INTRODUCTION — Parainfluenza viruses (PIV) are important respiratory pathogens in children and adults. Parainfluenza viruses cause a variety of upper and lower respiratory tract illnesses, ranging from mild cold-like syndromes to life-threatening pneumonia, particularly in immunocompromised patients.
The virology, clinical manifestations, diagnosis, and treatment of PIV in children will be reviewed here. The clinical syndromes caused by PIV in children and PIV in adults are discussed separately:
VIROLOGY — Parainfluenza viruses (PIV) belong to the Paramyxoviridae family, which includes mumps, measles, and henipaviruses .
Four major human serotypes have been described based upon complement fixation and hemagglutinating antigens: PIV-1, PIV-2, PIV-3, and PIV-4 . PIV-1 and PIV-3 belong to the Respirovirus genus; PIV-2 and PIV-4 belong to the Rubulavirus genus . In national surveillance for PIV infections in children and adults, PIV-3 were detected most frequently (approximately 55 percent of PIV-positive tests), followed by PIV-1 (18 percent), PIV-2 (14 percent), and PIV-4 (13 percent) . The clinical manifestations vary with serotype. (See 'Clinical presentation' below.)
PIV are single stranded, enveloped RNA viruses . The virions are pleomorphic and range in diameter from 150 to 200 nm. The single strand of negative-sense RNA is approximately 15,500 nucleotides in length and encodes six structural viral proteins :
●The hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins project through the lipid envelope and form the major antigenic targets for neutralizing antibody . Their hydrophobic tails project into the virion, where they interact with the matrix (M) protein to aid in virus assembly .
●The nucleocapsid core is composed of the nucleocapsid protein (NP), the phosphoprotein (P), and RNA polymerase (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 .
Each PIV also expresses at least one nonessential protein [8,9]:
●PIV-1 and PIV-3 RNA encode short C proteins, which inhibit the host innate immune response; PIV-3 also expresses a D protein, the function of which is unknown.
●PIV-2 RNA encodes a V protein, which inhibits the host innate immune response.
PATHOGENESIS — Parainfluenza viruses (PIV) initially infect the epithelial cells of the nose and oropharynx  and can spread distally to the large and small airways . The extent of infection correlates with disease severity: Limited infection of the nasopharynx is associated with mild upper respiratory infection; spread of infection to the large and small airways is associated with more severe disease . Progression to the lower respiratory tract and severity of disease are related to virus load in the upper respiratory tract, previous exposure to the specific virus, and genetic susceptibility [4,13,14].
In an animal model, viral replication increases during the first day of infection and peaks at two to five days . Viral antigen was detected in respiratory epithelial cells from days 1 to 6 of infection, with a decrease on day 7 .
Direct viral effects of PIV appear to cause minimal cellular or tissue damage [8,11,16,17]. As with other respiratory viruses, the host immune response plays an important role in the pathogenesis of PIV infection. PIV induce innate immune responses, CD8+ and CD4+ T cell responses, interferon production, and local and systemic immunoglobulin (Ig)A and IgG responses, which contribute to the clearing of the virus [15,18]. The increase in airway responsiveness that often is associated with PIV-3 infection (and other respiratory viruses, such as respiratory syncytial virus) may result from IgE, increased stromal interleukin-11 production, and enhanced acetylcholine release [19-21].
NATURAL IMMUNITY — Natural immunity to parainfluenza virus is incomplete, and reinfection is common. In immunocompetent children, reinfections tend to be milder than initial infection and restricted to the upper respiratory tract .
Although antibodies are produced to all viral proteins, only antibodies to the surface proteins (ie, hemagglutinin-neuraminidase and fusion proteins) are neutralizing . T cell immunity contributes to viral clearance and confers transient resistance to reinfection [8,23].
Prevalence — Parainfluenza viruses (PIV) are most commonly recovered in children younger than five years of age with upper respiratory infections [24,25].
In surveillance in the United States from 1998 to 2010, the annual estimated PIV-associated hospitalization rates in children <5 years of age were 0.2 per 1000 children for bronchiolitis, 0.4 per 1000 children for croup, and 0.5 per 1000 children for pneumonia . The majority of PIV-associated hospitalizations occurred in children younger than two years.
In separate population-based studies, PIV accounted for 7 percent of pneumonia-related hospitalizations in children [24,27]. Most of the hospitalizations occurred in children younger than two years. PIV-3 accounted for approximately one-half of PIV-associated hospitalizations .
The age at first infection varies with serotype. In serologic studies, as many as 50 percent of children have been infected with PIV-3 by their first birthday . PIV-1, PIV-2, and PIV-4 typically affect children at three to five years of age [22,28-30].
Seasonality — PIV infections occur throughout the world and throughout the year. In tropical countries, PIV do not exhibit seasonal variation . In countries with temperate climates, certain serotypes predominate during the spring or fall [32,33].
●PIV-1 usually causes biennial outbreaks during the fall of odd-numbered years (figure 1).
●PIV-2 occurs in annual epidemics in the fall.
●PIV-3 occurs in annual epidemics in the spring.
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.
●PIV-4 is most commonly seen during the fall, peaking in winter of each year .
Transmission and incubation period — PIV are transmitted by direct person-to-person contact and exposure to aerosolized respiratory secretions and fomites . Spread within families is extensive .
The incubation period ranges from two to six days .
Risk and protective factors
●Risk factors for severe infection – Immunocompromised patients are at increased risk for severe infection; this includes children with:
•HIV infection .
•Severe T cell deficiencies .
•Hematologic malignancy (particularly acute lymphoblastic leukemia) and leukopenia [38-40].
In a retrospective study of children with hematologic malignancies, PIV were detected in 10 percent of children tested for respiratory infections (second only to influenza) ; 90 percent of PIV infections were community associated. PIV-3 accounted for 61 percent of PIV infections. Although 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.
•Hematopoietic cell transplantation recipients; these patients are at particular risk of severe PIV-associated pneumonia, with prolonged shedding and mortality rates of up to 30 percent [37,42-46].
•Solid organ transplant recipients.
In a multicenter retrospective study of acute respiratory virus infections in the six months after solid organ transplant, PIV occurred in 16 percent and was the third most frequently identified virus (following rhinovirus and respiratory syncytial virus) . PIV-related complications included fever, lower respiratory tract disease, and at least one death. Complications such as bronchiolitis obliterans and acute and chronic rejection have been reported in lung transplant patients with PIV and other respiratory viral infections [48,49].
●Protective factors – In observational studies, breastfeeding and pneumococcal vaccination have been associated with reduced risk of severe infection [12,50]. Pneumococcal vaccination has been associated with decreased risk of pneumonia in infants with PIV and other respiratory virus infections, suggesting that pneumococcus may play a role in the pathogenesis of virus-associated pneumonia. (See "Pneumococcal vaccination in children", section on 'Pneumonia and empyema'.)
Respiratory tract illness — 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 acute respiratory infections in outpatients than in hospitalized children. Immunocompromised patients are at increased risk for severe infection. (See 'Risk and protective factors' above.)
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 [51,52]. Approximately 15 percent of PIV infections in children involve the lower respiratory tract.
Specific PIV serotypes are strongly associated with certain clinical syndromes in children [53,54]:
●PIV-1 is the leading cause of laryngotracheitis (croup), which is characterized by hoarseness, barking cough, and stridor. (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, which is isolated from children more frequently than other serotypes [25,32], is associated with lower respiratory tract infection (eg, bronchiolitis, pneumonia), particularly in young infants. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Clinical features' and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation'.)
●PIV-4 typically causes only mild URI symptoms . 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 (eg, developmental disabilities, chronic cardiopulmonary disease, immunosuppression) [55-57].
In patients with underlying asthma, PIV may cause acute exacerbations that can be refractory to standard asthma therapy . (See "Role of viruses in wheezing and asthma: An overview", section on 'Specific viruses'.)
Otitis media and sinusitis can result from either primary viral infections or secondary bacterial superinfection. (See "Acute otitis media in children: Epidemiology, microbiology, and complications" and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis".)
Other manifestations — Nonrespiratory complications of PIV are rare but include:
●Myocarditis and pericarditis [60,61] (see "Clinical manifestations and diagnosis of myocarditis in children")
●Guillain-Barré syndrome  (see "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis")
●Acute disseminated encephalomyelitis [63,64] (see "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis")
DIAGNOSIS — Most immunocompetent children who present with clinical syndromes that typically are caused by parainfluenza viruses (PIV) or other respiratory viruses (eg, croup, bronchiolitis) do not require microbiologic testing. In these children, knowing the causative pathogen does not affect management.
Laboratory confirmation may be helpful in excluding other infections in children who are hospitalized with community-acquired pneumonia, seriously ill, and/or immunocompromised. In such patients, knowing the etiologic pathogen may affect management (eg, antimicrobial therapy). Laboratory confirmation also may be helpful in evaluating the possibility of a community outbreak.
When laboratory confirmation is necessary, detection of viral RNA with polymerase chain reaction (PCR) of nasopharyngeal and/or oropharyngeal specimens is the preferred diagnostic test . PCR has high sensitivity, high specificity, and rapid turn-around time . Some multiplex respiratory panels include PIV. Although PCR does not differentiate noninfectious genomic particles from infection, PIV are more frequently detected in children with acute respiratory symptoms than in children who are asymptomatic [66,67].
Multiplex PCR assays permit the detection of PIV and other respiratory viruses in nasopharyngeal and oropharyngeal secretions with reported sensitivities of 95 to 100 percent and specificity of >97 percent [1,65,68-71]. Collection of paired oropharyngeal and nasopharyngeal samples may increase the sensitivity [72,73]. The yield of detection of PIV-3 is greater with PCR than with viral culture .
If PCR is not available, rapid antigen detection or viral culture may establish the diagnosis.
●Rapid immunofluorescence antigen detection of PIV-1 to PIV-3 is specific, but the reported sensitivity is generally lower than that of PCR [75-78].
●Viral culture of nasopharyngeal samples (nasopharyngeal swabs, aspirates, or washes) is also available but not clinically practical because cell culture may take up to seven days . Specimens should be placed in viral transport media and kept at 4°C because the virus loses infectivity at room temperature . Hemadsorption and immunofluorescence typing are routinely used for identification, as observed cytopathic effects can be variable.
TREATMENT — Parainfluenza virus (PIV) infections usually are self-limited, and immunocompetent children are treated with supportive measures. There are no licensed antiviral agents with proven clinical efficacy.
Supportive care for specific clinical syndromes is discussed separately:
●Croup (see "Management of croup")
●Bronchiolitis (see "Bronchiolitis in infants and children: Treatment, outcome, and prevention")
●Community-acquired pneumonia (see "Community-acquired pneumonia in children: Outpatient treatment", section on 'Supportive care' and "Pneumonia in children: Inpatient treatment", section on 'Supportive care')
Immunocompromised patients (primarily hematopoietic transplant and solid organ transplant recipients) may benefit from reduction of immune suppression in addition to supportive care.
Although ribavirin inhibits PIV in in vitro studies, proven benefit in controlled trials is lacking. 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'.)
DAS181 (an inhaled sialidase fusion protein) is an investigational agent for the treatment of PIV infections. It cleaves the sialic acid containing receptors of PIV in respiratory cells. It has in vitro antiviral activity against influenza and PIV. In case reports and clinical trials, DAS181 has been reported to successfully treat PIV in patients with hematopoietic cell and lung transplantation and/or decrease viral load [80-87]. DAS181 has been evaluated for the treatment of PIV in children and adults who received it through compassionate use and in various clinical trials, but it is not available for clinical use [87-89].
●All patients – Hand hygiene, respiratory hygiene, and cough etiquette may help to prevent parainfluenza virus (PIV) transmission in all settings . (See "Infection control in the outpatient setting".)
●Children who are hospitalized – For infants and children who are hospitalized with documented PIV infection, contact precautions are recommended for the duration of illness (in addition to standard precautions) . (See "Infection prevention: Precautions for preventing transmission of infection".)
Pending results of microbiologic testing or if microbiologic testing is not performed, droplet precautions are also recommended; droplet precautions can be discontinued if influenza and adenovirus have been excluded . (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Droplet precautions'.)
Vaccine development — There is no licensed vaccine for PIV . However, studies of vaccine candidates are ongoing.
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 [91-93].
●Sendai virus (SeV) is a mouse PIV-1 candidate vaccine for hPIV-1, as well as a vector for other respiratory viruses [94,95]. An SeV-based vaccine carrying the respiratory syncytial virus (RSV) F gene demonstrated safety and transient viral genome detection in a phase 1 study in adults, an initial step toward developing a combination RSV and hPIV-1 vaccine for children .
●A live attenuated, cold-adapted PIV-3 vaccine candidate, hPIV-3-cp45, the cp45 derivative of the JS strain of wild-type hPIV-3, was safe and immunogenic in a phase 2 trial in healthy seropositive and seronegative infants and children . A combined hPIV-3-cp45/RSV experimental vaccine has been studied in 6- to 18-month-old seronegative children, showing antibody responses similar to the monovalent vaccine components .
●Reverse genetics technology has contributed to the development of additional vaccines with promising results, including a complementary DNA (cDNA) derived live attenuated recombinant virus vaccine, recombinant hPIV-3-cp45 [8,98], monovalent cDNA-derived chimeric B/hPIV-3 virus vaccine (rB/hPIV-3) , bivalent chimeric rB/hPIV-3 and RSV vaccine , and PIV-1 and PIV-2 vaccines [8,91,101-103].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Croup" and "Society guideline links: Bronchiolitis in infants and children" and "Society guideline links: Pediatric pneumonia".)
SUMMARY AND RECOMMENDATIONS
●Virology – Parainfluenza viruses (PIV) are single stranded, enveloped RNA viruses belonging to the Paramyxoviridae family. Four major serotypes of human PIV (PIV-1, PIV-2, PIV-3, PIV-4) have been described. (See 'Virology' above.)
●Natural immunity – Natural immunity to PIV is incomplete, and reinfection is common. In immunocompetent children, reinfections tend to be milder than initial infection. (See 'Natural immunity' above.)
●Epidemiology and transmission – PIV are most commonly recovered in children younger than five years of age with upper respiratory infections. Immunocompromised children are at increased risk for severe infection. (See 'Epidemiology' above.)
PIV are transmitted through direct person-to-person contact and exposure to aerosolized respiratory secretions and fomites. The incubation period ranges from two to six days. (See 'Transmission and incubation period' above.)
●Clinical presentation – 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 generally are associated with croup, PIV-3 with pneumonia and bronchiolitis, and PIV-4 with mild upper respiratory tract illness. (See 'Respiratory tract illness' above.)
●Laboratory confirmation – Most immunocompetent children who present with clinical syndromes that typically are caused by PIV or other respiratory viruses (eg, croup, bronchiolitis) do not require microbiologic testing. Laboratory confirmation may be helpful in excluding other infections in children who are hospitalized with community-acquired pneumonia, seriously ill, and/or immunocompromised. (See 'Diagnosis' above.)
When laboratory confirmation is necessary, detection of viral RNA with polymerase chain reaction (PCR) testing is preferred, given its high sensitivity, high specificity, and rapid turn-around time. If PCR is not available, rapid antigen detection or viral culture may establish the diagnosis. (See 'Diagnosis' above.)
●Management – PIV infections usually are self-limited, and immunocompetent children are treated with supportive measures. There are no licensed antiviral agents with proven clinical efficacy. Supportive care for children with specific clinical syndromes is discussed separately (see 'Treatment' above):
•Croup (see "Management of croup")
•Bronchiolitis (see "Bronchiolitis in infants and children: Treatment, outcome, and prevention")
•Community-acquired pneumonia (see "Community-acquired pneumonia in children: Outpatient treatment", section on 'Supportive care' and "Pneumonia in children: Inpatient treatment", section on 'Supportive care')