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. 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 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 is a double-edged sword, reducing the cells producing virus but 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 infection after vaccination. This event has greatly inhibited 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 co-infection 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 is no longer detectable.

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 about 30%, suggesting viral-bacterial interactions that we currently do not fully understand.

Clinical Manifestations

Typically, the first sign of infection in infants with RSV is rhinorrhea. Cough may appear simultaneously but more often does so after an interval of 1-3 days, at which time there may also be sneezing and a low-grade fever. Soon after the cough develops, the child who experiences bronchiolitis begins to wheeze audibly. If the disease is mild, the symptoms may not progress beyond this stage. Auscultation often reveals diffuse fine inspiratory crackles and expiratory wheezes. Rhinorrhea usually persists throughout the illness, with intermittent fever. Chest radiograph findings at this stage are frequently normal.

If the illness progresses, cough and wheezing worsen and air hunger ensues, with increased respiratory rate, intercostal and subcostal retractions, hyperexpansion of the chest, restlessness, and peripheral cyanosis. Signs of severe, life-threatening illness are central cyanosis, tachypnea of >70 breaths/min, listlessness, and apneic spells. At this stage, the chest may be significantly hyperexpanded and almost silent to auscultation because of poor air movement.

Chest radiographs of infants hospitalized with RSV bronchiolitis have normal findings in about 30% of cases, with the other 70% showing hyperexpansion of the chest, peribronchial thickening, and interstitial infiltrates. Segmental or lobar consolidation is unusual and pleural effusion is rare.

In some infants, the course of the illness may resemble that of pneumonia, the prodromal rhinorrhea and cough being followed by dyspnea, poor feeding, and listlessness, with a minimum of wheezing and hyperexpansion. Although the clinical diagnosis is pneumonia, wheezing is often present intermittently and the chest radiographs may show air trapping.

Fever is an inconstant sign in RSV infection. In young infants, particularly those who were born prematurely, periodic breathing and apneic spells have been distressingly frequent signs, even with relatively mild bronchiolitis. Apnea is not necessarily caused by respiratory exhaustion, but rather appears to be a consequence of alterations in central control of breathing.

RSV infections in profoundly immunocompromised hosts may be severe at any age of life. The mortality associated with RSV pneumonia in the first few weeks after hematopoietic stem cell or solid organ transplantation in both children and adults is high. RSV infection does not seem to be more severe in HIV-infected patients with reasonable control of HIV disease, although these patients may shed virus for prolonged periods.

Diagnosis

Bronchiolitis is a clinical diagnosis. RSV can be suspected with varying degrees of certainty on the basis of the season of the year and the presence of the virus in the community. Other epidemiologic features that may be helpful are the presence of colds in older household contacts and the age of the child. The other respiratory viruses that attack infants frequently during the first few months of life are parainfluenza virus type 3, human metapneumovirus, and influenza. Rhinovirus is frequently found in the respiratory tract of children, and there is growing evidence that this virus may contribute to lower respiratory tract disease.

Routine laboratory tests are of minimal diagnostic use in most cases of bronchiolitis or pneumonia caused by RSV. The white blood cell count is normal or elevated, and the differential cell count may be normal with either a neutrophilic or mononuclear predominance. Hypoxemia as measured by pulse oximetry or arterial blood gas analysis is frequent and tends to be more marked than anticipated from the clinical findings. A normal or elevated blood CO₂ value in a patient with a markedly elevated respiratory rate is a sign of respiratory failure.

The most important diagnostic concern is to identify bacterial or chlamydial involvement. When bronchiolitis is not accompanied by infiltrates on chest radiographs, there is little likelihood of a bacterial component. In infants 1-4 mo of age, interstitial pneumonitis may be caused by Chlamydia trachomatis (Chapter 218). With C. trachomatis pneumonia there may be a history of conjunctivitis, and the illness tends to be of subacute onset. Coughing and inspiratory crackles may be prominent; wheezing is not. Fever is usually absent.

Lobar consolidation without other signs or with pleural effusion should be considered of bacterial etiology until proved otherwise. Other signs suggesting bacterial pneumonia are neutrophilia, neutropenia in the presence of severe disease, ileus or other abdominal signs, high temperature, and circulatory collapse. In such instances, antibiotics should be initiated.

Definitive diagnosis of RSV infection is based on the detection in respiratory secretions of live virus by cell culture. The presence of viral RNA (detected by a molecular diagnostic test using reverse transcription PCR [RT-PCR]) or viral antigens (detected by a rapid diagnostic test, usually a membrane blotting test incorporating antibody detection of viral proteins) is strongly supportive in the right clinical setting. The antigen test is less sensitive than culture, and RT-PCR analysis is more sensitive. An aspirate of mucus or a nasopharyngeal wash from the child’s posterior nasal cavity is the optimal specimen. Nasopharyngeal or throat swabs are less preferable but acceptable. A tracheal aspirate is unnecessary, but endotracheal tube lavage fluid from patients intubated for mechanical ventilation can be tested. The specimen should be placed on ice, taken directly to the laboratory, and processed immediately for culture, antigen detection, or PCR analysis.

Treatment

The treatment of uncomplicated cases of bronchiolitis is symptomatic. Humidified oxygen and suctioning are usually indicated for hospitalized infants who are hypoxic. Many infants are slightly to moderately dehydrated, and therefore fluids should be carefully administered in amounts somewhat greater than those for maintenance. Often intravenous or tube feeding is helpful when sucking is difficult because of tachypnea.

There is disagreement among experts regarding the usefulness of epinephrine or β₂-agonists in RSV bronchiolitis. Most patients do not receive lasting benefit from prolonged therapy, which is associated with a relatively high frequency of side effects. Corticosteroid therapy is not indicated except in older children with an established diagnosis of asthma, because its use is associated with prolonged virus shedding and is of no proven clinical benefit.

In nearly all instances of bronchiolitis, antibiotics are not useful, and their inappropriate use contributes to development of antibiotic resistance. Interstitial pneumonia in infants 1-4 mo old may be caused by C. trachomatis, and macrolide therapy may be indicated for that infection.

Ribavirin is an antiviral agent delivered through an oxygen hood, face mask, or endotracheal tube with use of a small particle aerosol generator most of the day for 3-5 days. Early small trials of its use suggested a modest beneficial effect on the course of RSV pneumonia, with some reduction in the duration of both mechanical ventilation and hospitalization. Subsequent studies failed to document a clear beneficial effect of ribavirin. Most medical centers do not use ribavirin currently for RSV infection. The monoclonal antibody palivizumab is licensed for prophylaxis in high-risk infants, but small clinical trials using the antibody as a therapy during established infection have not shown benefit to date.

Prognosis

The mortality rate of hospitalized infants with RSV infection of the lower respiratory tract is low in the developed world. Almost all deaths occur among young, premature infants or infants with underlying disease of the neuromuscular, pulmonary, cardiovascular, or immunologic system. It is estimated, however, that hundreds of thousands of children worldwide in resource-poor settings die each year from RSV.

Many children with asthma have a history of bronchiolitis in infancy. There is recurrent wheezing in 30-50% of children with severe RSV bronchiolitis in infancy. The likelihood of recurrence is increased in the presence of an allergic diathesis (e.g., eczema, hay fever, or a family history of asthma). With a clinical presentation of bronchiolitis in a patient >1 yr of age, there is an increasing probability that, although the episode may be virus induced, this is likely the first of multiple wheezing attacks that will later be diagnosed as hyperreactive airways disease or asthma. Asthma is difficult to diagnose in the first years of life. It is not clear at this time whether early, severe RSV wheezing disease causes some cases of asthma or whether subjects destined to suffer asthma present with symptoms first when provoked by RSV infection during infancy.

Prevention

In the hospital, the most important preventive measures are aimed at blocking nosocomial spread. During RSV season, high-risk infants should be separated from all infants with respiratory symptoms. Gowns, gloves, and careful handwashing should be used for the care of all infants with suspected or established RSV infection. A high level of compliance with contact isolation is essential. Viral laboratory tests are adequate for diagnosis in the setting of acute disease, but they are not designed to detect low levels of virus. Therefore, contact precaution isolation should be observed for most patients admitted for acute disease assigned for the duration of hospitalization; rapid antigen tests should not be used to determine whether or not a patient still requires isolation. Ideally, patients with RSV or metapneumovirus infections are housed separately, because co-infection may be associated with more severe disease.