Parainfluenza Virus

Etiology

The parainfluenza viruses belong to the Paramyxoviridaie family.[1] It is genetically and antigenically divided into four main serotypes, numbered as HPIV-1 to HPIV-4, with further subtypes of HPIV-4a and HPIV-4b.[3] The human parainfluenza viruses 1 and 3 belong to the genus of Respirovirus, and the genus Rubulavirus includes HPIV-2 and 4.[1] HPIV-1 to HPIV-3 are one of the leading causes of lower respiratory infections in infants, young children, adults, the immunocompromised, and the elderly.[3]

The virions of the parainfluenza viruses are pleomorphic, in which diameter ranges from 150 to 200 micrometers.[1] These six proteins their RNA encodes for include:

• The nucleocapsid protein (NP)
• the phosphoprotein (P)
• the fusion glycoprotein (F)
• the matrix protein (M)
• The hemagglutinin-neuraminidase (HN) glycoprotein
• The RNA polymerase (L)[1]

HPIVs share similarities in their structural and biological characteristics, but each of them infects people at different ages and causes different symptoms and illnesses.[3]

Epidemiology

The human parainfluenza virus is a community-acquired respiratory pathogen, that has some predisposing factors including:

• Malnutrition
• Overcrowding
• Vitamin A deficiency
• Environmental smoke or toxins[3]

HPIVs are one of the main causes of hospitalization in children less than 5 years of age due to acute respiratory tract infection, with a rate accounting for up to 17% of hospitalizations.[5] Serological surveys have demonstrated that 60% of children infected with HPIV-3 are around 2 years of age, whereas for children around 4 years of age, the rate of HPIV-3 infection increases to up to 80%.[6] Co-infections of HPIV and other respiratory viruses are frequent and may cause a more serious, severe, and prolonged disease course.[5]

The seasonality of HPIV is specific to each of the four. HPIV-1 follows a biennial pattern, marked by a dramatic increase in cases in the months of September to December of odd-numbered years.[7][8] Biennial fall epidemics of HPIV-1 have been reported in many studies.[9] Outbreaks of HPIV-3 infections occur annually, primarily from April to June. During the even-numbered years, when HPIV-1 is not circulating, HPIV-3 often has a longer spring season that extends into the fall or a second increase in activity from November to December of that year. Outbreaks of HPIV-2, which are smaller in magnitude, occur biennially to alternate years with HPIV-1, or they can cause yearly outbreaks.[7][8][9] HPIV-4 is infrequently isolated with seasonality similar to that of HPIV-3.[7]

The parainfluenza virus spreads through direct person-to-person contact or from large droplets. Outbreaks can occur, for example, in nursing homes and daycare facilities.[1]

Pathophysiology

The pathogenesis of the parainfluenza virus consists of the host immune response and viral mechanisms.[7] The attachment and the fusion of the virus to the host cell are mediated by the virus surface proteins hemagglutinin-neuraminidase (HN) and fusion glycoproteins (F) with the sialic acid residues on the surface of host epithelial cells respectively.[1] Transcription and maturation are mediated by the actin and the cytoskeleton, which also play a role in the movement of viral glycoproteins towards the surface of the host cells.[3]

The HN protein cleaves the sialic acid residue and facilitates the release of new virions from the host cell.[1] The fusion glycoproteins, as well as the HN proteins, are the most important targets for neutralizing antibodies.[1] The inner surface of the virus envelope is covered by the matrix protein.[1] A template for the RNA-dependent RNA polymerase, containing the P and L proteins, is generated by binding and coating the viral RNA with the NP protein, to facilitate transcription, the P gene also encodes more nonessential viral replication proteins that vary among the four serotypes.[1] HPIV-2 RNA encodes a V protein, and HPIV-1 and HPIV-3 RNAs encode short C proteins, both of which decrease type 1 interferon activity of the host cell, which results in inhibiting the host immune response. The D protein is expressed by HPIV-3, but the relevance and function of it remain unclear. Replication occurs in the cytoplasm of the host cell, and the negative-sense RNA strands are then exported as a new virion.[1]

The infection with parainfluenza virus first starts at the pseudostratified mucociliary airway epithelium of the nose and oropharynx, then spreading to the large and small airways.[8] The attachment and the replication of the virus occur in the ciliated epithelial cells of the upper and lower respiratory tract, with peak replication 2 to 5 days after the initial infection.[1] The extent of infection and the severity of the disease correlates with the location, that is, mild symptoms are associated with upper respiratory tract infection, and more severe ones, croup, bronchiolitis, and pneumonia occur with infection in the distal airways or lower respiratory tract.[8] 

When the infection of epithelial cells of the small airways occurs, inflammatory infiltrates develop, and the host immune response is thought to contribute to disease pathogenesis.[1] The first morphologic changes seen when a cell is infected with the HPIV, are the cytoplasm and nucleus increasing in size, focal rounding, and the host cell mitotic activity is decreased as soon as 24 hours after inoculation of the HPIV.[3] Basophilic or eosinophilic inclusions can be found as well, as more changes, including single or multilocular cytoplasmic vacuoles and the formation of multinucleated giant cells, are noticed.[3] These giant cells are generally observed late in the infection, and they contain between two and seven nuclei. Paramyxoviruses are one family of pathogens that cause apoptosis in tissue culture cells.[3] 

HPIV usually causes a mild and rapidly repaired focal tissue destruction that may even be unnoticed.[3] Giant-cell pneumonia can lead to death in immunocompromised hosts.[3] Viremia and infection beyond the respiratory epithelium can also cause death, although they are rare and typically only found in immunocompromised patients.[8]

History and Physical

Human parainfluenza virus is associated with upper and lower respiratory tract illnesses in all age groups, including:

• The common cold
• Croup
• Tracheobronchitis
• Bronchiolitis
• Pneumonia[6]

Exacerbations of underlying diseases are also frequent including:[8]

• Asthma
• Chronic obstructive pulmonary disease
• Congestive heart failure

These infections can be mild in healthy individuals, but they may lead to more serious respiratory illnesses in young age children and immunocompromised adults.[6]

Clinical presentation can differ by type; HPIV-1 and HPIV-2 are associated with croup and cold-like symptoms, while HPIV-3 often causes bronchiolitis and pneumonia. HPIV-4 is less well-characterized but has been suggested to have symptoms similar to HPIV-3.[8]

• Croup: Most children present with fever, inspiratory stridor, a hoarse barking cough, as well as laryngeal obstruction. Some of the lower airway signs, such as wheezing and air trapping, also occur.[1][3] The subglottic region of the trachea is encircled by the cricoid cartilage, which is less distensible than other parts of the trachea and makes it more prone to inflammatory obstruction, which involves both the larynx and this subglottic region. The inflammation then extends lower into the bronchi causing the croup, otherwise known as laryngotracheobronchitis.[1] On chest or neck radiographs, the croup's characteristic sign called the “steeple sign” can be seen.[1]

• Bronchiolitis: Due to the infant's terminal airways being so small, bronchiolitis is observed only in infants and young children.[3] The typical illness starts 1 to 3 days before the onset of lower respiratory signs and symptoms. It starts with a fever, and nasal congestion then spreads to the lower respiratory tract, causing cough, rales, tachypnea, and chest wall retractions. The median duration of symptoms is from 8 to 15 days, and most healthy children recover from bronchiolitis within 21 days.[1] It can be caused by all four types of HPIV, but most commonly is caused by HPIV-1 and HPIV-3. Both of the types can be the cause of bronchiolitis in 10% to 15% of nonhospitalized children. However, HPIV-1 causes fewer cases in hospitalized children compared to HPIV-3. Only second to the respiratory syncytial virus, parainfluenza virus is considered as one of the main causes of bronchiolitis and pneumonia in young infants.[3]

• Pneumonia: Pneumonia is one of the main causes of hospitalization among US adults.[8] Fever, cough, and rales are considered to be the main clinical symptoms present in children with pneumonia. In addition, infiltrates or consolidations are found on chest radiographs. Whereas all parainfluenza serotypes can be associated with pneumonia, HPIV1 and HPIV3 are more likely to cause it. HPIV-3 causes from 2% to 12% of pneumonia hospitalizations in children, while HPIV-1 causes from 1% to 6%.[1] Parainfluenza has been reported as the cause of 0.2%–11.5% of pneumonia-related adult hospitalizations.[8] Pneumonia was most common (10.5%) in patients more than 15 years of age, out of all hospitalized patients infected with HPIV.[8]

• Tracheobronchitis: Lower respiratory tract signs and symptoms that do not fit with the croup, bronchiolitis, or pneumonia often receive a diagnosis of tracheobronchitis.[3] In general, it is the inflammation of the lower and large airways.[1] It is mostly associated with cough and rhonchi on auscultation, but patients may also experience a fever and upper respiratory tract infection. 20% to 30% of children with lower respiratory tract infections are diagnosed with tracheobronchitis.[3]

Although HPIVs primary infection location is the respiratory tract, dissemination of the infection has been described, affecting other organ systems, including neurologic, renal, rheumatologic, and gastrointestinal tract.[9] Studies of infection of adults with HPIV demonstrated a high rate (75%) of asymptomatic shedding. In addition, a prolonged asymptomatic shedding period of HPIV-1 and HPIV-3 in healthy young adult males was found to continue for up to >8 months.[8]

Evaluation

Although human parainfluenza virus 1 (HPIV-1) is commonly associated with croup and may be diagnosed only based on clinical presentations, other HPIV serotypes do not have certain clinical features that allow them to be diagnosed clinically.[1] Therefore, laboratory testing is needed for a specific viral diagnosis.[1][3] When collecting swabs, it is recommended that flocked swabs be used in preference to cotton swabs due to enhanced yield.[1] Many types of samples are approved for testing, which include nasopharyngeal swabs, nasal aspiration and washes, nose and throat swabs, sputum, and bronchoalveolar lavage.[1] 

The timing of the sample collection is important. Early in the illness, it is more convenient to test samples from the upper airway, which have shown to be positive. Later in the illness, it is better to test secretions such as sputum and bronchoalveolar fluid from the lower airways.[1]

HPIV-3 has been isolated in children from as early as 6 days prior to 6 weeks past the first symptom. Immunocompromised patients and adults have been noted to shed HPIV-1, HPIV-2, and HPIV-3 for many months.[3]

• Viral culture: Considered for years to be the gold standard for diagnosis. The detection of hemadsorption (HAD) to the monolayers or the development of structural changes in host cells called cytopathic effect (CPE), the existence of either one of them is significantly important for viral isolation on the cell culture.[1] The hemadsorption and the CPE can be confirmed by the use of the fluorescent-labeled monoclonal antibodies (Mab) that are viral-specific.[1] Viral culture is rarely used as it is time-consuming and takes much more time for the results to be available.[2]

• Fluorescent antibody assays: As a rapid method of diagnosis, it has been used since the 1970s and is based on the identification of viral antigens directly on clinical samples.[1] For some viruses, there is a newly developed commercial colorimetric enzyme-linked immunoassays (EIAs), but unfortunately, for the parainfluenza virus, there is no availability in terms of a commercial rapid antigen test.[1] Specific immunofluorescent-labeled antibodies are possible for direct detection of HPIV 1–3 with sensitivities of 63 to 95%; yet, antibodies to HPIV-4 are not available.[1] Therefore, because of the narrowing of clinical features of the HPIV infection, clinical samples tested by the immunofluorescent assay (IFA) may be a logical alternative.[1]

• Molecular assays: Polymerase chain reaction (PCR) assays can be used easily and efficiently to detect and diagnose the HPIV infection. Based on the sensitivity, specificity, and rapidity of the PCR, it is the most accurate test for HPIV diagnosis.[1] Compared to viral culture and IFA testing, the PCR has been reported to have superior sensitivity and specificity. With the developed commercial assays being accessible, it became more widely available to use in clinical microbiology laboratories.[1]

• Serologic diagnosis: Rarely used in clinical practice and is primarily a research tool.[1]

Treatment / Management

Treatment of HPIV infection is basically symptomatic in healthy children and adults. Unfortunately, no antiviral agent with proven efficacy for human parainfluenza virus infection is available.[1]

Treatment of croup: Corticosteroids have been shown to be beneficial for mild and moderate to severe croup.[1] Corticosteroids may be administered orally or given intramuscularly, and both have been shown to be superior to inhaled therapy.[1] The dosing is a single dose of dexamethasone at 0.6 mg/kg, although lower doses have been proposed. Epinephrine can be used nebulized, which results in some relief of symptoms within 30 minutes, but treatment effects do not last for more than 2 hours. This treatment may be beneficial and cause some relief while waiting for the anti-inflammatory activity of steroid therapy to take effect.[1]

The exacerbation of chronic respiratory diseases caused by different viruses, including HPIVs, can be potentially prevented by early treatment with some of the antivirals. Although there is no effective antiviral treatment for HPIV in clinical practice, new strategies are being developed that may be practical and available for HPIV respiratory infections. The most direct approach consists of removing the sialic acid receptors, which are necessary for the attachment and fusion by the parainfluenza's HN and F proteins, thereby inhibiting the first step in infection. It is the DAS181, a recombinant sialidase protein, that has been proposed to inhibit HPIV infection effectively.[6] Peptide insertion into the cell membrane is also another therapeutic concept that can be used, which may allow the use of fusion-inhibitory peptides like peptides derived from the HR region, to inhibit the fusion of viruses to the host cells. It has been reported that the antiviral potency of a paramyxovirus HRC-derived peptide can be significantly increased by adding a cholesterol moiety.[6]

The most severe disease is found in immunocompromised patients, and treatment at present remains largely supportive.[6]

Differential Diagnosis

Viruses are the most common etiological agents of acute respiratory tract infection (ARTIs). HPIV shares practically the same signs and symptoms of respiratory tract infection with other bacterial and viral pathogens, which makes it more difficult to have a diagnosis based only on clinical features. Some of the common viral respiratory pathogens that are considered in the differential diagnoses of HPIV include:

• Respiratory syncytial virus
• Influenza types A and B
• Human rhinovirus
• Human metapneumovirus
• Adenoviruses
• WU polyomavirus
• Human bocavirus[4]

Prognosis

Parainfluenza viruses represent one of the main causes of respiratory viral infection. They can cause more severe and serious problems that may lead to death in immunocompromised patients than they do in the healthy general population.[10] Thus in healthy children and adults, HPIV infection has a better prognosis and outcome with only symptomatic treatment.[1] However, once viral replication and invasive infections take place in the immunocompromised population, it worsens the prognosis, which can be grave.[10] Therefore, early diagnosis and treatment of viral infections continue to be of supreme importance in immunocompromised patients.[10]

Complications

Infection with the human parainfluenza virus in immunocompromised and older patients is generally associated with a range of diseases, from mild upper respiratory tract symptoms to more severe diseases in the lower respiratory tract, which might require mechanical ventilation and can lead to death.[2] The infection with HPIV-3 is associated with more serious illness in immunocompromised patients, followed by HPIV-1 and HPIV-2; HPIV-4 is rarely associated with serious illness.[2]

Early childhood infection with the Paramyxoviridae family of viruses (especially respiratory syncytial virus and human parainfluenza virus) is strongly associated with the development of asthma and COPD later in life.[11]