Advancements in Respiratory Syncytial Virus (RSV) Prevention and Treatment in Pediatrics

Abstract

Respiratory syncytial virus (RSV) is a major contributor to global morbidity and mortality, disproportionately affecting young children and infants. Annual worldwide estimates suggest more than 30 million cases of lower respiratory infection and 100,000 deaths are attributed to RSV in children younger than 5 years of age, making RSV prevention and treatment a global priority. Recently approved monoclonal antibodies and vaccines for the prevention of RSV in infants and children have the potential to significantly alter disease burden. Disease prevention is paramount as treatments with rigorously proven clinical efficacy are limited, and supportive care remains the primary management strategy for the majority of patients who contract RSV. However, new entities continue to be evaluated for the treatment of RSV in the pediatric population. This review aimed to synthesize and evaluate existing data on the approved RSV preventative therapies nirsevimab, RSVpreF, clesrovimab, and palivizumab. RSV disease, including its spread, virology, diagnosis, clinical presentation, and treatment, is also discussed.

Introduction

Respiratory syncytial virus (RSV) is a significant contributor to global morbidity and mortality.¹ Respiratory syncytial virus primarily affects young children and older adults, with the greatest disease burden occurring in children 5 years of age and younger. In this age group, surveillance data from 2019 found an estimated 33 million cases of acute lower respiratory infection worldwide were attributed to RSV, leading to 3.6 million hospitalizations and more than 100,000 deaths.² Disease burden was highest in infants aged 2 to 6 months, resulting in more than 45,000 RSV attributable deaths, accounting for 3.6% of all deaths in this age group.² In the United States, RSV makes up nearly 10% of infant hospitalizations, making it the leading cause of hospitalizations in this age group.³ The majority of nonsevere disease burden occurs in term infants. However, infants born preterm, with underlying lung or heart disease, or immunocompromise are at an increased risk for severe disease. The Centers for Disease Control and Prevention (CDC) estimates that RSV annually contributes to more than 2 million outpatient visits in children younger than 5 years of age.⁴ These numbers are likely underestimated, as many children will not be definitively diagnosed with RSV. A study published in 2024 estimated that medically attended RSV in children younger than 1 year of age contributes a combined direct and indirect cost of 1.6 billion dollars annually to the US economy.⁵ The pharmacological landscape of RSV has changed in recent years, primarily in the setting of preventative medicine, while treatment strategies have remained the same.⁶ This review aimed to synthesize and evaluate existing data and recommendations for the US Food and Drug Administration (FDA)-approved RSV preventative therapies of nirsevimab, RSVpreF, clesrovimab, and palivizumab. Although no new treatment options have become available in the past decade, a summary of data on therapies and investigational studies is presented. This review also summarizes pertinent aspects of RSV disease spread, virology, diagnosis, and presentation as they relate to treatment and prevention.

History of RSV

Respiratory syncytial virus was first described more than 120 years ago as “acute catarrhal bronchitis,” but was not isolated until the 1950s from chimpanzees with an upper respiratory illness and was initially termed “chimpanzee coryza agent” after being isolated in humans in 1957.^7,8 Shortly after this discovery, work on preventative agents began with the development of a formalin-inactivated vaccine in the 1960s. The development of this vaccine was ultimately halted because of children aged 6 months to 7 years demonstrating worse outcomes, including death, in the vaccine arm versus the comparator arm.⁹ These poor outcomes were seen primarily in infants who were RSV seronegative at the time of immunization. It is thought that the initial exposure to these vaccines did not lead to sufficient immune system priming and poor antibody production, allowing for aggressive host CD4 and cytokine responses. Sub-unit vaccines were evaluated in clinical trials in the 1990s, but they did not confer protection from RSV in children.¹⁰

Also, during this time, several passive immunization strategies with different formulations of intravenous immunoglobulins (IGIV) were studied. In 1996, RSV-IGIV was the first preventative strategy approved by the FDA for certain high-risk infants. The use of RSV-IGIV had practical limitations, including multiple hour-long infusions, infusion reactions, interference with vaccine responses, unreliable availability, and high cost.⁹ These complexities and the advent of palivizumab 2 years later led to limited use, and RSV-IGIV was eventually discontinued by the manufacturer in 2004. Palivizumab, the first RSV monoclonal antibody, was approved in 1998 and became the standard for RSV preventive therapy in the high-risk pediatric population. In the 2010s, the prefusion structure of the RSV fusion (F) protein was identified, reigniting interest in advancing preventive strategies.¹¹ Between 2023 and 2025, several new pharmacological agents were FDA approved for RSV prevention. Currently, 3 monoclonal antibodies and 1 maternal vaccine are approved for the prevention of RSV in infants and children.^12,13

Viral Characteristics and Pathogenesis.

Respiratory syncytial virus is a member of the mononegavirales order along with other viruses such as Ebola and measles.¹⁴ Members of the mononegavirales order are single-stranded, nonsegmented, negative-sense RNA viruses. More specifically, RSV is a member of the Paramyxoviridae family and Pneumovirinae subfamily. RSV is closely related to human metapneumovirus, which is also a member of the Pneumovirinae subfamily. Respiratory syncytial virus, also known as Orthopneumovirus hominis, belongs to the Orthopneumovirus genus along with O. bovis and muris. As with all RNA viruses, RSV is prone to viral mutations due to a lack of RNA sequence proofreading during replication.^14,15

Respiratory syncytial virus is composed of 11 different proteins, each having an important role in the RSV life cycle. Respiratory syncytial virus can be further divided into RSV A and RSV B due to antigenic differences. These antigenic differences can contribute to reinfection with the other subtype, as well as differences in resistance mechanisms. Two notable proteins are the attachment protein (glycoprotein G) and the fusion protein (glycoprotein F). The G protein is highly variable between subtypes, while the F protein is conserved. Owing to this conservation, various specific sites on the F protein in both pre- and post-fusion configurations have been targets for many recent therapeutics. Unlike influenza, which undergoes antigenic shifts, RSV cannot because it has a nonsegmented genome.^14,15

Respiratory syncytial virus tends to spread in a season-dependent fashion in the continental US. In temperate climates, spread tends to begin in late fall (October), reach a peak during winter (December and January) and continue through early spring (April), although cases may occur throughout the year.¹⁶ Respiratory syncytial virus case distribution tends to be more even throughout the year in tropical climates such as Florida and Hawaii. The temperature itself is not the primary driver of disease spread, but the concentration of the population in confined indoor spaces, which tends to be higher in winter months. Of note, during the coronavirus pandemic, typical seasonal patterns were disrupted by varying public health ordinances.¹⁶

Respiratory syncytial virus is spread through both large and small respiratory droplets and direct contact.^17,18 The spread can occur when droplets are directly introduced to a mucous membrane from a cough or sneeze. Additionally, large droplets can survive on surfaces for 2 to 6 hours and on human skin for 30 minutes. These qualities allow a noninfected person to unknowingly touch a contaminated surface and eventually self-introduce the virus into a mucous membrane. Small or aerosolized droplets can linger in the air, allowing for a prolonged risk of inhalation to unknowing persons.¹⁴ Viral incubation time is between 3 and 5 days, while viral shedding varies from 3 to 7 days in adults to 3 weeks in infants younger than 6 months of age with severe disease.^19–21 The prolonged incubation and viral shedding contribute to the highly contagious nature of RSV, leading to 1 infected person spreading the disease to an estimated 1 to 5 people.^22,23

Respiratory syncytial virus primarily replicates in the nasopharynx after introduction through the nasopharyngeal or ocular membranes.^19,24 Respiratory syncytial virus is typically contained in the respiratory tract, while primarily binding to the bronchiolar epithelium, leading to cellular necrosis. The presence of RSV in these cells leads to increased mucous production, resulting in inflammation of the surrounding submucosa, luminal obstruction of the small airways, air trapping, and atelectasis. Much of the damage is caused by the host’s own hyperinflammatory immune response mediated by interleukins, chemokines, and leukotrienes.^19,24–26

Disease Presentation and Severity.

The symptomatology of an RSV infection varies. Mild cases often present with common cold symptoms, including cough, rhinorrhea, conjunctivitis, and elevated temperatures. Decreased intake, sleep changes, and fussiness are also common in infants and young children. Croup or lower respiratory tract disease can also occur and may result in a medically attended infection. Diffuse cough, wheezing, and/or crackles across both lung fields are present in 50% of infections and are considered hallmark symptoms of bronchiolitis.⁷ Bronchiolitis is a lower respiratory tract disease involving inflammation and mucus production in the small airways. Fevers and lower respiratory symptoms often peak in severity around days 3 to 5. However, the cough can last 1 to 2 weeks on average in children with bronchiolitis. It is possible for some symptoms to take up to 4 weeks to completely resolve.^7,27,28 Prolonged wheezing and an increased risk of wheezing with future viral infections are also seen.¹⁹ Some patients’ disease can progress and include increased tachypnea, apnea (common in premature and young infants), hypoxemia (definitions range between <95% to <90%), increased work of breathing (e.g., grunting, nasal flaring), respiratory failure requiring invasive cardiorespiratory support (e.g., mechanical ventilation or extracorporeal membrane oxygenation), and death.^29–35

It is not always clear why one patient exhibits a different disease presentation compared with another, but patient age and underlying disease states are the patient characteristics most commonly associated with clinically significant and/or severe disease. Patients with mild disease may not seek care or be tested for RSV, but are often important drivers of infection spread. Generally, patients who are preterm and/or younger at disease onset are considered at risk for more severe disease, likely due to the inability of their underdeveloped or damaged airways at baseline to compensate for the inflammation and airway obstruction associated with RSV.³⁶ Patients younger than 2 years are an important cohort because nearly all patients are exposed to RSV for the first time by 2 years of age (based on data before extensive preventative measures). The first exposure or RSV infection is more severe because of a more robust initial immune response compared with subsequent exposure or infections, especially in neonates or infants who were born preterm and likely have underdeveloped airways.^37,38 Patients with significant chronic heart or lung disease or immunocompromise are also at higher risk for severe disease. When palivizumab was the sole prophylactic option, various combinations of age and disease-state qualifiers were used to identify the patients who would most benefit from prophylaxis during the RSV season.³⁶ Strain disease severity also exists with RSV A, typically considered to present with more severe disease, but RSV B can also cause severe disease.^39,40 See Table 1 for more details regarding notable high-risk categories for disease severity.

Table 1.

Patient factors associated with respiratory syncytial virus (RSV) disease risk³⁷

Characteristic*	Comments
Preterm birth (< 29 wk gestation at birth) AND the patient is <1 yr at RSV season start	Considered among the highest risk groups and is part of AAP palivizumab use guidance
Infants <3 mo regardless of gestational age at birth	Higher risk for RSV hospitalization compared to older patients
Infants 3–12 mo regardless of gestational age at birth	High risk for RSV infection, but severity may depend on other factors
Infants 13–24 mo regardless of gestational age at birth
Chronic lung disease and the patient is <2 yr at the RSV season start	Considered among the highest risk group if <2 yr and is part of palivizumab use guidance Highest risk is in those requiring medical management (e.g., diuretics, oxygen)
Congenital heart disease requiring treatment and the patient is <2 yr at the RSV season start	Considered among the highest risk group and is part of palivizumab use guidance Hemodynamically significant lesions are considered very high risk for severe disease Not as high of risk if the lesions are corrected
Immunocompromised patients	Data are limited, <2 yr is still the highest risk within this group Hematopoietic stem cell transplant patients may be most at risk
Down’s syndrome and cystic fibrosis	Potentially at risk for more severe RSV infection when <2 yr, but data are limited

AAP, American Academy of Pediatrics

* When multiple of the above characteristics are present, the patient is likely at higher risk.

Diagnosis.

Respiratory syncytial virus diagnostic testing, including radiographic and laboratory testing, is not routinely recommended by the American Academy of Pediatrics (AAP) bronchiolitis guidelines in either the outpatient or inpatient setting due to limited clinical utility.⁴¹ The diagnosis of RSV-related disease (e.g., bronchiolitis, croup) can be made using patient history, clinical symptoms, and physical exam, and additional testing can be associated with interpretation challenges, extraneous cost, patient discomfort, and limited ability to alter disease management. Nasal swabs to detect the presence of RSV are often used for diagnostic testing because of their ease of collection in a clinical setting, but still require some patient discomfort, especially in young children and infants. Nasopharyngeal washes and tracheal secretions are higher-quality specimens for testing but are more difficult to collect. The quality of the specimen affects the sensitivity and specificity of all testing modalities.⁴² Multiple methods to test for RSV are available; however, they rarely change patient management.⁴¹ Testing can be considered for multiple reasons, including infection control, parental reassurance, antimicrobial stewardship, and epidemiological surveillance. Although RSV is the most common cause of bronchiolitis, many other viruses can cause a similar presentation.²⁸ This can complicate the prevalence estimates of the disease when microbiologic confirmation is not done. The gold standard of RSV testing in today’s practice is the reverse transcriptase polymerase chain reaction (RT-PCR) test due to its high sensitivity and specificity (near 100%).^42–44 Multiplex RT-PCR tests can detect a variety of respiratory viruses, including influenza and coronaviruses, while retaining an estimated pooled sensitivity of 96% and specificity of 100% according to a recent meta-nalysis.⁴³ These tests may also differentiate between RSV A and B strains. This information may give insights into disease severity, although the pharmacologic management is the same between the types, and thus, the utility of this information for therapeutic decisions is limited. Reverse transcriptase polymerase chain reaction tests often require 30 minutes to 4 hours for results. Direct fluorescent antibody and rapid antigen detection tests, including enzyme immunoassays, may also be used but have lower sensitivity than RT-PCR tests. Direct fluorescent antibody tests have a reported sensitivity of 93% to 98% and specificity of 92% to 97%, but require specialized training to conduct.⁴² Enzyme immunoassay tests have a lower sensitivity at 59% to 97%, but do have a higher range of specificity at 75% to 100%. Enzyme immunoassay tests have high clinical utility during RSV surges, thanks to ease, cost, and rapid turnaround time of approximately 30 minutes, but are unreliable for diagnosis outside of RSV surges due to higher rates of false positives. Respiratory syncytial virus viral culture may be performed, but requires 3 to 4 days for growth, severely limiting its clinical utility.

Preventative Therapies

Palivizumab.

Palivizumab, a humanized murine monoclonal antibody, was the gold standard for prophylaxis against RSV-associated hospitalization in high-risk infants from its FDA approval in 1998 until recent approvals of new monoclonal antibodies (Table 2).⁴⁵ Palivizumab binds to the antigenic site II of the RSV F protein, thus preventing the virus from binding to host cells. Palivizumab is administered at a dose of 15 mg/kg intramuscular (IM). Owing to the relatively short half-life of palivizumab (∼20 days), it is typically administered monthly, up to 5 times, beginning just before RSV season.⁴⁵

Table 2.

Indications for preventative options for respiratory syncytial virus (RSV)

Medication	FDA Indication	ACIP 2025 qualifiers
Palivizumab	Prevention of serious LRTD from RSV in children with a history of premature birth, BPD, or hemodynamically significant CHD45 ≤6 mo age for premature infants ≤24 mo for BPD or hemodynamically significant CHD	Only recommended for patients eligible when nirsevimab is not available and the mother did not receive RSVpreF ≥14 days before birth in the following patients based on previous AAP guidance36,44: <8 mo of age entering first season: CLD of prematurity or hemodynamically significant CHD Preterm birth prior <29 wk gestation Pulmonary abnormalities Immunocompromise Cystic fibrosis ≥8 to ≤19 mo of age CLD of prematurity requiring medical management Immunocompromise Cystic fibrosis with severe pulmonary manifestations
Nirsevimab	Prevention of RSV LRTD51 Neonates and infants born during or entering their first RSV season High risk infants up to 24 months entering their second season	All infants <8 mo of age entering their first RSV season who have not received clesrovimab or whose mother did not receive RSVpreF ≥14 days befpre birth*51,55 If born during or shortly before RSV season,† administer within 7 days of birth If born outside of season, administer shortly before RSV season Infants aged 8–19 mo at risk for severe RSV entering their second season Shortly before RSV season
Clesrovimab	Prevention of RSV LRTD 60 Neonates and infants born during or entering their first RSV season	All infants <8 mo of age entering their first RSV season who have not received nirsevimab or whose mother did not receive RSVpreF ≥14 days vefore birth*66,67
RSVpreF	Prevention of LRTD and severe LRTD caused by RSV in infants from birth through 6 mo of age66 Administration to pregnant individuals to 32–36 wkgestation	Administration to pregnant persons 32–36 wk gestation during September to January in temperate climates56

AAP, American Academy of Pediatrics; ACIP, Advisory Committee on Immunization Practices; BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; CLD, chronic lung disease FDA, Food and Drug administration; LRTD, lower respiratory tract disease

* Shared decision-making in high-risk individuals was an alternative recommendation by the Centers for Disease Control and Prevention in 2026.

† RSV season in temperate climates is traditionally October to April.

Consensus guidelines were created after approval, which recommended use only in the highest-risk patients.⁴⁶ In 2025, the AAP announced it no longer recommended palivizumab use, with an added caveat that if future supply chain issues with other monoclonal antibodies occurred, additional guidance would be provided.⁴⁷ At the time of writing this publication, no updated guidance on palivizumab use for RSV prevention has been issued by the CDC or Advisory Committee on Immunization Practices (ACIP), although the manufacturer discontinued production at the end of 2025.⁴⁸

Palivizumab’s approval initially came from 1 large, randomized trial, designated “IMpact-RSV.”⁴⁹ This trial enrolled 1502 infants who were at high risk for severe RSV disease (Table 3). Participants received monthly palivizumab or placebo for 5 months. Palivizumab demonstrated a 55% (95% CI, 38–72; p < 0.001) reduction in RSV hospitalizations when compared with placebo. When analyzing the individual cohorts, premature infants demonstrated a 78% reduction (p < 0.001) in RSV hospitalizations, and patients with bronchopulmonary dysplasia (BPD) demonstrated a 39% reduction (p = 0.038). In addition, palivizumab was found to significantly reduce the risk of intensive care unit (ICU) admission (57%; p = 0.026), hospital length of stay (63 vs 36 days; p < 0.001), and length of supplemental oxygen requirement (51 vs 30 days; p < 0.001). No significant differences were found in mechanical ventilation rates, mechanical ventilation duration, or mortality. Adverse events deemed related to the study drug were seen in 10% of the placebo group compared with 11% in the palivizumab group. Common adverse events reported included fever, nervousness, and injection site reactions.

Table 3.

Food and Drug Administration approval studies for efficacy of respiratory syncytial virus (RSV) preventative therapies

	Study	Population	Intervention	Outcomes
Palivizumab	IMPACT-RSV Study Group49	Infants (≤35 wk gestation and ≤6 mo of age) or infants and children ≤2 yr of age with a clinical diagnosis of BPD who required ongoing therapies (supplemental oxygen, bronchodilators, corticosteroids, or diuretics in the past 6 mo IM) Select exclusion criteria: mechanical ventilation requirement, CHD (except uncomplicated or hemodynamically insignificant patent ductus arteriosus or septal defect) hospitalization that was anticipated to last >30 days, active or recent RSV infection, receipt of RSV immune globulin in the past 3 mo	Palivizumab 15 mg/kg or placebo IM every 30 days for 5 doses	Primary outcome: 55% reduction (95% CI, 38–72; p < 0.001) in hospitalizations due to RSV Secondary outcomes: decreased total days of hospitalization with palivizumab (36.4 vs 62.6; p < 0.001) Decreased days with increased oxygen with palivizumab (30.3 vs 50.6; p < 0.001) Decreased days with a lower respiratory score of 3 or higher with palivizumab (29.6 vs 47.4; p < 0.001)
Nirsevimab	Griffin32	Healthy preterm infants (29 to 34 6/7 weeks) born and ≤1 yr of age entering their first full RSV season Select exclusion criteria: infant meets local, national, or AAP recommended guidelines for RSV prophylaxis; acute illness at randomization; previous RSV infection; received palivizumab; received any investigational RSV monoclonal antibody or vaccine (including maternal)	Nirsevimab 50 mg IM × 1 or placebo administered during a 2- mo period before the RSV season starting	Primary outcome: 70.1% reduction (95% CI, 52.3–81.2; p < 0.001) in MA RSV LTRI (inpatient or outpatient) through 150 days post dose Secondary Outcome: 78.4% reduction (95% CI, 51.9–90.3; p < 0.001) in RSV associated hospitalization through 150 days post dose
Nirsevimab	Hammitt and Muller33,34	Healthy late-preterm infants (≥35 wk) and term infants who were ≤1 yr of age and entering first RSV season Select exclusion criteria: infant met national or local criteria for palivizumab; fever/acute illness within 7 days; had RSV infection at or before randomization	Nirsevimab 50 mg IM × 1 if <5 kg, 100 mg IM × 1 if ≥5 kg, or placebo	Primary Outcome: 76.4% (95% CI, 62.3–85.2; p < 0.001) reduction in MA RSV LRTI through 150 days post dose Secondary outcome: 76.8% (95% CI, −48.8 to 91; p = 0.07) decrease in RSV hospitalization through 150 days post dose 78.6% (48.8–91.0) decrease in very severe medically attended RSV-associated LRTI through 150 days post dose
Clesrovimab	CLEVER62,63	Healthy preterm and full-term infants (birth to 1 yr of age) and entering first RSV season	Clesrovimab 105 mg or placebo IM × 1	Primary outcome: 60.4% (95% CI, 44.1–71.9, p < 0.001) reduction in RSV-associated MALRI requiring ≥1 indicator of LRI or severity through 150 days post dose Secondary outcome: 84.2% (95% CI, 66.6–92.6, p < 0.001) reduction in RSV-associated hospitalizations through 150 days post dose Tertiary outcomes: 90.9% (95% CI, 76.2–96.5) reduction in RSV-associated LRI hospitalizations through 150 days post dose 91.7% (95% CI, 62.9–98.1) reduction in severe MALRI through 150 days post dose 52.0% (95% CI, 39.5–61.9) reduction in acute respiratory infection through 150 days post dose
Clesrovimab	SMART62,64	Infants recommended to receive palivizumab due to prematurity (≤35 wk gestational age), CLD of prematurity, or hemodynamically significant CHD and entering first RSV season	Clesrovimab 105 mg IM on day 1 and placebo IM on day 28 or palivizumab 15 mg/kg IM monthly for 3–5 doses	Primary outcome: incidence rates for MALRI requiring ≥1 indicator of LRI/severity clesrovimab 3.6% (95% CI, 2.0–6.0) versus palivizumab 3.0% (95% CI,1.6–5.3) Secondary outcome: incidence rates for RSV hospitalization: clesrovimab 1.3% (95% CI, 0.4–3.0) vs palivizumab 1.5% (95% CI, 0.6–3.3)
RSVpreF	Kampmann31	Pregnant women aged 18–49 yr whose fetus’ gestational age was 24–36 wk and the infants of this population Select exclusion criteria: non-singleton pregnancy, any known risk for increased pregnancy complications, infants who received any monoclonal antibody with efficacy against RSV, blood transfusions >20 mL/kg within 180 days of birth	RSVpreF 120 μg IM x1 or placebo	Primary outcomes: Reduction of severe MA RSV LRTI: 90 days after birth: 81.8% (99.5% CI, 40.6 –96.3) 120 days after birth: 73.9% (97.58% CI, 45.6–88.8) 150 days after birth: 70.9 (97.58% CI, 44.5–85.9) 180 days after birth: 69.4% (97.58% CI, 44.3–84.1) Reduction in MA RSV LRTI: 90 days after birth: 57.1% (99.5% CI, 14.7–79.8, not statically significant) 120 days after birth: 56.8% (97.58% CI, 31.2–73.5) 150 days after birth: 52.5% (97.58% CI, 28.7–68.9) 180 days after birth: 51.3% (97.58% CI, 29.4–66.8) Secondary outcomes: reduction in RSV-associated hospitalization 90 days after birth: 67.7% (99.17% CI, 15.9–89.5) 180 days after birth: 56.8% (99.17% CI, 10.1–80.7) Reduction in MA LRTI from any cause: 90 days after birth: 7.0%; 99.17% CI, −22.3 to 29.3, not statically significant)

BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; CLD, chronic lung disease; IM, intramuscular; LRI, lower respiratory infection; LRTD, lower respiratory tract disease; LRTI, lower respiratory tract infection; MALRI, medically attended lower respiratory infection; MA LRTI, medically attended lower respiratory tract illness; MA RSV LRTI, medically attended RSV lower respiratory tract infection

In 2003, palivizumab gained additional FDA approval for the prevention of serious RSV disease in infants and children with hemodynamically significant congenital heart disease (CHD) due to results from “The Cardiac Synagis Study Group.”^45,50 This trial enrolled 1287 infants and children younger than 24 months of age with hemodynamically significant CHD. Participants were randomized 1:1 to receive monthly palivizumab or placebo for 5 months. Of note, infants with severe CHD with poor prognosis were excluded from this trial. Palivizumab demonstrated a 45% reduction (95% CI, 23–67; p = 0.003) in RSV hospitalizations. When categorized into cyanotic and acyanotic or other strata, patients with acyanotic or other disease experienced a 58% reduction (p = 0.003) in RSV hospitalizations, compared with a 29% reduction (p = 0.285) in the cyanotic group. Additionally, palivizumab demonstrated a 56% reduction in hospitalization days and a 73% reduction in RSV hospitalization days, with increased oxygen requirements per 100 children. No statistically significant difference was observed for ICU admission, days of ICU stay, mechanical ventilation, days of mechanical ventilation, or mortality. Adverse events deemed related to the intervention were similar between the groups.

Nirsevimab.

In 2023, Nirsevimab was approved in the US for prevention of RSV lower respiratory tract infection (RSV LRTI) in infants and young children entering their first RSV season and high-risk children entering their second season (Table 2).⁵¹ Nirsevimab’s mechanism of action differs from palivizumab and clesrovimab as it targets a different antigenic site, site 0, which is only on the prefusion configuration of the RSV F protein whereas palivizumab’s and clesrovimab’s target site is on both pre- and post-fusion configurations.^52–54 Nirsevimab is administered during the first RSV season as a 1-time IM dose of 50 mg for infants weighing less than 5 kg, 100 mg for infants weighing 5 kg or more, and 200 mg for high-risk children entering their second RSV season.⁵⁴ The 2025 ACIP recommendations recommend administration to occur within 1 week of birth for infants born during or close to the beginning of RSV season (traditionally October to March depending on geographic location) and shortly before the beginning of RSV season for infants born out of RSV season (traditionally April to September) who are not protected by maternal immunization or clesrovimab; another novel RSV monoclonal antibody.⁵⁶

Nirsevimab was FDA approved based on the results of 3 large clinical trials demonstrating safety and efficacy. The first trial was a phase 2b study enrolling healthy infants born 29 to 34 6/7 weeks of gestation during their first year of life to receive nirsevimab or placebo. Through 150 days, nirsevimab demonstrated a 70.1% reduction (95% CI, 52.3–81.2; p < 0.001) in medically attended RSV lower respiratory tract infection (MA RSV LRTI) and 78.4% reduction (95% CI, 51.9–90.3; p < 0.001) in RSV-associated hospitalization.³² The phase 3 MELODY trial enrolled healthy infants born 35 weeks of gestation or older during their first year of life (Table 3). Participants were randomized 2:1 to receive either nirsevimab or placebo. Through 150 days, nirsevimab demonstrated a 76.4% reduction (95% CI, 62.3–85.2; p < 0.001) in MA RSV-associated LRTI. The secondary outcome of RSV-associated hospitalization did not meet statistical significance, though an underpowered analysis of the northern hemisphere population did find a reduction.³² The MEDLEY trial, a phase 2b/3 study, enrolled infants and children who would currently qualify for palivizumab prophylaxis entering their first or second RSV season. Participants were randomized (2:1) to receive either nirsevimab or palivizumab. The MEDLEY trial found similar rates of adverse events between the 2 groups and a similar incidence of MA RSV-associated LRTI through 150 days in both seasons. In addition, pharmacokinetic markers were collected to compare antibody responses with results in the phase 2b and MELODY trials.³⁵ A combined analysis was conducted using the results of both the phase 2b study and the MELODY study. In this pooled analysis, through 150 days, nirsevimab demonstrated a 79.5% reduction (95% CI, 65.9–87.7; p < 0.001) in MA RSV-associated LRTI and a 77.3% reduction (95% CI, 50.3–89.7; p < 0.001) in hospitalization for RSV-associated LRTI. In addition, this analysis reported that patients in the MEDLEY trial achieved pharmacokinetic goals 94% of the time.⁵⁷ The phase 3b HARMONIE trial, published after approval, enrolled infants born older than 29 weeks of gestation and younger than 1 year of age. Participants were randomized (1:1) to receive either nirsevimab or placebo. Nirsevimab demonstrated an 83.2% reduction (95% CI, 67.8–92; p < 0.001) in hospitalizations due to RSV-associated LRTI.⁵⁸ In all of the aforementioned studies, no significant adverse events were noted to be due to nirsevimab. The most common nonsignificant event reported was a minor injection site reaction. An additional study has provided pharmacokinetic data in immunocompromised children, although extensive outcomes data are lacking.⁵⁹

Clesrovimab.

In 2025, Clesrovimab was FDA approved in the US for the prevention of RSV lower respiratory tract disease in infants entering their first RSV season (Table 2).⁶⁰ Clesrovimab is a fully humanized monoclonal antibody that targets site IV of the RSV F protein, which is on the pre- and post-fusion configuration.⁵⁴ This antibody is unique for RSV prevention because dosing is not weight based; all patients are recommended to receive 105 mg IM for first-season prophylaxis. The 2025 ACIP recommendations recommend administration of clesrovimab (or nirsevimab) to all infants younger than 8 months of age born during or entering their first RSV season who are not protected by maternal vaccination. In comparison to nirsevimab, clesrovimab is not currently FDA approved for second-season RSV prophylaxis.⁶¹

Clesrovimab was approved based on the results of 2 large clinical trials, a phase 2b/3 study (CLEVER) and a phase 3 study (SMART).^62–65 CLEVER enrolled 3614 healthy preterm and term infants entering their first RSV season (Table 3). Participants were randomized 2:1 to receive either clesrovimab 105 mg once or placebo. Preliminary analysis demonstrated a 60.4% reduction (95% CI, 44.1–71.9, p < 0.001) in the primary outcome of RSV-associated medically attended lower respiratory infection (MALRI) with more than 1 indicator of LRTI severity through 150 days post dose. Additionally, clesrovimab demonstrated an 84.2% reduction (95% CI, 66.6–92.6, p < 0.001) in the secondary outcome of RSV-associated hospitalization through 150 days post dose. Clesrovimab was well tolerated as compared with placebo, with 1 hypersensitivity reaction (bronchospasm) noted in the clesrovimab group and none in the placebo group.^63,64

Preliminary data from the phase 3 SMART study were presented to the FDA and ACIP. This study enrolled infants 1:1 who were candidates to traditionally receive palivizumab to either receive clesrovimab 105 mg once or palivizumab 3 to 5 times during the infant’s first RSV season (Table 3).^62,64 Another arm of the study investigated clesrovimab in high-risk children entering their second RSV season, but these data have not been presented at the time of writing this manuscript. A total of 896 infants were included in the preliminary data presented. Safety outcomes between the 2 cohorts were similar. It must be noted that deaths were higher in the clesrovimab group (1.8% vs 0.9%); however, no deaths were thought to be attributable to the study drug per the investigators. Rates of RSV MALRI with more than 1 indicator of LRTI or severity through 150 days post dose and RSV-associated hospitalization were similar between both cohorts (Table 3). In a pharmacokinetic comparison to the previously mentioned study, infants had similar 150-day area under the curve measurements. The authors concluded this would suffice as surrogate data for efficacy in this patient population. Clesrovimab’s approval now gives providers a choice of monoclonal antibodies for RSV prevention in infants, additional options in the case of supply chain issues, and a second option in the case of the emergence of escape mutants to 1 agent.

RSVpreF.

In 2023, 2 novel RSV vaccines were approved by the FDA for use in select adults, while only 1 gained approval for use in pregnant mothers (Table 2). RSVpreF vaccine (Abrysvo) was approved for maternal administration in the US in 2023 for the prevention of severe and nonsevere RSV lower respiratory tract disease in infants from birth to 6 months of age.⁶⁶ RSVpreF is comprised of equivalent components of RSVpreF A and B proteins. These proteins stimulate the mother’s own immune system to produce neutralizing antibodies that are then distributed through placental transfer and later potentially through breastmilk.⁶⁷ RSVpreF is administered as a 1-time IM injection at a dose of 120 mcg during 32 to 36 weeks of gestation. Additionally, the ACIP recommends that administration occur between September and January in areas that follow a seasonal RSV distribution.^66,68 Administration of nirsevimab is recommended to infants who were born less than 14 days after maternal administration of RSVpreF due to concerns for inadequate maternal antibody production and placental transfer.⁵⁶ If there is a clinical reason that antibody transfer from RSVpreF may be inadequate, such as the pregnant woman having an immunocompromising condition or the infant having cardiopulmonary bypass or extracorporeal membrane oxygenation, then nirsevimab or clesrovimab may be considered in those infants for RSV prevention.

RSVpreF was approved based on the results of 2 large randomized clinical trials.^31,57 The first trial was a randomized placebo-controlled phase 2b study investigating the safety and immunogenicity profile of RSVpreF in healthy pregnant women between 24 and 36 weeks of gestation and their infants after birth.⁵⁷ Pregnant women were randomly assigned to the 120-mcg group, the 240-mcg group, either group with the addition of aluminum hydroxide, or the placebo group. An interim analysis found higher rates of local reactions in the cohorts receiving the adjunct aluminum hydroxide. Other safety data were similar in both maternal and infant cohorts. Infant immunogenicity markers were found to be higher in the non-aluminum hydroxide cohorts, while they were similar between the 120 and 240 mcg groups, leading to the selected dosing for further investigation to be 120 mcg. Of note, a higher numerical rate of preterm birth was reported in the 120 mcg RSVpreF cohort compared with placebo (5.2% vs 2.6%; relative risk [RR], 2.03; 95% CI, 0.52–7.94), although not statistically significant.

The second trial, the MATernal Immunization Study for Safety and Efficacy (MATISSE), was a phase 3b trial enrolling the same population as the phase 2b trial (Table 3).³¹ Pregnant women were randomized to either receive 120 mcg of RSVpreF or placebo. At both 90 and 180 days post birth, RSVpreF demonstrated an 81.8% (99.5% CI, 40.6–96.3) and 69.4% reduction (97.58% CI, 44.3–84.1) in severe MA RSV LRTI. In addition, RSVpreF demonstrated a statistically significant reduction in nonsevere MA RSV LRTI at both 120 and 180 days post birth (Table 3). Of note, rates of preterm birth were once again numerically higher in the RSVpreF cohort, although not reaching statistical significance (5.7% vs 4.7%; RR, 1.19; 95% CI, 0.97–1.45).

Additional analysis of both trials by the FDA concluded that administration to pregnant women at 32 to 36 weeks of gestation had a lower potential risk of preterm birth, 1.15 (95% CI, 0.82–1.61) in the 32 to 36 weeks of gestation versus 1.20 overall (95% CI, 0.99–1.46). After this analysis, RSVpreF was only FDA approved for administration at 32 to 36 weeks of gestation.^56,69 The ACIP then recommended administration be limited seasonally, September through January. Post marketing surveillance through the Vaccine Adverse Event Reporting System revealed an increased risk of developing Guillain-Barré Syndrome 42 days post vaccination in adults aged older than 60 years when compared with Pfizer-BioNTech mRNA vaccines for background prevalence (4.4/million vs 0.43/million doses).⁷⁰ At this time, no increased risk of Guillain-Barré Syndrome has been identified in the maternal recipients. In addition, vaccine safety data link from September 22, 2023, to January 31, 2024, demonstrated no increase in risk of preterm birth in pregnant women who received RSVpreF versus those who did not (4% vs 4.5%; RR, 0.90; 95% CI, 0.80–1.00).⁷¹

Investigational Products.

Multiple agents intended to protect infants and children from RSV disease are in various stages of development, including live attenuated vaccines and messenger RNA vaccines.^72,73 Of note, in late 2024, the FDA halted a phase 1 trial of an RSV vaccine in infants due to increased incidence of severe RSV lower respiratory tract disease in the messenger RNA vaccine group, provoking memories of the failed formalin vaccine in the 1960s.⁷⁴

Preventative Therapies—Clinical and Practical Considerations.

Currently, 4 preventive medications are FDA approved for the prevention of RSV in infants, including palivizumab, nirsevimab, clesrovimab, and maternal RSVpreF vaccine.^45,51,60,66 Future use of palivizumab is unlikely as the AAP has recommended against its continued use, and the manufacturer plans to discontinue the product. This change in recommendation is likely due to the availability of effective, longer-acting monoclonal antibodies, nirsevimab and clesrovimab, which are available at a decreased cost.⁴⁷

In clinical trials, most outcomes used to determine the efficacy of preventive therapies include RT-PCR or antigen-based microbiologic confirmation combined with an assessment of symptoms and/or level of care used for diagnosing an RSV infection. The definitions used to determine significant RSV disease widely across studies and can affect the use or interpretation of the findings. Table 4 provides a comparison of the main outcome measures used in trials of the medications currently approved by the FDA for prevention of RSV infection in neonates and at-risk infants. Of note, some of the more recent studies leading to approval had outcomes related to medically attended lower respiratory tract infection in primarily healthy near-term patients. In contrast, palivizumab data were focused on high-risk patients with an outcome of severe RSV disease requiring hospitalization. Between monoclonal antibodies and maternal immunization, it is difficult to recommend one over the other due to varying definitions of outcomes and a lack of head-to-head clinical trials. The ACIP does not recommend preference for nirsevimab or clesrovimab administration or make a recommendation regarding whether maternal immunization or infant monoclonal antibody administration is preferred.⁶¹

Table 4.

Definitions of outcomes used between randomized studies for lower respiratory tract infection (RSV) prevention options

Study (Drug)	General Population	Medically Attended RSV ARI Definition	RSV LRTI Definition	RSV Hospitalizations Definition	Severe and Hospitalized RSV LRTI Definition
IMPACT-RSV49 (Palivizumab)	Newborns and infants born preterm (≤35 wk GA) or with chronic lung disease	N/A	N/A	Hospitalized and RSV antigen positive (primary outcome)	Lower respiratory infection score (1–5 scale from no disease to mechanical ventilation), mechanical ventilation and ICU days also assessed (mostly secondary outcomes)
Griffin32 (MELODY, Nirsevimab)	Late preterm ≥29 to <35 wk GA newborns or infants	N/A	RSV positive, lower respiratory tract physical exam finding and 1 objective finding of severity (hypoxemia <92–95%, signs of resp distress, or high respiratory rate)	RSV infection and hospitalized	N/A
Hammitt33 (MELODY, Nirsevimab)	Near term or term (>35 wl GA) newborns or infants	N/A	Same as Griffin32	RSV infection and hospitalized	N/A
Muller34 (MELODY, Nirsevimab)	Near term or term (>35 wk GA) newborns or infants	N/A	Same as Griffin32	RSV infection and hospitalized	Supplemental oxygen or intravenous fluids during hospitalization
Domachowske35 (MEDLEY, Nirsevimab)	Primarily safety study of newborns and infants born preterm infants (≤35 wk), chronic lung disease, and significant congenital heart defects	N/A	Similar to other Griffin32 but significant changes in respiratory support from baseline were included as an objective severity finding for patients with underlying disease states	N/A	N/A
Drysdale58 (HARMONIE, Nirsevimab)	Newborns and infants born ≥29 wk GA	N/A	N/A	RSV infection and hospitalized	Hospitalized and O2 saturation <90% needing oxygen
Kampmann31 (RSVpreF)	Infants born to mothers near term	RSV positive and ≥1 RTI finding: nasal discharge, difficulty breathing, cough, decreased feeds, apnea, and any other respiratory symptom	RSV positive, ≥1 RTI finding, and ≥1 lower RTI finding, including tachypnea, <95% SpO2 saturation, indrawing chest	RSV infection and hospitalized	One of the following: Severe tachycardia SpO2 <93% Supplemental oxygen ICU admission for >4 hr Failure to respond/unconscious
CLEVER62,63 (Clesrovimab)	Infants healthy and at least 29 wk	RSV positive and one sign of an ARI: includes same signs as LRTI but also included runny nose, stuffy nose, fever, difficulty eating	Cough or difficulty breathing, and RSV PCR positive, and at least 1 other symptom (wheezing, chest wall retraction, rales/crackles, hypoxemia, tachypnea or dehydration) An alternative outcome included having 2 of the LRI severity symptoms	RSV infection and hospitalized, and another outcome of RSV positive with LRTI symptoms and hospitalized	RSV positive with cough/difficulty breathing and one of the following: Need for high-flow nasal cannula Need for oxygen mask Need for mechanical ventilatory support

ARI, acute respiratory infection; GA, gestational age; ICU, intensive care unit; MA RSV LRTI, medically attended RSV lower respiratory tract infection; N/A, not applicable; RSV LRTI, RSV lower respiratory tract infection; RTI, respiratory tract infection

Important formulary considerations for each agent exist. Nirsevimab is the only agent approved for use during the second RSV season in select infants, so it may be beneficial for centers caring for high-risk infants in the second season to have nirsevimab available. Practical considerations for nirsevimab include the need to use the medication within 8 hours of removing refrigeration and the necessity of centers stocking both 50 mg/0.5 mL and 100 mg/1 mL formulations to immunize all infants, with second-season administration requiring 2 injections.⁵¹ Clesrovimab provides the convenience of a standardized dose for all infants (105 mg/0.7 mL) and can be stored at room temperature for up to 48 hours before discarding. Additionally, clesrovimab requires only 1 formulation to be kept for first-season immunization with less injection volume compared with nirsevimab for infants weighing 5 or more kg.^51,60 RSVpreF offers protection for infants at birth but requires maternal administration during a limited window during both pregnancy and time of year, leading to some pregnant women being excluded as vaccine candidates. RSVpreF must be used within 4 hours of removal from refrigeration.⁶⁶ This preventative strategy would be employed more in centers that provide prenatal care. Regardless of which preventive measure is used, institutions should have processes to identify eligible patients during RSV season and incorporate this into encounter workflows to record whether mothers or newborns received one of the options.

Additionally, knowledge gaps do exist for all agents. These include long-term outcomes data and limited efficacy and safety data in infants younger than 29 weeks of gestational age. Maternal and caregiver education about the disease and options for prevention is essential to best protect the infant.

Treatment

In 2014, the AAP issued a guideline regarding the diagnosis and management of bronchiolitis, which remains influential in current clinical practice.⁴¹ Supportive care continues to be the fundamental approach to treating bronchiolitis. Standard interventions include oral or intravenous hydration, saline nose drops to clear nasal obstruction, nasal bulb suction or deep suctioning if hospitalized, and nutrition for the patient. Routine nasal suctioning, particularly before feedings, can be effective in clearing the nasal passages. Most infants can be treated at home. However, hospitalization should be considered for those who are ill, dehydrated, have poor feeding or apnea, develop respiratory distress, or need supplemental oxygen when oxygen saturations consistently drop below 90%.⁴¹ The majority of previously healthy children admitted to the hospital will show improvement with supportive care and are typically discharged within 2 to 3 days.⁴⁴ This subsection provides a general overview of treatment outcomes, focusing on strategies that remain controversial, have been proven ineffective, or represent emerging areas of therapy.

Chest Physiotherapy and Oxygen Therapies.

Various chest physiotherapy techniques used in RSV infections have not demonstrated a reduction in disease severity, length of hospital stay, or recovery time, and may be associated with adverse events.⁴¹ However, slow expiratory techniques in moderately severe acute bronchiolitis may result in mild to moderate improvement in disease severity in children younger than 2 years of age and could be considered for this type of patient.⁷⁵ Continuous positive airway pressure has not demonstrated a reduction in the need for mechanical ventilation or duration of hospitalization in children younger than 12 months of age.⁷⁶ One small trial found a decrease in respiratory rates but no change in pCO₂. Larger studies are needed to evaluate the benefit of continuous positive airway pressure in bronchiolitis. High-flow oxygen therapy compared to low-flow in infants younger than 2 years of age resulted in a reduction of hospital stay (mean difference [MD] −0.65 days; 95% CI, −1.23 to −0.06; 7 trials) and oxygen therapy duration (MD −0.59 days; 95% CI, −1 to −0.18; 7 trials).⁷⁷ Additionally, respiratory rate and heart rate improved at various times in the first 24 hours, and a reduced incidence of treatment escalation was found with high-flow therapy compared with low flow. Adverse events were similar between groups.

Hypertonic Saline.

The use of nebulized hypertonic saline for bronchiolitis is still debated due to varying evidence. According to the 2014 AAP bronchiolitis guideline, nebulized hypertonic saline may be administered to hospitalized patients with bronchiolitis; however, it should not be administered in the emergency department (ED) due to a lack of strong data demonstrating reduced hospitalization rates and unclear efficacy after less than 24 hours of use.⁴¹ A 2023 Cochrane review analyzed 34 trials, including 2727 infants younger than 2 years of age with acute bronchiolitis who received hypertonic saline.⁷⁸ The majority of trials used 5% hypertonic saline, 6 trials used 5% to 7% concentrations, and several trials coadministered with bronchodilators (some providers consider this to prevent potential bronchospasm). Of the trials, 21 were in the inpatient setting, 2 in the outpatient setting, 10 in the ED, and 1 in the outpatient and ED setting. Hospitalization rates decreased by 13% (RR, 0.87; 95% CI, 0.78–0.97; 21 trials) with nebulized hypertonic saline compared with normal saline in the outpatient and ED settings. The length of hospital stay was reduced by 9.6 hours (MD, −0.40 days; 95% CI, −0.69 to −0.11; 8 trials) with nebulized hypertonic saline compared with normal saline. The Wang clinical severity score, a common method for assessing bronchiolitis severity, decreased during the first 3 days of therapy with hypertonic saline in the outpatient and inpatient settings. The ED setting did not demonstrate a similar outcome in a short time frame of 30 to 120 minutes. There were no differences seen between treatment regimens, and hypertonic saline did not decrease the risk of readmission after discharge. Adverse effects were mild and spontaneously resolved, and no significant adverse events were observed. A remaining controversy is whether normal saline is the best comparator to hypertonic saline in clinical trials. In the ICU setting, a retrospective study of 104 children younger than 2 years of age with severe bronchiolitis showed that using 3% hypertonic saline reduced respiratory support duration by 28% and ICU stay length by 19%, compared with standard care.⁷⁹ Clinically, institutional use differs due to variations in practitioners’ interpretations of the data and their patients’ outcomes.

Heliox.

Heliox, a mixture of oxygen and helium, has a lower density than air, allowing for increased oxygen flow through restricted passageways. A Cochrane database review of 7 studies on heliox use in children younger than 2 years with respiratory distress found no reduction in intubation rates or treatment length.⁸⁰ However, heliox shortened treatment duration for infants needing nasal continuous positive airway pressure compared with the use of air or oxygen. Four studies reported a lower modified Wood Clinical Asthma Score within the first hour of treatment, but no improvement in gas exchange. Further research is needed on the use of heliox as a bronchiolitis intervention.

Bronchodilators and Corticosteroids.

Bronchodilators and corticosteroids are not recommended for treating bronchiolitis, as they do not consistently improve the illness course, duration, or hospital stay.^41,81,82 Bronchodilators demonstrate no benefit on oxygen saturation, and their use in the inpatient and outpatient settings does not reduce hospitalization rates or duration or illness duration.⁸¹ However, these medications might benefit older infants and children with reactive airway disease exacerbations secondary to bronchiolitis. It is an option to trial a dose of albuterol with pre- and post-assessments to accurately assess for improvement. If no significant improvement is noted, albuterol should not be continued. Epinephrine is also ineffective and not advised for bronchiolitis treatment.⁴¹

Antibiotics.

Studies have evaluated the use of antibiotics, primarily penicillins and macrolides, in patients with bronchiolitis for disease improvement, length of stay, and readmissions, but no benefit was determined.⁸³ The AAP bronchiolitis guideline suggests antibiotics should only be prescribed for patients with highly suspected or confirmed concomitant bacterial infections, which are uncommon in cases of bronchiolitis.⁴¹

Ribavirin.

Aerosolized ribavirin is the only FDA-approved drug for the treatment of patients with an RSV infection. However, it is not recommended for treating RSV bronchiolitis due to its failure to show a reduction in ICU or hospital stay duration or the need for mechanical ventilation.⁴⁴ Additionally, its adverse effects, teratogenicity, administration challenges, and cost restrict its use. Several small studies have indicated a statistically significant increase in oxygen saturation from aerosolized ribavirin, while oral ribavirin has been used in adult patients undergoing stem cell transplants.⁴⁴ Consequently, it may be considered for treatment in certain patients with severe, life-threatening infections.

Immunoglobulin and Monoclonal Antibodies.

Additional treatments for bronchiolitis have been evaluated but lack strong evidence. The use of RSV immunoglobulin and monoclonal antibodies (palivizumab and motavizumab) for an acute RSV infection has not been shown to affect hospitalization duration (MD, −0.13 days; 95% CI, −0.37 to 0.12; 6 studies).⁸⁴ Additionally, palivizumab did not prevent ICU admission or hospital readmissions within 3 weeks post-discharge.⁸⁵

Surfactant, Leukotriene Receptor Antagonists, and Dornase Alfa.

Three small, randomized controlled trials involving intubated, severely ill patients (ages 1 week to 2.5 years) with an RSV infection evaluated surfactant with mechanical ventilation versus ventilation alone.⁸⁶ Two studies showed reduced ventilation use and duration in the ICU, while 1 found no difference. No adverse effects were reported. More data are needed to confirm the benefits of surfactant use in bronchiolitis. Evidence from 2 small trials on the short-term inpatient use of montelukast is inconsistent, with outcomes suggesting a lack of benefit.^87–89 Long-term use of leukotriene receptor antagonists found no reduction in symptom-free days or recurrent wheezing.⁸⁹ More research is needed to identify if they have a role in bronchiolitis. Lastly, dornase alfa does not improve clinical outcomes or reduce hospitalization duration in patients younger than 2 years.⁹⁰

Trials in Progress.

Clinical trials are evaluating both existing medications and new treatments for RSV infections in infants and children. A 5-day treatment with ziresovir, an RSV F oral protein inhibitor, was studied in a randomized, double-blind, placebo-controlled, phase 3 trial in infants 1 to 24 months of age hospitalized with an acute RSV infection.⁹¹ Ziresovir resulted in a −0.8 reduction (30%) in the Wang bronchiolitis clinical score (95% CI, −1.3 to −0.3; p = 0.002) compared with placebo from baseline to day 3 (48 hours after treatment initiation). There was no difference in score from days 4 to 6. Ziresovir also reduced viral load with activity against RSV A and B. Adverse events were similar between groups, with the most common in the ziresovir group being diarrhea (4%), increased liver enzymes (3%), and rash (2%). Three patients discontinued ziresovir due to the rash. A resistant mutation occurred during treatment in 9% of patients (n = 14) in the ziresovir group.

A 3-day treatment with intravenous azithromycin is currently being studied for reducing the duration of hospitalization, oxygen use, and ICU stay in children younger than 2 years who are admitted to the ICU and require mechanical ventilation.^92,93 However, a 2024 meta-analysis determined that azithromycin reduced the duration of hospitalization by 0.27 days (95% CI, −0.47 to −0.07) but did not prevent recurrent wheezing or readmission in children younger than 2 years.⁹⁴ A twice-daily inhaled human Interferon α-1b solution is being evaluated for the treatment of an acute RSV infection in children younger than 2 years.⁹⁵ Another study is evaluating inhaled Peginterferon α-2b with recombinant human interferon α-2b for an acute RSV infection in infants greater than 6 months to 2 years.⁹⁵ Antivirals, such as obeldesivir, deuremidevir hydrobromide, and remdesivir, are also being studied in the pediatric population for treatment of acute RSV infections.^96–99

Treatment—Clinical Considerations and Summary.

The standard treatment for bronchiolitis continues to be supportive care. Overall, treatment interventions have not shown significant effects on clinical disease severity, rates of ICU admission, hospitalization frequency, length of hospital stay, or readmission rates associated with RSV infections. Nebulized hypertonic saline has evidence suggesting a potential modest benefit in reducing hospital length of stay, improving clinical severity scores, and decreasing the risk of hospitalization in patients in the ED and outpatient settings. However, most therapies studied offer limited or no efficacy for treating acute RSV infections. Ongoing investigational studies are examining both current and new pharmaceutical entities for acute RSV infections. The most effective approach to RSV disease management at the time of writing this review is prevention; thus, recent research has focused on this area.

Conclusion

The recent advent of additional RSV preventative therapies for nearly all infants has revolutionized care. Providers and caregivers now have multiple options demonstrating efficacy and safety in clinical and postmarketing trials; however, formulary availability and logistical considerations must be taken into account. Prospective comparative data are limited, and varying study definitions make it difficult to directly compare options or promote one therapy as optimal. Treatment strategies have remained relatively unchanged over the last 2 decades, with supportive care remaining the standard of care, but new antiviral entities are being investigated.

ABBREVIATIONS

AAP

American Academy of Pediatrics;

ACIP

Advisory Committee on Immunization Practices;

BPD

bronchopulmonary dysplasia;

CDC

Centers for Disease Control and Prevention;

CHD

congenital heart disease;

ED

emergency department;

F

fusion;

FDA

Food and Drug Administration;

ICU

intensive care unit;

IM

intramuscular;

IGIV

intravenous immunoglobulins;

LRI

lower respiratory infection;

LRTI

lower respiratory tract infection;

MD

mean difference;

MALRI

medically attended lower respiratory infection;

MA LRTI

medically attended lower respiratory tract infection;

MA RSV LRTI

medically attended RSV lower respiratory tract infection;

RR

relative risk;

RSV

respiratory syncytial virus;

RT-PCR

reverse transcriptase polymerase chain reaction