key: cord-0010326-f6mpdo1o
authors: Branche, Angela R.; Falsey, Ann R.
title: Parainfluenza Virus Infection
date: 2016-08-03
journal: Semin Respir Crit Care Med
DOI: 10.1055/s-0036-1584798
sha: 97309ae72b08e072b58de042f1a0dd7f724279ee
doc_id: 10326
cord_uid: f6mpdo1o

Human parainfluenza viruses (HPIVs) are single-stranded, enveloped RNA viruses of the Paramyoviridaie family. There are four serotypes which cause respiratory illnesses in children and adults. HPIVs bind and replicate in the ciliated epithelial cells of the upper and lower respiratory tract and the extent of the infection correlates with the location involved. Seasonal HPIV epidemics result in a significant burden of disease in children and account for 40% of pediatric hospitalizations for lower respiratory tract illnesses (LRTIs) and 75% of croup cases. Parainfluenza viruses are associated with a wide spectrum of illnesses which include otitis media, pharyngitis, conjunctivitis, croup, tracheobronchitis, and pneumonia. Uncommon respiratory manifestations include apnea, bradycardia, parotitis, and respiratory distress syndrome and rarely disseminated infection. Immunity resulting from disease in childhood is incomplete and reinfection with HPIV accounts for 15% of respiratory illnesses in adults. Severe disease and fatal pneumonia may occur in elderly and immunocompromised adults. HPIV pneumonia in recipients of hematopoietic stem cell transplant (HSCT) is associated with 50% acute mortality and 75% mortality at 6 months. Though sensitive molecular diagnostics are available to rapidly diagnose HPIV infection, effective antiviral therapies are not available. Currently, treatment for HPIV infection is supportive with the exception of croup where the use of corticosteroids has been found to be beneficial. Several novel drugs including DAS181 appear promising in efforts to treat severe disease in immunocompromised patients, and vaccines to decrease the burden of disease in young children are in development.

HPIV4 subdivided into two genera (HPIV4a and HPIV4b). 11 HPIV1 and HPIV3 are members of the genus Respirovirus and the genus Rubulavirus includes HPIV2 and HPIV4. Parainfluenza virions are pleomorphic, ranging in diameter from 150 to 200 µm (►Fig. 1). 12, 13 They contain a single, negativesense RNA strand which encodes six essential proteins in a conserved order: the nucleocapsid protein (NP), the phosphoprotien (P), the matrix protein (M), the fusion glycoprotein (F), the hemagglutinin neuraminidase (HN) glycoprotein, and the RNA polymerase (L).

The HN and fusion glycoproteins are surface proteins which mediate attachment to the sialic acid residues on the surface of host epithelial cells (HN) and fusion of the viral envelope with the host cell membrane (F), respectively (►Fig. 2). 13, 14 The HN protein also facilitates release of new virions from the cell by cleaving the sialic acid residue. 15, 16 These two proteins are the major targets for neutralizing antibodies. The matrix protein coats the inner surface of the envelope. The NP protein binds and coats the viral RNA, creating a template for the RNA-dependent RNA polymerase, consisting of the P and L proteins, to facilitate transcription. The P gene also encodes additional proteins which vary among the four serotypes and are not essential for virus replication. 17 HPIV1 and HPIV3 RNAs encode short C proteins and HPIV2 RNA encodes a V protein both of which suppress the host immune response by decreasing type 1 interferon activity. A third nonessential protein, D protein, is expressed by HPIV3, though the relevance and function of this protein remains unclear. Replication occurs in the cytoplasm of the host cell and once produced the negative-sense RNA strands are packaged and exported as new virions.

The hemagglutinin neuramindase proteins are more stable for parainfluenza viruses compared with those of influenza A viruses. However, antigenic differences have been noted over time, producing strains serologically and genetically different from earlier isolates and impeding vaccine development. 11, [18] [19] [20] Pathogenesis Parainfluenza viruses bind and replicate in the ciliated epithelial cells of the upper and lower respiratory tract. 13, 21 Infection begins in the nose and oropharynx and then spreads to the lower airways with peak replication 2 to 5 days after initial infection. 22 The extent of infection correlates with location, that is, cold symptoms are associated with infection in the upper airways, infection of the larynx and trachea results in croup and bronchiolitis, and pneumonia occurs with replication in the distal airways. 23, 24 Once epithelial cells of the small airways become infected, inflammatory infiltrates develop and the host immune response is thought to contribute to disease pathogenesis. 25, 26 The classic signs of croup include hoarseness, cough, and stridor which are due to obstruction from inflammation of the subglottic region of the trachea (►Fig. 3). 27 This area is less distensible than other parts of the trachea because it is encircled by the cricoid cartilage. The impeded airflow produces the high pitched inspiratory vibrations known as stridor and increased work of breathing due to this obstruction may lead to fatigue and hypoxia and eventually respiratory failure in severe cases. Adult illness is generally mild, although airway hyper responsiveness may occur in persons with asthma due to release of cytokines and chemokines. 28 Immunology Host defense against HPIV is mediated by both humoral and cellular immunity. 11 Serum antibodies directed against the two surface glycoproteins, F and HN, are neutralizing and protective against challenge. 29, 30 Secretory immunoglobulin A (IgA) also develops after natural infection and has been shown to neutralize virus and ameliorate disease. 11 Neutralizing antibody appears to be serotype specific with little cross protection afforded by antibodies between HPIV serotypes 1 to 4. 31 Cytotoxic T lymphocyte responses are important for clearance of virus, and T cell epitopes have been demonstrated on the HN, P, and NP proteins of HPIV. 11, [32] [33] [34] Repeated infections are often needed to fully protect a child's lower respiratory tract from HPIV infection and eventual protection may be a combination of high levels of neutralizing antibody and cellular immunity. 11, 35 Immunity to HPIV is incomplete and reinfections with any of the HPIV serotypes can occur throughout life. 

HPIVs were first isolated from children with croup in 1955 and were referred to as croup-associated viruses. 36, 37 They have been shown to cause upper respiratory tract infection (URTI) in children and adults, and LRTI in children younger than 5 years and elderly or immunocompromised adults, demonstrating a distinctly bimodal pattern of age distribution. 38 Transmission occurs through direct person-to-person contact or from large droplets, and household outbreaks have been well described in the literature, as have outbreaks in nursing home and daycare facilities. 39 Parainfluenza virus infections occur throughout the world with seasonal variations in serotype-specific rates of infection which is determined by region. 38 Seasonal patterns of infection noted in the northern hemisphere are absent in tropical and subtropical regions with little variation in infection rates throughout the year. 40 In the United States, HPIV1 typically causes biennial outbreaks in odd-numbered years during the fall and may be responsible for 50% of croup cases in the United States during epidemic seasons (►Fig. 4). 3,6,11 Epidemics of HPIV2 infections occur annually in the fall and HPIV3, and the most prevalent serotype causes seasonal outbreaks in the spring, usually following influenza epidemics. 38 In years when HPIV1 is not actively circulating, a second smaller HPIV3 epidemic may occur in the fall. In contrast, the epidemiology of the HPIV4 infections has not been well studied with only few reports of small number viruses isolated from children and adults. [41] [42] [43] This is due to the fact that illness related to HPIV4 infection is often mild and subclinical and the virus more difficult to detect. 41, [43] [44] [45] Other trends in rates and severity of infection with HPIV have been described including reduced risk of severe illness in breast-fed infants and after pneumococcal vaccination. Increased risk of progressive to severe illness is noted in immunocompromised hosts, especially in those with hematologic malignancies, hematopoetic stem cell transplant (HSCT), or solid-organ transplantation. Additionally, socioeconomic factors such as malnutrition, overcrowding, vitamin A deficiency, and environmental smoke or toxins have also been shown to predispose children to HPIV infections. 11, [46] [47] [48] [49] Finally, gender and ethnicity also appear to play a role, as PIV-associated bronchiolitis reportedly occurs more often in nonwhite males.

Serotype prevalence: HPIV3 is the most commonly isolated serotype in symptomatic disease for both children and adults. 38 In the National Respiratory and Enteric Viruses Surveillance System study conducted from 1990 to 2004, HPIV3 was the most commonly identified serotype (52%), followed by HPIV1 (26%), HPIV2 (12%), and HPIV4 (2%). 38 Fig. 2 Cycle of attachment, fusion, and replication for parainfluenza viruses. The HN glycoproteins attach to sialic acid residues on the surface of host epithelial cells and fusion glycoprotein mediate fusion of the viral envelope with the host cell membrane. After attachment, the genetic material is uncoated and replication occurs in the cytoplasm of host cells. The NP protein binds the viral RNA, creating a template for the RNAdependent RNA polymerase, consisting of the P and L proteins. Once replication is completed, HN and F proteins are transferred to the host cell membrane which forms the envelope for new virons which is coated on the inner surface by the matrix protein. However, during epidemic years, HPIV1 is associated with significant disease burden and hospitalizations in children. 3,4,6,11,50,51 Moreover, several studies have demonstrated the importance of this virus as a cause of yearly hospitalizations in adults and nursing outbreaks associated with bacterial coinfection and fatal pneumonia. 52 Acquisition of HPIV3 usually occurs earliest in life with 50 and 92% of children infected by 1 and 3 years of age, respectively (►Fig. 5). 1,5 Primary infection with HPIV1 and HPIV2 occurs later in childhood (age 2-6 years).

Children: There are more than 5 million cases of children with LRTI in the United States each year, and HPIV accounts for 20 to 40% of these illnesses. 1,2,53 Population-based studies estimate 1.9 to 12 per 1,000 children younger than 1 year and 0.5 to 2.0 per 1,000 children aged 1 to 4 years are infected each year with HPIV. [54] [55] [56] In outpatient studies, HPIV accounts for approximately 17% of viral respiratory illnesses identified in children (18% of upper respiratory illnesses, >20% of LRTI, and >50% of croup cases). 5, 53 The U.S. 2000 Census estimates that rates of medically attended acute respiratory illness, LRTI, and hospitalization in children younger than 5 years associated with HPIV3 infection were 3.2 million, 1.1 million, and 29,000, respectively. 57 Other reports estimate 7,600 to 48,000 pediatric hospitalizations annually in the United States, and 7% of pediatric hospitalizations for febrile or respiratory illnesses in children younger than 5 years are due to HPIV. In composite, pediatric hospitalizations and emergency room visits due to HPIV constitute a cost of more than $200 million annually. 4

Adults: New molecular viral diagnostics have resulted in greater understanding of the impact of HPIV infections in adult populations and reinfection has been found to be common. 58-62 PIV infections account for 1 to 15% of respiratory illnesses in adults with infrequent reports of pneumonia in young adults and higher risk for severe disease in frail older adults. 38, 60 It is estimated that 2 to 11.5% of adult hospitalizations for respiratory illnesses are due to HPIV infection. 59, 61, [63] [64] [65] Furthermore, HPIV is frequently implicated in acute exacerbations of chronic obstructive pulmonary disease with HPIV usually the 2nd or 3rd most commonly detected virus (►Fig. 6). [66] [67] [68] [69] HPIV infection has also been reported in long-term care facilities with prospective studies documenting 4 to 14% of nursing home residents infected annually. Fatal bronchopneumonia is an infrequent but reported outcome in this population and has been associated with HPIV1 outbreaks. 52, 60, [70] [71] [72] [73] [74] [75] [76] During epidemic seasons, HPIV1 and HPIV3 outbreaks have been reported and with very high attack rates. 52, 73 One report from an Alabama nursing home described attack rates of 22 and 28% in residents and employees, respectively. 71 In an outbreak at a California state mental hospital, 56% of residents were infected. 71 Finally, severe LRTI disease and pneumonia have been reported in immunocompromised hosts, particularly patients with hematologic malignancies and HSCT recipients. Reports indicate an incidence of HPIV-associated respiratory illness in the HSCT population of 2 to 7%, with HPIV3 accounting for 90% of infections and nosocomial epidemics reported in bone marrow transplant wards during peak seasons. 7-10 Pneumonia has been reported in 24 to 55% of HSCT patients infected with HPIV and is associated with up to 50% acute mortality rate and 75% mortality rate at 6 months. 7,77-79 Though not as frequently reported in patients with solid-organ transplants, severe disease has also been documented in this population. HPIV infection may result in severe complications for lung transplant recipients including bronchiolitis obliterans, reduced lung function, and allograft rejection. [80] [81] [82] 

Parainfluenza viruses are associated with both upper and lower respiratory tract disease in children and adults, and the spectrum of illness typically includes otitis media, pharyngitis, conjunctivitis, croup, tracheobronchitis, and pneumonia. Uncommon respiratory manifestations include apnea, bradycardia, parotitis, and respiratory distress syndrome. Although HPIV primarily infects respiratory tissues, disseminated infection has been described as having a variety of illnesses affecting other organ systems, including neurologic, renal, and rheumatologic diseases.

Pediatric disease: In children, 40 to 60% of HPIV infections result in URTIs (colds and pharyngitis) and approximately 30 to 50% of these illnesses are complicated by otitis media. 5,53,83 URTI is the predominant presentation for all serotypes and less than 20% of HPIV infections result in lower respiratory tract disease other than croup.

HPIV1 and HPIV2 are the leading causes of croup, accounting for 60 to 75% of croup illnesses and contributing 27,000 to 66,000 pediatric hospitalizations yearly (►Fig. 7). 3-6, 53 Croup caused by HPIV2 is generally milder but can result in significant airway compromise and hospitalization. In contrast, HPIV3 infection is more commonly associated with LRTI than other serotypes causing bronchiolitis and pneumonia in neonates and infants with illness that is clinically indistinguishable from RSV infection. 84 Illness related to HPIV4 infection appears to be most commonly associated with URTI symptoms.

Croup (acute laryngotracheitis and acute laryngotracheobronchitis): The characteristic anatomic finding of croup is inflammation of the larynx and trachea otherwise known as laryngotracheitis. When inflammation extends into the bronchi (laryngotracheobronchitis), lower airway signs such as wheezing and air trapping also occur. These two terms are used interchangeably to represent croup disease and are often clinically indistinct. Extension of disease into the lower airways increases the risk for bacterial infection with typical respiratory pathogens (Staphylococcus aureus, Strepotococcus pneumonia, Morxaxella catarrhalis, and Haemophilus influenza) which may present as mucopurulent bacterial tracheitis or pneumonia.

Croup incidence peaks at 1 to 2 years of age and reports indicate that disease occurs more frequently in male children who have a 1.43 higher risk of having croup than their female counterparts, with the highest risk to boys noted between the ages of 6 and 12 months. 3 Epidemiological studies in Milwaukee have also reported increased risk for disease in white children compared with black children. Approximately 8 to 15% of children with croup will require hospitalization and 1 to 3% will require intubation. 55, [85] [86] [87] [88] Children with croup typically present initially with fever, hoarseness, and rhinorrhea with or without pharyngitis which progresses in 12 to 48 hours to the characteristic hoarse "barking" cough. Laryngeal obstruction follows in moderate to severe cases, manifested by inspiratory stridor. The characteristic "steeple sign" can be seen on chest or neck radiograph (►Fig. 8). As airway obstruction progresses, chest wall retractions are generally accompanied by worsening agitation and increased inspiratory effort which paradoxically exacerbates the obstructive process. Hypoxia, cyanosis, and respiratory fatigue may develop, requiring intubation which can rarely be fatal (<0.5% of intubated patients). 89 The diagnosis of croup is made clinically and severity measured by five clinical factors known as the Westley scale: mental status, the presence of absence of pallor or cyanosis, the presence of absence of inspiratory stridor at rest, the degree of chest wall retractions, and the amount of air entry (►Table 1). 90 Mild croup is characterized by the absence of stridor at rest and can often be managed symptomatically at home. In contrast, children with moderate to severe croup will present with inspiratory stridor at rest accompanied by variable degrees of respiratory compromise and should be evaluated in an acute care setting. Symptoms of croup typically resolve in 1 to 3 days with appropriate therapy (see section "Treatment") but may persist for up to 7 days. Worsening symptoms after a period of improvement should prompt evaluation for bacterial complications. 91 Bronchiolitis: Bronchiolitis results from infection of the small airways (bronchioles) of infants and young children and 90% of illnesses are due to viral infection, mostly often with respiratory syncytial virus (RSV). 92 However, all four HPIV serotypes can cause this syndrome and 10 to 20% of confirmed viral bronchiolitis infections due to HPIV1 and HPIV3. 47, 56 Typical illness begins with a prodrome of fever and nasal congestion 1 to 3 days prior to the onset of lower respiratory signs and symptoms (cough, expiratory wheezing, tachypnea, rales, and chest wall retractions). Symptoms peak at 5 to 7 days and 90% of children without underlying cardiopulmonary disease recover from bronchiolitis within 21 days, with a median duration of symptoms of 8 to 15 days. 91, 93 However, 10% of children will have persistent symptoms of cough and wheezing for 1 to 2 weeks longer and disease may be more severe and the course prolonged in premature or young infants and those with comorbid 

Notes: 2, mild; 3-7, moderate; 8-11, severe; 12, impending respiratory failure. conditions (i.e., bronchopulmonary dysplasia, congenital heart defects, or immunosuppression). Children with severe disease are at risk for complications including apnea and respiratory failure requiring mechanical ventilation. 92 Pneumonia: Pneumonia in children classically presents with fever, cough, and rales with infiltrates or consolidation on chest radiographs. Though all four parainfluenza serotypes have been associated with pneumonia in children, HPIV1 and HPIV3 are most often implicated, accounting for 1 to 6% and 2 to 12% of HPIV-related hospitalizations, respectively. 11, 47, 56 The clinical syndrome of HPIV pneumonia in children is not distinctive. Pneumonic infiltrates are usually described as bilateral interstitial infiltrates, though alveolar infiltrates can be seen. 94 Although data are limited, bacterial complications of HPIV in a normal child appear uncommon (<15%) and may be associated with severe and necrotizing pneumonia (►Fig. 9). 94, 95 Treatment is supportive and expectation of recovery is similar to that for bronchiolitis disease.

Tracheobronchitis: Tracheobronchitis is a term used to describe disease that does not fit well into other classical syndromes but generally involves inflammation of the large airways, that is, trachea and bronchi, in the absence of symptoms of croup and radiologic findings of pneumonia. In addition to upper respiratory tract symptoms and fever, patients may have a productive cough, wheezing, and rhonchi. It is generally a clinical syndrome seen in older children and associated with HPIV viral infection in a fourth of all cases. 47 HPIV3 is most commonly associated with this syndrome, though some reports have noted a pattern of large airway disease with HPIV4 infections as well. 96 Adult disease in immunocompetent hosts: HPIV infections in healthy adults are generally mild, self-limited URTIs with typical cold symptoms (rhinorrhea, cough, and sore throat) with or without fever. 56, 58, 60, 61, 73, 97, 98 Otitis media and sinusitis may occasionally complicate adult infection. 99 HPIV may also cause pneumonia, particularly in frail older adults. 59, 64, 66, [100] [101] [102] Signs and symptoms of HPIV infection are indistinguishable from other viruses such as influenza and RSV and may be overshadowed by findings associated with exacerbations of chronic medical conditions such as chronic obstructive pulmonary disease (COPD) and congestive heart failure. 103 Radiographic findings consist of patchy unilateral or bilateral infiltrates, though 50% of HPIV-associated pneumonia may be complicated by bacterial infection. 104 HPIV infection is also increasingly recognized as a cause of acute exacerbation of COPD and asthma. 68, 69, [105] [106] [107] [108] [109] [110] Infection may result in severe illness, deterioration of lung function, and prolonged hospitalization requiring ICU care and mechanical ventilation.

Immunocompromised hosts: Parainfluenza viruses cause severe infections in immunocompromised children and adults and have been associated with significant morbidity and mortality. Recent studies in HSCT and leukemic patients estimated the incidence of symptomatic HPIV infections to be between 2 and 7%. 7, 9, 48, 78, 111 The majority of these illnesses are community acquired (80%), though outbreaks in HSCT wards have been described with 90% due HPIV3. 77, 78 At presentation, most patients (70%) will have upper respiratory tract symptoms of cough, rhinorrhea, and sore throat with or without fever. 112 The presence of URTI symptoms may be the best clue that illness is due to a respiratory virus and distinguishes infection from the myriad of other infectious agents affecting this population. 111 Progression to lower respiratory tract involvement occurs in 43% of HSCT recipients and 55% of leukemia patients and results in high rates of mortality (37-50%). 7,9,77,78,111 Mortality hazard ratio for HPIV-related URTI is 1.3 compared with 3.4 for LRTI. 78 In a recent retrospective report, 30% of the 80 leukemic and 120 HSCT patients at a large cancer center diagnosed with HPIV infections presented with pneumonia. Of those with URTI symptoms initially, 61% of leukemic patients and 39% of HSCT subjects progressed to pneumonia during their illness. 112 In children, similar rates of progression to LRTI disease have been reported with one retrospective study finding that 47% of all viral infections in 274 pediatric HSCT recipients were caused by HPIV viruses and of Parainfluenza Virus Infection Branche, Falsey 545 those, 41% had pneumonia. 113 Similarly, risk for severe disease is also increased in children undergoing chemotherapy, with the highest risk noted in children younger than 2 years with hematologic malignancies. 114 Other factors associated with progression to lower respiratory tract disease include dosedependent treatment with steroids, allogenic SCT (vs. autologous), time from transplantation (majority of cases in HSCT patients occur in <100 days posttransplantation), presence of lymphopenia, and pediatric age group. 7, 78, 114 HSCT and leukemic patients with HPIV pneumonia or pneumonitis will commonly present with fever (77-89%), cough, (62-85%), dyspnea (43-82%), sputum production (67%), nasal congestion or rhinorrhea (52%), and sore throat (30%). 7,77 Chest imaging may reveal a wide variety of findings, including unilateral or bilateral infiltrates on chest radiograph and CT scan findings of interstitial infiltrates, groundglass opacities, peribronchial nodules, and/or airspaces consolidations (►Fig. 10). 115, 116 Diagnosis is made by identifying HPIV in respiratory secretions. Appropriate workup should be obtained to rule out bacterial and fungal copathogens because they frequently (26-61%) complicate HPIV infections and contribute significantly to mortality in this population. 7, [77] [78] [79] In one report from a single center, 53% of patients with HPIV3 pneumonia were found to be coinfected with other pathogens and mortality in this group was 35% at 30 days and 75% at 180 days. 78 In another study reporting 37% mortality associated with PIV pneumonia, 7 of the 10 patients who died had concurrent infections with other respiratory pathogens. 7 The most frequently isolated organisms are Aspergillus fumigatus, often associated with fatal pneumonia, cytomegalovirus, and Pseudomonas aeruginosa with a variety of other gram-negative bacterial pathogens reported as well. 7, [77] [78] [79] Limited studies have demonstrated a more modest impact of HPIV infections in solid-organ transplants recipients. Anecdotal reports have described isolated cases of HPIV infection associated with acute rejection in renal and liver transplant patients. 117, 118 However, the majority of studies have assessed disease associated with HPIV infections in lung transplant patients with incidence ranging from 5 to 12% and rates of lower respiratory tract disease of 10 to 66%. 9,80,119,120 Notably, infection has been shown to have long-term complications in this population, including decreased lung function, bronchiolitis obliterans, and links to allograft rejection. [80] [81] [82] In one study, 82% of lung transplant patients with acute PIV infections who underwent transbronchial biopsy were shown to have acute allograft rejection and 32% subsequently developed bronchiolitis obliterans. 80 Finally, increased risk of infection and persistent or severe disease has also been demonstrated in other special populations including children with other immunodeficiency syndromes such as severe combined immunodeficiency syndrome (SCIDS) who may have atypical presentations like parotitis or rapidly fatal giant cell pneumonia. 121 Though HPIV disease has not been well described in HIV populations, the correlation between lymphopenia and increased morbidity and mortality in leukemic and HSCT patients suggests that risk for severe disease likely increases with T cell depletion.

Other syndromes: Although HPIV infection is generally associated with respiratory tract illnesses, nonrespiratory complications of HPIV infection have been described in both adults and children. Parotitis may be an unusual manifestation of primary infection in children and has been described with HPIV1 and HPIV3 infections. 122, 123 Infants with HPIV infection also may develop apnea and bradycardia, and infection in older children has been associated with exacerbation of nephrotic disease, hepatitis, and fatal rhabdomyolsis. 11, [124] [125] [126] [127] [128] In adults, HPIV3 has been associated with myocarditis and pericarditis. 129 Neurologic disease: Reports have described both acute and chronic neurological disease in children and adults associated with HPIV infections. Febrile seizures have been reported in young children, occurring with 62% of HPIV4 infections and 17% of PIV3 infections, and ventriculitis and encephalitis have been described in a few isolated cases. 124, 130, 131 Meningitis is a rare complication in both children and adults. [132] [133] [134] Interestingly, PIV infections have also been linked serologically to multiple sclerosis disease in adults, though evidence of true pathogenesis is lacking and MS has similarly been associated with other viral infections. Finally, PIV3 was isolated from the CSF of an adult with Guillain-Barre syndrome and other demyelinating syndromes have been described in adults with concurrent or recent PIV infections. 132, 135 Diagnosis Laboratory diagnosis: Although the clinical syndrome of croup is commonly associated with HPIV1, most other presentations of HPIV infection do not have unique features which allow viral infection to be diagnosed on clinical grounds alone. Thus, if the specific viral diagnosis is desired, laboratory testing is needed and can be accomplished by viral detection or host antibody response to infection.

Sample collection: Detection of virus whether by culture, fluorescent antibody assays, or molecular testing depends on the collection of an adequate sample. Several sample types are acceptable for testing and include nasopharyngeal swabs (NPS), combined nose and throat swabs (NTS), nasal washes, sputum, and bronchoalveolar lavage (BAL). The sample type will in part depend on the age and immune status of the patient and the severity and stage of the illness. Nasal washes which are commonly used in children are poorly tolerated by acutely ill older adults and NTSs are reasonable alternate specimens to collect. 103 If swabs are to be collected, it is recommended that flocked swabs be used in preference to cotton swabs due to enhanced yield. 136 The timing of sample collection during illness may also be important with upper airway samples being positive early in illness, whereas, later in illness, it may be more important to test lower airway secretions such as sputum and BAL fluid. In a study of hospitalized patients with documented parainfluenza illnesses, molecular testing of sputum added 33% to the diagnostic yield of collecting NTS alone. 137 BAL is generally reserved for severely ill or immunocompromised patients.

Viral culture: For many years, viral culture has been considered the gold standard for diagnosis. Viral isolation on cell culture depends on the development of cytopathic effect (CPE) or detection of hemadsorption (HAD) to the monolayers. 138, 139 Confirmatory testing of CPE and HAD is accomplished through the use of viral-specific fluorescentlabeled monoclonal antibodies (Mab). Traditional viral culture demands an experienced clinical laboratory, and time to diagnosis limits clinical utility (5-14 days). 138 In an attempt to simplify the process, several commercially available mixed cell lines such as "R-Mix" have been used to successfully grow a variety of respiratory viruses including HPIV. 139 To accelerate the time to identification, the shell vial culture system utilizes low speed centrifugation of the inoculum on monolayers with Mab staining at 24 hours and expedites the time to diagnosis. 140 Fluorescent antibody assays: Detection of viral antigens performed directly on clinical samples has been used since the 1970s as a rapid method for viral diagnosis. 139 Simple commercial colorimetric enzyme-linked immunoassays (EIAs) have been developed for RSV and influenza and perform reasonably well in children with primary infection where viral titers are high. No commercial rapid antigen test for HPIV is available. Direct detection of HPIV 1-3-specific immunofluorescent-labeled antibodies can be done with sensitivities of 63 to 95%; however, antibodies to HPIV-4 are generally not available. 11, 139, 141 Thus, when clinical resources are limited, testing of clinical samples by immunofluorescent assay (IFA) is a reasonable alternative.

Molecular assays: If available, molecular assays such as polymerase chain reaction (PCR) assays are the diagnostic test of choice for HPIV infection on the basis of optimal sensitivity, specificity, and rapidity of diagnosis. 21, [142] [143] [144] Though PCR testing for the diagnosis of HPIV infection has been clearly shown to have superior sensitivity to viral culture and IFA testing, the clinical utility of PCR assays was at first limited by cost and the need for technical expertise to use for research and in tertiary-care facilities. [145] [146] [147] [148] However, molecular testing has become more widely available with the development of commercial assays simplified for use in general clinical microbiology laboratories with rapid turnaround times of approximately 1 hour. 144, 149, 150 Initially developed as single-target assays, HPIV molecular assays are currently often imbedded in multiplex real-time PCR assays which test for respiratory viral pathogens including HPIV 1-4, with minimal loss of sensitivity for individual targets, though some variation in the sensitivity for different HPIV serotypes exists. 151, 152 This variation may in part be due to the fact that though PCR primers are generally directed toward the HN gene, the specific sequence used varies by assay. Low viral loads can also be detected with PCR assays which may be important for early therapy and infection control in transplant populations. 146 Several sample types can be used for PCR testing including NPS, NTS, nasal washes, and BAL fluid. Sputum has been rarely used in molecular assays due to the viscous nature of the specimen, but new techniques have been described which allow the use of sputum samples for fully automated molecular assays. 137 Serologic diagnosis: Serologic diagnosis is rarely used in clinical practice and is primarily a research tool. Complement fixation and EIA assays are available but require collection of convalescent sera to show fourfold or more rise in antibody titer and confirm acute infection. Cross-reactive immune responses to HPIV1 and 3 antigens make serotype-specific diagnosis of these infections by antibody response alone difficult. 153 Detection of HPIV-specific IgM has been described in children with HPIV infection, but commercial assays are not readily available. 154

Currently, there are no antiviral agents with proven efficacy for parainfluenza virus infection. Treatment of HPIV infection is generally symptomatic in healthy children and adults. 11 Croup: Croup, commonly caused by HPIV1 and HPIV2 infection, presents with symptoms of a barking cough and stridor due to swelling and obstruction in the subglottic area of the trachea. 155 Corticosteroids are the primary treatment for croup and have been shown to be beneficial for mild and moderate to severe croup. 156, 157 A fivefold reduction in rates of intubation has been noted in children with severe croup treated with corticosteroids compared with those not treated. 157 Among less ill children, corticosteroid treatment results in shorter emergency room visits, less frequent return medical visits, and improved sleep. 155 Corticosteroids may be administered by mouth or given intramuscularly in the form of dexamethasone or prednisolone and both have been shown to be superior to inhaled therapy with budesonide. Conventional dosing is a single dose of dexamethasone at 60 mg/kg, although lower doses have been proposed. The use of nebulized epinephrine is associated with short-term relief of symptoms at 30 minutes, but treatment effects generally disappear after 2 hours. 158 This treatment may offer symptom relief while waiting for the anti-inflammatory activity of steroid therapy to take effect. Racemic and L-epinephrine are felt to have equivalent efficacy. 155 Despite a long history of using mist tents for croup, humidified air is not an effective treatment for croup. Heliox, which is a mixture of helium and oxygen has been proposed as a treatment for croup but is difficult to administer and does not offer significant benefits over conventional treatments. 155 Antiviral agents: Presently there are no licensed antiviral agents for the treatment of HPIV infection. Data on the use of antiviral agents is primarily derived from animal studies, case reports, and small uncontrolled series in immunocompromised children and adults. The majority of treatment regimens utilize aerosolized or systemic ribavirin in combination with intravenous immunoglobulin (IVIG) and/or corticosteroids. 159 The nonrandomized nature of the these studies and differing routes of administration as well as the different underlying immune defects and type of HPIV infections treated (upper vs. lower tract disease) prohibit definitive conclusions for HPIV treatment. However, active research for new effective antiviral agents for HPIV is ongoing and several new agents show promise in vitro and in vivo.

Ribavirin: Ribavirin is a synthetic nucleoside analogue which has broad-spectrum in vitro and in vivo activity against many RNA and DNA viruses. 160 Aerosolized ribavirin is currently licensed for the treatment of severe RSV in young children and oral and intravenous ribavirin has been used for the treatment of other viral infections such as hepatitis C and Lassa fever. 161, 162 Aerosolized ribavirin is generally well tolerated, although increased cough and bronchospasm may occur and systemic ribavirin can be associated with a reversible hemolytic anemia. 163, 164 Unfortunately, most of the information regarding the utility of ribavirin comes from case reports or uncontrolled case series of patients with a variety of immunosuppressive conditions. 163, [165] [166] [167] [168] [169] [170] [171] [172] [173] The bulk of the data are derived from persons with hematopoietic stem cell transplants (HSCT) which include solid-organ transplant recipients and primary immunodeficiencies. In children with SCIDS and HPIV infection, aerosolized ribavirin has been administered over long periods of time (3-10 months) without apparent toxicity. 164 Consensus indicates that ribavirin is not effective for HPIV pneumonia when given late in the course of illness, especially if respiratory failure has ensued. 7,9,174 Wendt and colleagues reported HPIV infection in 12 adults and 15 children undergoing HSCT with survival rates of 78% in those who received ribavirin as well as those who were not treated. 9 However, treatment was started after 11 days of illness on average. Nichols et al reported the treatment and outcomes of 253 HSCT patients with HPIV infection who were administered ribavirin within 48 hours of diagnosis and found no effect on 30-day mortality and the highest risk of death in patients with bacterial and fungal copathogens. 78, 174 Finally, the largest series to date consisting of 544 HSCT recipients with HPIV infection treated at the Fred Hutchinson Cancer Center demonstrated that the use of inhaled ribavirin was significantly associated with reduced overall mortality but not mortality specifically from respiratory failure in multivariable analysis. 159 Moreover, in the subset with proven HPIV LRTI, there was no difference in mortality with ribavirin use.

Although the efficacy of ribavirin for the treatment of LRTI appears poor, early treatment to prevent progression to pneumonia remains an unanswered question with failures clearly documented. 163, 168, 170 In addition, the role of ribavirin to prevent long-term pulmonary sequelae has not been adequately studied. 7, 80, 172 In a small series of heart-lung transplant patients with HPIV infection, the use of a multidrug approach including IVIG, steroids, and ribavirin was associated with slower decline in lung function compared with historical controls. 175 In composite, the majority of studies do not provide compelling evidence that ribavirin provides significant benefit in the treatment of immunocompromised persons with HPIV infection and more effective treatments are critically needed.

DAS181: A novel approach which appears promising is a drug initially developed to treat influenza which acts on the host cell receptor for HPIV to prevent binding rather than exerting a direct effect on the virus. 176 The HN protein recognizes sialic acid containing glycolipids and glycoproteins on the host target cells and allows binding to occur. 177 DAS181 is an inhaled recombinant sialidase fusion protein that interferes with the initial binding of HN with the host cell sialic acid containing receptor. 13, 178 Since sialic acid residues serve as the cellular receptors for both influenza and HPIV, DSA181 has been explored for HPIV antiviral activity. 179 This agent has been used under a compassionate use protocol to treat HPIV pneumonia in a lung transplant and an HSCT recipient with evidence of subjective and objective improvement. 178, 180 Recently, DAS181 was used to treat two severely ill HSCT patients requiring mechanical ventilation and was successfully delivered via a nebulized formulation through the ventilator with significant decrease in viral load. 181 The drug was well tolerated with only a mild increase in serum alkaline phosphatase noted. Finally, four immunocompromised children infected with HPIV demonstrated clinical and radiographic improvement along with decreased viral load after treatment with DAS181. 182 The limited data available are encouraging and a phase 2 clinical trial in immunocompromised subjects with HPIV LRTI is ongoing (www. clinicaltrials.gov).

Other antiviral agents: Several other small molecules with in vitro activity against HPIV are in development. [183] [184] [185] The discovery of the 3D structure of the HPIV HN has allowed the design of inhibitors that fit into the binding site of the globular head to prevent binding and fusion of the virus. 13 Additional antiviral agents in development are HN inhibitors, BCX 2798 and BCX 2855, which bind to the catalytic binding site of HPIV and have been shown effective in the mouse HPIV model. 186, 187 Immunoglobulins: Immunoglobulin preparations contain neutralizing antibody to HPIV and may have anti-inflammatory effects. The administration of serum immunoglobulin (IVIG) has shown antiviral effects in the cotton rat model of HPIV3 infection. 188 The combination of steroids with IVIG produced the most favorable results by reducing both viral titers and inflammation. 189, 190 Although animal data are encouraging, data on the use of IVIG in immunosuppressed patients are conflicting. Case reports claim dramatic results with the use of IVIG, while larger observational studies find no benefit. 171, 172, 191, 192 A recent report in which investigators noted no relationship between posttransplant levels of serum HPIV3-specific antibody and outcomes in HPIV3-infected HSCT recipients would suggest a limited role for IVIG in the treatment of established HPIV infection. 193 Prevention Vaccines: Currently, there is no licensed vaccine for the prevention of parainfluenza infection. Antibody to the two surface glycoproteins, F and HN are neutralizing and serum and nasal antibody to either protein protects against HPIV infection and ameliorates disease. 11, 29, 194 Thus, vaccines to boost serum and or mucosal antibody may offer benefit, yet several challenges to successful vaccine development remain. Cross protection between different HPIV serotypes is minimal or short lived, necessitating multiple or multivalent HPIV vaccines. Currently, most vaccine efforts are focused on HPIV3 which is the primary cause of severe disease and pneumonia in infants and in older adults. In young children, maternal antibody and the immature immune system are impediments to active immunization. 194 However, HPIV1-and HPIV2associated croup infections occur at an older age and therefore the timing of vaccination could be delayed. Because of the disastrous results of the formalin-inactivated RSV vaccine trials performed in the 1960s during which enhanced disease with natural infection was observed, most HPIV vaccine research has avoided subunit vaccines. 195 Several approaches have included cold passaged attenuated live HPIV vaccines, bovine HPIV, and recombinant bovine/human HPIV vaccines. 194, 196, 197 As RSV and HPIV3 affect the same age group, recombinant vaccines that express both RSV and HPIV proteins are being explored. [196] [197] [198] [199] Several candidate vaccines are now in phaseI/II clinical trials in children.

Infection control: Transmission of HPIV is thought to be via large particle aerosols and fomites with self-inoculation. 11, 21 Young children can excrete high quantities of virus which may be viable on porous surfaces for up to 10 hours. 200, 201 Because small particle aerosols are not felt to be important mechanisms for transmission, droplet isolation is believed to be sufficient to prevent nosocomial spread in most health care settings. 21 However, prolonged shedding of low levels of HPIV has been documented in normal asymptomatic healthy adults as well as immunocompromised persons. Interestingly, two HPIV outbreaks occurred in healthy young adults 10 and 29 weeks after complete social isolation at the South Pole and were likely due to persistent low level shedding in some individuals. 202 Outbreaks of HPIV after HSCT have been reported in inpatient and outpatient settings and, despite aggressive infection control measures, have been difficult to control. 203, 204 In several instances, outbreaks appeared to be centered in the outpatient facilities where waiting rooms were sometimes crowded and common infusion areas were utilized. 205 Because HPIV may cause prolonged asymptomatic infection, symptom-based infection control strategies which have been successful in curtailing RSV and influenza outbreaks may be less effective to prevent nosocomial spread of HPIV. 206 When HPIV outbreaks are detected in settings where immunocompromised patients are cared for, enhanced infection control measures are recommended including strict visitor and patient-to-patient contact limitation, cohorting, masking of personnel and visitors in contact with HPIVinfected patients, and frequent cleaning of environmental surfaces. 205 Screening of asymptomatic patients and staff may be indicated in difficult-to-control outbreaks. 206

HPIVs cause a significant burden of disease in children and adults. A wide spectrum of illness including colds, croup, bronchiolitis, and pneumonia are attributed to these ubiquitous pathogens. The most severe disease is found among immunocompromised patients and treatment at present remains largely supportive. Several promising antiviral drugs are in development and are in early-stage clinical trials. Continued research for new vaccines and therapeutics is needed. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Parainfluenza viruses

Parainfluenza viruses

Entry of parainfluenza virus into cells as a target for interrupting childhood respiratory disease

From the National Institute of Allergy and Infectious Diseases and the World Health Organization. Respiratory syncytial and parainfluenza viruses

Hemagglutinin-neuraminidase of human parainfluenza 3: role of the neuraminidase in the viral life cycle

Interaction of human parainfluenza virus type 3 with the host cell surface

Pathogenesis of acute respiratory illness caused by human parainfluenza viruses

Distinct hemagglutinin and neuraminidase epitopes involved in antigenic variation of recent human parainfluenza virus type 2 isolates

Strain variation in parainfluenza virus type 4

Monoclonal antibodies to human parainfluenza virus type 1 detect major antigenic changes in clinical isolates

Parainfluenza viruses

Replication of parainfluenza type-3 virus and bovine respiratory syncytial virus in isolated bovine type-II alveolar epithelial cells

Neuenschwander SB. Pathogenesis of bronchiolitis and pneumonia induced in neonatal and weanling rats by parainfluenza (Sendai) virus

Parainfluenza virus bronchiolitis. Epidemiology and pathogenesis

Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection

Pathogenesis of human parainfluenza virus 3 infection in two species of cotton rats: Sigmodon hispidus develops bronchiolitis, while Sigmodon fulviventer develops interstitial pneumonia

Croup in children (acute laryngotracheobronchitis)

Naturally occurring parainfluenza virus 3 infection in adults induces mild exacerbation of asthma associated with increased sputum concentrations of cysteinyl leukotrienes

Protective effect of antibody to parainfluenza type 1 virus

Expression of the F and HN glycoproteins of human parainfluenza virus type 3 by recombinant vaccinia viruses: contributions of the individual proteins to host immunity

Human parainfluenza virus induces a type-specific protective immune response

Pulmonary cell-mediated cytotoxicity in hamsters with parainfluenza virus type 3 pneumonia

Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8þ T cells

Viral cross-reactivity and antigenic determinants recognized by human parainfluenza virus type 1-specific cytotoxic T-cells

Acquisition of serum antibodies to specific viral glycoproteins of parainfluenza virus 3 in children

Association of a new type of cytopathogenic myxovirus with infantile croup

New viruses observed in children with respiratory diseases

Seasonal trends of human parainfluenza viral infections: United States

Potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus 3 and rhinovirus 14

Seasonal trends of viral respiratory tract infections in the tropics

The isolation of parainfluenza 4 subtypes A and B in England and serological studies of their prevalence

Parainfluenza virus type 4 infections in pediatric patients

Human parainfluenza type 4 infections

Recovery and identification of human myxoviruses

Antigenic variation among newly isolated strains of parainfluenza type 4 virus

Epidemiology of acute respiratory infections in children of developing countries

The clinical impact of human respiratory virus infections

Epidemiology of acute viral respiratory tract infections in Korean children

Pathogenesis of severe acute respiratory infections in the developing world: respiratory syncytial virus and parainfluenza viruses

Acute lower respiratory tract infections in nonhospitalized children

Principles and Practices of Infectious Diseases

Outbreak of pneumonia in a long-term care facility: antecedent human parainfluenza virus 1 infection may predispose to bacterial pneumonia

Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children < 5 years old

New Vaccine Surveillance Network. Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization

Viral respiratory diseases in children: classification, etiology, epidemiology, and risk factors

Human parainfluenza virus-associated hospitalizations among children less than five years of age in the United States

Medical burden of respiratory syncytial virus and parainfluenza virus type 3 infection among US children. Implications for design of vaccine trials

Respiratory syncytial virus and parainfluenza virus

Other respiratory viruses are important contributors to adult respiratory hospitalizations and mortality even during peak weeks of the influenza season

Viral pneumonia in older adults

Frequency of detection of upper respiratory tract viruses in patients tested for pandemic H1N1/09 viral infection

Direct detection of respiratory syncytial virus, parainfluenza virus, and adenovirus in clinical respiratory specimens by a multiplex reverse transcription-PCR assay

Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model

Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation

The role of viruses in the aetiology of community-acquired pneumonia in adults

Respiratory viral infections in adults with and without chronic obstructive pulmonary disease

Impact of respiratory virus infections on persons with chronic underlying conditions

Viral infections as a cause of chronic obstructive pulmonary disease (COPD) exacerbation

A communitybased, time-matched, case-control study of respiratory viruses and exacerbations of COPD

Parainfluenza infections in the elderly 1976-82

Anonymous Parainfluenza outbreaks in extended-care facilities-United States

Viral respiratory infections in the institutionalized elderly: clinical and epidemiologic findings

A respiratory outbreak due to parainfluenza virus type 3 in a home for the aged-Ontario

Upper respiratory tract infection and serum antibody responses in nursing home patients

Epidemiology of acute respiratory illness during an influenza outbreak in a nursing home. A prospective study

Acute respiratory tract infection in daycare centers for older persons

Respiratory disease due to parainfluenza virus in adult leukemia patients

Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome

A parainfluenza-3 outbreak in a SCT unit: sepsis with multi-organ failure and multiple co-pathogens are associated with increased mortality

The epidemiology of parainfluenza virus infection in lung transplant recipients

Influenza and parainfluenza respiratory viral infection requiring admission in adult lung transplant recipients

Respiratory viruses and chronic rejection in lung transplant recipients

Epidemiology of documented viral respiratory infections and acute otitis media in a cohort of children followed from two to twenty-four months of age

National disease burden of respiratory viruses detected in children by polymerase chain reaction

Croup presentations to emergency departments in Alberta, Canada: a large population-based study

The need for intubation in serious upper respiratory tract infection in pediatric patients (a retrospective study)

Hospitalized croup (bacterial and viral): the role of rigid endoscopy

Review of intubation in severe laryngotracheobronchitis

Nebulized racemic epinephrine by IPPB for the treatment of croup: a double-blind study

Hay AD; TARGET Programme Team. Duration of symptoms of respiratory tract infections in children: systematic review

Trends in bronchiolitis hospitalizations in the United States

Duration of illness in ambulatory children diagnosed with bronchiolitis

Community-acquired pneumonia in the Conjugate Vaccine Era

Community-acquired pneumonia among U.S. children

Parainfluenza virus type 4: case report and review of the literature

The Seattle Virus Watch. VI. Observations of infections with and illness due to parainfluenza, mumps and respiratory syncytial viruses and Mycoplasma pneumoniae

Acute upper respiratory tract viral illness and influenza immunization in homes for the elderly

The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies

Infections with viruses, Mycoplasma pneumoniae and bacteria in acute respiratory illness. A study of hospitalized patients, patients treated at home, and healthy subjects

Acute respiratory illness in the community. Frequency of illness and the agents involved

On the epidemiology and etiology of pneumonia in adults

The diagnosis of viral respiratory disease in older adults

Bacterial complications of respiratory tract viral illness: a comprehensive evaluation

Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis

Viral and bacterial infections in adults with chronic asthma

Viral epidemiology of acute exacerbations of chronic obstructive pulmonary disease

Understanding the mechanisms of viral induced asthma: new therapeutic directions

A virologic study of chronic bronchitis

The similarities and differences of epidemic cycles of chronic obstructive pulmonary disease and asthma exacerbations

Parainfluenza virus infection in adult bone marrow transplant recipients

The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation

Respiratory virus infections in pediatric hematopoietic stem cell transplantation

Symptomatic parainfluenza virus infections in children undergoing hematopoietic stem cell transplantation

Respiratory viral infections in transplant recipients

Parainfluenza virus type 3 pneumonia in bone marrow transplant recipients: multiple small nodules in high-resolution lung computed tomography scans provide a radiological clue to diagnosis

Association of parainfluenza virus type 3 infection with allograft rejection in a liver transplant recipient

Parainfluenza type 3 in a transplant unit

Community respiratory viral infection in adult lung transplant recipients

Respiratory viral infections in lung transplant recipients: radiologic findings with clinical correlation

Disseminated parainfluenza infection in a child with severe combined immunodeficiency

Recovery of parainfluenza viruses from adults with upper respiratory tract illnesses

Inhibition of human parainfluenza virus-3 replication by interferon and human MxA

Prenatal ultrasonographic diagnosis of fetal hydrocephalus due to infection with parainfluenza virus type 3. Ultrasound

Outbreak of parainfluenza virus type 3 in a neonatal nursery

A simultaneous outbreak of respiratory syncytial virus and parainfluenza virus type 3 in a newborn nursery

Parainfluenza type 3 in newborns

Role of respiratory viruses in exacerbations of primary nephrotic syndrome

Myopericarditis associated with parainfluenza virus type 3 infection

Acute childhood encephalitis and Mycoplasma pneumoniae

Diagnosis and clinical significance of parainfluenza virus infections in children

Isolation of parainfluenza virus type 3 from cerebrospinal fluid

Parainfluenza virus type 3 meningitis in an 11-month-old infant

Report of two cases and review of the literature

Parainfluenza virus type 3: isolation from CSF of a patient with Guillain-Barré syndrome

Improved detection of respiratory viruses in pediatric outpatients with acute respiratory illness by real-time PCR using nasopharyngeal flocked swabs

Detection of respiratory viruses in sputum from adults by use of automated multiplex PCR

Experiences in laboratory diagnosis of parainfluenza viruses in routine medical practice

Role of cell culture for virus detection in the age of technology

Isolation of seven respiratory viruses in shell vials: a practical and highly sensitive method

Human parainfluenza type 4 infection: a case report highlighting pathogenicity and difficulties in rapid diagnosis in the post-transplant setting

ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus

Rapid simultaneous diagnosis of infections with respiratory syncytial viruses A and B, influenza viruses A and B, and human parainfluenza virus types 1, 2, and 3 by multiplex quantitative reverse transcription-polymerase chain reaction-enzyme hybridization assay (Hexaplex)

The FilmArray® respiratory panel: an automated, broadly multiplexed molecular test for the rapid and accurate detection of respiratory pathogens

Comparison of real-time PCR assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children

Comparison of conventional and molecular detection of respiratory viruses in hematopoietic cell transplant recipients

Polymerase-chainreaction-based diagnosis of viral pulmonary infections in immunocompromised children

New Vaccine Surveillance Network Study Group. Superiority of reverse-transcription polymerase chain reaction to conventional viral culture in the diagnosis of acute respiratory tract infections in children

Comparison of the Luminex xTAG respiratory viral panel with in-house nucleic acid amplification tests for diagnosis of respiratory virus infections

Evaluation of the BioFire FilmArray respiratory panel and the GenMark eSensor respiratory viral panel on lower respiratory tract specimens

Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza a and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4

Comparison of the Luminex xTAG respiratory viral panel with xTAG respiratory viral panel fast for diagnosis of respiratory virus infections

Serological diagnosis of parainfluenza virus infections by enzyme immunoassay with special emphasis on purity of viral antigens

Diagnosis of parainfluenza virus infection in children and older patients by detection of specific IgM antibody

Pediatric Emergency Research Canada Network. A randomized trial of a single dose of oral dexamethasone for mild croup

Steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials

Inhalation of racemic adrenaline in the treatment of mild and moderately severe croup. Clinical symptom score and oxygen saturation measurements for evaluation of treatment effects

Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the lung predicts outcome

Biochemistry and clinical applications of ribavirin

American Academy of Pediatrics Committee on Infectious Diseases. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections

The role of ribavirin in the combination therapy of hepatitis C virus infection

Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study

Long-term therapy with aerosolized ribavirin for parainfluenza 3 virus respiratory tract infection in an infant with severe combined immunodeficiency

Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections

Successful treatment of parainfluenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient

Treatment of parainfluenza virus 3 pneumonia in a cardiac transplant recipient with intravenous ribavirin and methylprednisolone

Parainfluenza virus type 3 infections in hematopoetic stem cell transplant recipients: response to ribavirin therapy

Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation

Parainfluenza virus 3 infection after stem cell transplant: relevance to outcome of rapid diagnosis and ribavirin treatment

Successful clearance of human parainfluenza virus type 2 viraemia with intravenous ribavirin and immunoglobulin in a patient with acute myocarditis

A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients

Treatment of respiratory viral infection in an immunodeficient infant with ribavirin aerosol

Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience

Perspective: emerging challenges in the treatment of influenza and parainfluenza in transplant patients

Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181

Syntheses of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified by N-sulfonylamidino groups at the C-4 position and biological evaluation as inhibitors of human parainfluenza virus type 1

Treatment of parainfluenza 3 infection with DAS181 in a patient after allogeneic stem cell transplantation

Inhibition of primary clinical isolates of human parainfluenza virus by DAS181 in cell culture and in a cotton rat model

DAS181 treatment of severe parainfluenza type 3 pneumonia in a lung transplant recipient

DAS181 treatment of hematopoietic stem cell transplant patients with parainfluenza virus lung disease requiring mechanical ventilation

Successful treatment of parainfluenza virus respiratory tract infection with DAS181 in 4 immunocompromised children

A RhoA-derived peptide inhibits syncytium formation induced by respiratory syncytial virus and parainfluenza virus type 3

Inhibition of human parainfluenza virus type 3 infection by novel small molecules

N-terminally truncated C protein, CNDelta25, of human parainfluenza virus type 3 is a potent inhibitor of viral replication

Effect of hemagglutininneuraminidase inhibitors BCX 2798 and BCX 2855 on growth and pathogenicity of Sendai/human parainfluenza type 3 chimera virus in mice

Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice -further evaluation

Topical immunoglobulin is an effective therapy for parainfluenza type 3 in a cotton rat model

A cotton rat model of human parainfluenza 3 laryngotracheitis: virus growth, pathology, and therapy

Treatment of parainfluenza virus type 3 bronchiolitis and pneumonia in a cotton rat model using topical antibody and glucocorticosteroid

First report of severe parainfluenza virus 4B and rhinovirus C coinfection in a liver transplant recipient treated with immunoglobulin

Severe parainfluenza pneumonia in a case of transient hypogammalobulinemia of infancy

Parainfluenza virus type 3 Ab in allogeneic hematopoietic cell transplant recipients: factors influencing post-transplant Ab titers and associated outcomes

Progress in the development of human parainfluenza virus vaccines

The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines

The cDNA-derived investigational human parainfluenza virus type 3 vaccine rcp45 is well tolerated, infectious, and immunogenic in infants and young children

Evaluation of two chimeric bovine-human parainfluenza virus type 3 vaccines in infants and young children

Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children

Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children

Parainfluenza viral infections in children: correlation of shedding with clinical manifestations

Survival and disinfection of parainfluenza viruses on environmental surfaces

Persistent parainfluenza virus shedding during isolation at the South Pole

Prolonged outbreak of human parainfluenza virus 3 infection in a stem cell transplant outpatient department: insights from molecular epidemiologic analysis

Control of an outbreak of human parainfluenza virus 3 in hematopoietic stem cell transplant recipients

Epidemiology and clinical characteristics of parainfluenza virus 3 outbreak in a Haematooncology unit

Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection

Images in clinical medicine. Steeple sign of croup