Parainfluenza Virus

Human parainfluenza viruses (HPIVs) are single-stranded, linear, negative-sense RNA viruses of the family Paramyxoviridae and the genus Paramyxovirus. Human parainfluenza viruses are the 2nd most common cause of lower respiratory disease in children, after the respiratory syncytial virus. Upper respiratory infections, including croup, are caused by HPIVs as well, but to a lesser extent. Management of HPIV infections relies on supportive care, racemic epinephrine, and steroids.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of 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 (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

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

General Characteristics

Structure

  • Genus Paramyxovirus (now split into Respirovirus and Rubulavirus)
  • Subfamily Paramyxovirinae
  • Family Paramyxoviridae
  • Single-stranded, linear, negative-sense RNA
  • Enveloped virus
  • Large, helical capsid that carries RNA-dependent RNA polymerase within virions

Clinically relevant species

  • The family Paramyxoviridae consists of 3 genera:
    • Paramyxovirus: includes the parainfluenza viruses (Respirovirus) and mumps virus (Rubulavirus) 
    • Pneumovirus: includes the respiratory syncytial virus (RSV)
    • Morbillivirus: includes the measles virus
  • The Paramyxoviridae family causes 30%–40% of all acute respiratory infections in infants and children.
  • Human parainfluenza viruses (HPIVs) are currently divided into 5 serotypes on the basis of antigenic and genetic characteristics: 
    • HPIV-1
    • HPIV-2
    • HPIV-3
    • HPIV-4a
    • HPIV-4b
  • The serotypes are classified into 2 different genera: 
    • Respirovirus (HPIV-1 and HPIV-3) 
    • Rubulavirus (HPIV-2 and HPIV-4)
Structure parainfluenza virus

The tertiary structure of human parainfluenza virus type 3

Image: “Fusion glycoprotein trimer, Human parainfluenza virus 3 (hPIV3)” by Yin et al. License: CC BY 4.0

Pathogenesis

Transmission

  • Humans are the only reservoir.
  • Transmission occurs mainly via airborne respiratory droplets that come into contact with the mucous membranes of the eyes, mouth, or nose.
  • Direct contact with infected fomites is also a frequent route of transmission.
  • Incubation period: 2–4 days

Virulence factors

HPIVs have 6 main proteins:

  • Hemagglutinin-neuraminidase (HN): located on the viral surface, responsible for viral attachment and cell entry
  • Fusion protein: located on the viral surface, responsible for fusion to the host cell and cell entry
  • Matrix protein: located in the viral envelope, responsible for viral assembly
  • Nucleoprotein: located in the nucleocapsid, forms part of the RNA genome complex
  • Phosphoprotein: located in the nucleocapsid, forms part of the RNA polymerase complex
  • Large protein: located in the nucleocapsid, forms part of the RNA polymerase complex

Replication cycle

  1. Viral replication occurs after entry into a host cell by attachment and fusion with the host’s cellular membrane and is aided by HN and fusion protein.
  2. The viral nucleocapsid enters the host cell cytoplasm.
  3. Genomic transcription occurs in the cytoplasm via RNA-dependent RNA polymerase (large protein).
  4. The translation and synthesis of the viral proteins are performed by the host’s ribosomes.
  5. The RNA polymerase synthesizes a positive-sense antigenome, a complementary template strand used to construct negative-sense RNA, which is then associated with the nucleoprotein.
  6. The viral RNA is packaged into nucleocapsids and transported to the plasma membrane for assembly and budding. 
  7. Alternatively, the RNA can also be used for subsequent rounds of transcription and replication.

Pathophysiology

HPIVs cause inflammation of the airway through the up-regulation of inflammatory cytokines, including:

  • Interferon α (IFN-α) 
  • Interleukins (IL-2, IL-6)
  • Tumor necrosis factor α (TNF-α)

Virus-specific IgE antibodies mediate the release of histamine in the respiratory tract, contributing to the symptoms and pathogenesis of croup.

Risk factors

  • Immunocompromised state
  • Malnutrition
  • Overcrowding, such as in nursing facilities and daycare centers
  • Vitamin A deficiency
  • Lack of breastfeeding

Diseases Caused by Human Parainfluenza Viruses

Human parainfluenza viruses are mainly limited to the respiratory tract. These viruses have been associated with every type of upper and lower respiratory tract illness. The serotypes can cause illnesses that vary in severity.

  • Serotypes 1 and 2: croup (laryngotracheobronchitis)
  • Serotype 3: acute bronchiolitis and pneumonia
  • Serotype 4: mild cold-like syndrome
  • Rarely, HPIVs have been associated with febrile seizures, viral meningitis, and Guillain-Barré syndrome.
Table: Diseases caused by HPIVs
SerotypeDiseases causedMain clinical features
HPIV-1 and 2Croup (laryngotracheobronchitis)
  • Infection of the lower respiratory tract
  • Mainly affects children 2–5 years of age
  • Clinical presentation:
    • Fever
    • Coryza
    • Intercostal and subcostal retractions
    • Tachypnea
    • Irritability
    • “Seal bark” cough
    • Inspiratory stridor
    • Tracheal swelling with “steeple sign” on chest X-ray
HPIV-3Acute bronchiolitis and pneumonia
  • Mainly affects infants or immunocompromised/elderly patients
  • Clinical presentation:
    • Fever
    • Coryza
    • Tachypnea
    • Coughing
    • Wheezing
HPIV-4a and 4bMild cold-like syndrome
  • May be asymptomatic
  • Clinical presentation:
    • Coryza
    • Nasal congestion
    • Mild cough

Epidemiology

  1. In the United States, by 1 year of age 50% of children and by age 6 almost all children have been infected with HPIV-3.
  2. 80% of children have antibodies for HPIV-1 and HPIV-2 by age 10.
  3. Although HPIV-4 causes few clinical illnesses, 70%–80% of children have antibodies by age 10.
  4. Morbidity and mortality rates are higher in developing countries.

Diagnosis

  • Isolation and identification of the virus in cell culture
  • Direct detection of the virus in respiratory secretions by ELISA or PCR
  • IgM antibodies
  • A significant increase in IgG antibodies between collected paired serum specimens
  • X-rays of the neck or chest are important if epiglottitis, croup, or pneumonia is suspected.
    • In croup, the “steeple sign” is seen on a chest X-ray; this formation is caused by subglottic swelling with narrowing of the trachea.
    • In epiglottitis, the “thumb sign” is seen on lateral neck views; the condition is due to enlargement of the epiglottis and ballooning of the hypopharynx.
Steeple Sign

Chest X-ray showing subglottic stenosis, known as steeple sign (between red arrows)

Image: “Steeple sign” by Jayshil J. Patel, Emily Kitchin, and Kurt Pfeifer. License: CC BY 4.0

Management

Management depends on the severity of the disease.

Mild croup:

  • Supportive care
  • Cool blow-by oxygen mist
  • Fever control

Moderate croup:

  • Cool oxygen mist
  • Corticosteroids for the airway inflammation
  • Racemic epinephrine with a nebulizer
  • IV fluids for hydration

Severe croup:

  • Observe the patient for signs of impending respiratory failure (e.g., retractions, tachypnea, altered mental status).
  • Repeat racemic epinephrine nebulization.
  • Intensive care monitoring
  • Endotracheal intubation may be required in patients with severe respiratory obstruction from swelling.
  • Indications for hospitalization:
    • Respiratory distress
    • Dehydration
    • Hypoxia
    • Stridor at rest, after receiving therapy
    • Need for repeated doses of racemic epinephrine
    • Rebound laryngospasm in patients who receive racemic epinephrine

Clinical Relevance

  • Croup: also known as laryngotracheobronchitis: Croup is a disease that leads to severe inflammation of the upper airway, and it usually presents in children < 5 years of age. Patients develop a hoarse, “seal-like” barking cough and inspiratory stridor. Human parainfluenza viruses account for the majority of cases, followed by RSV, adenovirus, rhinovirus, and enteroviruses. Croup is usually diagnosed clinically or with X-ray imaging (steeple sign). Management consists of steroids and epinephrine.
  • Acute bronchiolitis: respiratory condition caused by 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, wheezing, crackles, and hypoxia. Diagnosis is clinical, and treatment is directed at improving oxygenation and hydration. The disease is self-limited and has a good prognosis with appropriate management.
  • Pneumonia: infection of the lower respiratory tract that results in air sacs filling with fluid or pus. Symptoms of pneumonia include cough with phlegm, fever, chills, and difficulty breathing. For management of bacterial causes, antibiotics are indicated. Some forms of pneumonia can be prevented by vaccines.

References:

  1. Ison, M. (2020). Parainfluenza viruses in adults. UpToDate. Retrieved February 8, 2021, from: https://www.uptodate.com/contents/parainfluenza-viruses-in-adults
  2. Munoz, F. (2020). Parainfluenza viruses in children. UpToDate. Retrieved February 8, 2021, from: https://www.uptodate.com/contents/parainfluenza-viruses-in-children#H14
  3. Parijua, S. (2020). Human parainfluenza viruses (HPIV) and other parainfluenza viruses treatment & management. Emedicine. Retrieved February 8, 2021, from: https://emedicine.medscape.com/article/224708-treatment#d9

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