Parainfluenza Virus 

Parainfluenza viruses (PIVs) are paramyxoviruses. Over the last decade, both the nomenclature and the taxonomic relationships of human parainfluenza viruses (HPIVs) have changed considerably.

The first HPIV discovered was the Sendai virus in 1952 in Japan. In 1955, HPIV type 2 (HPIV-2) was isolated from children with acute laryngotracheobronchitis (croup), and, in 1985, HPIV type 3 (HPIV-3) was isolated from children with respiratory tract infection. In 1960, HPIV type 4 (HPIV-4) was isolated from children with mild respiratory tract infections. HPIV-4 consists of A and B subtypes. Thus, HPIVs are now classified under 2 genera: the genus Respirovirus (HPIV-1, HPIV-3) and the genus Rubulavirus (HPIV-2, HPIV-4).

HPIVs are pathogens that primarily affect young children, in whom the pathogenic spectrum includes upper and lower respiratory tract infections. HPIVs are responsible for 30%-40% of all acute respiratory tract infections in infants and children. These conditions include common cold with fever, croup, bronchiolitis, and pneumonia. HPIVs are also a cause of community-acquired respiratory tract infections of variable severity in adults. HPIV-1 is most commonly associated with croup. HPIV-2 is also associated with croup. HPIV-3 is second only to respiratory syncytial virus (RSV) as a cause of pneumonia and bronchiolitis in infants and young children. HPIV-4 is detected in patients less often, perhaps because HPIV-4 causes less-severe disease.

Reinfection with HPIV can occur throughout life, with elderly and immunocompromised persons being at a greater risk for serious complications of infections.

The seasonal patterns of HPIV-1, HPIV-2, and HPIV-3 are curiously interactive. HPIV-1 causes the largest, most defined outbreaks, which are marked by sharp biennial rises in croup cases in the autumn of odd-numbered years. Outbreaks of infection with HPIV-2, although erratic, usually follow HPIV-1 outbreaks. Outbreaks of HPIV-3 infections occur yearly, mainly in spring and summer, and last longer than outbreaks of HPIV-1 and HPIV-2. HPIV-4 is infrequently isolated and, hence, relatively unknown and uncharacterized.^[1]

The following are clinical conditions caused by the various HPIV types:

• Croup - HPIV-1, HPIV-2, HPIV-3
• Bronchitis - HPIV-1, HPIV-3
• Bronchopneumonia - HPIV-1, HPIV-3
• Minor upper respiratory tract disease - HPIV-1, HPIV-3, HPIV-4
• Pneumonia and bronchiolitis - HPIV1, HPIV3

In recent years, various aspects of the viruses, such as genomic organization, replication, and host immunity evasion mechanisms have been the subjects of intense study, as this knowledge will be crucial for development of intervening strategies (including vaccines) in the future.

Taxonomy

As noted above, the taxonomy of HPIVs has recently changed. HPIVs are now composed of 5 serotypes—HPIV-1, HPIV-2, HPIV-3, HPIV-4a, and HPIV-4b. These serotypes display substantial serologic cross-reactivity. Presently, these viruses are included in the order Mononegavirales, the family Paramyxoviridae, and the subfamily Paramyxovirinae . They belong to 2 different genera: HPIV-1 and HPIV-3 belong to the Respirovirus genus, and HPIV-2 and HPIV-4 belong to the Rubulavirus genus. HPIV-4 has two serotypes (a and b) that are differentiated based on the hemadsorption inhibition pattern and monoclonal antibody reactivity.^[2]

Structural organization

HPIVs are pleomorphic viruses whose envelope is derived from the host cell they last infected. These viruses are 150-300 nm in diameter and possess a single-stranded, nonsegmented, negative-sense RNA genome with nucleoprotein P and L proteins. The HPIV genome contains approximately 15,000-16,000 nucleotides. These are organized to encode at least 6 common structural proteins. A lipid bilayer covered with glycoprotein spikes surrounds a helical nucleocapsid that measures 12-17 nm in diameter and matrix protein resides between the core and the envelope. These glycoproteins are hemagglutinin-neuraminidase (HN) and fusion (F) proteins, which play a major role in the pathogenesis of the disease caused by the viruses.

Pathogenesis

Viral transmission occurs via direct inoculation of contagious secretions from the hands or via large-particle aerosols into the eyes and nose. Prolonged survival of HPIV on skin, cloth, and other objects emphasizes the importance of fomites in nosocomial spread. Respiratory epithelium appears to be the major site of virus binding and subsequent infection. The viruses attach to the host cells through hemagglutinin, which specifically combines with neuraminic acid receptors in the host cells. Subsequently, the viruses enter the cell via fusion with the cell membrane mediated by F1 and F2 receptors.

When HPIV infects a cell, the first observable morphologic changes may include focal rounding and growing of the cytoplasm and nucleus and decreased host-cell mitotic activity. Other observable changes include single or multilocular cytoplasmic vacuoles, basophilic or eosinophilic inclusions, and formation of multinucleated giant cells. These giant cells (fusion cells) usually develop late in the infection, and each giant cell contains between 2 and 7 nuclei.

Mechanisms of airway inflammation

HPIV infection in the respiratory tract leads to secretion of high levels of inflammatory cytokines such as interferon (IFN)–alpha, interleukin (IL)–2, IL-6, and tumor necrosis factor (TNF)–alpha. The peak duration of secretion is 7-10 days after initial exposure. Increasing levels of certain chemokines such as RANTES (regulated upon activation, normal T-cell expressed and secreted) and macrophage inflammatory protein (MIP)–K are detected in the nasal secretion of pediatric patients. These are responsible for pathological changes in the respiratory tract and clinical manifestations of this condition.

Studies have shown a possible role of virus-specific immunoglobulin E (IgE) antibodies earlier and in larger amounts in patients with HPIV upper respiratory tract illness than in age-matched controls. Faster and increased production of this virus-specific IgE mediates histamine release in the trachea and the subglottic region, in turn producing croup.^[3]

The chief pathological features include airway inflammation, necrosis and sloughing of respiratory epithelium, edema, excessive mucus production, and interstitial infiltration of lung. Edema of the mucus layer causes swelling in the vocal cords, larynx, trachea, and bronchi. These changes lead to obstruction of the airway inflow and subsequent stridor, which is characteristic of croup.

In animal models, increased levels of histamine and eosinophils are detected in bronchoalveolar lavage (BAL) samples following infection with HPIV, suggesting a state of hyperresponsiveness of the respiratory tract.

HPIV-2 and HPIV-3 infection in humans is known to induce expression of intercellular adhesion molecule-1 (ICAM-1) in tracheal and other cells of the respiratory tract. These molecules serve as receptors for rhinoviruses, thus paving the way for rhinoviral superinfection.

The virus continues to be excreted in respiratory exudates for 3-16 days following primary infection and 1-4 days following infection.

Immunology

Host defense against HPIVs is mediated largely by humoral immunity to both surface glycol proteins of the virus—HN and F. Most children are born with neutralizing antibodies to all 4 types of HPIV, but these titers quickly fall during the first 6 months of life. Most antibody response appears to involve serum immunoglobulin G1 (IgG1), but levels of serum immunoglobulin G3 (IgG3), immunoglobulin G4 (IgG4), serum immunoglobulin A (IgA), and immunoglobulin M (IgM) rise significantly in 30% of adults. Secretory IgA plays an important but not fully defined role in the protection against natural HPIV infections. A cell-mediated immune response to HPIV antigens, in addition to an HPIV-specific IgE response, has been documented to be greater among infants with HPIV bronchiolitis than among infants who developed only upper respiratory tract illness.^[3]

After natural infection with HPIV, most children and adults develop measurable levels of these antibodies in the serum; these antibodies have been shown to be correlated with disease prevention and amelioration in adults. Local interferon production has been noted in about 30% of children with HPIV infection. Although immunity to HPIV infection is long-lasting, reinfection may occur many times throughout life and at variable intervals, even in the presence of neutralizing antibodies. This cannot be explained merely based on the relatively stable antigenic determinants of HPIVs; thus, more research is needed.

In recent years, interesting facts regarding cell-mediated immunity have emerged. HPIV infections tend to be more severe in individuals with defective cell-mediated immunity, indicating that T cells may have a greater role in containing the disease.

Epidemiology

Respiratory secretions from infected humans are the source of infection. Transmission is via respiratory droplets or via direct person-to-person contact with infected secretions. The inoculating dose is very small.

HPIVs are common community-acquired respiratory pathogens without ethnic, socioeconomic, gender, age, or geographic boundaries. Many factors have been found that predispose individuals to these infections, including malnutrition, overcrowding, vitamin A deficiency, lack of breastfeeding, and environmental smoke or toxins.

Frequency

United States

Infections with HPIV-1 and HPIV-2 occur during autumn months. Infections with HPIV-3 occur throughout the year but appear to peak in the spring. HPIV-3 is the second most common cause of lower respiratory tract infections treated in the United States, second only to RSV. HPIV-4 infection patterns are not well-defined.

HPIV-3 infections occur earliest and most frequently. Based on seroepidemiological studies, 50% of US children aged 1 year and almost all US children aged 6 years have been infected by HPIV-3 . Antibodies against HPIV-1 and HPIV-2 develop less rapidly, but 80% of children have antibodies against these types by age 10 years. HPIV-4 induces few clinical illnesses, but infections with this type are common nonetheless, as 70-80% of children aged 10 years have antibodies against HPIV-4.

International

Internationally, HPIV-1, HPIV-2, HPIV-3, and HPIV-4 have worldwide distribution, and epidemics are known to occur, particularly with HPIV-1.

Parainfluenza viruses are responsible for disease throughout the year, but winter outbreaks of respiratory tract infections, especially croup, in children throughout the temperate zones of the northern and southern hemispheres represent peak periods of prevalence. Most infections are endemic, but sharp small epidemics involving HPIV-1 and HPIV-2 occasionally occur. The first reported outbreak of HPIV-4 infection occurred in Hong Kong in autumn of 2004. The outbreak involved 38 institutionalized children and 3 staff members during a 3-week period in a developmental disabilities unit.^[2]

Mortality/Morbidity

Mortality induced by HPIV is unusual in developed countries and occurs almost exclusively in young infants or immunocompromised or elderly people. However, the preschool population in developing countries is at considerable risk for HPIV-induced death. Whether because of primary viral disease or because of facilitating secondary bacterial infections in malnourished children, lower respiratory tract infection causes 25-30% of the death in this age group, and HPIV causes at least 10% of lower respiratory tract infections.

Race

HPIVs have no predilection for any race.

Sex

HPIVs have no predilection for either sex.

Age

HPIV-1 can cause lower respiratory tract infection in young infants but is rare in those younger than 1 month. The full burden of HPIV-1 in adults and elderly persons has not been determined, but studies have shown that this virus causes yearly hospitalizations in healthy adults and may play a role in bacterial pneumonias and death in nursing-home residents.

HPIV-2 accounts for 60% of all infections that develop in children younger than 5 years, with peak incidence between ages 1 and 2 years.

Young infants (< 6 mo) are particularly vulnerable to infection with HPIV-3. Unlike other HPIVs, 40% of HPIV-3 infections occur in the first year of life.