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    Respiratory Syncytial Virus Infection

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    Sep.24.2024

    Respiratory Syncytial Virus Infection

    Synopsis

    Key Points

    • RSV (respiratory syncytial virus) infection is a common source of upper and lower respiratory tract infections, including bronchiolitis and pneumonia
    • Most people have repeated infections over the lifespan, which are self-limited and mild in healthy individuals
    • Infants with congenital heart disease, history of prematurity, or underlying pulmonary disease may have more severe disease; children and adults with immunosuppression or chronic heart or lung disease and older adults in general are also at risk for severe disease
    • Among immunocompromised adults, especially transplant recipients, upper respiratory tract infections frequently evolve to lower respiratory tract infections with high morbidity and mortality rates
    • Main form of treatment is supportive care
    • Hypoxia and dehydration may complicate RSV bronchiolitis and require hospital admission
    • High-flow nasal cannula and noninvasive airway support are effective options for respiratory support
    • In immunocompromised patients with RSV infection, ribavirin in combination with corticosteroids and/or IV immunoglobulin may prevent or treat lower respiratory tract involvement
    • Monoclonal antibodies (nirsevimab, palivizumab) provide effective prevention for infants, especially those at high risk
    • Several new vaccines are effective for prevention of severe disease in older individuals and for use during pregnancy to prevent severe disease in infants; more are in development

    Urgent Action

    • Provide supplemental oxygen for infants with pulse oximetry readings less than 90% to 92% and for adults with readings less than 94% (less than 88% for adults at risk for hypercapnia) r1r2
    • Utilize high-flow nasal cannula and noninvasive airway support as indicated for respiratory distress
    • Endotracheal intubation and mechanical ventilation for respiratory failure
    • IV fluids to correct dehydration
    • Early antiviral therapy for severely immunocompromised patients (eg, transplant recipients)

    Pitfalls

    • Failure to recommend administration of monoclonal antibody to patients in high-risk populations may result in severe disease
    • Failure to admit young infants with apnea or hypoxia
    • Failure to consider diagnosis for immunocompromised patients who would benefit from antiviral therapy

    Terminology

    Clinical Clarification

    • RSV (respiratory syncytial virus) is a common cause of respiratory tract infections in all age groups r3
      • RSV causes upper respiratory tract infection with rhinorrhea and nasal congestion that is clinically indistinguishable from numerous other viruses
        • Nearly all persons will be infected by age 2 years, and repeated infections occur throughout life r3r4
      • RSV causes several types of lower respiratory tract infection including bronchiolitis, pneumonia, and exacerbation of underlying cardiopulmonary disease (eg, asthma, chronic obstructive pulmonary disease, congestive heart failure)
      • RSV is the most common cause of lower respiratory tract infection in young children, estimated to cause 33 million global infections, more than 100,000 global deaths, and more than 100,000 hospitalizations in the United States among children aged 0 to 5 years r5
      • RSV is increasingly recognized as a common and underreported cause of respiratory tract infection in adults, particularly adults aged 60 years and older and individuals with immunocompromise or heart or lung disease r3r6

    Classification

    • Single-stranded RNA virus of the Paramyxoviridae family
      • 2 subtypes: A and B r7
        • Subtype A usually causes more severe disease r7
      • Dominant strains shift each year r7

    Diagnosis

    Clinical Presentation

    History

    • Upper respiratory tract symptoms, including rhinorrhea and cough over 2 to 5 days, are usually present r8r9c1c2
    • Symptoms may progress to wheezing and difficulty breathing c3c4
    • Apnea or cyanosis may be the presenting problem in infants c5c6c7c8
    • Caregivers may report poor feeding by infants and young children (aged 5 years and younger); vomiting and diarrhea are also reported r10c9c10
    • Adults frequently experience myalgias, cough with sputum production, shortness of breath, and fever; malaise and headache are also reported but are not reported among children r10
    • In children and adults with preexisting asthma or chronic obstructive pulmonary disease, may present as an exacerbation c11c12c13c14
      • RSV infection is one of the most common precipitants of infection-induced wheezing in patients with known asthma

    Physical examination

    • Cough is the most common symptom across all ages and settings (hospitalized patients and outpatients); sputum production is commonly reported by adults r10
    • Fever is common in all age groups (greater than 40%); often low-grade (below 39 °C)r11r9r10c15
    • Rhinorrhea and nasal congestion are often observed c16
    • Tympanic membranes may be cloudy or inflamed, with poor light reflex; frank acute otitis media is often caused by RSV r12r13c17c18c19
    • Tachypnea may be present as disease progresses c20
    • In infants, use of accessory muscles and/or nasal flaring may be evident, indicating respiratory distress c21c22c23c24c25
    • Auscultatory findings range from normal to prolonged expiratory phase, rhonchi, diffuse polyphonic wheezing, and coarse crackles (rales) throughout the lung fields r10c26c27c28

    Causes and Risk Factors

    Causes

    • Transmission of RSV particles occurs through contact with respiratory secretions of infected people (directly or via contaminated objects) r13c29

    Risk factors and/or associations

    Age
    • Highest rates of severe disease appear to be among infants and older adults c30c31
    • Majority of clinically recognized cases in children occur in infants younger than 1 year; however, this reflects significant underdiagnosis in adults r3r14r15c32c33
      • Lower respiratory tract infection rates in children peak between birth and age 3 months (in low-income and lower-middle-income countries) or between the ages of 3 and 6 months (in upper-middle-income and high-income countries) r5c34c35
    • Clinical impact of RSV in older adults may approach that of nonpandemic influenza; high-risk groups include: r16
      • Adults with underlying cardiopulmonary disease r17c36
      • People living in long-term care facilities c37
      • Severely immunocompromised people (especially hematopoietic cell transplant recipients) c38c39
    • Age-related defects in cell-mediated immunity may lead to increased susceptibility and severe disease in older adults r18
    Sex
    Genetics
    • Down syndrome has been associated with an increased risk of severe RSV infection, independent of other recognized risk factors (eg, congenital cardiac disease, prematurity) r20r21c42c43c44
    • Patients with cystic fibrosis are at increased risk for severe disease r22c45
    • Genetic susceptibility is complex; it appears that a number of genetic variants may contribute to the risk for severe disease manifestations, including genes coding for host defense mechanisms, immune responses, and cytokine activation r23c46
    • Disease severity has been associated with genetic polymorphisms affecting the following proteins: TLRs, CCL5, JUN, IFNA5, NOS2, CX3CR1, interleukins, and VDR r19
    Ethnicity/race
    • Native American and Alaska Native children develop severe disease requiring hospitalization more often than other children, and it is unclear whether confounding environmental or social effects fully account for the difference r22c47c48
    Other risk factors/associations
    • Outbreaks occur with greater frequency during winter months in temperate climates; in tropical climates, disease frequency (and outbreak potential) is less predictable r13r24
      • Highest incidence of infection has traditionally been between December and March in the northern hemisphere r1c49
      • During the COVID-19 pandemic, public health measures (eg, masking, school closures) affected RSV transmission, with substantially lower rates of RSV in 2020 and a later-than-usual season in 2021-2022 r25r26
    • Exposure to air pollution (eg, particulate matter, nitrogen dioxide) r27
    • Risk factors for children:
    • Risk factors for severe disease in children:
      • Age 6 months or younger, particularly 3 months and younger r1r28c56
      • Prematurity r1r28r29c57
      • Low birth weight r29c58
      • Underlying comorbidity including congenital heart disease, lung disease, or Down syndrome r1r28c59
      • Any coinfection r28
      • Immunodeficiency, including: r1c60
        • History of organ transplant r30c61
        • Severe combined immunodeficiency c62
        • HIV infection c63
    • Risk factors for adults:
      • Living in long-term care facilities r3r31c64
      • Senior day care programs r32c65
      • Immunodeficiency, particularly history of organ transplant r13
    • Risk factors for severe infection in adults: r33
      • Older than 65 years r34c66
      • Residence in nursing home or other long-term care facility r3
      • Chronic lung disease (chronic obstructive pulmonary disease, asthma, interstitial lung disease, cystic fibrosis) r3r34c67
      • Cardiovascular disease (heart failure, coronary artery disease, congenital heart disease) r3c68
      • End-stage renal disease or renal replacement therapy
      • Diabetes mellitus with end-organ damage
      • Severe obesity (BMI 40 kg/m² or greater)
      • Liver disease (eg, cirrhosis)
      • Neurologic or neuromuscular conditions causing impaired airway clearance or respiratory muscle weakness
      • Hematologic disorders (sickle cell disease, thalassemia)
      • Moderate or severe immunocompromise
        • Especially leukemia, hematopoietic cell transplant, or solid organ transplant r3c69c70c71c72
      • Frailty

    Diagnostic Procedures

    Primary diagnostic tools

    • History and physical examination findings usually suffice to suggest diagnosis for pediatric patients with a compatible illness during the endemic season r1c73
      • Be alert for off-season cases, as the typical seasonal pattern has not fully resumed since the COVID-19 pandemic began r26
      • Do not routinely obtain laboratory studies for pediatric patients with typical clinical presentations r1
    • Laboratory confirmation of the diagnosis may be helpful for certain patients (eg, immunocompromised children or adults, those with chronic underlying cardiopulmonary conditions, those receiving prophylactic palivizumabr1) and for establishing the cause of hospital outbreaksr35
      • Maintain a high degree of suspicion on evaluation of people with immunocompromise, who may benefit from antiviral therapy
      • Set a very low threshold to test for RSV in health care settings in which an outbreak of respiratory disease is suspected r35
    • Chest radiography is not routinely recommended for children with bronchiolitis, but it is appropriate in cases of severe disease r1r11
    • Chest radiography is recommended for adults in whom pneumonia is suspected r36r37
    • Measure oxygen saturation in children with symptoms suggesting lower respiratory tract disease (bronchiolitis, pneumonia) and adults with suspected pneumonia r1r11r36
      • Oxygen and carbon dioxide levels may help to determine need for hospital admission and set a baseline for monitoring
      • Be aware that pulse oximetry has been demonstrated to be less effective in patients of all ages with darker skin tones, with risk of occult hypoxemia (ie, arterial oxygen saturation less than 88% with concurrent pulse oximetry value of 92% or more) highest for Black patients r38r39r40

    Laboratory

    • RT-PCR (reverse transcription polymerase chain reaction) r41c74
      • RT-PCR is considered the reference standard r3r13r14
        • Better sensitivity and specificity than antigen detection or viral culture
        • Results are available rapidly (within minutes to hours)
        • Available as a single test or multiplex, which concurrently tests for additional respiratory pathogens such as SARS-CoV-2, influenza, or others, but with a lower sensitivity r14
      • RT-PCR may be performed on nasopharyngeal swab or aspirate; nasal swab; oropharyngeal, saliva, or sputum samples; or lower respiratory tract specimens from intubated patients r14
      • Yield increases substantially when more than 1 site is sampledr42 or when coupled with serology
        • Sensitivity is estimated to be 84% or better for adults and 89% to 96% for children, with specificity of 98% to 99% r3r43
        • 2 or more tests (RT-PCR or serology) increased detection by 28% to 320%, depending on site and number of specimens r14r42
      • Commercially available RT-PCR tests that target antigenic site I, II, or IV on the RSV F (fusion) protein will not be affected if the patient has received nirsevimab r44
    • Rapid antigen detection test r45c75
      • First-generation testing has a pooled sensitivity and specificity of 80% and 97% r45
        • Sensitivity is higher for children (81%) than for adults (29%) r45
      • Second-generation rapid test has sensitivity of 78.6% and specificity of 93.9% r46
        • Sensitivity is highest (85%) during the first 2 days of illness and when nasopharyngeal swabs are used r46
      • Rapid antigen tests have low sensitivity for adults (10%) r3
      • Rapid antigen tests will not be affected if the patient has received nirsevimab r44
    • Serology
      • Paired serum samples (eg, preseason and postseason or acute and convalescent) with a 4-fold rise in titers may retrospectively diagnose recent RSV infection r3r14
      • Serology results may be affected if the patient has received nirsevimab; use RT-PCR or rapid antigen testing instead r44
    • Culture c76c77
      • Highly sensitive and specific for infants r47
      • Not as sensitive for adults
        • Adults shed considerably less virus for a shorter duration than infants
      • Longer turnaround time limits practical application

    Imaging

    • Do not routinely obtain radiographic studies when bronchiolitis is diagnosed on the basis of history and physical examination findings r1c78
    • Obtain chest radiographs in the following settings: c79c80
      • Children with bronchiolitis who do not show improvement at the expected rate
      • Adults with suspected pneumonia r36r37
      • Disease is severe, requiring further evaluation
      • Patient is immunocompromised or has significant comorbidity
      • Another diagnosis is suspected
    • Detection of atelectasis may predict a more severe course r48
    • New infiltrates (mostly atelectasis) during mechanical ventilation correlate with a longer duration of mechanical ventilation r49

    Functional testing

    • Pulse oximetry c81
      • Low values (less than 90%) in infants with bronchiolitis are associated with need for hospitalization r50r51
      • Continuous pulse oximetry is not mandatory for infants and children with a diagnosis of bronchiolitis r1
    • Transcutaneous PCO₂ monitoring r52c82
      • Good correlation with PvCO₂ (partial pressure of carbon dioxide in venous blood) in infants
      • Tool for trending and continuous assessment in emergency department and inpatient settings

    Differential Diagnosis

    Most common

    • Other viral pneumonias c83
      • Clinical presentation similar to that of RSV with cough, tachypnea, and wheezing
      • Types include:
        • Human rhinovirus c84
        • Parainfluenza viruses c85
        • Adenovirus c86
        • Influenza viruses c87d1
        • Coronaviruses, including common cold viruses and SARS-CoV-2 c88d2
        • Human metapneumovirus c89
        • Other viruses c90
      • Differentiate from RSV via viral culture, PCR, or rapid antigen detection d3
        • Specific therapy is not available for most viral respiratory illnesses; therefore, differentiation is not always needed r3
    • Bacterial pneumonia c91d4
      • Like patients with RSV, patients have cough and fever, sometimes associated with wheezing and dyspnea
      • Factors that differentiate from bronchiolitis: d5
        • Rhinitis is usually not associated with bacterial pneumonia but is a common feature of RSV
        • Cough may produce purulent sputum; Gram stain showing numerous polymorphonuclear leukocytes and a predominance of bacteria of uniform morphology suggests bacterial pneumonia
        • Radiograph usually shows focal infiltrate in bacterial pneumonia
        • In children, serum C-reactive protein level of greater than 80 mg/L was found to correlate with bacterial pneumonia with a specificity of 72%, but with a low sensitivity (52%) r53
        • Fever is usually present and is often high (above 39 °C) r11
    • Chlamydial pneumonia c92d6
      • Like RSV, presents as cough that may be associated with dyspnea and a low-grade fever
      • Factors that differentiate from bronchiolitis:
        • History of insidious onset, staccato cough, and lack of wheezing
        • Respiratory symptoms are often preceded by or associated with sore throat
        • Rhinorrhea is usually not present
        • Laboratory testing
          • WBC count is usually within reference range, but eosinophils may be elevated
          • Nucleic acid amplification tests can also be used to amplify the organism's DNA or RNA by PCR, which has been shown to have high sensitivity and specificity compared with culture but is not currently approved by FDA for neonates
          • Serologic testing differentiates chlamydia infection from RSV but is retrospective
    • Cystic fibrosis c93d7
      • Genetic condition characterized by chronic sinopulmonary and gastrointestinal dysfunction
        • Before a clinical pattern of chronicity is established, respiratory exacerbation may present as bronchiolitis with cough, dyspnea, and fever
        • Conversely, an unusually severe episode of RSV infection may be an early clue to underlying cystic fibrosis
      • Later in the course of disease, may be differentiated from RSV infection by:
        • Chronic recurrent history, associated gastrointestinal involvement, weight loss, and failure to thrive
        • At least 1 phenotypic characteristic (eg, chronic sinopulmonary disease, pancreatic insufficiency) and elevated sweat chloride concentration (greater than 60 mmol/L) r54
        • 1 established cystic fibrosis–causing mutation on each copy of the cystic fibrosis transmembrane regulator (CFTR) gene
        • Clubbing is a late finding that suggests chronic hypoxemic lung disease
        • Diagnosis confirmed by hyperinflated lung fields on chest radiograph and pulmonary function test results consistent with obstructive disease
    • Foreign body in airway c94
      • History of sudden episode of coughing or choking with subsequent wheezing, coughing, or stridor
      • On physical examination, there may be new abnormal airway sounds (eg, wheezing, stridor, decreased breath sounds); may be unilateral
      • Differentiate from RSV infection
        • Radiograph can reveal an area of focal overinflation or an area of atelectasis
        • Bronchoscopy (diagnostic and therapeutic)

    Treatment

    Goals

    • Maintain oxygenation r1
    • Maintain hydration
    • Treat secondary infections
    • Prevent complications

    Disposition

    Admission criteria

    Infants with:

    • Apnea r11
    • Persistent hypoxemia on room air: r11
      • SpO₂ (oxygen saturation) less than 90% for children aged 6 weeks and older r11
      • SpO₂ less than 92% for infants younger than 6 weeks of age or any children with underlying health conditions r11
    • Persistent tachypnea (more than 70 respirations/minute) or other signs of respiratory distress (eg, grunting, chest recession) r11
    • Oral fluid intake less than 75% of usual volume r11

    Infants, children, or adults with severe underlying disease (eg, chronic cardiopulmonary disease or immunocompromised state, especially organ and hematopoietic cell transplant recipients)

    Premature birth (especially before 32 weeks of gestation) and age younger than 3 months are risk factors for severe illness that may justify admission in borderline cases r11

    For adults with community-acquired pneumonia, guidelines recommend use of PSI (Pneumonia Severity Index), along with clinical judgment, to determine inpatient versus outpatient treatment r36

    Criteria for ICU admission
    • For patients of any age, respiratory failure (need for mechanical ventilation) or hemodynamic instability (need for vasopressors)
    • For infants younger than 12 months with bronchiolitis, ICU admission is recommended for any of the following: r55
      • Apnea
      • Altered consciousness or hypotonia
      • Severe respiratory distress
      • SpO₂ less than 92% on low-flow oxygen
      • If capillary or venous blood gas is available, pH less than 7.3 and/or partial pressure of carbon dioxide less than 60 mm Hg
    • For adults, use Infectious Diseases Society of America/American Thoracic Society criteria for severe community-acquired pneumonia, along with clinical judgment, to determine need for ICU admission r36

    Recommendations for specialist referral

    • Infectious diseases specialist for patients in ICU and immunocompromised patients
    • Pulmonologist for patients in ICU

    Treatment Options

    Supportive care is the primary treatment for otherwise healthy patients with RSV

    • Support airway and maintain oxygenation
      • Suctioning may be needed, particularly for children with feeding difficulties, apnea, or respiratory distress
      • Utilize bronchodilators for adults r56
    • Administer fluids if patient is unable to maintain hydration
      • For children, nasogastric or orogastric feeding may be preferred if tolerated; IV feeding may be safer for those with impending respiratory failure r1r11

    Medications are recommended for a subset of patients

    • Early antiviral therapy is recommended for severely immunocompromised patients (eg, transplant recipients) r56r57
    • Ribavirin is recommended for treatment of RSV in immunocompromised patients with documented infection r9
      • Treatment at the upper respiratory tract stage reduces the likelihood of developing lower respiratory tract infection, and treatment of lower respiratory tract infection reduces mortality r9
      • May be administered intravenously, orally, or nebulized, which requires a specialized device such as a small-particle aerosol generator r57
        • Some evidence supports aerosolized ribavirin as the preferred means of delivery to limit systemic toxicities, but care must be taken to avoid exposing others to the aerosol (eg, negative pressure room, hoods) r57r58
        • IV ribavirin is an alternative for patients with pulmonary consolidation that prevents distribution of aerosolized medication
        • Limited evidence shows oral ribavirin to be effective, less expensive, and easier to administer r57r59
      • American Society of Transplantation recommends aerosolized or oral ribavirin for treatment of lung transplant recipients, with consideration of adjunctive corticosteroids and/or IV immunoglobulin; treatment with aerosolized or oral ribavirin should also be considered for patients who have received a transplant other than lung transplant r60
    • IV immunoglobulin has been used as an adjunct to ribavirin for transplant recipients; an RSV-specific version (RSV-IVIG) was not shown to have any efficacy for infants and children and has been withdrawn from the market r56r57r59r60
    • Palivizumab (a monoclonal antibody directed at RSV F protein) has been investigated for treatment r56r57r61
      • Evidence of efficacy in any age group is extremely limited, and use in adults is prohibitively expensive r56r57r59r60

    Numerous additional therapies have been attempted based on pathophysiology; avoid use of the following, which currently lack evidence of efficacy:

    • Chest physiotherapy for children with bronchiolitis (except those with neuromuscular comorbidities, which inhibit clearance of secretions) r1r11r57r62
    • Albuterol, salbutamol, or other bronchodilators for children with bronchiolitis (except for those with a comorbidity such as asthma) r1r11r57
    • Nebulized epinephrine (adrenaline) for children with bronchiolitis r1r11r57
    • Leukotriene inhibitors for children with bronchiolitis r11r57
    • Nebulized human recombinant deoxyribonuclease or N-acetylcysteine for children with bronchiolitis r57
    • Glucocorticoids, systemic or inhaled, are not recommended r1r11r57
      • No clinically relevant effect of systemic or inhaled glucocorticoids on need for admission or length of hospitalization of infants or children r1r63
      • Not shown to improve clinical outcomes for adults; may be associated with secondary infection and prolonged hospitalization r9
      • Systemic glucocorticoids may be considered as adjunctive therapy to ribavirin for transplant recipients r59r60
    • Antibiotics should not be given routinely
      • Avoid antibiotics for children with bronchiolitis unless a bacterial coinfection is diagnosed or strongly suspected r1r11r57
      • For adults with community-acquired pneumonia, before identifying a pathogen, follow guidelines for empiric antibiotic coverage and cessation r36r37r64

    Drug therapy

    • Ribavirin r65c95c96
      • Oral dosage
        • Ribavirin Oral solution; Infants, Children, and Adolescents: 15 to 25 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 to 12 hours for 7 to 10 days or until symptoms have resolved based on very limited data in high-risk pediatric oncology patients.
        • Ribavirin Oral tablet; Adults weighing less than 75 kg: Optimal dosing not established and variable dosage regimens reported. Most common dosage regimens are: fixed dose of 600 mg PO 2 to 3 times daily or a weight-based dose of 10 mg/kg loading dose (Max: 600 mg/dose) PO on day 1, followed by 10 to 30 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 hours. Treatment duration is usually 5 to 10 days; however, longer treatment may be needed for those with severe infections.
        • Ribavirin Oral tablet; Adults weighing 75 kg or more: Optimal dosing not established and variable dosage regimens reported. Most common dosage regimens are: fixed dose of 800 mg PO twice daily or 600 mg PO 3 times daily or a weight-based dose of 10 mg/kg loading dose (Max: 600 mg/dose) PO on day 1, followed by 10 to 30 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 hours. Treatment duration is usually 5 to 10 days; however, longer treatment may be needed for those with severe infections.
      • Inhalation dosage
        • Intermittent aerosolization
          • Ribavirin Nebulizer solution; Neonates: 2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days; longer treatment may be needed for those with severe infections.
          • Ribavirin Nebulizer solution; Infants, Children, and Adolescents: 2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days; longer treatment may be needed for those with severe infections.
          • Ribavirin Nebulizer solution; Adults: 2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days; longer treatment may be needed for those with severe infections.
        • Continuous aerosolization
          • Ribavirin Nebulizer solution; Neonates: 6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days; longer treatment may be needed for those with severe infections.
          • Ribavirin Nebulizer solution; Infants and Children: 6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days; longer treatment may be needed for those with severe infections.
          • Ribavirin Nebulizer solution; Adolescents†: 6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days; longer treatment may be needed for those with severe infections.
          • Ribavirin Nebulizer solution; Adults: 6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days; longer treatment may be needed for those with severe infections.
    • IV immunoglobulin c97
      • Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents: 400 to 500 mg/kg/dose IV with aerosolized or systemic ribavirin; dosing frequency has ranged from one-time to every 48 hours for 5 to 7 doses.
      • Immune Globulin (Human) Solution for injection; Adults: 500 mg/kg/dose IV with aerosolized or systemic ribavirin; dosing frequency has ranged from one-time to every 48 hours for 5 to 7 doses.

    Nondrug and supportive care

    • Supplemental oxygen c98
      • Administer supplemental oxygen if the oxyhemoglobin saturation is less than 90% to 92% in infants and children with a diagnosis of bronchiolitis r1r11
        • National Institute for Health and Care Excellence guidelines recommend oxygen for children aged 6 weeks and older if saturation is less than 90% and for babies younger than 6 weeks or any children with underlying health conditions if saturation is less than 92% r11
        • American Academy of Pediatrics guidelines offer a weak recommendation for not instituting supplemental oxygen unless the oxygen saturation falls below 90% (except for children with acidosis or fever) r1
      • Administer to adults with hypoxemia, titrated to achieve a target saturation of 94% to 96%r66 or 88% to 92% for those at risk of hypercapnic respiratory failure r2
    • Ventilatory support
      • Various guidelines recommend or suggest noninvasive ventilation over invasive ventilation for patients not needing immediate intubation r11r55r64
      • CPAP r67c99
        • Allows for recruitment of collapsed or nonventilated alveoli, increases functional residual capacity, improves ventilation to perfusion ratio, optimizes respiratory dynamics, reduces respiratory load, and improves gas exchange
        • Reduces infectious complications and need for intubation r67
        • Provides adequate oxygenation for 80% of infants receiving respiratory support for severe bronchiolitis r68
      • High-flow nasal oxygen c100
        • Heated, humidified, and blended air/oxygen via nasal cannula administered at flow rate of 1.5 to 2 L/kg/minute; improves breathing pattern and rapid unloading of respiratory musclesr69 but may not be as effective as CPAPr70
      • Noninvasive or mechanical ventilation is required for about 11% of adults hospitalized for RSV infection; higher rates are likely among immunocompromised patients r9c101
    • Management of secretions
      • Nasal saline drops or bulb suction to relieve nasal obstruction c102c103
      • Airway suctioning should not routinely be performed for all infants and children but is recommended as needed (eg, for respiratory distress, feeding difficulties, apnea)
      • Nebulized hypertonic saline c104c105
        • Evidence is limited and mixed on effectiveness of 3% hypertonic saline for children with bronchiolitis r1r11r57

    Comorbidities

    • Infants and children with severe underlying cardiopulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease, hemodynamically significant congenital heart disease) are at high risk for complications r1c106c107c108c109c110c111c112c113c114c115
    • Infants with any of the following characteristics are candidates for prophylactic palivizumab: r1
      • Hemodynamically significant heart disease r1
      • Chronic lung disease of prematurity (prematurity defined as younger than 32 weeks and 0 days of gestation) r1
        • Requirement of greater than 21% oxygen for at least the first 28 days of life r1
      • Infants born before 29 weeks of gestation who are younger than 12 months at the start of the RSV season (generally in the fall; seasonality may vary by geography) r1

    Special populations

    • Very young infants (younger than 3 months) and infants born at less than 32 weeks of gestation are at higher risk for severe disease r11
    • Immunocompromised adults, especially transplant recipients, are at high risk for severe disease

    Complications and Prognosis

    Complications

    • Pediatric respiratory failure c116
      • Approximately 3% of children hospitalized require assisted ventilation r71
    • Pediatric asthma c117
      • Severe, early RSV bronchiolitis is associated with an increased prevalence of allergic asthma persisting into early adulthood r72
      • 20% to 40% likelihood of recurrent asthmalike episodes after RSV lower respiratory tract infection during infancy r72
    • Bacterial superinfection c118
      • Affects 15% of patients; a significant contributor to mortality r34
    • Older adults of advanced age or patients with underlying chronic lung diseases or other major medical comorbidities
      • More than 70% develop severe lower respiratory tract complications, including pneumonia, acute bronchitis, and exacerbations of chronic underlying lung conditions (eg, chronic obstructive pulmonary disease, asthma) r34c119c120c121c122c123c124c125c126c127c128
      • Approximately 22% of adults aged 50 years or older hospitalized with RSV infection developed an acute cardiac event (commonly acute heart failure), of whom 8.5% had no documented underlying cardiovascular disease r73c129c130

    Prognosis

    • RSV infection bronchiolitis is typically a self-limiting disease with an excellent long-term prognosis
      • 2% to 3% of children are hospitalized r74
      • Overall mortality rate of acute bronchiolitis is less than 1% among children r75
        • Majority of deaths are observed among infants younger than 6 months r5r76
        • Risk factors are premature birth, concomitant cardiopulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease, hemodynamically significant congenital heart disease), immunodeficiency, and difficult socioeconomic conditions r76
      • Symptoms resolve within 14 days in 40% of cases; they can persist for up to 4 weeks in about 10% of cases r77
      • Up to 40% of children with bronchiolitis have wheezing episodes through age 5 years, and 10% have wheezing episodes after age 5 years r78
    • Among healthy working adults aged 18 to 60 years, 26% had lower respiratory tract infection symptoms and 38% required time away from work r79
      • Healthy adults have also been shown to have altered airway reactivity for weeks after RSV infection r80
    • RSV infection in adult hospitalized patients had an ICU utilization rate of 15% and a mortality rate of 6% to 8%r82r81

    Screening and Prevention

    Screening c131

    Prevention

    • Optimize environment for all infants, particularly those who are preterm, to prevent respiratory tract infection
      • Encourage breastfeeding
        • Any breastfeeding (compared with never breastfeeding) decreases risk of RSV–related lower respiratory tract infection and hospitalization r83
        • Exclusive breastfeeding for at least the first 4 to 6 months of life lowers risks of RSV-related hospitalization, length of stay if hospitalized, need for supplemental oxygen, and admission to ICU and decreases morbidity of respiratory tract infections in general r1r83c132
      • Avoid attendance in large-group childcare during an infant's first winter season whenever possible c133
      • Household contacts should be immunized against respiratory diseases, practice hand and cough hygiene, and refrain from smoking in the home c134
    • To prevent further spread of infection within the household or care setting:
      • Disinfect hands before and after direct contact with infected child, after contact with inanimate objects in the direct vicinity of the child, and after removing gloves c135c136
      • Use alcohol-based rubs for hand decontamination when caring for children with bronchiolitis r1c137
      • Public health measures implemented to control the spread of SARS-CoV-2 (eg, wearing face mask, avoiding sick people, quarantine and isolation) caused a dramatic decrease in RSV and other respiratory diseases, suggesting 1 or more of these measures may be effective for minimizing RSV spread in households or institutions r25
    • It is recommended that all infants are protected from RSV-associated lower respiratory tract infection via either maternal RSV vaccination during pregnancy or administration of the monoclonal antibody nirsevimab during the first year of life r84
    • Monoclonal antibodies
      • Nirsevimab is an extended half-life monoclonal antibody directed at the RSV F glycoprotein, locking the F protein into a prefusion configuration and blocking viral entry r57
        • Approved in the European Union and United Kingdom (November 2022), in Canada (April 2023), and in the United States (July 2023) r85r86r87r88
          • Authorizations are for a single dose before the RSV season for infants in the first year of life; some jurisdictions, including the United States, also authorize a second dose for high-risk children up to the age of 24 months entering their second RSV season
        • Evidence for the use for infants comes primarily from the following clinical trials:
          • Several randomized trials have demonstrated nirsevimab's safety and efficacy in preventing RSV lower respiratory tract infection requiring medical attention and RSV-associated hospitalization in healthy term and preterm (older than 29 weeks) infants r89r90
            • A randomized controlled trial of 1490 healthy late preterm and term infants (gestational age, 35 weeks or more) demonstrated 74.5% efficacy in preventing medically attended RSV lower respiratory tract infection and a safety profile similar to that of the placebo r91
            • A randomized controlled trial reported that a single intramuscular injection of nirsevimab in healthy preterm infants (29 weeks through 34 weeks and 6 days of gestation) resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV seasonr92
          • Studies conducted in the real-world setting confirm nirsevimab is effective in prevention of RSV-associated hospitalizations r93r94
          • Safety and pharmacokinetic data following the first RSV season from a randomized controlled trial of palivizumab versus nirsevimab, planned to span 2 seasons, demonstrated similar efficacy and safety for infants with congenital heart disease, chronic lung disease, or prematurity (less than 35 weeks of gestation) r95
        • CDC and American Academy of Pediatrics recommend use of nirsevimab for infants younger than 8 months born during or entering their first RSV season and for infants and children aged 8 to 19 months at increased risk for severe disease entering their second RSV season r96r97
          • Infants younger than 8 months are recommended to receive nirsevimab for their first RSV season when: r98
            • The infant's birthing parent did not receive RSV vaccine during pregnancy
            • The RSV vaccine status of the birthing parent is unknown
            • The infant was born within 14 days of RSV vaccination during pregnancy
          • In general, nirsevimab is not needed for infants aged 8 months or younger who were born 14 or more days after receipt of RSV vaccination during pregnancy r44
            • Clinicians may consider administration for these rare exceptions:
              • The birthing parent who received RSV vaccination may not mount an adequate immune response (eg, pregnant person with severe immunocompromise)
              • The birthing parent who received RSV vaccination has a condition associated with decreased transplacental antibody transfer (eg, HIV)
              • Infants who undergo procedures that may remove antibodies (eg, cardiopulmonary bypass or extracorporeal membrane oxygenation)
              • Infants with substantial increased risk for severe RSV disease (eg, hemodynamically significant congenital heart disease, intensive care admission with ongoing oxygen requirement at discharge)
          • Children considered high risk who are recommended to receive nirsevimab for a second RSV season include: r44r98
            • Children with chronic lung disease of prematurity who needed corticosteroids, diuretics, or supplemental oxygen at any time during the 6 months before the start of the second RSV season
            • Children with severe immunocompromise
            • Children with cystic fibrosis who have severe lung disease (hospitalization for lung disease before age 12 months or persistent abnormal findings on chest imaging) or who have weight for length below the 10th percentile
            • Native American and Alaska Native children
          • A second dose of nirsevimab is not needed during the same season for any child except those undergoing cardiopulmonary bypass r44
            • A second dose is recommended after surgery that requires cardiopulmonary bypass; dose varies
              • During the first RSV season: dose is based on weight if the surgery is performed within 90 days of initial receipt of nirsevimab; dose is 50 mg regardless of body weight if the surgery is performed more than 90 days after initial receipt of nirsevimab
              • During the second RSV season: dose is 200 mg if the surgery is performed within 90 days of initial receipt of nirsevimab; dose is 100 mg if the surgery is performed more than 90 days after initial receipt of nirsevimab
        • During the 2023-2024 season, availability of nirsevimab was limited and CDC provided the following guidance for prioritization of supply: r99
          • For infants weighing less than 5 kg, recommendations are unchanged (high-priority group)
          • Among infants weighing 5 kg or more, prioritize infants younger than 6 months and infants up to age 8 months with underlying conditions at high risk for severe disease
            • Also prioritize Native American and Alaska Native children younger than 8 months and those aged 8 to 19 months (not palivizumab-eligible) who live in remote regions where transportation to a higher level of medical care is difficult or who live in communities with known high rates of RSV among older infants and toddlers
          • Avoid using 2 50-mg doses for a patient who needs 100 mg
          • Children aged 8 to 19 months who are eligible for palivizumab should receive palivizumab instead of nirsevimab
          • Encourage RSV vaccination of pregnant persons, which will reduce the number of infants who require nirsevimab
          • American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the American Academy of Pediatrics support CDC guidance and additionally recommend: r100
            • Prenatal providers should stock and administer RSV vaccine where possible to minimize access difficulties
            • Prenatal providers should clearly document receipt of RSV vaccine during pregnancy to avoid immunization of infants who are already protected
        • Dosage and timing r96
          • Prophylaxis for first RSV season
            • Nirsevimab Solution for injection; Neonates and Infants weighing less than 5 kg: 50 mg IM once.
            • Nirsevimab Solution for injection; Neonates and Infants weighing 5 kg or more: 100 mg IM once.
          • Prophylaxis for second RSV season
            • Nirsevimab Solution for injection; Infants and Children 1 to 24 months: 200 mg IM once. Administer as 2 IM injections (2 x 100 mg).
            • Administer the 2 injections at the same time at different injection sites r97
          • Administer nirsevimab in the first week of life to infants born shortly before or during the RSV season
          • Administer nirsevimab shortly before the start of the RSV season to other infants younger than 8 months and to infants and toddlers aged 8 to 19 months who are at high risk and entering their second season
            • For most of the United States, administration will be October through March; outside the continental United States, including Alaska and Hawaii, timing will vary based on geography
            • Find national and regional RSV activity in the United States at CDC's National Respiratory and Enteric Virus Surveillance System websiter101
          • Administer nirsevimab at any time during the RSV season to any eligible child who has not yet received a dose
          • Healthy children should only receive 1 dose of nirsevimab; only at-risk children should receive 2 doses, 1 before or during the first season and 1 before the second season
          • Nirsevimab may be administered simultaneously with any age-appropriate vaccine
        • Nirsevimab and palivizumab r96
          • Children who receive nirsevimab should not receive palivizumab later that season
          • If nirsevimab is unavailable, high-risk children should receive palivizumab until nirsevimab is available
          • If administration of palivizumab is started in a season, but fewer than 5 doses are administered, nirsevimab may be administered if available and no further doses of palivizumab should be given
      • Palivizumab is a monoclonal antibody directed at the RSV F protein in postfusion configuration r3c138c139
        • Reduces severe RSV infections among infants by 55% r102
        • Administer during the first year of life to infants with hemodynamically significant heart disease or chronic lung disease of prematurity, defined as preterm infants younger than 32 weeks and 0 days of gestation who require greater than 21% oxygen for at least the first 28 days of life r1
        • Administer to infants born before 29 weeks of gestation who will be younger than 12 months at the start of RSV season (usually the fall months; may vary geographically) r1
        • Because of the COVID-19–related shift in seasonality of respiratory viruses, clinicians may consider starting prophylaxis early and/or giving additional doses (more than 5) if local RSV activity is high r26r103
        • May be a prophylactic option for high-risk adults, although the weight-based repeated dosing required is prohibitively expensive r58r59r60
        • Prophylaxis for high-risk children:
          • Palivizumab (Murine) Solution for injection; Neonates: 15 mg/kg/dose IM once monthly starting before and given throughout RSV season. If patient undergoes cardiopulmonary bypass or extracorporeal membrane oxygenation, give dose after procedure even if less than 1 month since last dose.
          • Palivizumab (Murine) Solution for injection; Infants and Children 1 to 2 years: 15 mg/kg/dose IM once monthly starting before and given throughout RSV season. If patient undergoes cardiopulmonary bypass or extracorporeal membrane oxygenation, give dose after procedure even if less than 1 month since last dose.
    • Vaccines
      • Overview
        • A formalin-inactivated RSV vaccine in the 1960s caused vaccine-enhanced disease, resulting in an 80% hospitalization rate and the deaths of 2 infants, as well as significant delays in subsequent vaccine development r4r57
        • Current vaccine research targets infants, pregnant patients to protect newborns, and older adults and includes numerous vaccine types r4
      • Arexvy is an adjuvanted recombinant vaccine against the antigen RSVpreF3 (F glycoprotein stabilized in prefusion conformation); approved by FDA on May 3, 2023, for vaccination of adults aged 60 years and older r104
        • Approval was granted using 5 clinical studies, 2 of which are ongoing, to evaluate immunogenicity, safety, and efficacy r104
          • One ongoing randomized placebo-controlled study in 17 countries including approximately 25,000 adults aged 60 years and older is evaluating efficacy of a single dose and annual revaccination doses through 3 RSV seasons r104r105
            • Initial results after the first RSV season showed the vaccine reduced risk of lower respiratory tract disease by 82.6% compared with placebo r104r105
        • Subsequently FDA has licensed Arexvy for use in people aged 50 to 59 years who are at increased risk of RSV lower respiratory tract disease (June 2024); however, CDC has not made a recommendation for use in patients aged 50 to 59 years at this time r33
      • Abrysvo is a recombinant vaccine against 2 RSVpreF antigens (RSVpreF-A and RSVpreF-B) r106
        • Approved by FDA on May 31, 2023, for vaccination of adults aged 60 years and older
          • 6 clinical studies formed the basis of efficacy and safety data; the largest is an ongoing multicenter randomized, double-blind, placebo-controlled trial of more than 35,000 adults aged 60 years and older, with data from the first RSV season of a planned 2-season span r106r107
            • Vaccine efficacy against RSV lower respiratory tract disease with 2 or more symptoms was 66.7%; a higher efficacy of 85.7% was found against lower respiratory tract disease with 3 or more symptoms r106r107
        • Also approved by FDA on August 21, 2023, for vaccination of pregnant persons between 32 and 36 weeks of gestation to protect infants r108
          • In an ongoing randomized, double-blind, placebo-controlled clinical study of 3682 pregnant individuals who received Abrysvo and 3675 who received placebo, Abrysvo decreased the risk of severe lower respiratory tract disease among infants by 81.8% in the 90 days following birth and by 69.4% in the 180 days following birth r109
            • The subset of individuals vaccinated at 32 through 36 weeks of gestation (approximately 1500 each in intervention and control groups) showed vaccine efficacy of 91.1% in the first 90 days of an infant's life with continuing vaccine efficacy of 76.5% at 180 days of life against severe lower respiratory tract disease
            • Modest efficacy was also seen against (nonsevere) lower respiratory tract disease and hospitalization through 180 days after birth
          • Safety was demonstrated in 2 studies, 1 ongoing, totaling approximately 7500 individuals (half placebo) in which the most common adverse effects were pain at the injection site, headache, muscle pain, and nausea r109
            • Serious adverse effects in more individuals receiving Abrysvo versus placebo included preeclampsia, preterm birth, low birth weight, and neonatal jaundice
              • Data were not sufficient to determine a causal relationship; FDA is requiring postmarketing studies to assess risk of preterm birth and hypertensive disorders of pregnancy
            • In the ongoing study, infants are followed up for 12 to 24 months
            • Studies were performed in otherwise healthy individuals with no history of pregnancy complications during singleton pregnancies; generalizability is unknown
            • Range of gestational age at vaccination was 24 to 36.9 weeks in the 2 studies; FDA warns against administering before 32 weeks of gestation to avoid the potential risk of preterm birth
      • mResvia is a nucleoside modified mRNA vaccine encoding the RSVpreF (F protein stabilized in the prefusion conformation) r33
        • Approved by FDA for vaccination of adults aged 60 years and older
        • In an ongoing randomized trial of 35,541 participants, vaccine efficacy was 83.7% against RSV-associated lower respiratory tract disease with at least 2 signs or symptoms and 68.4% against RSV-associated acute respiratory disease r110
      • CDC Advisory Committee on Immunization Practices recommendations and dosage
        • Single dose of RSV vaccine is recommended for all adults aged 75 years and older; also recommended for adults aged 60 to 74 years who are at increased risk of severe RSV disease r33r111
          • Not recommended for adults aged 60 to 74 years who are not at increased risk of severe RSV disease
          • Any 1 of the 3 RSV vaccines licensed for use in adults aged 60 years and older in the United States may be used (Arexvy, Abrysvo, or mResvia)
          • Guillain-Barré syndrome is a potential vaccine safety concern identified in clinical trials of Arexvy and Abrysvo and in subsequent voluntary vaccine adverse event surveillance reporting; however, the estimated benefits are believed to outweigh the potential risk r112
        • RSV vaccination with Abrysvo is recommended for pregnant individuals at 32 through 36 weeks of pregnancy during September through January to prevent RSV-associated lower respiratory tract disease in infants during the first 6 months of life r84r113
        • Arexvy dosage
          • Recombinant RespiratorySyncytial Virus Pre-Fusion F Protein Suspension for injection; Adults 50 years and older: 0.5 mL IM as a single dose.
        • Abrysvo dosage
          • Older adults
            • Recombinant Stabilized RSV A Prefusion F Antigen, Recombinant Stabilized RSV B Prefusion F Antigen Solution for injection; Adults 60 years and older: 0.5 mL IM as a single dose.
          • Pregnant persons (32 to 36 weeks gestation)
            • Recombinant Stabilized RSV A Prefusion F Antigen, Recombinant Stabilized RSV B Prefusion F Antigen Solution for injection; Pregnant Persons 32 to 36 weeks gestation: 0.5 mL IM as a single dose.
        • mResvia dosage
          • Recombinant RespiratorySyncytial Virus Pre-Fusion F Protein, SM-102, PEG2000-DMG, Cholesterol, 1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOCHOLINE Suspension for injection; Adults 60 years and older: 0.5 mL IM as a single dose.
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