Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs and respiratory tract and spreads via respiratory droplets. Respiratory syncytial virus is a leading cause of lower respiratory tract infections in infants and young children. Complications include bronchiolitis, pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, and otitis media. Respiratory syncytial virus is managed with supportive care.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Classification

Rna viruses flowchart classification

RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure. RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure genome viruses can be further characterized by either a single- or double-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure. “Enveloped” viruses are covered by a thin coat of cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure dependent RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase, a viral enzyme, to transcribe their genome into messenger RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Taxonomy and structure

  • Genus Pneumovirus 
  • Family Paramyxoviridae
  • Single-stranded, linear, negative-sense RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
  • Enveloped virus
  • Large helical capsid carries RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure-dependent RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase in virion

Basic features

  • Absence of hemagglutinin
  • Consists of 2 serotypes
  • Limited to the respiratory tract
  • Two subtypes (A and B) are present in outbreaks; type A causes more severe disease.

Clinically relevant species

  • The Paramyxoviridae family consists of 3 genera:
    • Paramyxovirus, which includes the parainfluenza and mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps viruses 
    • Orthopneumovirus, which includes the respiratory syncytial virus (RSV)
    • Morbillivirus, which includes the measles virus Measles Virus Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Morbillivirus. It is highly contagious and spreads only among humans by respiratory droplets or direct-contact transmission from an infected person. Measles Virus
  • The Paramyxoviridae family causes 30%–40% of all acute respiratory infections in infants and children.
Rsv respiratory syncytial virus

Electron micrograph of respiratory syncytial virus

Image: “Electron micrograph of RSV” by CDC. License: Public Domain

Pathogenesis

Transmission and replication cycle

Transmission: 

Respiratory droplets from an infected individual come into contact with the mucosa of the eyes, mouth, or nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose of another individual.

Replication cycle:

  • Once an individual is exposed, there is a fusion of the viral and host cell membranes. 
    • The viral surface glycoproteins F and G control viral attachment and the initial stages of infection.
    • The viral nucleocapsid and polymerase enter the host cell cytoplasm.
  • RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure-dependent RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase transcribes the viral genome into mRNA, which is translated by host proteins.
  • The RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase synthesizes a positive-sense antigenome, a complementary template strand used to construct negative-sense RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.
  • The resultant RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure is packaged into nucleocapsids and transported to the plasma membrane for assembly and budding.
Schematic image of rsv respiratory syncytial virus life cycle

Schematic image of respiratory syncytial virus (RSV) life cycle

Image: “Schematic image of RSV life cycle” by Bawage S et al. License: CC BY 3.0, cropped by Lecturio.

Natural reservoirs

  • Humans
  • Cattle
  • Sheep
  • Goats

Pathophysiology

  • The infection spreads within the respiratory tract, without systemic spread.
  • RSV spreads by cell-to-cell transfer along intracytoplasmic bridges (syncytia) from the upper to the lower respiratory tract (the terminal bronchioles)
  • Lytic viral replication causes epithelial cell sloughing → exposing nociceptive nerve fibers → stimulating the cough reflex
  • Influx of PMNs into the airway → replaced by lymphomononuclear infiltration of the peribronchiolar tissue and increased microvascular permeability → submucosal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and swelling
  • Mucous secretions increase in quantity and viscosity → widespread mucous plugging

Diseases Caused by Respiratory Syncytial Virus

Although RSV is limited to the respiratory tract, it can manifest as illnesses of varying severity depending on the individual’s age and state of the immune system.

Diseases caused

  • Infants:
    • Acute bronchiolitis Acute bronchiolitis Acute bronchiolitis is a respiratory condition caused by inflammation of the bronchioles. The condition is a common cause of hospitalization in children in the United States, with the majority of cases caused by respiratory syncytial virus (RSV). Acute Bronchiolitis
    • Pneumonia
    • Acute otitis media Acute Otitis Media Acute otitis media is an infection in the middle ear characterized by mucosal inflammation and retention of fluid. The most common pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The condition can present with fever, otalgia, and diminished hearing. Acute Otitis Media
    • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
  • Immunocompromised or elderly adults: 
    • Pneumonia
    • Acute exacerbation of underlying chronic illness (e.g., chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)), asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma, congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure)

Epidemiology

  • Incidence: affects 4 million–5 million children < 4 years of age per year 
    • Primarily a disease of young infants and children
    • Peak incidence at 2–8 months of age
  • > 125,000 patients with RSV infection are hospitalized annually in the United States.
  • In mild presentations of RSV, there is an equal incidence among boys and girls.
  • However, boys are 2 times more likely to require hospitalization because of RSV infections.

Risk factors

  • Premature infants
  • Infants with chronic lung disease
  • Children with congenital heart disease
  • Low birth weight
  • Maternal smoking during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • No breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding

Clinical presentation

  • Incubation time: 4–5 days
  • Upper respiratory tract infection
    • Cough
    • Rhinorrhea
  • Lower respiratory tract infection
    • Tachypnea
    • Intercostal and subcostal retractions
    • Cyanosis
    • Wheezing and rales
    • Fever
  • Associated with otitis media, dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration, and apneic episodes

Diagnosis

  • Laboratory studies are not typically indicated in well-appearing patients who are breathing room air, are well hydrated, and are feeding adequately. 
  • RSV-specific diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests
    • Antigen detection (point-of-care testing)
    • Molecular probes ( PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) assays)
    • Culture
  • Antigen detection (point-of-care testing)
  • Molecular probes ( PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) assays)
  • Culture
  • Chest X-ray for suspicion of pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
Chest x-ray respiratory syncytial virus bronchiolitis

Chest X-ray of an infant with respiratory syncytial virus bronchiolitis

Image: “Chest X-ray on admission to the emergency room” by Di Nardo M et al. License: CC BY 2.0

Management

Supportive care is the mainstay of therapy for RSV infection, including oxygenation and hydration. 

Pharmacologic therapy:

  • Generally not recommended by the American Academy of Pediatrics but may be used in select cases.
  • In select cases, beta-agonists (albuterol), alpha-agonists (epinephrine), or corticosteroids may be used
  • In patients with significant underlying risk factors (e.g., transplant patients), ribavirin is used.

Prophylaxis: palivizumab, FDA-approved for children at high risk for severe RSV disease

  • Premature infants born at < 29 weeks, < 1 year of age
  • Premature infants born at < 32 weeks, < 1 year of age with chronic lung disease
  • In the 2nd year of life for children who need supplemental oxygen or long-term corticosteroid or diuretic therapy
  • Children < 24 months who have significant congenital heart disease or pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension

Differential Diagnosis

Acute bronchiolitis Acute bronchiolitis Acute bronchiolitis is a respiratory condition caused by inflammation of the bronchioles. The condition is a common cause of hospitalization in children in the United States, with the majority of cases caused by respiratory syncytial virus (RSV). Acute Bronchiolitis: respiratory condition caused by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the bronchioles. The majority of cases of acute bronchiolitis are caused by RSV. Patients usually present with upper respiratory symptoms, such as cough and congestion, and later develop lower respiratory signs, including dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, crackles, and hypoxia. Diagnosis is clinical, and treatment is directed at improving oxygenation and hydration. The disease is self-limiting and has a good prognosis with appropriate management.

References:

  1. Krilov L. (2019). Respiratory syncytial virus infection treatment & management. Emedicine. Retrieved February 6, 2021, from https://emedicine.medscape.com/article/971488-treatment#d8
  2. Welliver RC. (2009). Bronchiolitis and infectious asthma. Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, Eds. Textbook of Pediatric Infectious Diseases, 6th ed. Philadelphia: Saunders Elsevier, pp. 277–288.
  3. Centers for Disease Control and Prevention. (2018). Respiratory syncytial virus infection (RSV): trends and surveillance. https://www.cdc.gov/rsv/research/us-surveillance.html
  4. Graham B, Barr F. (2020). Respiratory syncytial virus infection: Treatment. UpToDate. Retrieved Feb 6, 2021, from https://www.uptodate.com/contents/respiratory-syncytial-virus-infection-treatment
  5. Ralson S, et al. (2014). Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 134:e1474–e1502.

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