125: Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is a large, enveloped RNA paramyxovirus. Two major strains (groups A and B) have been identified and often circulate concurrently.

Almost all children are infected at least once by 2 years of age. Humans are the only source of infection. Initial infection occurs most commonly during the child's first year. Reinfection throughout life is common. In the United States, RSV usually occurs in annual epidemics during winter and early spring (predominantly November through March). Communities in the southern United States, particularly some communities in the state of Florida, tend to experience the earliest onset of RSV activity (as early as July). RSV is the most common cause of acute lower respiratory tract infection (ALRI) in children <1 year of age. RSV is associated with up to 120,000 pediatric hospitalizations (1–3% of children in the first 12 months of life) each year in the United States. Approximately 400 deaths are attributed to RSV annually. Globally, an estimated 3.4 million new episodes of severe RSV ALRI necessitating hospital admission occur in children <5 years, of whom up to 200,000 die as a complication of infection. Also, RSV is a common cause of nosocomial infection. It can persist on environmental surfaces for several hours and for a half-hour or more on hands. Infection among hospital personnel and others may occur by hand-to-eye or hand-to-nasal epithelium self-inoculation with contaminated secretions.

The disease is generally limited to the respiratory tract. The inoculation of the virus occurs in the upper respiratory tract. The virus replicates in the nasopharynx and spreads to the small bronchiolar epithelium, sparing the basal cells. Subsequently, the virus extends to the type 1 and 2 alveolar pneumocytes in lung, presumably by cell-to-cell spread or via aspiration of secretions. In infants, the disease manifests itself as bronchiolitis or pneumonia. In very rare cases, RSV may be recovered from extrapulmonary tissues, such as liver, spinal, or pericardial fluid. Up to 20% of children with RSV bronchiolitis may be coinfected with another respiratory tract virus, such as human metapneumovirus or rhinovirus.

Risk factors include infants <6 months of age, premature infants born <35 weeks' gestation, infants born with lung disease, infants <2 years of age with heart disease, infants with school-aged siblings, infants who attend day care, family history of asthma, regular exposure to secondhand smoke or air pollution, multiple birth babies, peak RSV season (fall to end of spring), being male, immunocompromised patients (eg, severe combined immunodeficiency, leukemia, or undergoing organ transplant), <1 month or no breast-feeding, and others sharing the bedroom with the infant. High altitude increases the risk of RSV hospitalization. Risk factors for more severe or fatal RSV disease include a premature infant, an infant with complex congenital heart disease (CHD), especially those that cause cyanosis or pulmonary hypertension; an infant with bronchopulmonary dysplasia (chronic lung disease [CLD]); and an infant with immunodeficiency with lymphopenia or receiving therapy that causes immune suppression.

RSV usually begins in the nasopharynx with coryza and congestion. During the first 2–5 days, it may progress to the lower respiratory tract with development of cough, dyspnea, and wheezing. RSV is the most common cause of bronchiolitis and pneumonia in infants <2 years old. Lethargy, irritability, and poor feeding are commonly present in young infants. Apnea may be the presenting symptom in ∼20% of infants hospitalized with RSV and may be the cause of sudden, unexpected death. Most previously healthy infants infected with RSV do not require hospitalization. RSV infection may predispose to reactive airway disease and recurrent wheezing during the first decade of life; the association between RSV bronchiolitis early in life and subsequent asthma remains poorly understood.

1. Enzyme-linked immunosorbent assay (ELISA) and direct fluorescent antibody (DFA) tests utilize antigen capture technology that can be performed in <30 minutes on nasal wash or tracheal aspirate. Their sensitivity and specificity exceed 80–90% (in comparison with culture). False-positive test results are more likely to occur when the incidence of disease is low. Viral isolation from nasopharyngeal secretions in cell culture requires 1–5 days (shell vial techniques can produce results within 24–48 hours). Reverse transcriptase–polymerase chain reaction (RT-PCR) is an alternative to culture for confirming the result of rapid antigen detection assay (which is rarely needed). Culture and PCR may be needed to confirm rapid antigen detection initially to mark the start of the RSV season. Diagnostic serology is not helpful in infants because of the passive transplacental transfer of maternal antibody.

2. Chest radiograph usually reveals infiltrates or hyperinflation.

3. Blood gas analysis may show hypoxemia and occasionally hypercarbia. Development of hypercarbia is an ominous sign of impending respiratory failure.

Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F.

1. Immunization

   1. Passive

      1. Palivizumab (Synagis) provides passive immunity. It is a humanized RSV monoclonal antibody administered intramuscularly (15 mg/kg) monthly during RSV season. It is well tolerated with infrequent or minimal side effects. According to the American Academy of Pediatrics guidelines, palivizumab should be considered for:

         1. Infants and children <2 years with chronic lung disease who have required medical therapy (supplemental oxygen, bronchodilator, diuretic, or corticosteroid therapy) for CLD within 6 months before the anticipated start of the RSV season. These infants and young children should receive a maximum of 5 doses. Patients with the most severe CLD who continue to require medical therapy may benefit from prophylaxis during a second RSV season. Consultation with an infectious disease specialist is recommended.

         2. Infants born before 32 weeks' gestation (31 weeks, 6 days or less). Infants born at 28 weeks of gestation or earlier may benefit from prophylaxis during the RSV season, whenever that occurs during the first 12 months of life. Infants born at 29–32 weeks of gestation may benefit most from prophylaxis if <6 months of age at the start of the RSV season. Once an infant qualifies for initiation of prophylaxis at the start of the RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months or 12 months of age. A maximum of 5 monthly doses is recommended for infants in this category.

         3. Infants born at 32 to <35 weeks' gestation (defined as 32 weeks, 0 days through 34 weeks, 6 days). Prophylaxis may be considered for those infants who are born <3 months before the onset or during the RSV season and for whom at least 1 of 2 risk factors is present. Risk factors include attendance at child care (defined as a home or facility where care is provided for any number of infants or young toddlers in the child care facility), or presence of a sibling <5 years of age who lives permanently in the same household. Multiple births <1 year of age do not qualify as fulfilling this risk factor. Infants in this gestational age category should receive prophylaxis only until they reach 3 months of age and should receive a maximum of 3 monthly doses. Many of them will receive only 1 or 2 doses until they reach 3 months of age.

         4. Children who are ≤24 months of age with hemodynamically significant congenital heart disease. Decisions regarding prophylaxis should be made on the basis of the degree of physiologic cardiovascular compromise. Children who are most likely to benefit include infants who are receiving medication to control congestive heart failure, infants with moderate to severe pulmonary hypertension, and infants with cyanotic heart disease. Because a mean decrease in palivizumab serum concentration of 58% was observed after cardiopulmonary bypass, for children who still require prophylaxis, a postoperative dose of palivizumab (15 mg/kg) should be considered as soon as the patient is medically stable. Infants and children with hemodynamically insignificant heart disease (eg, secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus) are not at increased risk for RSV and generally should not receive immunoprophylaxis.

         5. Infants with congenital abnormalities of the airway or neuromuscular disease. Immunoprophylaxis may be considered for infants who have either significant congenital abnormalities of the airway or a neuromuscular condition that compromises handling of respiratory tract secretions. Infants and young children in this category should receive a maximum of 5 doses of palivizumab during the first year of life.

      2. Motavizumab is another, more potent RSV-neutralizing antibody that is being considered for RSV prevention (not yet U.S. Food and Drug Administration approved).

   2. Active. Several promising candidate RSV vaccines are currently in development both at the preclinical and early clinical stage.

2. Ribavirin has in vitro antiviral activity against RSV, but ribavirin aerosol treatment for RSV is not recommended routinely.

3. Surfactant two small, randomized studies showed that surfactant therapy improves gas exchange and shortens mechanical ventilation days and intensive care unit stay in infants with severe RSV-induced respiratory failure.

4. β-Adrenergic agents may be tried (once) for wheezing associated with RSV bronchiolitis. Repeated doses should be continued only in the small number of infants who demonstrate a well-documented improvement in respiratory function soon after the first dose.

5. Antibiotics, theophylline, and corticosteroids have not been shown to be helpful in the treatment of RSV.

6. Isolation. Contact precautions are recommended for the duration of the illness. RSV present in secretions remains viable for up to 6 hours on countertops. Gowns, gloves, and scrupulous hand-washing practices are required. Patients with RSV infection should be cared for in a single room or placed in a cohort.

The prognosis is generally excellent; however, infants with underlying cardiac or pulmonary conditions can have an increased risk of complications. In prematurely born infants with CLD who are hospitalized because of RSV in the first 2 years of life, there is a reduced airway caliber at school age. Even in normal infants, RSV infection in the first 3 years of life predisposes them to recurrent wheezing up to 11 years of age. Palivizumab prophylaxis given to premature infants in the first year of life has protective effect on physician-diagnosed recurrent wheezing through the ages of 2–5 years, especially in those children with no family history of asthma or atopy.