Respiratory Syncytial Virus Infection Treatment & Management

Supportive care is the mainstay of therapy for respiratory syncytial virus (RSV) infection. If the child can take fluids by mouth and tolerate room air, outpatient management (with close physician contact as needed) is reasonable, especially in the absence of significant underlying risk factors. The Clinical Practice Guidelines published by the American Academy of Pediatrics in 2014 does not recommend medications such as bronchodilators, epinephrine and corticosteroids as the available clinical data does not support their use in the treatment of typical RSV bronchiolitis. ^[19]

Although bronchodilators have been used, no convincing data as to their efficacy in this setting exist particularly in first time in care of first time wheezing associated with RSV.

For children who require hospitalization for RSV infection, supportive therapy is still the mainstay of care. Such therapy may include administration of supplemental oxygen (guided by respiratory rates, work of breathing, oxygen saturation, and arterial blood gas values, as indicated), mechanical ventilation, and fluid replacement, as necessary. Additionally, bronchodilator therapy with beta agonists is frequently used, though data on potential beneficial effects of such agents in this condition are not convincing

Most infants who are hospitalized with RSV infection are unable to tolerate milk or feedings well and frequently vomit or spit up. A brief course of intravenous (IV) fluids is generally administered in this setting, with resumption of normal feeding as the child recovers (typically over 2-3 days).

Although corticosteroids are administered at times to patients with RSV infection, the available clinical data do not support the use of corticosteroids in the treatment of typical RSV bronchiolitis. ^[20]

At least a subset of patients with RSV-related lower respiratory tract infection (LRTI) appear to benefit from bronchodilator therapy, and a trial with monitoring for effect on respiratory rate, pulse, and oxygenation may be reasonable in selected cases. Alpha agonists (eg, vaporized epinephrine) have also been used during acute bronchiolitis episodes, though again, available data do not clearly demonstrate efficacy.

Ribavirin, a broad-spectrum antiviral agent in vitro, is licensed by the US Food and Drug Administration (FDA;1985) for the aerosolized treatment of children with severe RSV disease. The recommended dose is 6 g of drug in 300 mL of distilled water via a small-particle aerosol generator (SPAG unit) over 12-20 hours per day for 3-7 days, depending on clinical response. There is some evidence to suggest that equivalent efficacy can be achieved by giving a higher concentration of the drug (6 g/100 mL distilled water) over 3 discrete 2-hour periods per day.

The use of ribavirin has been limited by its high acquisition cost and its lack of demonstrated benefit in decreasing hospitalization or mortality. Secondary toxicity to health care workers from exposure to aerosolized drug was a theoretical concern in the past, though such risk is unproved. For these reasons, ribavirin is primarily reserved for patients with significant underlying risk factors and severe acute RSV disease (eg, transplant recipients).

Transmission of RSV appears to occur via contact with infected secretions through hand-to-hand spread or fomites and respiratory droplets, with an incubation period of 3-5 days. ^[21] Aerosolized secretions appear to be less important in RSV transmission; thus, attention to handwashing and cleaning of environmental surfaces are important to prevent RSV transmission.

In the hospital setting, isolation of patients infected with RSV as a group and wearing of masks and gowns during close contact with infected children are important in controlling nosocomial spread. Transmission of RSV on pediatric units has been shown to be a significant problem. Despite good environmental hygiene, RSV infection is likely to occur with significant frequency.

Immunoglobulins

Immunoglobulin products with high anti-RSV antibody titers have proved beneficial when given monthly for prophylaxis in select groups of high-risk infants. The high cost of administering these products (approximately $5,000-6,000 per child per year) has led to debate regarding which children should receive such prophylaxis.

RSV immune globulin intravenous (RSV-IGIV) is a pooled polyclonal human immunoglobulin product prepared from donors with high titers of RSV antibodies. When administered to high-risk infants with prematurity or chronic lung disease, it has yielded a significant decrease in RSV-related hospitalization. Additionally, treated infants have had less severe hospital courses if admitted with RSV disease, fewer other respiratory infection hospitalizations, and fewer cases of otitis media than placebo recipients.

RSV-IGIV requires intravenous (IV) administration at a dose of 750 mg/kg monthly during RSV season (typically, November through May or April in temperate climates). The need for monthly IV infusion and fluid volume loading limited the number of children who could be protected. As a consequence of this limitation, as well as the licensure of palivizumab by the US Food and Drug Administration (FDA) in 1998, RSV-IGIV is no longer being manufactured.

Currently, passive protection against RSV is achieved successfully through injection of the humanized monoclonal anti-RSV antibody palivizumab at a dosage of 15 mg/kg/month intramuscularly (IM) per month. ^[22] This product demonstrated a 55% reduction in RSV hospitalization in premature infants born at less than 35 weeks’ gestation who were younger than 6 months chronological age and in infants who had bronchopulmonary dysplasia and were younger than 24 months chronological age. ^[20]

A separate study in infants younger than 2 years who had hemodynamically significant congenital heart disease also demonstrated safety and efficacy of palivizumab prophylaxis in this high-risk population; subsequent postmarketing studies continued to demonstrate efficacy. In November 2005, a stable liquid preparation of the drug became available, replacing the lyophilized form used previously. The dosing and concentration of the liquid preparation have not changed.

Palivizumab

Palivizumab is approved for prophylaxis of children at high risk for severe RSV disease. Clinical trials have demonstrated efficacy and safety in premature infants younger than 6 months and those with chronic lung disease of infancy and congenital heart disease younger than 2 years at the start of the RSV season. Infants with immunodeficiency or severe neuromuscular disease have not been studied in conjunction with these products, because the numbers of such patients are limited.

The American Academy of Pediatrics (AAP) guidelines for RSV prophylaxis attempted to address these issues by grading the indications for preventive therapy according to degree of prematurity or risk factor. ^[23] Until the results of further follow-up and economic impact studies become available, the AAP guidelines provide a rational approach to selecting candidates for RSV prophylaxis. 

Owing to the shift in RSV seasonality noted in spring 2021 and the surge of RSV cases in fall 2022, the American Academy of Pediatrics supports providing more than 5 consecutive doses of palivizumab to eligible children in regions with disease activity lasting more than the typical 6-month duration. ^[24]  

According to the 2022 modification of these guidelines, the following are candidates for palivizumab prophylaxis ^[24] :

• Infants younger than 24 months who have hemodynamically significant congenital heart disease (cyanotic or acyanotic lesions) or who have chronic lung disease and are off oxygen or pulmonary medications for less than 6 months at the start of the RSV season

• Premature infants born at 28 weeks’ gestational age or less who are younger than 1 year chronologic age at the start of the RSV season; once treatment is initiated, it should continue throughout the season and not stop at age 1 year

• Premature infants born at 29-32 weeks’ gestational age who are younger than 6 months chronologic age at the start of the RSV season; once treatment is initiated, it should continue throughout the season and not stop at age 6 months

• Infants born at 32-35 weeks’ gestational age who are younger than 3 months chronologic age at the start of or during the RSV season and who either (a) attend child care or (2) have 1 or more siblings or other children younger than 5 years living permanently in the same household; prophylaxis should be provided only until 3 months of age

The AAP guidelines highlight child care attendance, school-aged siblings, exposure to environmental pollutants, congenital anomalies of the airway, and severe neuromuscular disorders as primary additional risk factors for these patients.

According to updated recommendations from the AAP in 2022, palivizumab prophylaxis for RSV should be limited to infants born before 29 weeks' gestation and to infants with chronic illness such as congenital heart disease or chronic lung disease. ^{[25, 3]}

• Premature infants born before 29 weeks, 0 days’ gestation who are younger than 1 year chronological age at the start of the RSV season.
• Premature infants born before 32 weeks, 0 days’ gestation who are younger than 1 year chronological age at the start of the RSV season with chronic lung disease (CLD) of prematurity defined as need for greater than 21 % oxygen for at least 28 days after birth.
• Infants younger than 24 months who have hemodynamically significant acyanotic congenital heart disease requiring medications for heart failure or will need heart transplant or infants with moderate to severe pulmonary hypertension. The decision of prophylaxis is infants with cyanotic heart disease may be made in consultation with pediatric cardiologist as the benefit of palivizumab prophylaxis in cyanotic heart disease in unknown.
• An infant with cystic fibrosis with clinical evidence of CLD and/or nutritional compromise in the first year may be considered for prophylaxis. Continued use of palivizumab prophylaxis in the second year may be considered for infants with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight-for-length less than the 10th percentile.

Other updated recommendations include the following:

• Give infants who qualify for prophylaxis in the first year of life no more than five monthly doses of palivizumab (15 mg/kg per dose) during the RSV season

• In the second year of life, palivizumab prophylaxis is recommended only for children who needed supplemental oxygen for 28 days or more after birth and who continue to need medical intervention (supplemental oxygen, chronic corticosteroid, or diuretic therapy).

• Clinicians may consider prophylaxis for children younger than 24 months if they will be profoundly immunocompromised during the RSV season.

Rietveld et al analyzed retrospective data to examine the cost-effectiveness of passive immunization with palivizumab against RSV. ^[26] Their findings showed that cost-effectiveness varied substantially according to child characteristics and seasonal months. Hospital costs averted by palivizumab were high. The authors recommended a restrictive prophylaxis policy that would only include children with bronchopulmonary dysplasia in high-risk months.

Simoes et al, in a study involving preterm infants who had received palivizumab and were not hospitalized for RSV or who never received palivizumab, followed their subjects prospectively for 24 months, beginning at a mean age of 19 months; the subjects were assessed for recurrent wheezing by caretaker or physician report. ^[27] The investigators found that the incidences of recurrent wheezing and physician-diagnosed recurrent wheezing were significantly lower in the palivizumab-treated subjects, even after adjustment for potential confounding variables.

In a more recent study of children younger than 2 years with Down syndrome, who are at significant risk for RSV infection, prospective treatment with palivizumab was associated with a 3.6-fold reduction in the incidence rate ratio for RSV-related hospitalization. ^[19] Researchers compared the number of RSV events among 532 children with Down syndrome who prophylactically received palivizumab and 233 untreated children. In total, 31 (23 untreated, 8 treated) RSV-related hospitalizations were documented. ^[19]

A second-generation monoclonal antibody, motavizumab, with greater affinity for RSV than palivizumab, underwent investigation.

In a double-blind, multinational trial, motavizumab was compared with palivizumab in 6635 preterm infants with chronic lung disease of prematurity. ^[28] The 2 drugs had similarly low rates of hospitalization for RSV. A significant reduction (50% relative reduction) in outpatient, RSV-specific, medically attended LRTI was observed with motavizumab. Premature neonates taking motavizumab had fewer outpatient respiratory infections than those taking palivizumab, the current standard of treatment. However, owing to the lack of improved prevention of hospitalization with motavizumab and an increased occurrence of rash reaction in this group, motavizumab has not been approved by the US Food and Drug Administration (FDA) at this time and the manufacturer has decided not to pursue licensure at this time. A newer monoclonal antibody with extended half-life is currently in clinical trials.

Nirsevimab is a long-acting monoclonal antibody, which is given as a single intramuscular injection. Results from the MELODY study of nearly 1500 infants showed a 74.5% reduced incidence of medically attended LRTIs associated with RSV in those who received nirsevimab compared with those who received placebo. The product is in the clinical trials stage and has not received marketing approval from the FDA. ^{[29, 30]}

Vaccination

To date, attempts to develop a vaccine against RSV have been unsuccessful. ^[31]  A formalin-inactivated RSV vaccine was developed in the 1960s. Although initial serologic responses to this vaccine appeared promising, children who received it developed more severe disease when exposed to natural RSV infection, and a number of deaths were reported.

Several factors have accelerated vaccine development: (1) literature on RSV burden in infants and elderly, (2) success of palivizumab in high-risk infants, and (3) identification of newer pre-F RSV epitopes as vaccine targets. About 60 vaccine candidates are in preclinical and clinical (phase 1-3) trials. ^[32]  The various platforms used for vaccine development include live attenuated, particle based, subunit based, and vector based vaccines. Most candidate vaccines elicit immunity to prefusion F protein.These are being evaluated for potential immunization of young children and elderly adults, and also for administration to pregnant women during the last trimester to boost the levels of anti-RSV antibody transferred to the infant. Notable progress has been achieved, but a vaccine that is ready for use in clinical practice probably is still years away.

Vitamin D supplementation

In a prospective birth cohort study evaluating the concentrations of 25-hydroxyvitamin D (25-OHD) in cord blood plasma in 156 neonates, neonates born with 25-OHD concentrations lower than 50 nmol/L had a 6-fold greater risk of RSV LRTI in the first year of life than neonates with 25-OHD concentrations of 75 nmol/L or less. ^[33] These results indicate that vitamin D deficiency in healthy neonates is associated with an increased risk of RSV LRTI in the first year of life. Vitamin D supplementation during pregnancy may ameliorate RSV LRTI during infancy.

The primary caretaker manages most cases of RSV on an outpatient basis. Even in the hospitalized child with RSV disease, consultation with a subspecialist generally is not necessary. Hospitalists should be aware of different methods of providing supplemental oxygen such as nasal cannula, High flow oxygen (humidified).

Consultation with an intensivist is advised if the child requires mechanical ventilation or, even before intubation, if the child has marked respiratory distress and a high supplemental oxygen requirement. An intensivist may also be of assistance if difficult conditions (eg, congenital heart disease or bronchopulmonary dysplasia) are present in which assessment of hydration status and optimal fluid management may be complex.

An infectious diseases evaluation may be indicated if ribavirin therapy is being considered or if the viral origin of an infant’s acute respiratory illness is uncertain. Infectious disease specialists often also play a role in addressing epidemiologic concerns regarding patient isolation, nosocomial transmission, ^[34] and infection control.

A pediatric pulmonologist may be consulted if an infant has underlying lung disease (eg, bronchopulmonary dysplasia) ^[31] in conjunction with an acute RSV infection or if assistance is needed with decisions regarding bronchodilator therapy.