Respiratory Syncytial Virus

After completing this article, readers should be able to: RSV is the major pathogen responsible for yearly outbreaks of lower respiratory tract disease in young children. Approximately 75,000 to 125,000 infants in the United States are estimated to be hospitalized yearly because of bronchiolitis or pneumonia from RSV. Although its significance in the young pediatric population has been recognized for more than 40 years, only more recently has RSV been confirmed as an important cause of respiratory tract illness throughout life. Increased understanding of the virus and the host response to it has resulted in expanded therapeutic and preventive options. Although elimination of RSV disease currently does not appear to be a realistic objective, control of RSV infection is possible and is being rigorously pursued.RSV is a member of the Paramyxoviridae family, genus pneumovirus. It was identified initially in chimpanzees that had coryza and was named chimpanzee coryza agent. Subsequently, this virus was isolated from infants who had respiratory symptoms and was renamed respiratory syncytial virus because of the characteristic syncytial pattern observed in tissue culture. It is an enveloped virus that has a single, negative-strand genome of 5×106 kD. The genome encodes 10 mRNAs, each of which codes for an individual protein. Five proteins (F, G, SH, M, M2) are associated with the viral envelope. The F or fusion protein appears to initiate the fusion of viral and cellular membranes. The large G glycoprotein, notable for its high carbohydrate content, mediates attachment of the virus to host cells. The role of the small hydrophobic SH protein is unknown. The matrix proteins, M and M2, are believed to be involved in the association of the nucleocapsid with the viral envelope. Three proteins (L, N, P) are associated with the nucleocapsid and its function. Also found in infected cells are two nonstructural proteins, NS1 and NS2.RSV isolates may be divided into two major groups, A and B, based primarily on the differences in the G surface glycoprotein. This virus grows optimally at a pH of 7.5, and although temperature-sensitive, is recoverable for hours from countertops and for more than 1 hour from rubber gloves contaminated with RSV-infected nasal secretions. This stability in the hospital environment contributes to the efficacy of RSV as a nosocomial pathogen.RSV has a worldwide presence, with predictable, yearly epidemics. In temperate climates, RSV usually appears in the community in November or December and persists until April or May. The two strain groups can circulate concurrently during seasonal outbreaks, with the A strains usually being dominant. Reports about the role of strain variation in clinical severity conflict, but strain variation does not appear to have the same significant clinical impact as it does with strain variation in influenza.An epidemic of RSV may be recognized by the associated marked increase in cases of lower respiratory tract illness among young infants. The peak incidence of disease observed in hospitalized children occurs between 2 and 5 months of age. Within the first 2 years of life, most children will have had one or more RSV infections, verified by detectable antibody to the virus. More severe disease is observed in boys and children from lower socioeconomic groups. Although milder than a primary infection, reinfections are common and recur throughout life.The incubation period for RSV infection is 2 to 8 days. An individual is exposed to RSV following ocular or nasal contact with RSV-infected secretions. RSV may stay localized to the upper airway, resulting in cough and rhinorrhea, with 50% or more of primary infections in infancy spreading several days later to the lower respiratory tract. The pathology of bronchiolitis consists of a peribronchiolar infiltrate of lymphocytes and proliferation of bronchiolar epithelium (Fig. 1). Obstruction occurs due to mucus and sloughed epithelium and is followed by hyperinflation. Infants may have concurrent bronchiolitis and pneumonia. Interstitial infiltrates of mononuclear cells are observed in RSV pneumonia.The precise nature of the immune response to RSV is not well understood. Most of the research has been performed in animal models, which may not represent natural infection in humans. Investigators have proposed that different components of the immune system are involved not only in recovery from RSV infection, but also in its pathogenesis.Serum antibody appears to offer some protection against RSV infection. Higher levels of maternal antibody have been associated with lower infection rates in infancy. Prophylactic administration of antibody to RSV has been effective in the reduction, but not elimination, of severe disease due to RSV. No level of serum antibody, however, provides complete protection from RSV. The type of antibody generated also may be critical. The enhanced disease observed with the formalin-inactivated RSV vaccine in the 1960s may have resulted in part from a detrimental antibody response.Animal studies indicate that cell-mediated immunity is integral to viral clearance and recovery from infection. Infection is more severe and shedding of RSV is prolonged in both humans and animals who have T-cell deficiencies. As with serum antibody, the type of T-cell response stimulated by infection or vaccine may influence how well RSV is controlled. The type and extent of cytokine production also may play an important role in the inflammatory response to the virus.A wide spectrum of illness is associated with RSV infection, which rarely is asymptomatic. In young children, illness frequently begins with cough, nasal congestion, and fever. Otitis media is common. The risk of developing lower respiratory tract disease with a primary infection is at least 50%. After several days of upper respiratory tract signs, infants may develop tachypnea, dyspnea, and intercostal retractions. Difficulty in feeding and hypoxemia are common. The primary manifestations of lower respiratory tract disease in infants are bronchiolitis and pneumonia. These two syndromes may be difficult to distinguish and may occur simultaneously. The characteristic clinical features of bronchiolitis are wheezing and hyperaeration. Rales and rhonchi may be heard in infants who have either bronchiolitis or pneumonia. Occasionally, a young infant who has RSV infection may present with signs suggestive of overwhelming sepsis. Apnea may be the presenting manifestation of RSV disease, particularly in preterm infants. Croup due to RSV is reported in fewer than 10% of cases.Although most infants hospitalized for RSV infection have been healthy previously, certain children are at increased risk for severe disease, including preterm infants and infants who have chronic lung disease or functionally important congenital heart disease. Among the others at risk for more severe or complicated RSV infection are those who are immunocompromised, have certain neurologic disorders, or have multiple congenital anomalies.Repeated infections with RSV continue throughout life, although disease typically is milder and generally localized to the upper respiratory tract. Cough may be more severe and persistent, however, than that observed with other common cold agents, such as rhinovirus. Significant lower respiratory tract disease is uncommon, but can occur in healthy older children and adults, and infection may be followed by a prolonged period of airway hyperactivity. In the elderly, particularly those who have chronic illness, RSV may cause significant lower respiratory tract illness.Immunocompromised adults and children, especially those undergoing bone marrow transplantation, are at high risk for severe and often fatal RSV disease. Infection with RSV prior to engraftment of the bone marrow has been associated with severe pneumonia and a high mortality rate. Upper respiratory tract symptoms in these patients should raise concern about RSV infection. If RSV is identified early in the course of illness, therapeutic intervention may be beneficial.The acute complications of RSV include respiratory failure, apnea, and secondary bacterial infection. Children who are considered at high risk for severe RSV disease should be monitored closely for respiratory failure. Apnea occurs predominately in the very young infant and in preterm infants. Serious bacterial superinfection rarely is observed. Otitis media due to RSV or a bacterial pathogen is frequent.Evaluation of the possible long-term sequelae of RSV infection has been the focus of numerous studies. It has been suggested that RSV lower respiratory tract disease early in life may enhance the risk for the subsequent development of reactive airway disease. This association has been difficult to study because of the numerous factors believed to influence the course of hyperreactivity of the lungs and the high frequency of RSV and other respiratory viral infections during childhood. Recent studies have suggested that multiple infections early in life actually protect against the subsequent development of asthma. As more preventive and therapeutic agents are used, interventional studies may define better the relationship between RSV infection and chronic respiratory disease.RSV often is diagnosed accurately in young children based on the season plus a typical history and findings on physical examination. In older children and adults, however, the signs and symptoms of RSV are less characteristic and easily may be attributed to other pathogens.Roentgenographic findings observed with RSV lower respiratory tract infection in children vary, but often are much milder than suggested by the clinical presentation. Hyperinflation of the lung, peribronchial thickening, and increased interstitial markings are common abnormalities. Areas of consolidation, which may be due to atelectasis, characteristically are noted in the right upper or middle lobes (Fig. 2). In adults who have RSV pneumonia, the roentgenographic findings are nonspecific.Although a definitive diagnosis of RSV may not be necessary for children who have mild disease, laboratory confirmation often is important for the hospitalized patient and those at increased risk for severe disease. Determining the onset of the RSV season frequently is helpful. Accurate and timely diagnosis of RSV infection may limit further laboratory evaluation and antibiotic use.RSV may be identified by viral isolation or by one of numerous rapid assays. For infants, the nasal wash is the preferred method of obtaining a specimen. A tapered rubber bulb or narrow-gauge flexible tubing attached to a syringe can be used to instill and remove 3 to 7 mL of normal saline. If a wash is not possible, vigorous swabbing of both nasal turbinates combined with a swab of the pharynx is the preferred method for infants, older children, and adults. Specimens obtained in hospitalized patients by endotracheal tube aspirate or bronchoalveolar lavage are the most likely to be positive.If culture of RSV is desired, the specimen should be placed in a viral culture medium and kept cold during transport to the laboratory. RSV grows in multiple different cell lines, but Hep-2 and HeLa cells are preferred. The syncytial and giant cell pattern typical of RSV usually is observed within 3 to 7 days. If shell vial cultures are used, RSV may be identified more rapidly. Fluorescein-labeled antibody is applied to these cultures to detect RSV antigen in the specimen (Fig. 3). Although rapid assays are used more often for RSV detection, they generally are screening tests. Because the sensitivities of the assays vary widely, viral cultures may be very useful. Not only can viral cultures verify results of rapid testing, but they also can identify other pathogens. Many hospital laboratories, however, do not perform viral cultures.Several different types of rapid diagnostic tests are available for RSV. The assays used most commonly in clinical microbiology laboratories are fluorescent antibody tests and enzyme immunoassays. The enzyme immunoassay is more automated and may be easier to use and less expensive for a hospital laboratory. The reported sensitivity and specificity of these assays depends on the quality of the specimen and the technique of the laboratory. Detection of RSV by reverse-transcriptase polymerase chain reaction is being evaluated for possible clinical use. RSV also may be identified on culture of specimens obtained from lung biopsy or by immunohistochemistry. Giant cells and syncytia may be present on histologic examination.Serologic testing for RSV is not useful for the management of RSV infections. A reliable immunoglobulin (Ig) M assay for RSV generally is not available, and paired specimens are needed to verify a recent seroconversion. Immunofluorescence, neutralization, and enzyme-linked immunosorbent assays are some of the available assays. Serologic testing has been used for epidemiologic studies, but results may be difficult to interpret in certain populations such as the very young and immunosuppressed patients, who may not develop an antibody response.Therapy for RSV remains largely supportive. The need for supplemental oxygen and intravenous fluids should be monitored closely. Although bronchodilators frequently have been part of the treatment for RSV, their benefit is limited. Implementation of an evidence-based guideline for bronchiolitis, which recommended against the routine use of bronchodilators, was associated with fewer admissions and decreased days of hospitalization. If these agents are administered, patients should be monitored closely for a response and the treatment discontinued if not effective. Clinical improvement has not been demonstrated with the administration of corticosteroids alone or in combination with a bronchodilator in the management of bronchiolitis.Vitamin A supplementation, which has been recommended for some children 6 months to 2 years of age who are hospitalized with measles, has been evaluated for use in RSV infections. Despite lower serum concentrations of vitamin A in children hospitalized with RSV and an inverse correlation with disease severity, studies in the United States have not shown a beneficial effect of vitamin A supplementation for RSV disease.Ribavirin is the only antiviral agent that currently is licensed for the treatment of RSV infection. It is a synthetic nucleoside analog that interferes with expression of mRNA and inhibits protein synthesis. Administration of this drug by nebulization has been associated with clinical benefit and improved oxygenation, but a decrease in hospital stay has not been documented. Results of studies in mechanically ventilated children have been conflicting. Because of questions regarding efficacy relative to the cost of this drug, the use of ribavirin for the treatment of RSV has been controversial. Concerns also have been raised about possible adverse reactions to the drug and potential toxicity in caregivers. Toxicity has not been observed with therapy in infants. Although further studies of the use of ribavirin for treatment of RSV infections are needed, the American Academy of Pediatrics (AAP) has recommended that decisions about ribavirin therapy be based on the individual clinical situation and the physician’s experience. Ribavirin has been administered to adults who have RSV infection, although there are no guidelines for its use. Ribavirin is licensed for treatment of RSV by the aerosol route and is administered by oxygen hood, tent, or mask until improvement is seen (usually 3 to 7 days). Longer courses may be helpful in immunocompromised patients who have more severe disease and prolonged shedding. Ribavirin may be administered to a patient on a ventilator, but special care must be taken because deposition of drug in the system may cause clogging.Intravenous and inhaled immune globulin have been used to treat small numbers of patients who have RSV disease, but without significant benefit. Currently, the major use of RSV immune globulin for treatment of RSV disease is in immunocompromised patients, administered in combination with ribavirin. This approach may have some benefit, but controlled studies are lacking. The role of immune globulin preparations for the treatment of RSV is being investigated further.Other drugs that have been tried for the treatment of RSV bronchiolitis and pneumonia but require further clinical evaluation include intramuscular alpha-2a-interferon, surfactant, and recombinant human deoxyribonuclease I. Drugs that influence cytokine production in response to RSV infection also may be useful alone or in combination with drugs that have specific antiviral activity. Many new and novel antiviral agents that have activity against RSV are being developed and hold promise for expanded therapeutic options that yet may result in disease control.Various strategies can be used to prevent RSV transmission in the community and the hospital. Parents of newborns and children at high risk for serious RSV disease should be educated about the significance of respiratory viruses. Families often are unaware that a minor cold in a toddler can cause life-threatening illness in a young infant or older household member who has underlying chronic disease. Close contact with individuals who have respiratory symptoms or fever should be avoided when possible, and frequent hand washing is advised. Elective hospital admissions for children at high risk for severe disease should be postponed during the RSV season.In the hospital, annual discussions about RSV remind staff about infection control who have RSV infections should be identified on and placed in contact hand washing is and the most important method of infection should be educated about the of of RSV and that shedding of RSV typically about 3 to 8 but may for particularly in immunosuppressed Prophylactic administration of antibody to RSV has been shown to decrease severe disease. Currently, two have been for use in children at high risk for RSV disease. 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