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Respiratory Syncytial Virus

1998; American Academy of Pediatrics; Volume: 19; Issue: 2 Linguagem: Inglês

10.1542/pir.19.2.55

1529-7233

Toni Darville, Terry Yamauchi,

Viral Infections and Vectors

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children. Each year in the United States nearly 90,000 children are hospitalized due to infection with RSV. Outbreaks occur worldwide during the late fall, winter, and early spring. In the United States, the season generally begins in early November and continues through April. Symptoms of RSV infection range from those of a bad cold to severe bronchiolitis or pneumonia. Involvement of smaller intrapulmonary airways is the hallmark of RSV infection, with bronchiolitis being the most important and distinctive clinical syndrome produced.RSV is an enveloped, single-stranded RNA virus. Two glycosylated surface proteins, the attachment (G) and fusion (F) proteins, are essential for RSV to infect cells. The G protein is important for physical attachment to the cell; the F protein is responsible for fusing viral particles to target cells and for fusing infected cells to neighboring cells, resulting in characteristic syncytia formation. Both F and G proteins elicit neutralizing antibodies. There is antigenic variation among strains of RSV,and monoclonal antibodies have made it possible to divide RSV isolates into two major groups (A and B) and into subtypes within each group. The severity of infection may vary with subgroup; RSV A infections generally are more severe. The G protein exhibits the most antigenic diversity between groups. In contrast, the F protein is relatively conserved. Research, therefore, has concentrated on antibodies that neutralize at F sites because of the ease with which these antibodies can be obtained and their ability to neutralize both viral subgroups.RSV has a worldwide distribution. Outbreaks of infection occur yearly and have an unusually predictable and regular pattern. In temperate climates, RSV characteristically produces midwinter epidemics, with peak prevalence occurring in January to March. An epidemic of RSV infection in a community can be detected by an abrupt rise in the number of hospital admissions of young children who have acute lower respiratory tract disease. Fifty percent of all children develop RSV infection by 12 months of age; by 2 years of age,virtually all children have had RSV infection.Reinfections with RSV occur throughout life. Reinfection rates among preschool children can range from 40% to 70%. The annual risk of reinfection among school-age children,adolescents, and adults is approximately 20%. Reinfection illnesses are generally mild, with most children having only one infection associated with disease of the lower respiratory tract. RSV causes 50% to 90% of the cases of bronchiolitis. It is a relatively uncommon cause of croup, causing fewer than 10% of cases. RSV rarely is isolated in the absence of respiratory disease.Age, gender, and socioeconomic factors appear to influence the expression of RSV disease. The most severe illness occurs in the youngest infants. Boys have more severe disease and a higher incidence of hospitalization. Children from lower socioeconomic areas are hospitalized more frequently, perhaps because of more frequent exposure during the early months of life. In infants younger than 1 year of age, those who have lower cord serum RSV antibody titers and who have been breastfed minimally have been found to be at particular risk for lower respiratory tract disease in the first 5 months of life. Children whose cardiorespiratory or immune function is compromised are at increased risk of severe disease due to RSV infection. Disease in the immediate newborn period is uncommon, but nosocomial outbreaks of RSV have occurred in neonatal nurseries.RSV spreads easily from person to person through respiratory secretions. Spread within families is very high. A frequent scenario is a schoolchild who has a “cold” bringing RSV home and infecting younger siblings, who then develop more serious disease. RSV is a major nosocomial threat on pediatric wards, causing appreciable morbidity. The two primary modes of transmission for RSV include direct contact with large droplets of secretions and self-inoculation by hands made infectious by touching contaminated objects. Transmission by small-particle aerosol is not significant; thus, the risk of acquiring infection decreases with increasing distance from the patient. RSV-infected nasal secretions remain infectious on countertops for more than 6 hours. RSV can be recovered from rubber gloves for 1 hour and 30 minutes, from gowns for 30 minutes, and from hands for 25 minutes. Thus, RSV can survive for extended periods in the hospital environment, increasing the risk for infectious transfer from fomites to hands and then to the eyes and nose of a susceptible individual. The eyes and nose appear to be the primary entry sites for RSV; the mouth is an insensitive route of inoculation.RSV frequently is shed for prolonged periods, which increases its contagious nature. In a study of infants hospitalized for RSV infection, the mean duration of shedding was 6.7 days,with a range of 1 to 21 days. Viral shedding from asymptomatic patients does occur. In the immunocompromised host, viral shedding can extend beyond 6 weeks. Because immunity to this virus is short-lived, there is always a large number of susceptible individuals. Hospital nursery units, child care centers, and other institutions are at high risk for RSV outbreaks. Transmission among infants may not be as important as transmission between infants and staff. Visitors are another potential source of spread.The average incubation period of RSV-induced respiratory disease is 5 days. Inoculation of upper respiratory tract epithelial cells occurs via the eye and nose, with subsequent cell-to-cell transfer of the virus to the lower respiratory tract. Histopathologic descriptions from infant autopsy specimens document infection of the bronchiolar epithelium, with subsequent epithelial cell necrosis. In addition, there is peribronchiolar mononuclear infiltration and submucosal edema. As a result of these changes, plugs of mucus laden with cellular debris are formed, leading to areas of partial or complete airway obstruction. The small lumens of the infant’s airways are especially vulnerable to the obstruction. Air can flow into the narrowed airways on inspiration, but upon expiration, the airway lumen is narrowed further by positive expiratory pressure, resulting in outflow obstruction. Hyperinflation occurs following trapping of air peripheral to the sites of partial occlusion. Subsequently, with complete obstruction, multiple areas of atelectasis develop.Often infants who have lower respiratory tract disease from RSV exhibit pathologic evidence of both pneumonia and bronchiolitis. In cases of pneumonia, there is an interstitial infiltration of mononuclear cells, sometimes accompanied by edema and necrotic areas that lead to alveolar filling.How RSV infection gives rise to these pathogenic findings remains essentially a mystery. Because the infection is associated with recurrent wheezing, Welliver et al studied the role of RSV-specific immunoglobulin E (IgE) and other asthma-related mediators of wheezing and bronchoconstriction in RSV infection. They found RSV IgE in the nasopharyngeal secretions of 45% of RSV-infected children who had wheezing, but not in RSV-infected children who did not have wheezing. In a prospective study, they determined that the RSV IgE response would predict those infants at risk for recurrent wheezing after RSV infection.Leukotriene C4 is a chemical mediator that is both a potent smooth muscle constrictor and a stimulator of mucus production. Leukotriene C4 was detected in nasopharyngeal secretions from 67% of RSV-infected children who had symptoms of bronchiolitis compared with 33% of those whose symptoms were limited to the upper respiratory tract. Whether the presence of leukotriene C4 is a result of more severe inflammation or constitutes an intrinsic difference in host response is unclear.Immunity to RSV following natural infection is transient and imperfect. Infection (or reinfection) of the lower respiratory tract induces some resistance to disease; cumulative immunity from multiple reinfections protects older children and adults against bronchiolitis and pneumonia. Resistance to RSV infection in the upper respiratory tract most likely is mediated primarily by secretory IgA,which explains the transitory nature of immunity in this region. In contrast,the more durable resistance to RSV exhibited by the lungs appears to be mediated primarily by serum neutralizing antibodies. Data obtained from animal models and from human epidemiologic studies suggest that high titers of RSV-neutralizing antibody can prevent serious RSV infection. High titers of maternally derived neutralizing antibody in the first 4 weeks of life may explain the uncommon occurrence of RSV lower respiratory tract disease in this age group. Further data to support the protective role of neutralizing antibody come from recent clinical prophylaxis trials of RSV immune globulin. Monthly infusions of high-dose immune globulin containing high titers of RSV-neutralizing antibody significantly decreased both the incidence and the severity of RSV infection of the lower respiratory tract among children at high risk for this disease.Intact cell-mediated immunity appears to be necessary to terminate RSV infection, but there seems to be a fine balance between the protective and disease-producing effects of cytolytic T lymphocytes, and they may act as a double-edged sword in RSV infection. A formalin-inactivated virus vaccine tested in the mid-1960s failed to protect against RSV infection, and when infection occurred, disease usually was severe. The illnesses that developed were typical of RSV disease but were of much greater severity. Those who received vaccine developed a high titer of serum antibodies to the F glycoprotein of the virus, but these antibodies exhibited a low level of neutralizing activity. Thus, there was an excess of nonfunctional antibody without specific neutralizing activity. Other studies have suggested that those who received vaccine also experienced an imbalance in their cell-mediated immune response, with a predominance of virus-specific CD4+ T lymphocytes and a relative decrease in RSV-specific CD8+ cytotoxic T lymphocytes. This delicate balance in the immune response to RSV infection may make it impossible to dissociate beneficial host responses from pathologic ones.An infant’s first infection with RSV almost always is symptomatic, but the symptoms may range from those of a mild cold to severe bronchiolitis or pneumonia. Pneumonia or bronchiolitis has been estimated to occur in 30% to 70% of infants upon initial exposure to virus. Pneumonia and bronchiolitis are often difficult to differentiate, and many infants appear to have both syndromes. Wheezing and rales may be present on physical examination, and infiltrates may be seen on chest radiographs in both syndromes. In bronchiolitis, the infiltrates are due to atelectasis, but they may be difficult to distinguish from the inflammatory infiltrates of pneumonia. The two classic signs of bronchiolitis are wheezing and hyperexpansion of the lung.RSV infection frequently begins with nasal discharge, pharyngitis,and cough. Hoarseness or laryngitis is not common. Fever occurs in most young children during the initial 2 to 4 days of illness, with temperatures ranging from 38°C to 40°C (100.4°F to 104°F). By the time the child presents to the physician, fever may have resolved, but lower respiratory tract symptoms have increased. An increased cough may herald the lower respiratory tract involvement, which becomes more evident with the onset of dyspnea. As lower respiratory tract disease increases in severity,the work of breathing increases, and the respiratory rate may be remarkably elevated, often reaching 80 breaths/min. Substernal and intercostal retractions are noted during inspiration. The expiratory phase is prolonged,and the chest is hyperexpanded and hyperresonant, evidence of generalized expiratory airflow obstruction. On auscultation, the infant may have rales and wheezes, which may be intermittent and may fluctuate in intensity.Hypoxemia may be profound in many infants who have lower respiratory tract disease due to RSV, yet cyanosis is rarely evident on physical examination. The severity of the wheezing or intercostal retractions does not correlate with the severity of hypoxemia. The clinical finding that best correlates with hypoxemia is an increasing respiratory rate. However, use of the respiratory rate in clinical assessment is problematic because it may vary with fever and is technically difficult to ascertain in a child who is crying. In one group of hospitalized infants, the mean arterial oxygen saturation on admission was 87% (equivalent to a Pao2 of 53 mm Hg). Because the degree of hypoxemia is difficult to assess clinically, the infant’s arterial oxygen saturation must be measured.Clearly, patients who have underlying cardiopulmonary disease or immunodeficiency states are at increased risk from severe RSV disease. However, physicians frequently are faced with evaluating otherwise normal infants who have bronchiolitis and deciding which ones have more severe disease that may require hospitalization. Shaw et al prospectively evaluated 213 infants younger than 13 months of age who had bronchiolitis to identify clues at initial emergency department evaluation that would help to predict disease severity. They identified six independent clinical and laboratory findings that were associated strongly with more severe illness (Table 1). The infant’s oxygen saturation, as determined by pulse oximetry, was the single best objective predictor of more severe disease.Chest radiography most typically shows hyperexpansion and diffuse interstitial pneumonitis (Figure). Hyperinflation is a hallmark of RSV infection and occurs in more than 50% of children who are hospitalized. In approximately 15% of patients, it is the only radiographic abnormality. Consolidation is noted in about 25% of children,particularly in younger infants, and most commonly is subsegmental in the right upper or middle lobe.Apnea can be a relatively early manifestation of RSV infection in young infants. Infants at greatest risk for apnea are those younger than 6 weeks of age, those born prematurely, and those who have the lowest arterial oxygen saturation values on admission. The pathophysiology of apnea in RSV infection is not understood; therapy is supportive, with mechanical ventilation usually required for approximately 48 hours. Recurrent apnea postextubation is not common, and home apnea monitoring following hospital discharge usually is not indicated.RSV disease may occur in neonates, but it is easy to miss the diagnosis because clinical features may be variable and atypical in patients younger than 3 weeks of age. These babies rarely have clinical evidence of lower respiratory tract involvement. Symptoms of an upper respiratory tract infection are seen in fewer than 50%. Most have nonspecific signs, such as poor feeding, lethargy, and irritability. The reasons for the differing clinical features in the very young infant are unclear, but may be due to initial high levels of maternal antibody or other early immune factors.Although lower respiratory tract disease is uncommon after the first 2 years of life, RSV remains an important pathogen at all ages. Repeated or secondary infections are manifested most commonly as an upper respiratory tract illness or tracheobronchitis. Although asymptomatic infections occur, they are relatively uncommon. Nasal congestion and cough are the most common signs. “Colds” caused by RSV infection tend to be more severe and prolonged than those due to other respiratory viruses. Young, healthy adult medical personnel have been followed for clinical symptoms after acquiring RSV infection from infants. In about 50%, the illness is severe enough to cause some incapacitation. A high proportion develop prolonged coughing and signs leading to the diagnosis of tracheobronchitis or bronchitis.The acute complications of RSV infection in infants include respiratory failure,apnea, and rarely, secondary bacterial infection. Fatality rates range from less than 1% to 5%, with most deaths occurring in children who have underlying illnesses. The average duration of hospitalization for previously healthy infants is approximately 4 to 7 days; full recovery may take about 2 weeks. Secondary bacterial infection is unusual in RSV infection. In a 9-year prospective study of infants hospitalized with RSV lower respiratory tract disease, secondary bacterial infection occurred in only 1.2%.Long-term complications of RSV infections are difficult to delineate. An appreciably high rate of children hospitalized in early infancy with RSV lower respiratory tract disease have recurrent episodes of wheezing. These recurrences tend to diminish after the first couple of years, but may be associated with prolonged and silent alterations in pulmonary function. One study of children who had a history of mild bronchiolitis revealed no increased risk for airway hyperreactivity or pulmonary function abnormalities when these children reached 8 to 12 years of age.Complicated RSV infection is most likely to occur in very young infants and those who have underlying diseases, especially cardiopulmonary and congenital disorders. Included among these groups are patients who have bronchopulmonary dysplasia and cystic fibrosis, infants who have congenital heart disease, patients of all ages who are immunocompromised, and children who have underlying neurologic or metabolic diseases.Studies in the early 1980s demonstrated a 35% case fatality rate from RSV infection in young infants who have underlying cardiac,pulmonary, or immunodeficiency disease. More recent clinical investigations have indicated much lower case fatality rates in immunocompetent pediatric patients—1% to 2% in all infants and 3% to 4% in those who have underlying cardiac or pulmonary disease. The subgroup of patients who have pulmonary hypertension have a significantly higher risk of death (9.4%). The lower case fatality rate in recent years most likely can be attributed to improvements in medical, surgical, and critical care. In contrast, pediatric patients who have multiple risk factors requiring ventilation may have mortality rates of 10% to 15%, and immunocompromised children and adults have rates from 20% to 67%. Immunocompromised patients not only exhibit more severe disease, but experience prolonged shedding of the virus.During the evaluation of a child who has symptoms consistent with RSV infection, physicians should keep in mind three major points when determining whether hospitalization for observation and therapy is necessary: 1) global assessment is the most important clinical assessment; 2) risk of severe disease increases with the presence of functionally significant underlying conditions and young age; 3)decreased arterial oxygen saturation (as measured by oximetry) is the best objective indicator of the severity of disease.RSV may be diagnosed by isolation of the virus or by detection of viral antigen in respiratory secretions. Nasopharyngeal secretions canbe obtained with a small suction catheter or bulb syringe. Instillation of a small volume of preservative-free sterile saline facilitates collection of secretions; a nasal wash is more sensitive than a nasopharyngeal swab specimen in the recovery of RSV. Because RSV is quite labile at room temperature, samples of secretions should be placed in a viral transport medium on wet ice at the bedside and transported directly to the laboratory for immediate inoculation to cell cultures. Viral growth may be detected by the appearance of syncytial cytopathic effect in 5 to 7 days. Viral isolates may be identified by use of specific antisera.RSV infection can be diagnosed rapidly by antigen detection, using immunofluorescence techniques or enzyme-linked immunoassays. The advent of monoclonal antibodies has made these techniques sensitive, specific, and clinically useful. As for virus isolation, nasal wash is preferred to nasal swab for these assays. Direct and indirect immunofluorescence tests are useful clinically because the results usually are available the same day; their drawback is the need for an experienced fluorescent microscopist to perform them. Enzyme immunoassays employ a combination of monoclonal antibodies to capture the RSV antigens onto a solid support, followed by a labeled detector antibody, such as a peroxidase-labeled anti-RSV antibody. The sensitivity of these assays generally ranges from 70% to 90%. Most of these tests can be completed in about 30 minutes, and large numbers of specimens can be processed at one time. The advantage of simplicity of these tests has been offset by some loss in the degrees of sensitivity and specificity. Test accuracy can vary dramatically from those of published diagnostic indices if there is not strict adherence to the protocol designed for each assay.The mainstay of treatment for RSV infection is supplemental oxygen and hydration. Because the physiologic abnormality is primarily an unequal ratio of ventilation to perfusion, the response to relatively low concentrations of oxygen usually is good. Oxygenation and adequacy of ventilation should be monitored through the use of pulse oximetry and blood gas measurements. Progressive hypercarbia, hypoxemia unresponsive to oxygen administration, and apnea are indications for assisted ventilation.The only specific drug available for the treatment of RSV infections is ribavirin. In early trials, this synthetic nucleoside was mixed with sterile water and administered as aerosolized particles via an oxygen tent, head box, or mask for 12 to 20 hours per day for 3 or more days. Subsequent trials indicated that the drug could be administered safely to patients receiving mechanical ventilation. Comparison trials demonstrated that in children treated using an oxygen hood, high-dose ribavirin given for 2 hours three times a day was therapeutically equivalent and much more convenient than the longer term administration.Early trials with ribavirin showed improvement in the severity of illness and oxygen saturation but no impact on length of hospital stay in nonventilated patients. A 1991 study compared ribavirin with sterile water placebo in 28 mechanically ventilated patients, 25% of whom had serious underlying disease. The ribavirin group showed a decrease in the duration of mechanical ventilation, need for supplemental oxygen, and hospital stay, although no difference in blood gases was observed.Two recent uncontrolled studies suggest that ribavirin therapy is not effective in reducing the severity of RSV disease. A historical cohort study involved two different hospitals, one that used ribavarin therapy and another that did not. A multivariate analysis controlling for variables such as patient age, underlying disease,and severity of illness at the time of hospital admission found no significant benefit for ribavirin-treated patients in terms of length of hospital stay, the number of days that patients received oxygen therapy, or progression to need for mechanical ventilation. A 1994 randomized study of infants receiving mechanical ventilation found no difference between those treated with ribavirin and those treated with a saline placebo in terms of the number of days of oxygen therapy or mechanical ventilation, length of stay in the intensive care unit, or number of days of hospitalization. It should be noted that these infants were not matched for underlying disease.Ribavirin may be considered for children who have serious underlying disorders, but its efficacy has not been demonstrated conclusively. The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP)currently recommends consideration of ribavirin for children at high risk for serious RSV disease. In experimental RSV infections, treatment with ribavirin combined with RSV immune globulin administered either parenterally or by aerosol was more effective than therapy with either agent alone. Clinical trials are planned in children and immunocompromised adults with monoclonal antibody alone and in combination with ribavirin.Bronchodilators often are used to treat RSV infection,although the data on efficacy are somewhat conflicting. Patients given beta-agonists have shown improvement in clinical scores and arterial oxygen saturation, but several objective studies have not confirmed this finding. In addition, deterioration in lung function has been documented after beta-agonist inhalation. Because the response is unpredictable, it seems reasonable to try a bronchodilator by inhalation and to discontinue its use if no beneficial response can be documented.Several randomized studies have demonstrated improvement in clinical score, respiratory rate,pulmonary mechanics, oxygen saturation, and length of hospitalization when epinephrine was used as a broncho-dilator rather than albuterol. More studies are needed to confirm these results.Anti-inflammatory agents are being assessed for patients who have RSV bronchiolitis. Thus far, controlled studies have failed to show any benefit from steroids. A recent study reported that babies who had RSV bronchiolitis and received either cromolyn sodium or budesonide on the second day of hospitalization that was continued for 2 to 4 months after hospitalization had fewer subsequent wheezing episodes and hospitalizations for wheezing. More studies are needed to confirm these results.Prevention of infection by interrupting transmission of the virus is probably impossible at home. However, attempts to prevent spread of the virus are warranted in hospitals. Because there is no true aerosolization of virus, special airflow rooms and conventional masks are not needed. Use of gowns is indicated because soiling or contamination of clothing is likely and because fomites probably play a role in transmission. In fact, the use of gowns and gloves has been shown to decrease nosocomial spread of RSV significantly. Gloving is primarily a substitute for good hand-washing. Because epidemiologic studies document increased nosocomial RSV acquisition when infected infants are not isolated, it is appropriate to assign these patients to private or RSV-designated rooms. Staff who have respiratory symptoms should wear masks when caring for patients and should not care for high-risk infants. If possible, nurses caring for RSV-infected patients should not care for uninfected patients, especially on infant wards and transplant units.Previous attempts to prevent this disease with the use of vaccine were not successful. Recently, however, an RSV immune globulin intravenous (RSV-IGIV) has been released. The premise for its use is to provide enough circulating antibody passively to at-risk infants to protect them for a short period of time. RSV-IGIV has been licensed and is approved for the prevention of serious lower respiratory tract infections caused by RSV in children younger than 24 months of age who have bronchopulmonary dysplasia or a history of preterm birth (≤35 weeks’gestation). An intravenous dose of 750 mg/kg is administered once monthly during the period of peak RSV activity.In two large trials,administration of RSV-IGIV reduced the incidence of hospitalization by 41%to 57% and decreased the total days of hospitalization due to RSV infection by 53% to 97%. These findings have been demonstrated for preterm infants who did and who did not have bronchopulmonary dysplasia. Between 1% and 3.3% of children had medically significant adverse events related to RSV-IGIV administration, including fluid overload, oxygen desaturation, and fever. These findings are very encouraging, but RSV-IGIV prophylaxis is costly and logistically demanding. Most of these infants already have received numerous infusions, making venous access a real problem. In the original report, at least one problem was reported in 60% of the patients. Also, six infants died who were infused with RSV-IGIV. Five of these infants had cyanotic congenital heart disease. Hence, this product is not currently licensed for high-risk infants who have cyanotic heart disease.The AAP currently recommends that RSV-IVIG prophylaxis be considered for infants and children younger than 2 years of age who have bronchopulmonary dysplasia and are receiving or have received oxygen therapy within the 6 months prior to the anticipated RSV season. Infants who have a gestational age of 28 weeks or less should be considered for prophylaxis until they are 12 months of age,as should those of 29 to 32 weeks’ gestational age until they are 6 months of age. Some vaccines (measles, mumps, rubella) cannot be administered for 10 months to those who receive RSV-IGIV because the globulin will interfere with the activity of the vaccine. The chickenpox vaccine may fall under the same guidelines. Some data suggest that responses to inactivated vaccines may be inadequate, so some children may go years without the appropriate vaccines. Decisions should be individualized to the patient. Clinicians may wish to use RSV rehospitalization data from their own region to assist in decision making.