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.^{[37, 8]}

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Electron micrograph of respiratory syncytial virus (RSV). RSV is most common cause of bronchiolitis and pneumonia in children younger than 1 year. Ima....

Signs and symptoms

Patients with RSV infection may present with the following symptoms:

• • 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.

See Presentation for more detail.

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 count (CBC)
• 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.

See Workup for more detail.

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.^[22]

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 have been used in passive immunization to protect against RSV infection:

• RSV immune globulin intravenous (RSV-IGIV; no longer being manufactured)
• Palivizumab (FDA-approved for prophylaxis in children at high risk for severe RSV disease)

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 pre-fusion 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)
• Breast feeding may also provide some protection against severe RSV disease

See Treatment and Medication for more detail.

• References

Background

Infection with respiratory syncytial virus (RSV; see the image below), which manifests primarily as bronchiolitis or viral pneumonia,^[1] is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children.

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Electron micrograph of respiratory syncytial virus (RSV). RSV is most common cause of bronchiolitis and pneumonia in children younger than 1 year. Ima....

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.

For patient education resources, see the Cold and Flu Center, as well as Viral Pneumonia and Flu in Children.

• References

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.^{[2, 3]} 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.^[4]

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.^[5]

• References

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.^[6]
• 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.^[7]

• References

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.^{[37, 8]}  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. 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.

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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.^[8]

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. URT, as discussed above. 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.

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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.

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.^{[9, 10, 11]}

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.

• References

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.

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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.^{[12, 13]}

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.^[14]

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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.

• References

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.

• References

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.{ref 25}

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.^[18]

• References

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).

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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.^[16] 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.^[17] 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.^[18]

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 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.^[19] 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. According to the 2009 modification of these guidelines, the following are candidates for palivizumab prophylaxis^[20] :

• 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 2014, 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.^{[21, 22]}

• 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.^[23] 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.^[24] 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.^[25] 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.^[25]

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

In a double-blind, multinational trial, motavizumab was compared with palivizumab in 6635 preterm infants with chronic lung disease of prematurity.^[26] 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.  

Vaccination

To date, attempts to develop a vaccine against RSV have been unsuccessful^[30] . 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. A number of recent events has accelerated the vaccine development, i.e. a) literature on RSV burden in infants and elderly, b) success of palivizumab in high-risk infants, c) identification of newer pre F RSV epitopes as vaccine targets. Today they are around 60 vaccine candidates in preclinical and clinical (phase 1- 3) trials.{ref 32} The various platforms used for vaccine development include: live attenuated, particle based, subunit based and vector based vaccines. Most candidate vaccines illicit immunity to pre-fusion F protein.These are being evaluated for potential immunization of young children, elderly 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 5-10 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.^[28] 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.

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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,^[29] and infection control.

A pediatric pulmonologist may be consulted if an infant has underlying lung disease (eg, bronchopulmonary dysplasia)^[30] in conjunction with an acute RSV infection or if assistance is needed with decisions regarding bronchodilator therapy.

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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. 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%.^{[31, 32]} 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.^[33]

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Ribavirin (Virazole)

• Dosing, Interactions, etc.

Clinical Context:  Ribavirin is an analogue of the nucleic acid guanosine. It inhibits viral replication through an unknown mechanism.

• References

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.

• References

Albuterol (AccuNeb, Proventil, ProAir HFA)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Epinephrine racemic

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Palivizumab (Synagis)

• Dosing, Interactions, etc.

Clinical Context:  Palivizumab is a humanized monoclonal antibody directed against the F (fusion) protein of RSV. Administered monthly 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.

• References

Class Summary

Specific immunoglobulin products with anti-RSV activity have been developed for the prophylaxis of high-risk patients against RSV infection.

• References