Respiratory Syncytial Virus

Epidemiology
RSV

Incidence
1. Worldwide: 33 Million with 3.6 Million hospitalizations in 2019 (8.1 cases per 1000 per year)
2. United States: 2.1 Million children under age 5 years seek medical attention for RSV annually
Annual epidemics in U.S.
1. Post-Covid (2020) RSV epidemics peaked in sping and summer
2. Pre-covid RSV epidemics were in winter to early spring
  1. Range: November to April
  2. Peak: January to February
Overall hospitalization rate
1. U.S. 1-2% of children with RSV (57,000 per year, 2.9 cases per 1000)
2. Youngest children are at highest risk for hospitalization (esp. age <90 days)
  1. RSV Bronchiolitis results in hospitalization of 2-3% of infants <12 months old
  2. Severe RSV Bronchiolitis requiring hospitalization occurs in 25 per 1000 infants age <30 days
Attack rates
1. Daycare exposure: 100% infection rate
2. Sibling exposure: 40% infection rate
Cohorts Affected
1. Children under age 2 years (usually 1-6 months old)
2. Of infants at risk, 50% will be infected
  1. By age 2 years, nearly all children will have had one RSV infection (at least 90%)
  2. Prior infection is no protection against future infection
3. Older children and adults
  1. Common Cold-like Syndrome
  2. Rhinorrhea, Sore Throat, and cough
4. Elderly (esp. age >75 years)
  1. Severe Pneumonia may result
  2. In U.S., >160,000 older adults are hospitalized, and 10,000 die of RSV per year
5. Immunocompromised patients and significant comborbid conditions
  1. Diabetes Mellitus
  2. Chronic Lung disease (e.g. copd)
  3. Chronic Kidney Disease
  4. Cardiovascular disease

Risk Factors
More Severe Course

Young infants (esp. age <90 days)
Prematurity
Passive Smoke Exposure
Complex Congenital Heart Disease
Chronic lung disease
Immunosuppression
Neuromuscular disease
Metabolic disorder
Staat (2002) Semin Respir Infect 17:15-20 [PubMed]

Pathophysiology
RSV

Enveloped, nonsegmented, negative-strand RNA virus (Paramyxoviridae Family)
1. Subtypes A (causes more severe disease)
2. Subtypes B
Transmission
1. Close contact
2. Fingers or fomites
3. Self inoculation of Conjunctiva or anterior nares
4. Coarse aerosols from coughing or sneezing
Viral load peaks at 4 to 5 days
1. Corresponds to peak illness severity at 3-5 days
Incubation: 2 to 6 days (up to 8 days)
Virus shedding: 3 to 8 days (up to 4 weeks in infants)
Duration of illness (under age 2 years)
1. Initial symptoms start to abate at 7 days
2. Coughing and Wheezing often persist 2-3 weeks
3. Median: 12 days
4. Prolonged in 10% of cases as long as 4 weeks
Re-infection with different RSV forms is common
1. Prior RSV infection confers no Immunity against new infection
Infectious course
1. Viral replication starts in the nasopharynx
2. Spreads to the small Bronchiole epithelial lining
3. Results in small airway obstruction, air trapping and increased airway resistance
4. Lower respiratory tract infection onset within 3 days
  1. Increased airway edema and mucous production
  2. Ultimately tissue necrosis

Causes
Bronchiolitis

Respiratory Syncytial Virus (RSV)
1. Responsible for 50-80% of cases
2. Coninfection with other virus (e.g Rhinovirus) in up to 55% (up to 30% of hospitalized RSV cases)
  1. Mansbach (2012) Arch Pediatr Adolesc Med 166(8): 700-6 [PubMed]
Human Metapneumovirus (MPV)
1. Emerging paramyxovirus
2. Similar presentation as RSV
3. Hamelin (2004) Clin Infect Dis 38:983-90 [PubMed]
Parainfluenza
Rhinovirus
Influenza
Adenovirus
Human Bocavirus

Symptoms

Viral prodrome (initial 2-3 days)
1. Coryza
2. Rhinorrhea
Typical symptoms in infants and young children
1. Cough (98%)
2. Low grade fever (75%)
3. Labored breathing (73%)
4. Wheezing (65%)
5. Rhinorrhea
6. Mild systemic symptoms
Typical symptoms in older children
Severe illness
1. Grunting
2. Nasal flaring
3. Intercostal retractions
4. Tachypnea or Dyspnea
5. Hypoxia and Cyanosis
6. Apparent Life Threatening Event or Apnea
  1. Premature Infants or very young infants are at increased risk
  2. May occur without other signs of respiratory distress

Signs

See Clinical Severity Scoring System Tool
Respiratory
1. Common findings
  1. Diffuse Wheezing
  2. Rales
2. Other findings
  1. Rhonchi
  2. Tachypnea
  3. Cough
3. Respiratory distress or Respiratory Failure
  1. Accessory Muscle use (e.g. Intercostal retractions)
  2. Grunting
  3. Hypoxia (Oxygen Saturation <92%)
  4. Cyanosis
Hydration
1. Assess for Dehydration (mucous membranes, alertness, Skin Turgor, decreased Urine Output)

Differential Diagnosis

See Wheezing
Reactive airway disease
Foreign Body Aspiration
High fever suggests alternative diagnosis (e.g. Pneumonia)
1. Especially consider in unimmunized children

Evaluation
Age under 3 months

Infants under age 30 days
1. Complete full Neonatal Sepsis evaluation for febrile infants under 1 month of age (despite Bronchiolitis diagnosis)
Infants under age 60 days
1. Evaluation based on clinical evaluation
2. Consider admission of infants <6 to 8 weeks of age with Bronchiolitis due to apnea risk
Infants ages 60-90 days of age
1. Ill appearing, febrile infants should be evaluated for bacteremia (and coinfection)
2. Non-toxic febrile infants at 60-90 days with Bronchiolitis do not need a bacteremia work-up
  1. Blood Cultures and Lumbar Puncture are not needed
  2. Urinalysis and Urine Culture should still be performed
  3. Ralston (2011) Arch Pediatr Adolesc Med 165(10):951-6 [PubMed]

Labs

Blood Culture indications
1. Not needed in routine cases
2. Consider in toxic appearing children, fever >38.5 C (101.3 F) or ICU admission
Complete Blood Count (CBC) is not routinely recommended
Venous Blood Gas (VBG) Indications
1. Children who appear to be tiring
2. Severe respiratory distress
3. FIO2 requirements >40%
RSV swabs or washings of nasopharynx, throat, or Sputum
1. Precautions
  1. RSV is a clinical diagnosis based on symptoms and signs (see above)
  2. Routine testing is not recommended for confirmation
  3. RSV is only one cause of Bronchiolitis (e.g. MPV, parainfluenza, Influenza, Adenovirus, bocavirus)
  4. A negative RSV does not exclude other Bronchiolitis cause
2. Indications
  1. Febrile infants <3 months of age (evaluate for Neonatal Sepsis)
  2. Immunocompromised children
  3. Intensive Care Unit Admission
  4. Other diagnosis considered (e.g. Sepsis in age under 2-3 months)
    1. RSV positive puts a child at very low risk of serious Bacterial Infection
    2. However coninfection with other viruses is common (up to 55% of cases)
    3. Levine (2004) Pediatrics 113(6): 1728-34 [PubMed]
  5. Inpatient room placement (shared inpatient rooms)
    1. Consider grouping patients with similar symptoms instead of basing on lab criteria
  6. Epidemiologic data to define start of outbreak
3. Efficacy
  1. LAMP NAAT or PCR
    1. Test Sensitivity: 91 to 97% (LR- 0.03 to 0.09)
    2. Test Specificity: 97 to 99% (LR+ 30 to 97)
  2. Rapid Antigen
    1. Test Sensitivity: 83% (LR- 0.18)
    2. Test Specificity: 93% (LR+ 11)
  3. RSV Immunofluorescence
    1. Test Sensitivity: 81% (LR- 0.19)
    2. Test Specificity: 99% (LR+ 81)
  4. RSV Culture
    1. Test Sensitivity: 44 to 85%
    2. Test Specificity: 100%
Urinalysis and Urine Culture
1. Consider in patients with RSV severe enough to consider admission
2. Urinary Tract Infections are present in 2-5% of RSV cases
  1. However this is similar to baseline UTI rate in asymptomatic children
  2. Urinalysis is controversial in febrile children with Bronchiolitis (some guidelines recommend)
RSV is associated with a decreased risk of other conditions
1. Decreased risk of Meningitis
2. Decreased risk of bacteremia

Imaging
Chest XRay

Indications
1. Not routinely recommended in Bronchiolitis (very low yield)
  1. Chest XRay risks False Positives (e.g. Pneumonia) and Antibiotics overuse
2. High fever
3. Hypoxemia (Oxygen Saturation <90%)
4. Severe symptoms (e.g. ICU admission)
5. Comorbid cardiopulmonary disease
6. Respiratory complications (e.g. Pneumonia, Pneumothorax)
Findings consistent with Bronchiolitis
1. Hyperexpansion or hyperinflation
2. Peribronchial thickening or peribronchial markings
3. Atelectasis
4. Variable infiltrates or Viral Pneumonia
  1. May lead to False Positive Pneumonia diagnoses (and unnecessary Antibiotics)

Evaluation
Hospitalization Indications

Place in respiratory isolation if admitted
Central Apnea risk (1 to 24% of newborns with RSV)
1. Witnessed apneic event
2. RSV in infant under 6-8 weeks of age or birth weight <2.5 kg
  1. Prior recommendations were for hospitalizing children as old as age 2-3 months
  2. Apnea occurs with other Upper Respiratory Infections (not unique to RSV)
  3. Highest risk: Full-term infant <1 month of age OR Preterm Infant at <48 weeks post-conception
  4. Walsh (2015) Pediatrics 136(5): e1228-36 +PMID:26482666 [PubMed]
  5. Willmerth (2006) Ann Emerg Med 48(4): 441-7 [PubMed]
Comorbidity (one or more poorly-functioning systems)
1. Comorbid cardiopulmonary disease (e.g. Cystic Fibrosis, Congenital Heart Defect)
2. Comorbid Immunodeficiency
Dehydration
1. Inability to maintain adequate hydration, tolerate oral intake
2. Feeding difficulty (due to respiratory distress)
Respiratory distress
1. See Clinical Severity Scoring System Tool
2. See Respiratory Distress in Children with Pneumonia
3. See Pediatric Early Warning Score (PEWS Score)
4. Respiratory Rate (RR) consistenly >40 breaths per minute
  1. See Tachypnea for criteria based on age
  2. Tachypnea is frequently present in RSV and absolute threshold RR for admission is unclear
5. Oxygen Saturation <90%
  1. Brief minor desaturations are common with sleeping and eating
  2. Transient Hypoxia does not contraindicate disposition home in children with otherwise reassuring findings
  3. Principi (2016) JAMA Pediatr 170(6):602-8 +PMID:26928704 [PubMed]
6. Retractions (intercostal, supraclavicular, abdominal)
7. Grunting
8. Lethargy
9. Hypercarbia
10. Chest XRay changes (e.g. Atelectasis)
11. Cyanosis

Management
Effective Measures

General Measures
1. Constantly reassess for signs of impending Respiratory Failure
  1. May be signaled by a 'normalization' of the Respiratory Rate (due to respiratory muscle Fatigue)
2. Humidified Oxygen to keep Oxygen Saturation >90% (>88% while asleep)
  1. Low threshold to transition to Humidified High Flow Nasal Cannula as needed (see below)
  2. In practice, humidified High Flow Nasal Cannula (HHFNC) is typically used instead
3. Suctioning of secretions
  1. Paramount intervention both during the acute evaluation and for home
    1. Especially for the obligate nose breathers age <2 years
  2. Includes gentle Nasal Saline with suctioning (avoid Trauma and secondary edema)
  3. Provide parents with a hospital-grade nasal suction bulb
    1. Acorn manual nasal aspirator
    2. NoseFrida
  4. Avoid frequent deeper, nasopharyngeal suctioning (via nose into posterior pharynx and upper airways)
    1. Excessive deeper nasopharygeal suctioning increases airway irritation
    2. In hospital setting, twice daily nasopharyngeal suctioning is sufficient
    3. Contrast with frequent nasal suctioning (e.g. NoseFrida, acorn) which is a mainstay of treatment
  5. Consider nasal Decongestant (Neo-Synephrine)
    1. Neo-Synephrine (Phenylephrine) is preferred (If a nasal Decongestant is used in children)
    2. Avoid afrin (Oxymetazoline) in children
      1. Risk of Central alpha-2 Agonist, Clonidine-like CNS depression ("One Pill Can Kill" list)
4. Hydration and frequent feedings
  1. Parents should anticipate smaller volume feedings more frequently (every 3-4 hours) for the first 5 days of RSV
  2. Feedings should continue on High Flow Nasal Cannula
  3. If child is unable to take oral feedings, then consider Feeding Tube for Enteral Nutrition
Severe cases
1. Humidified High Flow Nasal Cannula (HHFNC)
  1. Indicated in increased Work of Breathing (e.g. retractions, grunting, apnea, nasal flaring) or Hypoxia
  2. Humidified High Flow Nasal Cannula starting at 1.5 to 2 L/kg/min and titrate as needed
    1. See Humidified High Flow Nasal Cannula for protocol
    2. Required rates above 2 L/kg/min are considered more severe (and typically admitted to PICU instead of ward)
  3. Efficacy
    1. Prevents airway collapse and Atelectasis
    2. Decreases work of breathing
    3. Effective and well tolerated
2. Nasal continuous positive airway pressure (nasal CPAP or nCPAP) or RAM Cannula
  1. Alternative to Humidified High Flow Nasal Cannula
  2. Offers greater PEEP than HHFNC
3. Endotracheal Intubation with Mechanical Ventilation
  1. Indicated in severe Hypoxia refractory to above measures
  2. Nasal CPAP has been effective at reducing the number of children requiring intubation for Bronchiolitis
4. Helium-Oxygen therapy
  1. Rarely used
  2. Martinon-Torres (2002) Pediatrics 109:68-73 [PubMed]

Management
Ineffective or Inconsistently Effective Measures

Nebulizer (not recommended as of 2014, per AAP)
1. Precautions: AAP 2014 Guidelines
  1. AAP recommends no nebulizer treatments (including Albuterol, Epinephrine and Hypertonic Saline)
  2. AAP recommends no Corticosteroids
  3. Supplemental Oxygen is optional when Oxygen Saturations are >90%
  4. http://pediatrics.aappublications.org/content/134/5/e1474
2. Nebulized Albuterol
  1. Albuterol is often trialed in the Emergency Department in moderate to severe cases (see below)
    1. AAP guidelines may reflect an RSV-specific lack of response to Bronchodilators
    2. However, undifferentiated Bronchiolitis symptoms (esp. with RAD, atopy) may respond
  2. Background per AAP
    1. Albuterol does not improve oxygenation in RSV
    2. Albuterol does not shorten hospital stay in RSV
    3. Albuterol may offer minor symptomatic relief in RSV
    4. Albuterol has adverse effects (e.g. Tachycardia)
  3. Older approach (prior to 2014 guidelines)
    1. May be effective in up to 50% of RSV patients (especially for children with history of Asthma or atopy)
    2. May still give a trial if atopic/RAD history or Warm Respiratory Scoring Tool >4
    3. If improvement with trial then continue every 6 hours (if not, then supportive care only)
  4. References
    1. Turner (2003) Ann Emerg Med 42:709-11 [PubMed]
3. Nebulized Atrovent
  1. See Reactive Airway Disease
  2. Some evidence as of 2011 suggesting Atrovent is effective (but not recommended by AAP 2014 Guidelines)
4. Nebulized racemic epinephrine
  1. Not recommended by AAP 2014 Guidelines
  2. Variable efficacy and use has declined since 2007
  3. Requires 2-4 hours of observation after administration due to transient effect with risk of rebound
  4. Wainright (2003) N Engl J Med 349:27-35 [PubMed]
5. Hypertonic Saline Nebulization (not recommended)
  1. Not recommended by AAP 2014 Guidelines for acute use (ED and short 1-2 day hospitalizations)
  2. Nebulizer dose: 4 ml of 3% Hypertonic Saline
  3. May shorten hospital stay (from >3 days)
  4. Increases cough
  5. Not effective in preventing hospitalization (may not be as useful for emergency care)
  6. Angoulvant (2017) JAMA Pediatr 171(8):e171333 PMID:28586918 [PubMed]
  7. Zhang (2008) Cochrane Database Syst Rev :CD006458 [PubMed]
Systemic Corticosteroids (not recommended)
1. Corticosteroids do not decrease severity of illness or shorten the disease course
2. Corticosteroids are not recommended for RSV Bronchiolitis by American Academy of Pediatrics
3. Atopic Patients and older patient's with Asthma may benefit
4. Data is mixed and some studies have shown benefit (e.g. Systemic Dexamethasone with Nebulized Epinephrine)
  1. Csonka (2003) J Pediatr 143:725-30 [PubMed]
  2. Plint (2009) N Engl J Med 360(20): 2079-89 [PubMed]
5. Some studies have shown benefit with decreased length of hospital stay (especially children under age 1 year old)
  1. Garrison (2000) Pediatrics 105(4): E44 [PubMed]
  2. Alansari (2013) Pediatrics 132(4): e810-6 [PubMed]

Management
Emergency Department Approach

Attempt to determine disposition (hospitalization versus home) in the first hour
Step 1: Supplemental Oxygen to maintain Oxygen Saturation >90%
Step 2: Nasal Suctioning
1. Assess patient (consider using a scoring system)
2. Nasal Saline and suction
3. Consider nasal Decongestant (Neo-Synephrine) as described above (avoid afrin)
4. Assess patient (consider using a scoring system)
Step 3: Nebulized Albuterol or Albuterol MDI with Aerochamber and mask
1. Not recommended by AAP as of 2014 but often trialed in Emergency Department
2. Cases in which Albuterol may have better efficacy
  1. Atopy (Eczema, Family History of Asthma) or reactive airway disease history
  2. Warm Respiratory Scoring Tool >4
  3. Older infants over age 6 months with rhinovirus Bronchiolitis
  4. Viral Bronchiolitis during non-RSV peak times
  5. Bronchiolitis chiefly presenting with Wheezing and subcostal retractions
  6. Nino (2020) ERJ Open Res 6(4): 00135-2020 +PMID:33083437 [PubMed]
3. Supply family with Albuterol for home if effective
4. Consider Dexamethasone (or other Corticosteroid) in those who respond to Albuterol (or have atopic/RAD risks)
  1. Also not recommended by AAP as of 2014
Step 4: High Flow Nasal Cannula (HHFNC)
1. Indicated in increased Work of Breathing (e.g. retractions, grunting, apnea, nasal flaring)
References
1. Sloas and Orman in Herbert (2014) EM:Rap 14(7): 1-3

Management
Therapies with variable or limited evidence

Montelukast
1. Improved post-RSV clinical symptoms (age 3-36 months)
2. Bisgaard (2003) Am J Respir Crit Care Med 167:379-83 [PubMed]
Surfactant
1. Tibby (2000) Am J Respir Crit Care 162:1251-6 [PubMed]
Aerosolized Ribavirin (Virazole)
1. Use limited to immunosuppressed children with severe disease (hospitalized)
2. May be useful early at maximal viral load
3. Variable efficacy
4. Cost exceeds $1000 per day
5. Randolph (1996) Arch Pediatr Adolesc Med 150:942-7 [PubMed]

Management
Therapies not found to be useful

Theophylline does not change the clinical course
Antibiotics without Bacterial Infection identified
Inhaled Interferon alfa-2a
RSV Immune globulin for acute treatment
1. Indicated for prophylaxis in high risk infants
2. No evidence for benefit in acute disease
Palivizumab for acute treatment
1. Indicated for prophylaxis in high risk infants
2. No evidence for benefit in acute disease
Racemic Epinephrine mixed with Hypertonic Saline
1. See above for AAP recommendations 2014 to not use Epinephrine nebs
2. Observe for at least 2-3 hours after dose

Prevention

General measures
1. Avoid contact with respiratory droplets
2. Avoid contagious exposures
3. Hand Washing
4. Cleaning of surfaces
5. Avoid Passive Smoke Exposure
6. Exclusive Breast Feeding for first 6 months of life
Medications for Infants
1. RSV Immune Globulin (RSV-IG, RespiGam)
  1. Pooled human Intravenous Immunoglobulin (IVIG) is still available for high risk, hospitalized infants
  2. RespiGam was discontinued in 2003
2. Palivizumab (Synagis)
  1. Given monthly for up to 5 months of RSV season
    1. Typically November 1 to March 1 pre-2020 Covid (spring-summer peak after 2020)
  2. See Palivizumab for indications
    1. Premature Infants born before 29 weeks gestation (<32 weeks if on oxygen >28 days)
    2. Cyanotic Congenital Heart Disease
    3. Chronic lung disease (Bronchopulmonary Dysplasia, Cystic Fibrosis)
    4. Neuromuscular disorders
3. Nirsevimab
  1. Single dose given at start of RSV season
  2. Effective in preventing hospitalization (FDA approval in 2023)
  3. Indications
    1. RSV Prophylaxis in all children age <8 months in their first RSV season (typically October to March in U.S.)
    2. RSV Prophylaxis in all children age 8 to 19 months in their second RSV season who are at risk for severe disease
      1. High risk infants may be given Nirsevimab and stop Palivizumab if less than 5 doses of Palivizumab given
  4. References
    1. Griffin (2020) N Engl J Med 383(5): 415-25 [PubMed]
    2. Hammitt (2022) N Engl J Med 386(9): 837-46 [PubMed]
Vaccinations in Pregnancy
1. Bivalent RSV Perfusion F Vaccine
  1. Administered to pregnant patients 24 to 36 weeks gestation (CDC recommends 32 to 36 weeks) during RSV season
  2. Effective in preventing severe RSV in first 6 months (esp. first 3 months)
  3. Kampmann (2023) N Engl J Med 388(16): 1451-64 [PubMed]
Older Adults (age >=60 years)
1. RSV Vaccine
  1. Especially higher risk patients (Diabetes Mellitus, chronic heart disease, COPD, Immunocompromised)
  2. Reduces Relative Risk of lower respiratory infection for 2 years after Vaccination

Prognosis

Severe episodes: 10-20% of cases
1. Present with Dehydration, Hypoxemia, nasal flaring, grunting, apnea, Respiratory Failure
2. Admission rates: 19-45% of cases
3. ICU Admission: 3% of cases
Mortality
1. Worldwide: 1% RSV case fatality rate
2. United States: 0.1%
  1. Deaths: 372 per year in United States (90% are under age 1 year)
More severe illness if comorbid underlying disease
1. Congenital Heart Disease (RSV Mortality as high as 37%)
2. Bronchopulmonary Dysplasia (and Pulmonary Hypertension)
3. Immunodeficiency
4. Age <3 months
5. Weight <11 pounds (5 kg)
6. Premature birth (<35 weeks gestation, esp. <29 weeks gestation)

Complications

Persistent reactive airway disease
1. Higher risk with more severe RSV infection or Rhinovirus
2. Wheezing episodes persist up to 5 years in 40% of children with RSV infection
3. Wheezing episodes persist beyond 5 years in 10% of children with RSV infection
Childhood Asthma
1. Three fold Relative Risk of childhood Asthma following RSV Bronchiolotis
2. Coutts (2020) Pediatr Pulmonol 55(5): 1104-10 [PubMed]

References

Hall (2024) Mayo Clinic Pediatric Days, attended 1/15/2024
Serrano (2014) Crit Dec Emerg Med 28(6): 2-10
Sloas and Orman in Herbert (2014) EM:Rap 14(8): 1-2
Warrington (2016) Crit Dec Emerg Med 30(7): 15-20
Dawson-Caswell (2011) Am Fam Physician 83(2): 141-6 [PubMed]
Panitch (2003) Pediatr Infect Dis J 22:S83-8 [PubMed]
Jafri (2003) Pediatr Infect Dis J 22:S89-93 [PubMed]
Joseph (2011) Pediatr Emerg Med Prac 8(3) [PubMed]
Oppenlander (2023) Am Fam Physician 108(1): 52-7 [PubMed]
Smith (2017) Am Fam Physician 95(2): 94-99 [PubMed]
Steiner (2004) Am Fam Physician 69:325-30 [PubMed]