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 Paramyxoviridae, along with parainfluenza and measles viruses, and is in the subfamily Pneumovirinae, which also contains the human metapneumovirus (Chapter 253). It is the only member of the genus Pneumovirus that infects humans. There are 2 antigenic subgroups of RSV, their differentiation based primarily on variation in 1 of the 2 surface proteins, the G glycoprotein that is responsible for attachment. This antigenic variation caused by point mutations due to infidelity of the virus RNA polymerase may to some degree contribute to the frequency with which RSV re-infects children and adults.

RSV replicates in a wide variety of cell line monolayer cultures in vitro, and in HeLa or HEp-2 cells produces characteristic syncytial cytopathology, from which the virus derives its name. Interestingly, it is now known that the virus does not cause large syncytia in polarized epithelial cells in vitro, and it is not clear that syncytium formation occurs to any significant degree in vivo.

Epidemiology

RSV is distributed worldwide and appears in yearly epidemics. In temperate climates, these epidemics occur each winter over 4-5 mo. 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 USA, such as Florida, report a moderate incidence year-round. In the Southern hemisphere, outbreaks also occur during winter months in that hemisphere. RSV outbreaks often overlap with outbreaks of influenza and human metapneumovirus but are generally more consistent from year to year and result in more disease overall, especially among infants <6 mo of age. In the tropics, the epidemic pattern is less clear. This pattern of widespread annual outbreaks and the high incidence of infection during the 1st 3-4 mo of life are unique among human viruses.

Transplacentally acquired anti-RSV maternal immunoglobulin (Ig) G serum antibodies, if present in high concentration, appear to provide partial but incomplete protection. These IgGs may account for the lower severity of RSV infections during the 1st 4-6 wk of life, except among infants born prematurely, who receive less maternal immunoglobulin. Breast-feeding provides substantial protection against severe disease to female infants but not to male infants. RSV is one of the most contagious viruses that affect humans. Infection is nearly universal among children by their 2nd birthdays. Re-infection occurs at a rate of 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 2nd and subsequent infections.

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

Asymptomatic RSV infection is rare in young children. Most infants experience coryza and pharyngitis, often with fever and frequently with otitis media due to 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 2 processes frequently coexist. All RSV diseases of the lower respiratory tract (excluding croup) have their highest incidence at 6 wk-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 diagnosis of virus-associated wheezing illnesses in toddlers is confusing, as these illnesses are variably termed wheezing associated respiratory infection (WARI), “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 this diagnostic term only later in life. Viral pneumonia is a persistent problem throughout childhood, although RSV becomes less prominent as the etiologic agent after the 1st 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 boys than in girls by a ratio of about 1.5:1. Other risk factors with similar impact include ≥1 sibling in the home, white race, rural residence, maternal smoking, and maternal education <12 yr. The medical factors in infants associated with highest risk are bronchopulmonary dysplasia, congenital heart disease, immunodeficiency, and prematurity. Still, most infants admitted to hospital because of RSV infection do not have strong easily identifiable risk factors. Therefore, any strategy for prophylaxis only of individuals with strong risk factors probably could prevent only about 10% of hospitalizations, even if it was 100% effective in treated high-risk individuals.

The incubation period from exposure to 1st symptoms is about 3-5 days. The virus is excreted for variable periods, probably depending on severity of illness and immunologic status. Most infants with lower respiratory tract illness shed infectious virus 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 undergoing re-infection. 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 becomes 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. Adults undergoing re-infection also have been implicated in spread of the virus. Contact precautions are sufficient to prevent spread when compliance is meticulous, as the virus is not usually spread by small particle aerosol. Adherence to isolation procedures by caregivers often is not complete, however.

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/radius⁴