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Parainfluenza viruses in children

Author:

Flor M Munoz, MD, MSc

Section Editors:

Morven S Edwards, MD

George B Mallory, MD

Deputy Editor:

Mary M Torchia, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2016. | This topic last updated: Jul 06, 2016.

INTRODUCTION — Human parainfluenza viruses are important respiratory pathogens in children and adults. In infants and young children, parainfluenza viruses are the most common cause of lower respiratory tract infections after respiratory syncytial virus (RSV) [1-4]. Lower respiratory infections (eg, bronchiolitis, interstitial pneumonitis, pneumonia) are a leading cause of morbidity and mortality in infants during the first year of life in the United States and in children younger than the age of six years in developing countries [1]. In adults, parainfluenza viruses generally cause mild upper respiratory infections (URIs) but can induce more severe disease in the elderly [5]. Immunocompromised patients, particularly lung and hematopoietic cell transplant recipients can experience life-threatening lower respiratory tract infections with parainfluenza virus [6-8].

The virology, clinical manifestations, diagnosis, and treatment of parainfluenza viruses in children will be reviewed here. Infection with parainfluenza viruses in adults is discussed separately. (See "Parainfluenza viruses in adults".)

MICROBIOLOGY

Virus — Parainfluenza viruses (PIV) are single-stranded, enveloped RNA viruses belonging to the genus paramyxovirus in the Paramyxoviridae family [9]. This family also includes human mumps, measles, and respiratory syncytial viruses and metapneumoviruses, as well as avian, bovine, and murine strains of these viruses.

The virions are pleomorphic and range in diameter from 150 to 200 nm. The single strand of negative-sense RNA is 15,462 nucleotides in length and encodes six common viral proteins: the nucleocapsid protein (NP), the phosphoprotein (P), the matrix protein (M), the fusion glycoprotein (F), the hemagglutinin-neuraminidase glycoprotein (HN), and the RNA polymerase (L) [10].

●The HN and F proteins project through the lipid envelope and form the major antigenic targets for neutralizing antibody [11]. Their hydrophobic tails project into the virion, where they interact with the M protein to aid in virus assembly [12].

●The nucleocapsid core is composed of NP, P, and L proteins in association with viral RNA. NP proteins bind tightly to the viral genome, creating a template for the RNA-dependent RNA polymerase composed of the P and L proteins [13].

The HN glycoproteins are involved in attachment of the virus to the host cell via interactions with sialic acid residues on the cell surface [14]. This interaction allows the F protein to mediate virus-cell membrane fusion, which is required for nucleocapsid entry and infection of the host cell. The neuraminidase portion of the HN protein [14] mediates budding of progeny virions from the surface of infected cells [15].

In addition, each parainfluenza virus expresses at least one non-essential protein: PIV1 and PIV3 RNA encode short C proteins, PIV2 RNA encodes a V protein, and PIV 3 also expresses a D protein. The C and V proteins inhibit the host innate immune response (host cell antiviral responses) by suppressing the activity of type I interferons; the function of the D protein is unknown [16,17].

Viral serotypes — Four major serotypes of human PIV (PIV-1, 2, 3, 4) have been described based upon complement fixation and hemagglutinating antigens [18]. Parainfluenza virus 5 (PIV-5) causes disease in animals (dogs, cats, pigs) but its role in human disease remains controversial [19].

PIV-3 is the most prevalent serotype, with 90 to 100 percent of children demonstrating antibody responses by age five [20]. In contrast, PIV-1 and PIV-2 infections are less common, with only 50 to 74 percent of five-year-olds demonstrating seropositivity. Fifty percent of six-year-old children and 70 to 90 percent of young adults have antibodies to PIV-4, despite the fact that infection is infrequently recognized [21,22]. PIV-1 particularly and PIV-2 are associated with croup in children, whereas PIV-3 is frequently associated with pneumonia and bronchiolitis in young infants. PIV-4 typically causes mild upper respiratory infection (URI) in both adults and children, but pneumonia and bronchiolitis have been described in infants and in children with underlying conditions [22-25]. (See 'Pathogenesis' below.)

PATHOGENESIS — Parainfluenza viruses (PIV) initially infect epithelial cells of the nose and oropharynx [26] and then spread distally to the ciliated and alveolar cells of the bronchial epithelium of large and small airways [27]. Significant viral replication is seen in the nose and lungs 24 hours after infection, with viral replication peaking after two to five days [28]. Viral antigen can be detected in the apical portion of respiratory epithelial cells from days one to six of infection, with a decrease on day seven [29].

The extent of infection correlates well with disease: mild upper respiratory infections (URIs) are associated with limited infection of the nasopharynx, whereas more severe disease involves spread of infection to the large and small airways [30]. PIV-1 and PIV-2, which are associated with croup, tend to infect the larynx and upper trachea, whereas PIV-3, which is associated with bronchiolitis and pneumonia, infects the distal airways [28]. Progression to the lower respiratory tract and severity of disease depend upon factors such as virus titer in the upper respiratory tract, previous exposure to the specific virus, and genetic susceptibility [9,31,32].

Pathologic examination of infected tissues in animal models of PIV infection suggests that minimal cellular or tissue damage is caused by direct viral effects [29]. Similarly, PIV infection does not result in extensive cytopathic effect in in vitro models of respiratory airway epithelium [16,27,33]. As is the case with other respiratory viruses, the host immune response plays an important role in the pathogenesis of PIV infection. PIV induces innate immune responses, CD8+ and CD4+ T cell responses, interferon production, and local and systemic immunoglobulin A (IgA) and IgG responses, which contribute to the clearing of the virus [28,34]. The increase in airway responsiveness that often is associated with PIV-3 infection (and other respiratory viruses, such as respiratory syncytial virus [RSV]) may result from IgE, increased stromal interleukin-11 production and enhanced acetylcholine release [35-37]. Preliminary experiments in animal models of infection suggest that a "two-pronged" approach to therapy, antiviral and anti-inflammatory, may be useful in PIV-related illness [38].

NATURAL IMMUNITY — Natural immunity to parainfluenza virus is incomplete, and reinfection is common; however, reinfections tend to be milder than initial infection and restricted to the upper respiratory tract [39]. Antibodies are produced to all viral proteins, although only antibodies to the surface proteins, HN and F, are neutralizing [9]. T cell immunity contributes to viral clearance and confers transient resistance to reinfection, albeit short lived [16,40].

EPIDEMIOLOGY

Transmission — Parainfluenza viruses (PIV) are transmitted by direct person-to-person contact and through exposure to contaminated nasopharyngeal secretions through respiratory droplets and fomites [41].

Incubation period — The incubation period ranges from two to six days [41].

Prevalence — Human PIV are recovered most commonly in children younger than five years of age with upper respiratory infections (URIs) [3,42]. Serologic studies have shown that as many as 50 percent of children have been infected with PIV-3 by their first birthday, whereas PIV-1 and PIV-2 most often affect preschool-aged children three to five years of age [43].

In population-based surveillance, PIV-1, 2, or 3 were identified in 8 percent of 7716 specimens obtained from pediatric outpatients with influenza-like illness between August 2010 and July 2014 [42]. Among these, 30 percent were PIV-1, 26 percent PIV-2, and 44 percent PIV-3. The annual incidence of each serotype varied between 88 and 100 per 100,000 children. In children younger than five years, the incidence of PIV was 259 to 1307 per 100,000. The median age at detection was lower for PIV-3 (3.4 years) than for PIV-1 (4.5 years) and PIV-2 (7.0 years).

PIV infections account for 20 to 40 percent of lower respiratory tract illnesses (eg, bronchiolitis, pneumonia) in children from which a virus is recoverable, and 2.8 per 1000 children with such infections require hospitalization [44]. PIV is responsible for approximately 30,000 (range 7600 to 48,000) pediatric hospitalizations annually in the United States [45]. A study based upon the National Hospital Discharge survey from 1994 through 1997 estimated hospitalization rates due to PIV-1 to 3 to range from 1.9 to 12 per 1000 children younger than one year and from 0.5 to 2.0 per 1000 children ages one to four years [46]. The highest overall hospitalization rates were for PIV-3, estimated at 0.48 to 2.6 per 1000 children. A population-based study in the United States (2000 to 2004) estimated that PIV accounts for up to 7 percent of all hospitalizations for fever, acute respiratory illness, or both in children younger than five years of age [3]; PIV3 is the cause of one-half of these hospitalizations. Data from the National Respiratory and Enteric Virus Surveillance System (NREVSS, 1998-2010) indicate an annual estimated PIV-associated hospitalization rate of 0.2 per 1000 children for bronchiolitis, 0.4 per 1000 children for croup, and 0.5 per 1000 children for pneumonia [47].The majority of PIV-associated hospitalizations occurred in children younger than two years.

PIV infections occur throughout the world and throughout the year, with certain serotypes predominating during the spring or fall. PIV-1 usually causes outbreaks biennially during the fall of odd-numbered years (figure 1) [48,49]. In contrast, PIV-2 and PIV-3 occur in annual epidemics in the fall and spring, respectively [48]. During years in which PIV-1 is not circulating, there is an increase in PIV-3 activity, manifested either as a longer spring PIV-3 season or as a second smaller peak in the fall. Seasonal patterns of PIV-4 infections have not been established, since the disease is usually mild, and the virus is difficult to detect. However, it is diagnosed more frequently between October and January [23]. In tropical countries, parainfluenza viruses do not exhibit seasonal variation [50].

Ethnicity and sex may play roles in the severity of PIV infection. Bronchiolitis occurs most commonly in non-Caucasian males [30]. Breast-fed infants have a reduced risk of serious infection. Spread within families is extensive, requiring only direct person-to-person contact or large droplet inhalation [51].

Pneumococcal vaccination has been associated with a reduction in the incidence of pneumonia in infants with PIV and other respiratory virus infections [52]. This observation suggests that the pneumococcus is an important pathogen in virus-associated pneumonia. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children".)

CLINICAL PRESENTATION — Parainfluenza viruses (PIV) cause a variety of upper and lower respiratory tract illnesses, ranging from mild cold-like syndromes to life-threatening pneumonia; they cause a greater proportion of respiratory infections in outpatients than in hospitalized patients.

In children, more than 50 percent of PIV infections are upper respiratory infections (URIs), of which 30 to 50 percent are complicated by otitis media [44,53]; approximately 15 percent of PIV infections involve the lower respiratory tract. Strong relationships exist between PIV infection and specific clinical syndromes in children.

●PIV-1 is the leading cause of croup or laryngotracheobronchitis in children [1]. Children initially present with fever, rhinorrhea, and pharyngitis and progress to cough, often "barking" in nature, with stridor, dyspnea, and chest wall retractions. Respiratory distress requiring hospitalization can occur and, rarely, hypoxemia from viral involvement in the lung parenchyma is seen. (See "Croup: Clinical features, evaluation, and diagnosis", section on 'Clinical presentation'.)

●PIV-2 also is associated with croup, although the illness generally is milder than with PIV-1.

●PIV-3 is associated with pneumonia and bronchiolitis in the first six months of life, mimicking respiratory syncytial virus (RSV) infection. (See "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Respiratory disease'.)

●PIV-4 typically causes only mild URI symptoms in both adults and children. However, PIV-4 has been isolated in cases of bronchiolitis, pneumonia, croup, apnea, and paroxysmal cough in young infants and in children with underlying conditions, such as developmental disabilities, chronic cardiopulmonary disease, or immunosuppression [23,24].

Otitis media and sinusitis can result from either primary viral infections or secondary bacterial superinfection. Nonrespiratory complications of PIV are rare but include meningitis [54], myocarditis and pericarditis [55], Guillain-Barré syndrome [56], and acute disseminated encephalomyelitis [57]. (See "Clinical manifestations and diagnosis of myocarditis in children" and "Guillain-Barré syndrome in adults: Treatment and prognosis" and"Viral meningitis: Clinical features and diagnosis in children", section on 'Clinical features'.)

Although most PIV infections are mild, severe disease can occur, particularly in immunocompromised patients. Immunocompromised children and adults, including those with human immunodeficiency virus (HIV) infection can progress from mild URI symptoms to severe pneumonia with prolonged viral shedding and dissemination [58-61]. Children with severe T cell deficiencies can succumb to fatal giant cell pneumonia after infection with PIV [62].

In a study of children with hematologic malignancies at a pediatric cancer center, PIV was the second most common respiratory viral infection after influenza, detected in 10 percent of children tested [63]. Ninety percent of PIV infections were community acquired. PIV 3 accounted for 61 percent of PIV infections. PIV infections were approximately four times more common in children with acute lymphoblastic leukemia than in those with other hematologic malignancies. Although most (80 percent) of children had upper respiratory tract illness, children who were young (median age 27 months) and presented with fever, severe neutropenia, or lymphopenia were at increased risk for lower respiratory tract infection.

In one report, 2.2 percent of 1253 children and adults who underwent bone marrow transplantation developed symptomatic PIV infection [64]. These patients are at particular risk of severe PIV-associated pneumonia, with prolonged shedding and mortality rates of up to 30 percent [62,64-70].

Solid organ transplant recipients are at an increased risk for pulmonary complications. Complications such as bronchiolitis obliterans, and acute and chronic rejection have been reported in lung transplant patients with PIV and other respiratory viral infections [6,71].

DIAGNOSIS — The diagnosis of parainfluenza virus (PIV) infection can be made clinically with a compatible presentation during an outbreak of PIV in the community. Laboratory confirmation may be useful in determining if a community outbreak exists or in excluding other infections in seriously ill patients.

When laboratory diagnosis is necessary, nasopharyngeal and/or oropharyngeal specimens can be obtained for polymerase chain reaction (PCR) as the preferred diagnostic test given its high sensitivity and rapid turn-around time. If PCR is not available, rapid antigen detection and viral culture may establish the diagnosis. Serology is not routinely used for the diagnosis of PIV.

PCR assays permit the detection of PIV and a number of respiratory viruses in nasopharyngeal and oropharyngeal secretions with reported sensitivities of 95 to 100 percent and excellent specificity [72-75]. Collection of paired oropharyngeal and nasopharyngeal samples may increase the sensitivity [76,77]. PCR increases the yield of detection of PIV-3 by 1.5-fold, compared with viral culture [78].

PIV also can be identified by culture from the nasopharynx (nasopharyngeal swabs, aspirates, or washes). Specimens should be placed in viral transport media and kept at 4ºC because the virus loses infectivity at room temperature [79]. Hemadsorption and immunofluorescence typing are routinely used for identification, as observed cytopathic effects can be variable.

Rapid antigen detection of PIV 1-3 by immunofluorescence is available with reported sensitivity that is generally lower than that of PCR [80-83].

Serologic testing also can be performed but is time-consuming and can be confounded by the presence of heterologous antibodies [21].

TREATMENT — There are no antiviral agents with proven efficacy for parainfluenza virus (PIV) infections, which are self-limited in most cases. Glucocorticoids and nebulized epinephrine may be used to treat croup (see "Croup: Approach to management"). The management of bronchiolitis is supportive. (See "Bronchiolitis in infants and children: Treatment; outcome; and prevention".)

Ribavirin and other agents that have been used to treat PIV in immunocompromised hosts are discussed separately. (See "Parainfluenza viruses in adults", section on 'Treatment'.)

Transplant recipients may benefit from reduction of immune suppression in addition to supportive care.

DAS181 is a sialidase fusion protein that cleaves the sialic acid containing receptors of PIV in respiratory cells. It has antiviral activity against influenza and parainfluenza viruses and has been reported to successfully treat PIV in patients with hematopoietic stem cell and lung transplantation [84-92]. In one report, four severely immunocompromised children who had received hematopoietic cell transplantation were treated with DAS181 for lower respiratory tract infection. Inhaled DAS181 was administered for 5 to 10 days. All patients tolerated the treatment well and had clinical improvement, with decreased oxygen requirement. Improvement in viral load was also documented [90]. DAS181 treatment of PIV in immunocompetent patients is being evaluated in a phase II clinical trial [93].

VACCINE DEVELOPMENT — There is no licensed vaccine for parainfluenza viruses (PIV) [10,94]. However, vaccine candidates are being studied in human populations, and a vaccine for use in infants, young children, and immunocompromised adults may be forthcoming.

Vaccine development began in the 1960s with the production of an inactivated mixture of PIV-1, -2, and -3. This vaccine produced variable antibody responses and did not protect against challenge [10]. Subunit vaccines containing purified HN and F glycoproteins of PIV were later shown to induce functional antibodies in animal models [10]. Using a different approach, a modified vaccinia recombinant, Ankara (MVA), expressing the HN or F protein of PIV-3 tested in non-human primates showed significant protection of the lower respiratory tract but failed to demonstrate significant upper respiratory tract protection against challenge with PIV-3 [95].

Several live attenuated intranasal vaccine candidates have been developed using cell culture passage or chemical mutagenesis for viral attenuation and reverse genetics technology:

●Bovine PIV-3 (BPIV-3), a virus that is antigenically related to human PIV-3 (hPIV-3), has been evaluated in clinical trials as a vaccine candidate to protect against PIV-3 in children and infants. However, seroconversion rates to hPIV-3 have been modest [94,96,97].

●Murine PIV (Sendai virus), another virus that is antigenically related to human PIV, has been evaluated in clinical trials as a nasally administered live attenuated xenotropic vaccine against human PIV-1, similar to the use of bovine PIV-3 [98].

●A live attenuated, cold-adapted PIV-3 vaccine candidate, hPIV-3-cp45, the cp45 derivative of the JS strain of wild-type human PIV-3, was developed in the 1990s. When administered intranasally, it provided almost complete protection against challenge with wild-type PIV-3 in both the upper and lower respiratory tracts in non-human primates [10]. HPIV-3-cp45 was found to be appropriately attenuated and immunogenic in children and infants as young as one month of age [99-101]. Similarly, this vaccine was found to be safe and immunogenic in a phase 2 trial of healthy seropositive and seronegative infants and children, with two or three doses needed to induce durable immunity [102]. A combined hPIV-3-cp45/respiratory syncytial virus (RSV) experimental vaccine has been studied in 6- to 18-month-old seronegative children, showing antibody responses similar to the monovalent vaccine components [103].

Reverse genetics technology has allowed the development of a cDNA derived recombinant virus rHPIV3-cp45 that is the focus of current clinical development [16]. The advantages of this technology include the ability to rapidly produce the vaccine virus with minimal risk of biologic contamination. Phase 1 and 2 clinical trials have shown that this live, attenuated recombinant rHPIV3-cp45 vaccine is well tolerated and immunogenic in infants 6 to 36 months of age, but a three dose regimen might be necessary to elicit protection in infants younger than 6 months of age [16,104,105].

To improve immunogenicity, two cDNA-derived chimeric bovine/human PIV3 virus (rB/HPIV3) constructs have been created by reverse genetics and tested in adults, and HPIV3 seropositive and seronegative infants and children, with promising results [106]. Chimeric rB/HPIV3 viruses modified to express the RSV F or both the F and G proteins are bivalent vaccine candidates currently undergoing testing in children to prevent RSV and PIV3 [107].

Through reverse genetics, several PIV-1 and PIV-2 candidate vaccines also have been developed and some are undergoing clinical testing [16,94,108-110]. A live-attenuated human PIV-1 vaccine (rHPIV-1/84/del170/942A) was studied in a phase I clinical trial, but insufficiently immunogenic in PIV-seronegative children [111]. A live attenuated recombinant bivalent PIV-1/RSV vaccine (rHPIV1-RSV-F) is undergoing preclinical evaluation [112].

SUMMARY AND RECOMMENDATIONS

●Parainfluenza viruses (PIV) are single-stranded, enveloped RNA viruses belonging to the genus paramyxovirus in the Paramyxoviridae family. Four major serotypes of human PIV (PIV-1, 2, 3, 4) have been described. (See 'Microbiology' above.)

●Parainfluenza viruses initially infect epithelial cells of the nose and oropharynx and then spread distally to the large and small airways. (See 'Pathogenesis' above.)

●PIV cause a variety of upper and lower respiratory tract illnesses, ranging from mild cold-like syndromes to life-threatening pneumonia. PIV-1 and PIV-2 are associated with croup and PIV-3 with pneumonia and bronchiolitis. PIV-4 typically causes mild upper respiratory infection, but pneumonia and bronchiolitis have been described in infants and in children with underlying conditions. Although most PIV infections are mild, serious complications can occur, particularly in immunocompromised patients. (See 'Clinical presentation'above.)

●The diagnosis of PIV infection can be made clinically with a compatible presentation during an outbreak of PIV in the community. Laboratory confirmation may be useful in determining if a community outbreak exists or in excluding other infections in seriously ill patients. (See 'Diagnosis' above.)

●There are no licensed antiviral agents with proven clinical efficacy for PIV infections. PIV infections are generally self-limited and treated with supportive measures. The management of specific clinical syndromes (eg, croup, bronchiolitis) is discussed separately. (See 'Treatment' above and "Croup: Approach to management" and "Bronchiolitis in infants and children: Treatment; outcome; and prevention".)

●Vaccine development is ongoing and the outlook is promising, given the availability of reverse genetics technology. (See 'Vaccine development' above.)

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