Respiratory Syncytial Virus Infection
Practice Essentials
Respiratory syncytial virus (RSV) (see the image below) is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children. Each year, 4-5 million children younger than 4 years acquire an RSV infection, and more than 125,000 are hospitalized annually in the United States because of this infection. The impact of RSV infection is not limited to only young children. In United States, it is responsible for 177,000 hospitalizations and 14,000 deaths in the elderly ≥ 65 years of age. [1, 2]
Electron micrograph of respiratory syncytial virus (RSV). RSV is most common cause of bronchiolitis and pneumonia in children younger than 1 year. Image courtesy of Centers for Disease Control and Prevention.
Signs and symptoms
Patients with RSV infection may present with the following symptoms:
Upper respiratory tract infection (URTI)
Cough
Tachypnea
Cyanosis
Retractions
Wheezing
Rales
Fever (typically low-grade)
Sepsislike presentation or apneic episodes (in very young infants)
Physical examination of the infant with RSV-related LRTI may reveal the following:
Evidence of diffuse small airway disease
Associated otitis media (viral, bacterial, or both)
Dehydration (assessed by evaluating skin turgor, capillary refill, and mucous membranes)
RSV LRTI in infancy may be linked with subsequent reactive airway disease, although this association remains controversial.
Diagnosis
Laboratory studies generally are not indicated in the infant with bronchiolitis who is comfortable in room air, well hydrated, and feeding adequately. When warranted, nonspecific laboratory studies may include the following:
Complete blood cell (CBC) count
Serum electrolyte concentrations
Urinalysis
Oxygen saturation
Specific tests for RSV may be indicated for therapeutic decision making, isolation of patients, and educating parents and staff. Specific diagnostic tests for confirming RSV infection include the following:
Culture (human epithelial type-2 [HEp-2])
Antigen-revealing techniques (rapid turnaround time [30 mins])
Molecular probes (commonly used multiplex PCR assays)
Chest radiography is frequently obtained in children with severe RSV infection, but for the most part, typical findings are neither specific to RSV infection nor predictive of the course or outcome.
Management
Supportive care is the mainstay of therapy for RSV infection. This includes supplemental oxygen when indicated, management of respiratory secretions and maintaining hydration. 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. [3, 4]
Pharmacologic therapies for RSV infection include the following:
Bronchodilators – These benefit at least a subset of patients with RSV-related LRTI
Alpha agonists – These have been used during acute bronchiolitis episodes, though their efficacy has not been established
Ribavirin – This agent is primarily reserved for patients with significant underlying risk factors and severe acute RSV disease (eg, transplant recipients) but has unproven clinical benefit and based on high acquisition cost it is rarely administered
The following agents may be considered for passive immunization to protect against RSV infection:
Palivizumab (Synagis) - Indicated for prophylaxis in children at high risk for severe RSV disease
Nirsevimab (Beyfortus) - Indicated for prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season
Another strategy for prevention of RSV infection in infants is through active immunization of pregnant women with the following:
Respiratory syncytial virus (RSV) vaccine (Abrysvo) is indicated for maternal vaccination at 32-36 weeks of gestation to help protect infants at birth through 6 months of life from lower respiratory tract disease (LRTD) and severe LRTD due to RSV
The American College of Obstetricians and Gynecologists (ACOG) recommends RSV vaccination for pregnant persons. [5]
According to American Academy of Pediatrics (AAP) 2014 guidelines for RSV prophylaxis and renewed in 2018, the following are candidates for palivizumab prophylaxis:
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 of prematurity defined as need for greater than 21 % oxygen for at least 28 days after birth
In the second year of life, for children who continue to require medical intervention (supplemental oxygen, chronic corticosteroid or diuretic therapy)
Infants younger than 24 months who have hemodynamically significant congenital heart disease (cyanotic or acyanotic lesions) requiring medications for heart failure or will need heart transplant or infants with moderate to severe pulmonary hypertension
Other measures proposed for preventive purposes include the following:
Vaccination: Improved understanding of the structure of RSV and the importance of the prefusion protein has led to a tremendous increase in RSV vaccine development over the past decade. Today there are 60 vaccine candidates in preclinical and clinical (phase 1-3) trials
Vitamin D supplementation (supplementation during pregnancy may ameliorate RSV LRTI during infancy)
Breastfeeding may also provide some protection against severe RSV disease
Background
Infection with respiratory syncytial virus (RSV), which manifests primarily as bronchiolitis or viral pneumonia, is the leading cause of LRTIs in infants and young children. The clinical entity of bronchiolitis was described at least 100 years ago. In 1956, Morris and colleagues initially isolated RSV from chimpanzees with upper respiratory tract infections (URTIs) and identified the virus as the causative agent of most epidemic bronchiolitis cases. Subsequently, RSV has been associated with bronchiolitis and LRTI in infants. Multiple epidemiologic studies have confirmed the role of this virus as the leading cause of LRTI in infants and young children.
The peak incidence of severe RSV disease is at age 2-8 months. Overall, 4-5 million children younger than 4 years acquire an RSV infection each year, and more than 125,000 are hospitalized annually in the United States because of this infection. Virtually all children have had at least 1 RSV infection by the age of 3 years. In view of the prevalence and potential severity of this condition, it is not surprising that the World Health Organization (WHO) has targeted RSV for vaccine development.
This article reviews aspects of the virology, epidemiology, clinical course, diagnosis, treatment, and prevention of RSV-related illness.
Pathophysiology
RSV infection is limited to the respiratory tract. Initial infection in young infants or children frequently involves the lower respiratory tract and most often manifests as the clinical entity of bronchiolitis. Inoculation of the virus occurs in respiratory epithelial cells of the upper respiratory tract. Spread of the virus down the respiratory tract occurs through cell-to-cell transfer of the virus along intracytoplasmic bridges (syncytia) from the upper to the lower respiratory tract.
The illness may begin with upper respiratory symptoms and progress rapidly over 1-2 days to the development of diffuse small airway disease characterized by cough, coryza, wheezing and rales, low-grade fever (< 101°F), and decreased oral intake. A family history of asthma or atopy is frequently obtained. [6, 7] In more advanced disease, retractions and cyanosis may be noted, and as many as 20% of patients may develop higher temperatures.
The incidence of concomitant or secondary serious bacterial infection in association with RSV infection appears to be quite low (< 1%), with the exception of otitis media, which may occur in as many as 40% of cases. In very young infants, apnea out of proportion to respiratory signs and symptoms may be present, and in infants younger than 6 weeks, a relatively nonspecific sepsislike picture has been described. [8]
Reinfection with RSV occurs at all ages; however, with recurrent infection and increasing age, RSV infections are more likely to be limited to the upper respiratory tract. RSV URTI is more severe than the common cold, as evidenced by the 7- to 10-day duration of illness and by the finding from one study of adults with RSV that the mean absence from work is 6 days. Studies have also demonstrated severe RSV disease in elderly persons. [9]
Etiology
In the community setting, a number of factors have been associated with an increased risk of acquiring RSV disease, including the following:
Childcare attendance
Older siblings in preschool or school
Crowding and lower socioeconomic status
Exposure to environmental pollutants (eg, cigarette smoke)
Multiple birth sets (especially triplets or greater)
Minimal breastfeeding
In infants with RSV infection, the following factors have been correlated with more severe disease and the need for hospitalization.
Prematurity. Even though the greatest risk for severe disease is in premature infants born at ≤ 29 week gestation, recent data continues to demonstrate increased risk up to 35 weeks gestation. [10]
Age younger than 3 months at the time of infection
Chronic lung disease
Congenital heart disease
Congenital immunodeficiency (eg, severe combined immunodeficiency [SCID])
Severe neuromuscular disease
Toxic appearance at time of presentation
Respiratory rate higher than 70 breaths/min on room air
Atelectasis or pneumonitis on chest radiography
Oxygen saturation lower than 95% on room air
Although infants in these groups are at higher risk for severe RSV disease than are normal full-term infants in terms of percentages, many more children in the normal full-term group are admitted to the hospital; thus, most admissions for RSV disease occur in otherwise normal infants. A family history of asthma and genetic factors are also correlated with more severe RSV disease, though the exact relations and mechanisms have not been elucidated.
A multicenter SENTINEL 1 study by Anderson et al reported that preterm infants 29 to 35 weeks gestational age are at high risk for severe respiratory syncytial virus. In the study, of the 702 infants who were hospitalized with community-acquired RSV disease, 42% were admitted to the ICU and 20% required invasive mechanical ventilation. Sixty-eight percent of the infants 29 to 32 weeks gestational age and under 3 months of age required ICU admission and 44% required invasive mechanical ventilation. [11]
Epidemiology
RSV LRT infection develops annually in 4-5 million children, and more than 125,000 children are admitted per year for RSV-related illness. The burden of RSV infection is not limited to only young children. In United States, it is responsible for 177,000 hospitalizations and 14,000 deaths in elderly ≥ 65 years of age. [1, 2] Seasonal variations in incidence are observed (see the image below). Reinfection occurs throughout life, with the disease generally limited to the upper respiratory tract in persons older than 3 years. RSV infection is primarily seen in the winter months throughout United States except in the state of Florida where it extends throughout much of the year. Nationally the onset of RSV season ranges from mid-September to mid-November, peaks from mid-December to mid-February, and the off-season occurs mid-April to mid-May. In tropical climates peak RSV activity correlates with the rainy season.
The COVID-19 pandemic disrupted the typical patterns of circulation for RSV. Starting in the southern United States, RSV circulation increased during the spring of 2021 and peaked in the summer. [12]
Severe RSV disease has been reported in older children and adults with SCID (eg, bone marrow transplantation), and RSV disease of the lower respiratory tract has been reported in elderly persons. RSV infection can also be severe in adults with COPD, those with immunodeficiency, and those ≥ 65 years of age.
Respiratory syncytial virus infection season, United States, by region and Florida. Image courtesy of Centers for Disease Control and Prevention.
Worldwide, RSV infection is prevalent, with clinical manifestations and early occurrence of RSV LRTI comparable to those seen in the United States. [2] Each year RSV infection causes more than 100,000 deaths among children younger than 5 years throughout the world. Nearly half of those deaths occur in infants younger than 6 months old. In addition, RSV infection accounts for an estimated 3.6 million hospital admissions globally each year. [13, 14]
Severe RSV disease is primarily a disease of young infants and children, with a peak occurrence at the age of 2-8 months. Reinfection with RSV occurs throughout life, with disease becoming increasingly limited to the upper respiratory tract with advancing age. Although boys and girls are equally affected by milder RSV disease, males are approximately twice as likely to be hospitalized for RSV disease. All races appear to be susceptible to RSV, showing similar disease patterns.
Prognosis
Children hospitalized secondary to RSV infection typically recover and are discharged in 3-4 days. High-risk infants remain hospitalized longer and have higher rates of admission to the intensive care unit (ICU) and of mechanical ventilation.
Morbidity/mortality
Even in children hospitalized with RSV infection, mortality is less than 1%, and fewer than 500 deaths per year are attributed to RSV in the United States. However, in select groups of high-risk patients, appreciable mortality and increased morbidity still may result from this infection. [15, 16, 17]
Infants with chronic lung disease of infancy (ie, bronchopulmonary dysplasia), congenital heart disease, or marked prematurity when hospitalized for this disease may have a 3-5% mortality rate. Additionally, such infants and patients with immunodeficient states have been shown to spend, on average, twice as long in the hospital as other patients with RSV infection (7-8 days vs 3-4 days in normal full-term infants).
Additionally, children hospitalized for RSV disease during infancy have higher rates of subsequent wheezing than age-matched controls not hospitalized for this condition over the next 10 or more years. Whether RSV itself leads to alterations of airways or immune responses contributing to these subsequent events or is just a marker for children at risk for reactive airway disease remains incompletely understood.
Complications
Infants hospitalized for RSV LRTI in infancy are at higher risk for subsequent wheezing and abnormal pulmonary function tests than age-matched control subjects who did not have such an admission, and this increased risk may persist for up to 10 years or longer.
RSV’s role in causing subsequent reactive airway disease remains controversial. Several small studies have suggested that infants who are hospitalized with RSV infection and treated with ribavirin have better pulmonary function on follow-up than infants who are not. If this finding is confirmed, it should help elucidate the link between RSV LRTI in infancy and subsequent reactive airway disease. Analyses comparing recipients of RSV prophylaxis with nonrecipients may also help answer this clinically important question. [18, 19]
A study by Kitsantas et al that included the records of 1,542 infants reported that approximately 10% of the children developed asthma and more than 9% developed hay fever or respiratory allergy by age 6. [20]
Clinical Presentation
History and Physical Examination
Patients with respiratory syncytial virus (RSV) infection may present with the following symptoms:
Fever (typically low-grade)
Cough
Tachypnea
Cyanosis
Retractions
Wheezing
Rales
Sepsislike presentation or apneic episodes (in very young infants)
Physical examination of the infant with RSV lower respiratory tract infection (LRTI) reveals evidence of diffuse small airway disease. On inspection, the characteristic examination findings are the presence of rhinorrhea, tachypnea, intercostal and subcostal retractions. Nasal flaring and tracheal tugging may be present in severe cases of bronchiolitis. On auscultation, the presence of coarse or fine crackles (rales) are typical, sometimes associated with prolonged expiratory phase.
The course of bronchiolitis varies and may require serial observations to adequately assess illness acuity. The decision to hospitalize an infant with RSV infection can be challenging. Among the more consistent and reliable findings in severe RSV disease are decreased oxygen saturations; thereby hypoxia (oxygen saturation ≤ 90 %) in an infant should be considered an indication for further inpatient monitoring. Rapid fluctuations in clinical manifestations are characteristic of RSV, thereby serial assessments either in the office or the hospital settings are helpful.
Differential Diagnoses
Diagnostic Considerations
High-risk groups for severe respiratory syncytial virus (RSV) infection include the following:
Premature infants in their first year of life (the younger the child is [in gestational and chronologic age] at the start of RSV season, the greater the risk)
Infants with chronic lung disease (eg, bronchopulmonary dysplasia or cystic fibrosis) during their first 2 years of life
Children with hemodynamically significant congenital heart disease, especially with increased pulmonary blood flow
Patients with immunodeficient states
Children with metabolic disorders, structural airway abnormalities, and neuromuscular disorders
Children of multiple births (triplets or greater)
Differential Diagnoses
Other respiratory viruses Upper respiratory tract infection, croup, and bronchiolitis caused by RSV is clinically indistinguishable from other respiratory infections
Human Parainfluenza Viruses (HPIV) and Other Parainfluenza Viruses
Workup
Laboratory Studies
Laboratory studies generally are not indicated in the infant with bronchiolitis who is comfortable in room air, well hydrated, and feeding adequately.
Nonspecific laboratory studies may include a complete blood count (CBC), assessment of serum electrolyte concentrations, urinalysis, and measurement of oxygen saturation. The CBC may reveal a normal or mildly elevated white blood cell (WBC) count and an elevated percentage of band forms. Blood cultures, although frequently obtained, are rarely positive for pathogenic bacteria. Arterial blood gas analysis may be indicated if carbon dioxide retention is a concern.
Specific diagnostic tests for confirmation of respiratory syncytial virus (RSV) infection are readily available. These tests can be performed on samples of secretions obtained by washing, suctioning, or swabbing the nasopharynx. Secretions can be analyzed for virus in the laboratory by means of culture, antigen-revealing techniques, or polymerase chain reaction (PCR). Molecular probes for revealing RSV in clinical specimens may be more sensitive than the aforementioned assays and are becoming clinically available, but they presently are more expensive. There are 6 commercially available multiplex PCR assays (nested PCR), with sensitivity and specificity of 100% and 89% respectively with some variability in performance.
The antigen detection methods offer the potential for diagnosis within hours and may be obtained reliably in the absence of a sophisticated virology laboratory. However, monitoring of test performance is critical for maintaining appropriate sensitivity and specificity. Specific tests for RSV may be indicated for therapeutic decision making (eg, withdrawal of unnecessary antibiotics), isolation of patients, and educating parents and staff about the nature of RSV disease.
Other Studies
Chest radiography
Chest radiography is frequently obtained in children with severe RSV infection. Typically, it reveals hyperinflated lung fields with a diffuse increase in interstitial markings. In 20-25% of cases, focal areas of atelectasis or pulmonary infiltrates are also noted. Generally, these findings are neither specific to RSV infection nor predictive of the course or outcome, except for the observation that infants who have the additional findings of atelectasis or pneumonia may have a more severe disease course.
Histologic findings
In infants who have died of RSV bronchiolitis, histologic study of lung tissue demonstrates mononuclear cell and neutrophil infiltration of the peribronchiolar areas, necrosis of the small airway epithelium, plugging of the lumens with exudate and edema, and atelectasis and hyperinflation.
Treatment & Management
Approach Considerations
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. [21]
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. [22]
Pharmacologic Therapy
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).
Prevention
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. [23] 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.
RSV monoclonal antibodies
Nirsevimab
Nirsevimab (Beyfortus) is indicated for prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants entering or during their first RSV season and children up to 24 months old who remain vulnerable to severe RSV disease through their second RSV season. It is a long-acting product administered as a single intramuscular injection.
In the MELODY phase 3 clinical trial, 994 infants were assigned to the nirsevimab group and 496 to the placebo group. Medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5%) in the placebo group. These results correspond to an efficacy of 74.5% (P< 0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, 62.1%; P = 0.07). [24]
Palivizumab
Palivizumab (Synagis) 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. [25] 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. [26]
According to the 2022 modification of these guidelines, the following are candidates for palivizumab prophylaxis [26] :
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 is administered as once-monthly intramuscular injection throughout the season and not stopped until 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
Rietveld et al analyzed retrospective data to examine the cost-effectiveness of passive immunization with palivizumab against RSV. [27] 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. [28] 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. [21] 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. [21]
Investigational monoclonal antibodies
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. [29] 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.
Guidelines
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. [30, 3, 4]
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.
Vaccination
Several factors have accelerated RSV 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 were in preclinical and clinical (phase 1-3) trials as of 2015. [31] 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.
Respiratory syncytial virus vaccine (Abrysvo) was approved in August 2023 for active immunization of pregnant individuals at 32 through 36 weeks' gestation for the prevention of lower respiratory tract disease (LRTD) and severe LRTD caused by RSV in infants from birth through 6 months of age. It was originally approved for older adults in Spring 2023.
Approval was based on results from the MATernal Immunization Study for Safety and Efficacy (MATISSE). In the study, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%). [32]
The American College of Obstetricians and Gynecologists (ACOG) supports RSV vaccination for pregnant persons. ACOG recommends seasonal administration of a single dose of RSV vaccine (Abrysvo) for pregnant individuals between 32 0/7 and 36 6/7 weeks of gestation. The Society for Maternal-Fetal Medicine endorses this recommendation. [5]
Early vaccine research
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.
Immunoglobulins
Immunoglobulin products with high anti-RSV antibody titers have proved beneficial when given monthly for prophylaxis in select groups of high-risk infants. One such product, RespiGam, was available in the United States until 2003, when it was largely replaced by palivizumab. RSV-IGIV is no longer being manufactured.
RSV immune globulin intravenous (RSV-IGIV) was 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 yielded a significant decrease in RSV-related hospitalization. Additionally, treated infants had had less severe hospital courses if admitted with RSV disease, fewer other respiratory infection hospitalizations, and fewer cases of otitis media than placebo recipients.
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. [33] 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. [22]
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.
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. [34] 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.
Consultations
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, [35] and infection control.
A pediatric pulmonologist may be consulted if an infant has underlying lung disease (eg, bronchopulmonary dysplasia) in conjunction with an acute RSV infection or if assistance is needed with decisions regarding bronchodilator therapy.
Medication
Medication Summary
Medications to treat respiratory syncytial virus (RSV) infection include the antiviral drug ribavirin, which can be used in severe high-risk cases, and bronchodilators. The efficacy of bronchodilators or racemic epinephrine in treating RSV disease remains unproved. If these agents are given, attempts to measure response to therapy should be documented. If these treatments have no demonstrable benefit, they should be discontinued.
Nirsevimab is a long-acting monoclonal antibody administered as a single IM 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. [24]
Palivizumab may be given for prophylaxis. A study evaluated the effectiveness of current regimens for palivizumab injections across different cities in order to design an optimized regimen. The study found that a 5-injection regimen using city-specific initiation dates would reduce the risk of RSV hospitalization by a median of 6.8%. [36, 31] A study by Lavoie et al found that abbreviated three-and four dose regimens had comparable outcomes to infants treated with the five-dose regimen. [37]
Respiratory syncytial virus vaccine (Abrysvo) was approved in August 2023 for active immunization of pregnant individuals at 32 through 36 weeks' gestation for the prevention of lower respiratory tract disease (LRTD) and severe LRTD caused by RSV in infants from birth through 6 months of age. [32]
Antiviral agents
Class Summary
Antiviral therapy for severe RSV disease may be indicated in high-risk patients. For effective inhibition of the replicating virus, treatment must be promptly initiated at the onset of the infection.
Ribavirin is an analogue of the nucleic acid guanosine. It inhibits viral replication through an unknown mechanism.
Beta2 Agonists
Class Summary
Bronchodilators act to decrease muscle tone in the small and large airways in the lungs, thereby increasing ventilation. Beta2 -adrenergic and alpha-adrenergic agents are frequently administered (via inhalation) in an attempt to treat the bronchospasm observed in bronchiolitis.
As a selective beta2-agonist, albuterol produces bronchial smooth muscle relaxation. Its efficacy in older children with reactive airway disease is well established, but its benefits in children with acute bronchiolitis are less well established. It is available in inhaled and oral preparations.
Racemic epinephrine consists of 1-1.125% of epinephrine base solution given by aerosol. It may be superior to beta2-adrenergic agents for treating RSV lower respiratory tract infection.
Monoclonal Antibodies
Class Summary
Humanized monoclonal antibody directed against the F (fusion) protein of RSV are indicated for prophylaxis of newborns and young infants during or entering RSV season.
Administered as a single IM dose per season. It is indicated for prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.
Administered as a monthly IM injection through the RSV season, it has been demonstrated to decrease the chances of RSV hospitalization in premature babies who are at increased risk for severe RSV-related illness. 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.
Vaccines
Class Summary
Active immunization for infants via maternal vaccination has been approved by the FDA.
Indicated for active immunization of pregnant individuals at 32 through 36 weeks gestation for the prevention of lower respiratory tract disease (LRTD) and severe LRTD caused by RSV in infants from birth through 6 months of age.
References
Respiratory Syncytial Virus Infection (RSV): Trends and Surveillance. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/rsv/research/us-surveillance.html. June 26, 2018; Accessed: February 14, 2019.
Bont L, Checchia PA, Fauroux B, Figueras-Aloy J, Manzoni P, Paes B, et al. Defining the Epidemiology and Burden of Severe Respiratory Syncytial Virus Infection Among Infants and Children in Western Countries. Infect Dis Ther. 2016 Sep. 5 (3):271-98. [QxMD MEDLINE Link].
American Academy of Pediatrics Committee on Infectious Diseases, American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. 2014 Aug. 134 (2):415-20. [QxMD MEDLINE Link].
Caserta MT, O'Leary ST, Munoz FM, Ralston SL, COMMITTEE ON INFECTIOUS DISEASES. Palivizumab Prophylaxis in Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection. Pediatrics. 2023 Jul 1. 152 (1):[QxMD MEDLINE Link]. [Full Text].
[Guideline] American College of Obstetricians and Gynecologists. Maternal Respiratory Syncytial Virus Vaccination. ACOG. Available at https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/09/maternal-respiratory-syncytial-virus-vaccination. 2023 Sep; updated 2023 Oct 10; Accessed: November 6, 2023.
Perez-Yarza EG, Moreno A, Lazaro P, Mejias A, Ramilo O. The association between respiratory syncytial virus infection and the development of childhood asthma: a systematic review of the literature. Pediatr Infect Dis J. 2007 Aug. 26(8):733-9. [QxMD MEDLINE Link].
Welliver RC. Bronchiolitis and infectious asthma. Feigin RD, Cherry JD, Demmler-Harrison G J, Kaplan SLeds. Textbook of Pediatric Infectious Diseases. 6th edition. Philadelphia, PA: Saunders Elsevier; 2009. 277-288.
Oray-Schrom P, Phoenix C, St Martin D, Amoateng-Adjepong Y. Sepsis workup in febrile infants 0-90 days of age with respiratory syncytial virus infection. Pediatr Emerg Care. 2003 Oct. 19(5):314-9. [QxMD MEDLINE Link].
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med. 2005 Apr 28. 352(17):1749-59. [QxMD MEDLINE Link].
Kong AM, Krilov LR, Fergie J, Goldstein M, Diakun D, Wade SW, et al. The 2014-2015 National Impact of the 2014 American Academy of Pediatrics Guidance for Respiratory Syncytial Virus Immunoprophylaxis on Preterm Infants Born in the United States. Am J Perinatol. 2018 Jan. 35 (2):192-200. [QxMD MEDLINE Link].
Anderson EJ, Krilov LR, DeVincenzo JP, Checchia PA, Halasa N, Simões EA, et al. SENTINEL1: An Observational Study of Respiratory Syncytial Virus Hospitalizations among U.S. Infants Born at 29 to 35 Weeks' Gestational Age Not Receiving Immunoprophylaxis. Am J Perinatol. 2017 Jan. 34 (1):51-61. [QxMD MEDLINE Link].
Olsen SJ, Winn AK, Budd AP, et al. Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic - United States, 2020-2021. MMWR Morb Mortal Wkly Rep. 2021 Jul 23. 70 (29):1013-9. [QxMD MEDLINE Link]. [Full Text].
Frellick M. RSV Kills 100,000 Kids Under Age 5 a Year Worldwide. Medscape Medical News. 2022 May 19. Available at https://www.medscape.com/viewarticle/974323.
Li Y, Wang X, Blau DM, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. 2022 May 28. 399 (10340):2047-64. [QxMD MEDLINE Link]. [Full Text].
Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003 Nov. 143(5 Suppl):S127-32. [QxMD MEDLINE Link].
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8. 289(2):179-86. [QxMD MEDLINE Link].
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009 Feb 5. 360(6):588-98. [QxMD MEDLINE Link].
Paes B, Mitchell I, Li A, Lanctôt KL, CARESS Investigators. A comparative study of respiratory syncytial virus (RSV) prophylaxis in premature infants within the Canadian Registry of Palivizumab (CARESS). Eur J Clin Microbiol Infect Dis. 2012 Oct. 31 (10):2703-11. [QxMD MEDLINE Link].
Winterstein AG, Hampp C, Saidi A. Effectiveness of palivizumab prophylaxis in infants and children in Florida. Pharmacoepidemiol Drug Saf. 2012 Jan. 21(1):53-60. [QxMD MEDLINE Link].
Kitsantas P, Nirmalraj L. Effects of Respiratory Syncytial Virus Infection in Infancy on Asthma and Respiratory Allergy in 6-Year-Old Children. South Med J. 2018 Nov. 111 (11):698-702. [QxMD MEDLINE Link].
Yi H, Lanctôt KL, Bont L, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics. 2014 Jun. 133 (6):1031-7. [QxMD MEDLINE Link].
Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998 Sep. 102(3 Pt 1):531-7. [QxMD MEDLINE Link].
Hall CB, Douglas RG Jr. Modes of transmission of respiratory syncytial virus. J Pediatr. 1981 Jul. 99(1):100-3. [QxMD MEDLINE Link].
Hammitt LL, Dagan R, Yuan Y, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med. 2022 Mar 3. 386 (9):837-46. [QxMD MEDLINE Link]. [Full Text].
Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Red Book 2021-2024: Report of the Committee on Infectious Diseases. 2021-2024.
[Guideline] American Academy of Pediatrics. Updated Guidance: Use of palivizumab prophylaxis to prevent hospitalization from severe respiratory syncytial virus infection during the 2022-2023 RSV season. Pediatrics. 2022 Nov 17. [Full Text].
Rietveld E, Steyerberg EW, Polder JJ, et al. Passive immunisation against respiratory syncytial virus: a cost-effectiveness analysis. Arch Dis Child. 2010 Jul. 95(7):493-8. [QxMD MEDLINE Link].
Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr. 2007 Jul. 151(1):34-42, 42.e1. [QxMD MEDLINE Link].
Carbonell-Estrany X, Simoes EA, Dagan R, et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics. 2010 Jan. 125(1):e35-51. [QxMD MEDLINE Link].
AAP Issues Guidelines to Combat Rise in Respiratory Illness. Medscape Medical News. Available at https://www.medscape.com/viewarticle/984378. 2022 Nov 21; Accessed: November 21, 2022.
Harding A. Spreading Out Palivizumab Shots Improves RSV Protection. Reuters Health Information. Available at http://www.medscape.com/viewarticle/840348. February 25, 2015; Accessed: June 26, 2015.
Kampmann B, Madhi SA, Munjal I, and the, MATISSE Study Group. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 20. 388 (16):1451-1464. [QxMD MEDLINE Link]. [Full Text].
Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytialvirus in young children with hemodynamically significant congenital heart disease. J Pediatr. 2003 Oct. 143(4):532-40. [QxMD MEDLINE Link].
Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin d deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics. 2011 Jun. 127(6):e1513-20. [QxMD MEDLINE Link].
Hall CB, Dougla RG, Geiman JM, Messner MK. Nosocomial respiratory syncytial virus infections. N Engl J Med. 1975. 293:1343-6. [QxMD MEDLINE Link].
Gutfraind A, Galvani AP, Meyers LA. Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection. JAMA Pediatr. 2015 Apr. 169 (4):341-8. [QxMD MEDLINE Link].
Lavoie PM, Solimano A, Taylor R, Kwan E, Claydon J, Turvey SE, et al. Outcomes of Respiratory Syncytial Virus Immunoprophylaxis in Infants Using an Abbreviated Dosing Regimen of Palivizumab. JAMA Pediatr. 2016 Feb. 170 (2):174-6. [QxMD MEDLINE Link].
Comments