, even if the prophylaxis was 100% effective in treated high-risk individuals.

The incubation period from exposure to first symptoms is approximately 3-5 days. The virus is excreted for variable periods, probably depending on the severity of illness and immunologic status. Most infants with lower respiratory tract illness shed infectious viruses for 1-2 wk after hospital admission. Excretion for 3 wk and even longer has been documented. Spread of infection occurs when large, infected droplets, either airborne or conveyed on hands or other fomites, are inoculated in the nasopharynx of a susceptible subject. RSV is probably introduced into most families by young schoolchildren experiencing reinfection. Typically, in the space of a few days, 25–50% of older siblings and one or both parents acquire upper respiratory tract infections, but infants become more severely ill with fever, otitis media, or lower respiratory tract disease.

Nosocomial infection during RSV epidemics is an important concern. Virus is usually spread from child to child on the hands of caregivers or other fomites. Adults experiencing reinfection also have been implicated in the spread of the virus. Contact precautions are sufficient to prevent spread when compliance is meticulous, because the virus is not spread by small particle aerosol to an appreciable degree, and a distance of about 6 ft is likely sufficient to avoid aerosol transmission. However, in practice, adherence to isolation procedures by caregivers often is not complete.

Pathogenesis

Bronchiolitis is caused by obstruction and collapse of the small airways during expiration. Infants are particularly apt to experience small airway obstruction because of the small size of their normal bronchioles; airway resistance is proportional to 1/radius ⁴ . There has been relatively little pathologic examination of RSV disease in the lower airways of otherwise healthy subjects. Airway narrowing likely is caused by virus-induced necrosis of the bronchiolar epithelium, hypersecretion of mucus, and round-cell infiltration and edema of the surrounding submucosa. These changes result in the formation of mucus plugs obstructing bronchioles, with consequent hyperinflation or collapse of the distal lung tissue. In interstitial pneumonia, the infiltration is more generalized, and epithelial shedding may extend to both the bronchi and the alveoli. In older subjects, smooth muscle hyperreactivity may contribute to airway narrowing, but the airways of young infants typically do not exhibit a high degree of reversible smooth muscle hyperreactivity during RSV infection.

Several facts suggest that elements of the host response may cause inflammation and contribute to tissue damage. The immune response required to eliminate virus-infected cells (mostly containing cytolytic T cells) is a double-edged sword, reducing the cells producing virus but also causing host cell death in the process. A large number of soluble factors, such as cytokines, chemokines, and leukotrienes, are released in the process, and skewing of the patterns of these responses may predispose some individuals to more severe disease. There is also evidence that genetic factors may predispose to more severe bronchiolitis.

Children who received a formalin-inactivated, parenterally administered RSV vaccine in the 1960s experienced more severe and more frequent bronchiolitis upon subsequent natural exposure to wild-type RSV than did their age-matched controls. Several children died during naturally acquired RSV infections after FI-RSV vaccinations. This event greatly inhibited the progress in RSV vaccine development, because of both an incomplete understanding of the mechanism and a reluctance to test new experimental vaccines that might induce the same type of response.

Some studies have identified the presence of both RSV and human metapneumovirus viral RNA in airway secretions in a significant proportion of infants requiring assisted ventilation and intensive care. It may be that coinfection is associated with more severe disease. Positive results of polymerase chain reaction (PCR) analysis must be interpreted carefully because this positivity can remain for prolonged periods after infection, even when infectious virus can no longer be detected.

It is not clear how often superimposed bacterial infection plays a pathogenic role in RSV lower respiratory tract disease. RSV bronchiolitis in infants is probably exclusively a viral disease, although there is evidence that bacterial pneumonia can be triggered by respiratory viral infection, including with RSV. A large clinical study of pneumococcal vaccine showed that childhood vaccination reduced the incidence of viral pneumonia by approximately 30%, suggesting viral-bacterial interactions that we currently do not fully understand.