Respiratory Syncytial Virus (RSV)

Virology

  • Member of Paramyxovirus Family (see Paramyxoviruses)
    • Pneumovirus Genus
    • Similar in structure to Parainfluenza Virus (see Parainfluenza Virus)
    • Pleomorphic (150-300 nm), enveloped virus with a single-stranded, nonsegmented RNA genome
    • Antigenic types A and B: primarily distinguished by differences in G glycoprotein
    • Group A strain infections appear to be more severe

Epidemiology

General Features

  • Worldwide Ditribution
  • Outbreaks: in temperate climates, outbreaks occur in late fall, winter, or spring
    • Epidemics are associated with increased pediatric hospitalizations and death in infants and young children (due to lower respiratory tract illness)

Childhood Cases

  • Infection in Early Life: nearly 50% of children are infected with RSV within the first year and almost all are infected within the first 3 years
  • Risk Factors for Severe RSV Infection in Infants
    • Crowding
    • Day Care Center Attendance
    • History of Allergic Disease
    • Lack of Breast Feeding
    • Low Socioeconomic Status
    • Maternal Smoking

Adult Cases

  • Burden of Disease: RSV infection may result in a greater disease burden in elderly than in infants
    • In patients >65 y/o in the US, RSV accounts for 170k hospitalizations per year and 10k deaths per year
  • Risk Factors for RSV Infection in Adults

Physiology

Viral Transmission

  • Large Particle Aerosol Transmission via Close Personal Contact
  • Hand Contamination by Infected Secretions with Self-Inoculation of Eyes/Nose

Infection Attack Rates/Reinfection

  • Pediatric Wards: RSV is a major nosocomial pathogen
    • Attack rates are 20-50% in hospital staff and patients during epidemics
  • Daycare Centers: attack rates may approach 100% during outbreaks
  • Family Setting : with RSV introduction by another child, rate of transmission to infants is 50% and rate of transmission to adult contacts is 33%
  • Reinfection: reinfection is common in children and adults (even with the same strain), suggesting that immunity is only partial
    • Reinfection may occur within weeks after the primary infection (and as early as 8 weeks in adults with secondary infections)

Viral Replication/Spread and Immune Response

  • Viral Replication and Spread: recplication begins in upper respiratory tract with gradual (4-5 day) progression to then involve the lower respiratory tract
  • Viral Shedding: 1-3 wks (in children)
  • Serum and Mucosal Antibody Responses: both occur, but offer only partial protection
    • Antibody response is less in younger infants
    • Increased circulating and mucosal antibody levels occur with each successive (re)infection and are associated with milder illness
    • Higher levels of serum neutralizing antibody are associated with lower risk of severe illness in infants/children
  • Cell-Mediated Immunity: important for viral clearance
    • Bone marrow transplant patients (with decreased cell-mediated immunity) are at high risk for severe RSV-related lower respiratory tract infection
    • AIDS patients (with decreased cell-mediated immunity), viral sheeding may continue for up to 6 mo even after a mild RSV infection
  • Severity of RSV Disease: modulated by genetic polymorphisms in TLR4, surfactant, and cytokine/chemokine genes

Clinical Presentations

General Comments

  • Clinical Manifestations are Age-Dependent/Immune Status-Dependent: most severe RSV infections occur in infants <6 mo old
  • Primary RSV Infection: almost all primary RSV infections are symptomatic
  • Rate of Hospitalization in Infants/Young Adults:
    • 1-2% of RSV infections result in hospitalization
    • 10% of hospitalized infants require ventilatory support

Acute Viral Rhinosinusitis (“Common Cold”)/Pharyngitis (see Acute Rhinosinusitis)

  • Epidemiology: as a group, parainfluenza virus/influenza virus/respiratory syncytial virus/adenovirus account for approximately 10-15% of “common cold” cases

Acute Bronchitis (see Acute Bronchitis)

Clinical

Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS)

  • Epidemiology: may occur

Acute Otitis Media (see Acute Otitis Media)

  • Epidemiology: common in infants/young children

Bronchiolitis (see Bronchiolitis)

Epidemiology

  • Peak Age Group: typically occurs in children <2 y/o (rare in adults)
    • Risk of Hospitalization and Severe Bronchiolitis: high in infants with congenital heart disease, immunodeficiency, prematurity, or chronic lung disease
    • Risk of Severe Bronchiolitis: high in infants with family history of asthma and second-hand smoke exposure
  • Viral Etiology: most cases with a defined viral etiology are due to respiratory syncytial virus (RSV accounts for 45-90% of bronchiolitis cases in infants/young children)

Physiology

  • Acute Inflammatory Disorder of Small Airways
    • Air Trapping/Hyperinflation
    • Atelectasis

Diagnosis

  • Arterial Blood Gas (ABG)
    • Hypoxemia: may persist for weeks after recovery
  • CBC: absence of leukocytosis (and normal differential)
  • CXR: hyperinflation (with air trapping), flattened diaphragms, peribronchial thickening, atelectasis, bronchopneumonia (consolidation)
  • Pulmonary Function Tests (PFT’s): increased airway resistance and peripheral airway obstruction (and hypoxemia) may be seen years later in children who have experienced repeated episodes of RSV bronchiolitis

Clinical

  • General Comments
    • Prodrome: several days of upper respiratory tract symptoms
  • Absence of Fever
  • Atelectasis (see Atelectasis, [[Atelectasis]])
  • Hyperinflation
  • Hyperresonant Chest Exam
  • Inspiratory Crackles on Chest Exam
  • Inspiratory/Expiratory Wheezing (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
  • Intercostal/Suprasternal Retractions
  • Nasal Flaring
  • Tachypnea (see Tachypnea, [[Tachypnea]])

Treatment

  • Treatment of Hypoxemia
  • Infection Control/Contact Precautions: crucial to prevent nosocomial spread (especially in immunocompromised populations)
  • Antibiotics: only indicated if secondary bacterial infection is present
  • Bronchodilators (see Albuterol, [[Albuterol]])
    • Meta-Analysis of Bronchodilator Use in Bronchiolitis (2014) [MEDLINE]: bronchodilators (albuterol, salbutamol) do not improve hypoxemia, decrease rate of hospital admission after outpatient treatment, decrease the duration of hospitalization, or decrease the time to resolution of illness at home
    • However, study was limited by small sample sizes, lack of standardized study design, and lack of validated outcomes across the studies
  • Nebulized Racemic Epinephrine (see Epinephrine, [[Epinephrine]])
    • Infants: not efficacious [MEDLINE]
  • Corticosteroids (see Corticosteroids, [[Corticosteroids]])
    • Infants: not recommended
    • Adults: useful to specifically treat exacerbation of bronchospasm (asthma, COPD) triggered by RSV infection
  • Ribavirin (see Ribavirin, [[Ribavirin]]): ribavirin is highly active against RSV in vitro
    • Immunocompromised Adults with Stem Cell Transplant: aerosolized ribavirin decreases mortality rate in RSV pneumonia in this population [MEDLINE] [MEDLINE]
    • Immunocompromised Adults with Stem Cell Transplant: oral and intravenous ribavirin have been shown to be efficacious in small trials [MEDLINE] [MEDLINE]
    • Immunocompromised Adults with Lung/Solid Organ Transplant: the efficacy of ribavirin in these patients is unknown [MEDLINE] [MEDLINE]
  • Palivizumab (Synagis) (see Palivizumab, [[Palivizumab]]): RSV-specific humanized monoclonal antibody
    • No clinical benefit in the therapy of RSV infection
    • Licensed for the prevention of serious RSV lower respiratory tract disease in children at high risk of RSV infection (prematurity, bronchopulmonary dysplasia, congenital heart disease)
  • Combination Ribavirin + Intravenous Immunoglobulin (IVIG) (see Ribavirin, [[Ribavirin]] and Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]]): may be indicated in severely ill patients with RSV
  • Combination Palivizumab (Synagis) + Intravenous Immunoglobulin (IVIG) (see Palivizumab, [[Palivizumab]] and Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]]): has not been studied
  • RSV-Specific Immunoglobulin (RSVIG): no longer available
  • Combination Ribavirin + Corticosteroids (see Ribavirin, [[Ribavirin]] and Corticosteroids, [[Corticosteroids]]): has been used in small series of lung transplant patients with RSV [MEDLINE]

Prognosis

  • Mild Cases: resolve within several days
  • Mortality Rates
    • Previously Healthy Infants: 0.5-1.5%
    • Infants with Immunodeficiency/Cancer Chemotherapy/Pulmonary or Heart Disease/Pulmonary Hypertension: 15-40%

Croup (see Croup)

Definitions

  • Acute Infectious Croup (Acute Laryngotracheobronchitis): contagious disease in otherwise health children
    • Often associated with respiratory illness in the family
  • Acute Spasmodic Croup: most common in young children who are prone to recurrent attacks
    • Possibly precipitated by a viral respiratory infection, allergic factors, or other factors
    • Fever is usually absent
    • Symptoms usually resolve within several hours

Epidemiology

  • Peak Age: <6 y/o

Diagnosis

  • CXR: glottic/subglottic edema -> may aid in differentiation from acute epiglottitis (although radiographs are of limited accuracy)

Clinical

  • General Comments
    • Symptoms are preceded by several days of an upper respiratory illness
    • Symptoms are often worse at night
    • A fluctuating course is typical
  • Brassy or Barking Cough (see Cough)
  • Dyspnea (see Dyspnea)
  • Hoarseness (see Hoarseness)
  • Inspiratory Stridor (see Stridor)

Treatment

  • Supportive Care
    • Humidified oxygen, mist therapy
    • Since most children have symptoms which decrease in intensity over several days, they can be managed at home: however, monitoring for upper airway obstruction is crucial
  • Nebulized Racemic Epinephrine (see Epinephrine): used for symptomatic relief of upper airway obstruction
    • Mechanism: alpha adrenergic effect is believed to cause mucosal vasoconstriction, resulting in decreased subglottic edema
    • Latency: min
    • Duration of Action: <2 hrs
    • Has not been demonstrated to improve oxygenation
  • Corticosteroids (see Corticosteroids): single-dose corticosteroids does not have significant adverse effects and is probably indicated for a child who has severe enough croup to be evaluated in a clinic or emergency room
    • Increase rate of symptomatic improvement
    • Decrease hospital length of stay
    • Decrease the rate of intubation
  • Anti-Viral Agents: have not been evaluated in croup

Exacerbation of Underlying Obstructive Lung Disease

Increased Risk of Future Asthma (see Asthma)

  • Wheezing from RSV Infection from Birth-3 y/o: increases odds ratio to 2.6 of developing asthma by age 6 (the odds ratio increased to 10.0 in presence of both RSV and rhinovirus-related wheezing illnesses from birth-3 y/o) [MEDLINE]
    • It is unclear if childhood RSV infection increases the risk of adult asthma

Increased Risk of Pneumococcal Pneumonia (Possible) (see Streptococcus Pneumoniae)

  • Study Citing Association Between RSV Infection and Pneumococcal Pneumonia in Infants (2014) [MEDLINE]: interestingly, the study also cited a decrease in RSV-coded hospitalizations after introduction of the seven-valent pneumococcal conjugate vaccine

Influenza-Like Illness

Clinical

  • General Comments: rapid onset of constitutional symptoms
    • Upper/lower respiratory tract symptoms occur concurrently or after the constitutional symptoms
  • Asthenia (see Asthenia): common in second week of illness
  • Clear Nasal Discharge without Obstruction: common
  • Dry (Often Persistent) Cough (see Cough): predominates later in the first week of illness
  • Excess Ocular Tearing: common early in the illness
  • Fatigue (see Fatigue): common in second week of illness
  • Fever/Chills (see Fever): common early in the illness
    • May peak to 39-40 degrees C
    • Lasts for 1-5 days
  • Headache (see Headache): common early in the illness
  • Mild Conjunctivitis (see Conjunctivitis): common
  • Mild, Tender Cervical Lymphadenopathy (see Lymphadenopathy): common
  • Myalgias (see Myalgias,): common early in the illness
  • Pain with Eye Movement: common early in the illness
  • Pharyngeal Injection/Pharyngitis (see Pharyngitis): common
  • Photophobia (see Photophobia): common early in the illness
  • Wheezing: more prominent feature in RSV than in influenza

Treatment

  • Anti-Pyretics: avoid aspirin in pediatric cases (due to risk of Reye’s syndrome)
  • Anti-Tussives
  • Bed Rest
  • Hydration
  • Infection Control/Contact Precautions: crucial to prevent nosocomial spread (especially in immunocompromised populations)

Pleural Effusion (see Pleural Effusion-Exudate)

  • Epidemiology: may occur in some cases

Pneumonia (see Pneumonia, [[Pneumonia]])

Epidemiology

  • Childhood Cases: RSV accounts for 40% of pneumonia cases in infants/young children
    • Most severe RSV infections occur in infants <6 mo old
    • CDC EPIC Study of Children Hospitalized for Community-Acquired Pneumonia (2015) [MEDLINE]
      • Annual Incidence of Community-Acquired Pneumonia Requiring Hospitalization: 15.7 cases per 10k children <18 y/o
      • A pathogen was identified in 81% of cases
      • RSV was the most common pathogen (being detected in 28% of pneumonia cases)
      • The greatest burden of RSV was found in children <2 y/o
  • Adult Cases: RSV pneumonia may occur in healthy adults

Diagnosis

  • Sputum Gram Stain/Culture + Sensitivity
  • Bronchoscopy
    • Bronchoalveolar Lavage: viral culture is positive/ELISA or IF viral antigen tests are positive
    • Transbronchial Biopsy: syncytial cells or viral cytoplasmic inclusions/immunohistochemical stains with monoclonal antibodies
  • CXR/Chest CT Patterns: air trapping, multilobular alveolar infiltrates, poorly-defined nodularity

Clinical

  • Acute Respiratory Failure (see Respiratory Failure)
    • Mechanical ventilation is required in 10% of elderly institutionalized patients who are hospitalized with RSV infection
    • Mechanical ventilation is required in 50% of myelosuppressed leukemics with RSV infection
    • Mechanical ventilation is required in 20% of lung transplant patients with RSV infection
  • Cough (see Cough)
  • Dyspnea (see Dyspnea)

Treatment

  • Treatment of Hypoxemia
  • Infection Control/Contact Precautions: crucial to prevent nosocomial spread (especially in immunocompromised populations)
  • Ribavirin (see Ribavirin): ribavirin is highly active against RSV in vitro
    • Immunocompromised Adults with Stem Cell Transplant: aerosolized ribavirin decreases mortality rate in RSV pneumonia in this population [MEDLINE] [MEDLINE]
    • Immunocompromised Adults with Stem Cell Transplant: oral and intravenous ribavirin have been shown to be efficacious in small trials [MEDLINE] [MEDLINE]
    • Immunocompromised Adults with Lung/Solid Organ Transplant: the efficacy of ribavirin in these patients is unknown [MEDLINE] [MEDLINE]
  • Palivizumab (Synagis) (see Palivizumab): RSV-specific humanized monoclonal antibody
    • No clinical benefit in the therapy of RSV infection
    • Licensed for the prevention of serious RSV lower respiratory tract disease in children at high risk of RSV infection (prematurity, bronchopulmonary dysplasia, congenital heart disease)
  • Combination Ribavirin + Intravenous Immunoglobulin (IVIG) (see Ribavirin and Intravenous Immunoglobulin): may be indicated in severely ill patients with RSV
  • Combination Palivizumab (Synagis) + Intravenous Immunoglobulin (IVIG) (see Palivizumab and Intravenous Immunoglobulin): has not been studied
  • RSV-Specific Immunoglobulin (RSVIG): no longer available
  • Combination Ribavirin + Corticosteroids (see Ribavirin and Corticosteroids): has been used in small series of lung transplant patients with RSV [MEDLINE]

Prognosis

  • Mortality in Leukemia-Related Cases: 83%
  • Mortality in Adults: 7-8% (similar to the mortality rates of influenza)

Vaccination

  • None available

References

  • Respiratory syncytial virus pneumonia in a lung transplant recipient: case report. J Heart Lung Transplant. 1992;11(1 Pt 1):77 [MEDLINE]
  • Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant. 1995;16(3):393 [MEDLINE]
  • Immunotherapy of respiratory syncytial virus pneumonia following bone marrow transplantation. Bone Marrow Transplant. 1996;17(6):1051 [MEDLINE]
  • Respiratory syncytial virus-associated infections in adult recipients of solid organ transplants. J Heart Lung Transplant. 1998;17(2):202 [MEDLINE]
  • Respiratory syncytial virus infection in adult BMT recipients: effective therapy with short duration nebulised ribavirin. Bone Marrow Transplant. 1998;21(4):423 [MEDLINE]
  • Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant. 2000;25(7):751 [MEDLINE]
  • Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation – a compassionate use experience. Bone Marrow Transplant. 2000;25(2):161 [MEDLINE]
  • Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000;13(3):371 [MEDLINE]
  • Respiratory syncytial virus infection of the lower respiratory tract: radiological findings in 108 children. Eur Radiol. 2001;11(12):2581-4. Epub 2001 May 3 [MEDLINE]
  • Safety and pharmacokinetics of palivizumab therapy in children hospitalized with respiratory syncytial virus infection. Pediatr Infect Dis J. 2004;23(8):707 [MEDLINE]
  • Treatment of respiratory syncytial virus pneumonia in a lung transplant recipient: case report and review of the literature. Pharmacotherapy. 2004;24(7):932 [MEDLINE]
  • Pharmacologic treatment of bronchiolitis in infants and children: a systematic review. Arch Pediatr Adolesc Med. 2004;158(2):127 [MEDLINE]
  • Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant. 2005;24(12):2114 [MEDLINE]
  • Wheezing Rhinovirus Illnesses in Early Life Predict Asthma Development in High-Risk Children. Am J Respir Crit Care Med. 2008 October 1; 178(7): 667–672 [MEDLINE]
  • Epinephrine for bronchiolitis. Cochrane Database Syst Rev. 2011 [MEDLINE]
  • Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342:d1714 [MEDLINE]
  • Racemic adrenaline and inhalation strategies in acute bronchiolitis. N Engl J Med. 2013 Jun;368(24):2286-93 [MEDLINE]
  • Respiratory viral infections among children with community-acquired pneumonia and pleural effusion. Scand J Infect Dis. 2013 Jun;45(6):478-83. doi: 10.3109/00365548.2012.754106. Epub 2013 Jan 3 [MEDLINE]
  • Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. Clin Infect Dis. 2013 Dec;57(12):1731-41. Epub 2013 Oct 8 [MEDLINE]
  • Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2013;48(12):1558 [MEDLINE]
  • Successful systemic high-dose ribavirin treatment of respiratory syncytial virus-induced infections occurring pre-engraftment in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2013 Aug;15(4):435-40. Epub 2013 May 20 [MEDLINE]
  • Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014;6:CD001266 [MEDLINE]
  • Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data. PLoS Med. 2015 Jan 6;12(1):e1001776. doi: 10.1371/journal.pmed.1001776. eCollection 2015 [MEDLINE]