Parainfluenza Viruses

PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

223 Parainfluenza Viruses Asunción Mejías and Octavio Ramilo

Human parainfluenza viruses (HPIVs) were first identified in humans in the late 1950s.1 HPIVs were initially described in children with croup, but the use of molecular diagnostic tools has elucidated their causative role in acute respiratory tract infections in patients who are immunocompromised, have chronic conditions, or are elderly.2–6 In otherwise healthy children, HPIVs commonly cause upper respiratory tract infections (URIs) and also lower respiratory tract infections (LRIs) such as pneumonia, bronchiolitis, and exacerbations of reactive airway disease.3,7 HPIVs are responsible for 6% to 11% of total hospitalizations of children younger than 5 years of age, highlighting the need for effective vaccines and antiviral therapies.3,8

DESCRIPTION OF THE PATHOGEN Microbiology HPIVs are pleomorphic, enveloped RNA viruses that belong to the Paramyxoviridae family. There are four antigenically distinct types, 1, 2, 3, and 4, with two antigenic subtypes, 4A and 4B.9,10 Parainfluenza viruses are divided into two genera based on complement fixation and hemagglutinating antigens. Parainfluenza types 1 and 3 belong to the Respirovirus genus, and parainfluenza types 2, 4A, and 4B belong to the Rubulavirus genus. Parainfluenza virus type 5 causes disease in animals, and its role in humans remains controversial.11 Other viruses in this family include mumps, measles, Hendra, and Nipah viruses; New Castle disease virus; respiratory syncytial virus (RSV); and human metapneumovirus (HMPV).The HPIV serotypes and subtypes display substantial serologic cross-reactivity. The singlestranded, negative-sense, nonsegmented RNA genome (−ssRNA) of HPIV contains approximately 15,000 nucleotides that encode six common structural proteins. The viral envelope is derived from the host cell and is covered with glycoprotein spikes. Two glycoproteins, the hemagglutinin-neuraminidase (HN) and fusion (F) proteins, play a major role in pathogenesis and are

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the major antigenic targets for neutralizing antibodies.12 HN is coupled with the activated F protein to permit the virion entry into the cell. Activation of the F protein is mediated by cellular proteases. The specific localization of these proteases may influence specific-member HPIV cellular tropism.

Pathogenesis and Immunity HPIVs replicate exclusively in cells of the respiratory epithelium, initially infecting epithelial cells of the nose and nasopharynx. Clinically, HPIVs most commonly affect the large airways of the lower respiratory tract, causing croup.13 Viral tropism for this anatomic location seems to be related to the abundant ciliated epithelial cells.14 In more severe cases, infection spreads to the distal airways and causes development of bronchiolitis or pneumonia. The mechanism of airway and parenchymal injury and resulting symptoms probably are a combination of the host immune response and to a lesser extent the direct viral cytopathic effect. Significant viral replication is detected in the upper (i.e., nose) and lower (i.e., lungs) respiratory tract within 24 hours of infection, with peak viral replication occurring between days 2 to 5. Necrosis and occasionally proliferation of the bronchiolar epithelium accompany the destruction of ciliated epithelial cells in children with pneumonia and bronchiolitis.15 A peribronchiolar infiltrate of lymphocytes, plasma cells, and macrophages appears along with edema and excessive mucus production, and if pneumonia is prominent, the alveoli are filled with fluid.16 Innate Immune Responses, Cytokines, and Chemokines.  By mechanisms that are not completely understood, HPIV-3 modifies the survival and functional properties of human antigen-presenting cells (i.e., monocytes and dendritic cells), which may prevent the development of efficient antiviral responses.17 HPIVs induce the production of cytokines and chemokines in animal models, under in vitro conditions and in children with acute infections.18,19 The magnitude of the cytokine response probably is related to the clinical syndrome and virus type.

Parainfluenza Viruses

waning immunity. After several infections, antibodies may develop that cross-neutralize different parainfluenza virus strains (e.g., HPIV-1 and -3, HPIV-2 and -4). In immunocompetent people, reinfections are more likely to cause only upper respiratory tract symptoms.30 In epidemiologic studies, HPIV-3 was isolated from 143 children (i.e., 50% of all HPIV isolates) younger than 5 years of age. Of those, 9% had subsequent reinfections with isolation of the same virus type less than 1 month after the initial infection. Although reinfections are thought to induce increased resistance to LRIs by the infecting serotype, protection appears not to be based entirely on increased humoral immunity.30,31 In these studies, the clinical manifestations of the reinfection episodes were not different from those of the initial episode. No reinfections were seen with HPIV-1 or HPIV-2.7

EPIDEMIOLOGY The different serotypes of HPIV have distinct epidemiologic patterns that depend on the geographic location. However, overall HPIV seasonal patterns are predictable and cyclic except for tropical countries, where HPIVs do not exhibit seasonal variation.32,33 HPIV-1 causes the largest, most defined outbreaks of croup in the fall of odd-numbered years. Outbreaks of HPIV-2, although more erratic and milder, usually follow HPIV-1 outbreaks.16 A major increase in the number of cases of croup in the autumn usually indicates an HPIV-1 or -2 outbreak.34 HPIV-3 is the most frequently recovered strain. It is endemic, and infection most commonly occurs during the spring and summer and extends into autumn, especially when other HPIV outbreaks are absent.7,30 The use of molecular diagnostic tools is elucidating patterns of HPIV-4 infections. A large, retrospective study conducted in Colorado between 2009 and 2012 showed that HPIV-4 had year-round prevalence, with biennial peaks during the fall of odd-numbered years (Fig. 223.1).35–37

50 45 40 35 30 25 20 15 10 5 0

RSV

14 12 10 8 6 4 2 0 14 12 10 8 6 4 2 0 14 12 10 8 6 4 2 0

HPIV-1

HPIV-3

HPIV-2

5 4 3 2 1 0

1 July 2003

1 July 2002

1 July 2001

1 July 2000

1 July 1999

1 July 1998

1 July 1997

1 July 1996

1 July 1995

1 July 1994

1 July 1993

1 July 1992

1 July 1991

HPIV-4 1 July 1990

Positive test Positive test Positive test Positive test Positive test result (%) result (%) result (%) result (%) result (%)

Local production of interferon γ (IFNγ) was detected in 30% of children with HPIV lower respiratory tract disease, and nasal wash concentrations of interleukin-8 (IL-8) were significantly higher in children infected with HPIV-3 or HPV-1 compared with other HPIV types and in those with lower rather than upper respiratory tract infection.19,20 A disruption in the mechanism that regulates metalloproteinases (MMPs) also has been associated with increased disease severity in infants with bronchiolitis caused by HPIVs or RSV.21 Cellular Immunity.  Host defense against HPIVs is mediated largely by humoral immunity and T-cell recognition of epitopes on the HN and F surface glycoproteins of the virus.22 Animal models of acute HPIV infection suggest that CD8+ T-lymphocyte–mediated immune responses are critical for viral clearance.23 Infants with HPIV-induced croup have defective regulation of cell-mediated immune responses compared with children with uncomplicated URIs.24 This and the prolonged viral shedding and severe disease manifestations observed in people with defective cell-mediated immunity indicate the important role of T lymphocytes in controlling infection.5,25,26 Humoral Immunity.  Mucosal immunity appears to play a key role in controlling disease. Studies of adults after an experimental challenge with HPIV-1 and HPIV-2 indicate that neutralizing antibody concentrations in secretions correlate better with protection than serum antibody concentrations.27,28 In children, secretory antibodies appear 7 to 10 days after the onset of symptoms and peak at about 2 weeks after disease onset.29 Most children are born with neutralizing antibodies to all four HPIV types, but titers fall sharply during the first 6 months of life. Most HPIV antibody responses involve serum immunoglobulin G1 (IgG1), but levels of serum IgG3, IgG4, IgA, and IgM rise significantly in 30% of adults. Antigenic variations in HPIV viruses are related to the heterogeneity within the viruses rather than to antigenic viral drift. Reinfections, which occur many times throughout life, most likely reflect

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Week ending date FIGURE 223.1  Seasonal trends of human parainfluenza virus (HPIV) infections are shown by the percentage of tests positive for serotypes 1, 3, 2, and 4 reported to the National Respiratory and Enteric Viruses Surveillance System (NREVSS) by week from July 1990 through June 2004. The percentage of antigen detection tests positive for respiratory syncytial virus (RSV) reported to NREVSS is shown for comparison. Notice that RSV and HPIV-4 have different axis scales than the other HPIV serotypes. (Modified from Fry AM, Curns AT, Harbour K, et al. Seasonal trends of human parainfluenza virus infections: United States, 1990–2004. Clin Infect Dis 2006;43:1016–1022.)

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

TABLE 223.1  Clinical and Epidemiologic Characteristics of Human Parainfluenza Virus Infections Characteristic

HPIV-1

HPIV-2

HPIV-3

HPIV-4

Age

1–5 yr

2–6 yr

<6 mo

1–4 yr

Seasonality

Fall, odd-numbered years

Year-round, may follow HPIV-1

Endemic; spring/summer

Year-round with biennial peaks in the fall or winter of odd-numbered years

Most common clinical manifestation

Croup ++

Croup +

LRI (pneumonia, bronchiolitis)

URI ++ and LRI + (not croup)

Viral sheddinga

2 wk

1 wk

3 wk

~1.5 wk

Hospitalization rates3

0.32–1.59/1000

0.1–0.86/1000

0.48–2.6/1000

Unknown

a

The age of primary infection varies by serotype. By 12 months of age, about 50% of infants have serologic evidence of HPIV-3 infection, and by 5 years of age, most children have been infected with HPIV-3.35,38,39 In contrast, only 50% to 75% of 5-year-old children are seropositive for HPIV-1 and -2. Acquisition of HPIV-4 occurs during preschool years, following the pattern observed with HPIV-1 and -2.40 A prospective surveillance study conducted in Houston, Texas, showed that rates of primary infection in the first and second year of life were 62 and 81 per 100 child-years, respectively.30 Infection with HPIV-3, the HPIV type that most closely resembles RSV, frequently occurs in young infants and is a prominent cause of bronchiolitis or pneumonia. Infections with HPIV-1 and HPIV-2 occur most commonly in children between 1 and 5 years of age. HPIV-4 infections are common in toddlers attending childcare centers and older children (mean age, 4 years) requiring hospitalization with more severe disease (Table 223.1).35,36 Traditionally, HPIVs have been considered the second most common cause of hospitalization for respiratory disease in children.3,41 HPIVs are associated with 30% to 40% of all acute respiratory tract infections in infants and children, and in the United States, they are responsible for 7% of all hospitalizations for fever or acute respiratory illness in children younger than 5 years of age.3,7 Annual rates of HPIV-related hospitalization for children younger than 5 years of age vary from 1.0 to 5.1 per 1000 children.7,8,42 Based on a 4-year longitudinal study, rates of hospitalization for US children younger than 5 years of age were similar for HPIVs, HMPV, and influenza virus: 1.02, 1.2, and 0.9 per 1000 children, respectively. Rates of hospitalization for RSV in the same population were threefold higher (3 of 1000).3,43 Rates of hospitalization for bronchiolitis, croup, and pneumonia due to HPIV infections in children younger than 5 years of age were estimated in a 12-year longitudinal study (1998–2010). The mean annual estimates were 0.2, 0.4, and 0.5 hospitalizations per 1000 children for bronchiolitis, croup, and pneumonia, respectively. The estimated annual costs attributed to these three conditions exceeded $250 million.42 Most hospitalizations occurred for children younger than 2 years of age. Pneumococcal vaccination has been associated with a reduction in the incidence of pneumonia in infants with HPIV and other respiratory viruses, suggesting that pneumococcus is an important pathogen in the development of virus-associated pneumonia.44 HPIVs also cause acute respiratory illness with substantial morbidity and mortality rates in immunocompromised patients, those with underlying chronic cardiopulmonary conditions, and in the elderly.5,6,45

TRANSMISSION HPIVs, particularly HPIV-3, are highly transmittable. Similar to RSV, HPIVs are transmitted from direct, close person-to-person contact through large respiratory tract droplets and by exposure to contaminated fomites. Climatologic factors may impact the shedding of HPIVs; in vitro studies have shown that aerosol particles of HPIV-3 survive longer when the relative humidity is 20% rather than 50% or 80%. Infection most likely is transmitted by hands contaminated with secretions containing virus, followed by autoinoculation. An adult volunteer study demonstrated that HPIV was not transferable readily to the fingers

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Diagnosis

In immunocompetent children. HPIV, human parainfluenza virus; LRI, lower respiratory tract infection; URI, upper respiratory tract infection; +, less common; ++, more common.

Fever Croup Coryza LRI Pharyngitis URI AOM Bronchiolitis Pneumonia Conjunctivitis Rash Diarrhea 0

10

20

30

40 50 Percent

60

70

80

FIGURE 223.2  Clinical illnesses caused by parainfluenza viruses. Orange indicates systemic symptoms, and blue indicates respiratory symptoms. AOM: acute otitis media; LRI, lower respiratory tract infection; URI, upper respiratory tract infection. (Modified from Reed G, Jewett PH, Thompson J, et al. Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children <5 years old. J Infect Dis 1997;175:807–813; Frost HM, Robinson CC, Dominguez SR. Epidemiology and clinical presentation of parainfluenza type 4 in children: a 3-year comparative study to parainfluenza types 1–3. J Infect Dis 2014;209:695–702).

of other volunteers after 20 minutes on contaminated hands.46 If kept from drying, HPIVs survive on porous surfaces for up to 4 hours and on nonporous surfaces for as long as 10 hours.47 In closed settings, HPIV-3 infection occurs in virtually all exposed children. Secondary attack rates for HPIV-1 and HPIV-2 are 65% to 79%.2 The usual incubation period for HPIV infection is 2 to 6 days.22 Depending on the serotype, children with primary HPIV infection can shed virus from 1 week before the onset of symptoms to more than 3 weeks after symptoms resolve. Children with primary HPIV-1 infection shed cultivatable virus for 4 to 7 days and viral RNA, which is measured by polymerase chain reaction (PCR), for up to 2 weeks.35 In the Houston Family Study, about 17% of children infected with HPIV-3 shed virus for as long as 3 to 4 weeks (see Table 223.1). Nosocomial infections and outbreaks of HPIV-3 infection are associated with high attack rates. Outbreaks in neonatal nurseries and in bone marrow transplantation units have been reported.48–53

CLINICAL MANIFESTATIONS HPIVs cause a variety of upper and lower respiratory tract illnesses (Fig. 223.2), which vary by age, virus serotype, and season. Most primary infections are symptomatic, and disease prevalence is greater among outpatients than inpatients. In healthy children, most illnesses involve the upper respiratory tract, and up to 35% of cases are complicated with otitis media.54,55 HPIV-1 and HPIV-2 typically are associated with croup, HPIV-3 with bronchiolitis and pneumonia, and HPIV-4 with mild URIs in children

Parainfluenza Viruses

and adults. HPIV-4 has been associated with severe LRIs in patients with underlying medical conditions.35,36,39,56 Croup is the most common HPIV-associated diagnosis.13,57 Upper Respiratory Tract Disease.  In children, HPIVs account for about 20 % of all URIs.58–60 Infection typically starts with coryza, cough, rhinorrhea, pharyngitis without cervical lymphadenopathy, and low-grade fever. All four serotypes have been recovered from children and adults with the common cold.33 URI is the typical manifestation of HPIV infection in immunocompetent adults. Croup.  Croup (i.e., laryngotracheobronchitis) is a term used to encompass a heterogeneous group of illnesses that affect the larynx, the trachea, and the bronchi. Croup affects about 3% of children annually, with a peak incidence between ages 6 months and 3 years.13,57 The incidence is 1.5 to 2 times higher among males than females. HPIVs, especially HPIV-1, are the most frequent cause of croup, accounting for almost 75% of cases.13,61,62 Croup is characterized by fever, laryngeal obstruction, dyspnea, inspiratory stridor, and a hoarse, barking cough. In mild to moderate cases, symptoms typically last 3 to 5 days. progression is unpredictable, however, and sudden respiratory failure can occur. In cases with severe stridor, differentiation from epiglottitis can be facilitated by lateral neck radiography. The typical finding in children with croup is subglottic narrowing (i.e., steeple sign).63 Repeated episodes of spasmodic croup can follow, and abnormalities in lung function can persist for several years in some children.64 It is unclear whether disposition precedes or results from viral infection. Bronchiolitis.  Historically, HPIVs have been considered the second in frequency to RSV as a cause of bronchiolitis. However, the use of molecular diagnostics has identified other respiratory viruses more frequently than HPIV as etiologic agents of bronchiolitis.65,66 All four types of HPIV can cause bronchiolitis, but HPIV-1 and HPIV-3 have been reported most frequently.3,8,42 More than 80% of cases of bronchiolitis occur during the first year of life, and most affect infants are younger than 6 months of age. HPIV-1 and HPIV-3 cause 5% to 15% of bronchiolitis cases in children, respectively, and approximately 0.2 per 1000 children with HPIV bronchiolitis require hospitalization.42 Most hospitalizations for bronchiolitis occur from November through April. Using US National Hospital Discharge Survey data over 18 years, HPIV-related bronchiolitis hospitalizations in children younger than 1 year of age peaked earlier during odd-numbered years than even-numbered years, resulting in a longer season.8 Predominant symptoms include fever, tachypnea, retractions, expiratory wheezing, rales, and air trapping. Bronchiolitis caused by HPIVs is clinically indistinguishable from that caused by other respiratory viruses. Virus-induced asthma and asthma exacerbations are more commonly associated with respiratory viruses other than HPIVs in children and adults.67,68 Nevertheless, asthma is diagnosed commonly in children older than 2 years of age with any type of HPIV infection.3,36 Pneumonia.  All HPIV types can cause pneumonia. HPIV-1, -2, and -3 are responsible for approximately 10% of pneumonia cases in the outpatient setting and 7% to 15% of cases in hospitalized children of all ages.69–73 The percentage of hospitalized children diagnosed with HPIV pneumonia, including those requiring admission to a pediatric intensive care unit, is higher in the first year of life, and as with bronchiolitis, it most often is associated with HPIV-3 infection.42,74 HPIV pneumonia occurs more frequently and is more severe in chronically ill or immunocompromised children.36,75 In hematopoietic stem cell transplant (HSCT) recepients, HPIV infection can result in refractory pneumonia with prolonged viral shedding, viral dissemination, and high mortality rates.5,26,76 Otitis Media.  In 10% to 35% of children with an HPIV URI, acute otitis media (AOM) follows 3 to 4 days after onset of the URI.54,55,77–81 In a study conducted over 20 years among previously healthy children younger than 5 years of age using culture techniques, the rate of AOM was higher for HPIV-3 than for HPIV-1 and HPIV-2 infection.7 Other data have confirmed these findings and also suggest that HPIV-4 is a common cause of AOM in children.36 Other Manifestations.  Neonates, particularly premature infants, infected with HPIV can have apnea.3,52 Fever and febrile seizures have been reported in young infants with HPIV infections, and it is the most

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common finding in older children with HPIV infections regardless of the HPIV type.36 A study conducted from 2000 to 2004 and enrolling 2798 children younger than 5 years of age showed that HPIVs accounted for 6.8% of all hospitalizations for fever or acute respiratory illness, or both.3 Conjunctivitis and gastroenteritis also occur frequently, with no HPIV type associations.33,36 Cases of parotitis, myopericarditis, aseptic meningitis, encephalitis, and Guillain-Barré syndrome are reported, suggesting possible neurotropism of some strains.82–84 Disseminated infection can occur in immunosuppressed people.85

LABORATORY FINDINGS AND DIAGNOSIS Specific diagnosis requires identification of the virus in respiratory secretions. PCR is the preferred diagnostic test because of its high sensitivity and rapidity. Because HPIVs rarely are isolated in otherwise healthy asymptomatic children, detection of the virus in the context of an acute respiratory illness suggests causality.86,87 Respiratory specimens for viral diagnosis should be collected early in the course of illness. Nasopharyngeal aspirates or swabs are the preferred samples. Rates of HPIV detection may be similar with a nasopharyngeal swab or NP aspirate, and a paired nasopharyngeal and oropharyngeal swab may increase sensitivity.88,89 Direct sampling by bronchoalveolar lavage or lung biopsy may be necessary to identify the virus and establish causality in immunocompromised hosts with lower respiratory tract disease.90 For virus isolation, immediate placement of samples on ice (or refrigeration at 4°C) and transport to the laboratory for tissue culture inoculation are critical. Reverse transcriptase PCR (RT-PCR) has replaced tissue culture and indirect immunofluorescence(IF) techniques for the identification of all HPIV types.91,92 RT-PCR is especially useful for the diagnosis of HPIV infections in critically ill patients, especially those who are immunocompromised.93–95 Rapid antigen diagnostic tests using IF techniques are available for HPIV-1, -2, and -3, and although specific, they are less sensitive than PCR.96 Serologic assays based on hemagglutination inhibition or enzyme immunoassays can be used to detect serum IgM or IgG antibodies against HPIV, but they have limited value in disease management.

TREATMENT No specific antiviral therapy is available for HPIV infection. Most HPIV infections are self-limited in immunocompetent hosts and do not require treatment. For the management of croup, dexamethasone and nebulized epinephrine have been associated with improved clinical outcomes.57 Management of bronchiolitis is supportive. Ribavirin has in vitro activity against HPIVs. The use of ribavirin (mostly inhaled) has been reported for immunocompromised children and adults with severe HPIV pneumonia with or without concomitant administration of immune globulin intravenous (IGIV); however, controlled studies are lacking.26,97,98 DAS181 is a sialidase fusion protein with activity against influenza and HPIV that removes sialic acid–containing receptors from the surface of respiratory epithelial cells, preventing virus binding. Use of DAS181 for the treatment of HPIV LRI in lung and HSCT patients, including children, has reduced viral loads and improved clinical symptoms.99–103 Other novel antiviral agents have activity against HPIV. The hemagglutinin-neuraminidase inhibitors (i.e., BCX 2855 and BCX 2798) appear promising. Although there are no data on use in humans, the agents have potent in vitro activity against HPIV and appear to be beneficial in animal models of infection.104–106 Nitazoxanide, originally developed as an antiprotozoan agent, has broad antiviral activity. In a randomized, placebo-controlled clinical trial enrolling patients with laboratory-confirmed influenza, nitazoxanide treatment reduced viral shedding and duration of symptoms.107 Its potential role in the treatment of HPIV infections is not known.108 There are anecdotal reports of using interferon α-2b in HPIV-infected patients.109 During the acute infection, efforts should be aimed at decreasing healthcare-associated infections. In addition to standard precautions, contact precautions are recommended for hospitalized infants and young children for the duration of illness. Prevention of environmental contamination by respiratory tract secretions and careful hand hygiene should control healthcare-associated spread.

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

SPECIAL CONSIDERATIONS Immunocompromised Hosts Parainfluenza infections are associated with substantial morbidity and mortality for children and adults with congenital or acquired immunodeficiencies, including HSCT and solid-organ transplant (SOT) recipients, children with cancer undergoing chemotherapy, and children with severe T-lymphocyte deficiencies. Although nosocomial infections have been described, most HPIV outbreaks in transplantation units coincide with the peak incidence of these infections in the community.110 Hematologic Malignancies.  In children with leukemia or lymphoma, HPIV has been detected in 10% of cases and was the second most common respiratory viral infection identified. Ninety percent of infections were acquired in the community, and 61% were caused by HPIV-3. Neutropenia and lymphopenia at onset of infection were associated with progression to LRI.111 Hematopoietic Stem Cell and Solid-Organ Transplantation.  Among patients undergoing HSCT, the incidence of HPIV infections ranges from 4% to 7%, of which up to 40% progress to LRI.90,106,112 In this setting, HPIV pneumonia is associated with prolonged viral shedding, viremia, and mortality rates of up to 40%. Most cases of HPIV pneumonia have been associated with HPIV-3.26,48,113–116 The most severe illnesses and 90% of the deaths related to HPIV pneumonia occur in the first 100 days after transplantation, when lymphopenia is most pronounced. Use of unrelated donors, myeloablative conditioning regimens, and high-dose corticosteroids for the treatment of graft-versus-host disease are identifiable risk factors for progression to pneumonia.26,112,117 Other respiratory copathogens frequently are identified in patients with HPIV-3 pneumonia and may contribute to the significant morbidity and mortality rates. Solid-organ transplant recipients, especially those undergoing lung transplantation, have increased HPIV-associated mortality rates and severe morbidity, including chronic rejection and development of bronchiolitis obliterans.118–121 Airflow decline has been linked to HPIV pneumonia and HPIV URIs in HSCT recipients.122

Congenital or Acquired Immunodeficiencies.  Patients with primary immunodeficiencies can have prolonged HPIV shedding, particularly when infected with HPIV-3. Fatal giant cell pneumonia has been described in children with severe combined immunodeficiency and IFNγ receptor deficiency syndrome.123,124 In children infected with the human immunodeficiency virus type1 (HIV-1), HPIV infections have been associated with increased morbidity and mortality rates in developing countries.75,125 Prolonged shedding occurs in HIV-infected children.126,127

PREVENTION The lack of durable immunity and full understanding of the mechanisms responsible for immune protection have hampered the development of HPIV vaccines.128 Formalin-inactivated vaccine preparations developed in the late 1960s were immunogenic in infants and did not cause enhanced disease, but they did not confer protection.129 Subsequently, subunit vaccine candidates containing HN or F protein showed some protection in animals against LRI but failed to protect against URI and have not been evaluated in human clinical trials.130 Live, attenuated and subunit vaccine candidates are being studied in humans. Two strategies have been used for the development of live, attenuated HPIV-3 vaccines: use of an antigenically related strain (i.e., bovine PIV-3) or Sendai virus (murine PIV-3), and use of a cold-adapted HPIV-3 strain. These candidate vaccines have been safe and well tolerated in children and adults.131–134 Improved seroconversion rates and immunogenicity have been demonstrated with live, attenuated candidate vaccines administered intranasally.135,136 Reverse genetics has allowed the development of recombinant rHPIV-1, -2 and -3 and chimeric bovine/human PIV-3 virus (rB/HPIV-3) candidate vaccines that are undergoing testing in seropositive and seronegative children. Early results are promising.137–142 This technology allows rapid production of the vaccine with minimal risk for contamination. All references are available online at www.expertconsult.com.

Key Points: Diagnosis and Management of Human Parainfluenza Virus (HPIV) Infections MICROBIOLOGY • Enveloped, negative-sense, single-stranded RNA paramyxovirus • Five types: HPIV-1, -2, -3, -4A, and -4B

• HPIV infection can result in refractory pneumonia, with a mortality rate of approximately 40% for hematopoietic stem cell transplant patients.

EPIDEMIOLOGY

DIAGNOSIS

• Different HPIVs have distinct epidemiologic patterns ■ HPIV-3 is endemic with peaks in the spring. ■ HPIV-1 and HPIV-2 cause outbreaks of croup. ■ HPIV-4 causes biennial peaks in the fall and winter. • Age of primary infection varies for each serotype. • By age 5 years, almost all children have been infected with all HPIVs. • HPIV infection does not confer protective immunity, and reinfections are common throughout life. • HPIVs are transmitted from person to person by direct contact and exposure to contaminated droplets and fomites.

• Polymerase chain reaction (PCR), direct fluorescent antibody, or viral culture from respiratory secretions (nasopharyngeal swab or aspirate) • PCR is the preferred method, especially for an HPIV-4 diagnosis and immunocompromised, critically ill children and elderly persons. • Bronchoalveolar lavage or lung biopsy may be required to confirm the cause of infection in immunocompromised or hematopoietic stem cell transplant (HSCT) patients.

CLINICAL FEATURES • HPIVs account for 18% to 45% of all upper respiratory tract illnesses in children. • Acute otitis media occurs in 10% to 35% of children after HPIV upper respiratory tract infection. • HPIV-1 and -2 are the most frequent causes of croup in children 1 to 5 years of age. • HPIV-3 is associated predominantly with bronchiolitis and pneumonia (children <1 year old). • HPIV-4 is mostly associated with upper respiratory infections in healthy children.

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TREATMENT • Most HPIV infections are self-limited in immunocompetent hosts and do not require treatment. • Ribavirin (inhaled) with or without immune globulin intravenous (IGIV) has been used in immunocompromised patients with severe pneumonia. • New antiviral therapies include DAS181 and hemagglutininneuraminidase inhibitors. • Several vaccine candidates (i.e., recombinant and live, attenuated viruses) are being tested. • Assiduous infection prevention measures are critical to prevent nosocomial transmission, especially for HSCT recipients.

KEY REFERENCES 3. Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization. J Pediatr 2009;154:694–699. 5. Seo S, Xie H, Campbell AP, et al. Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the lung predicts outcome. Clin Infect Dis 2014;58:1357–1368. 7. Reed G, Jewett PH, Thompson J, et al. Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children <5 years old. J Infect Dis 1997;175:807–813.

34. Fry AM, Curns AT, Harbour K, et al. Seasonal trends of human parainfluenza viral infections: United States, 1990–2004. Clin Infect Dis 2006;43:1016–1022. 36. Frost HM, Robinson CC, Dominguez SR. Epidemiology and clinical presentation of parainfluenza type 4 in children: a 3-year comparative study to parainfluenza types 1–3. J Infect Dis 2014;209:695–702. 39. Laurichesse H, Dedman D, Watson JM, Zambon MC. Epidemiological features of parainfluenza virus infections: laboratory surveillance in England and Wales, 1975–1997. Eur J Epidemiol 1999;15:475–484. 71. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015;372:835–845.

Parainfluenza Viruses

REFERENCES 1. Chanock RM, Parrott RH. Acute respiratory disease in infancy and childhood: present understanding and prospects for prevention. Pediatrics 1965;36:21–39. 2. Glezen P, Denny FW. Epidemiology of acute lower respiratory disease in children. N Engl J Med 1973;288:498–505. 3. Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization. J Pediatr 2009;154:694–699. 4. Falsey AR, Walsh EE. Viral pneumonia in older adults. Clin Infect Dis 2006;42:518–524. 5. Seo S, Xie H, Campbell AP, et al. Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the lung predicts outcome. Clin Infect Dis 2014;58:1357–1368. 6. Glezen WP, Greenberg SB, Atmar RL, et al. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000;283:499–505. 7. Reed G, Jewett PH, Thompson J, et al. Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children <5 years old. J Infect Dis 1997;175:807–813. 8. Counihan ME, Shay DK, Holman RC, et al. Human parainfluenza virus-associated hospitalizations among children less than five years of age in the United States. Pediatr Infect Dis J 2001;20:646–653. 9. Wang CY, Arden KE, Greer R, et al. A novel duplex real-time PCR for HPIV-4 detects co-circulation of both viral subtypes among ill children during 2008. J Clin Virol 2012;54:83–85. 10. Henrickson KJ. Parainfluenza viruses. Clin Microbiol Rev 2003;16:242–264. 11. Zhang L, Collins PL, Lamb RA, Pickles RJ. Comparison of differing cytopathic effects in human airway epithelium of parainfluenza virus 5 (W3A), parainfluenza virus type 3, and respiratory syncytial virus. Virology 2011;421:67–77. 12. Palmer SG, DeVito I, Jenkins SG, et al. Circulating clinical strains of human parainfluenza virus reveal viral entry requirements for in vivo infection. J Virol 2014;88:13495–13502. 13. Bjornson CL, Johnson DW. Croup. Lancet 2008;371:329–339. 14. Massion PP, Funari CC, Ueki I, et al. Parainfluenza (Sendai) virus infects ciliated cells and secretory cells but not basal cells of rat tracheal epithelium. Am J Respir Cell Mol Biol 1993;9:361–370. 15. do Carmo Debur M, Raboni SM, Flizikowski FB, et al. Immunohistochemical assessment of respiratory viruses in necropsy samples from lethal non-pandemic seasonal respiratory infections. J Clin Pathol 2010;63:930–934. 16. Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med 2001;344:1917–1928. 17. Plotnicky-Gilquin H, Cyblat D, Aubry JP, et al. Differential effects of parainfluenza virus type 3 on human monocytes and dendritic cells. Virology 2001;285:82–90. 18. Roger T, Bresser P, Snoek M, et al. Exaggerated IL-8 and IL-6 responses to TNFalpha by parainfluenza virus type 4-infected NCI-H292 cells. Am J Physiol Lung Cell Mol Physiol 2004;287:L1048–L1055. 19. El Feghaly RE, McGann L, Bonville CA, et al. Local production of inflammatory mediators during childhood parainfluenza virus infection. Pediatr Infect Dis J 2010;29:e26–e31. 20. Hall CB, Douglas RG Jr, Simons RL, Geiman JM. Interferon production in children with respiratory syncytial, influenza, and parainfluenza virus infections. J Pediatr 1978;93:28–32. 21. Elliott MB, Welliver RC Sr, Laughlin TS, et al. Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the respiratory tracts of human infants following paramyxovirus infection. J Med Virol 2007;79:447–456. 22. Parainfluenza viral infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds) Red Book: 2012 Report of the Committee on Infectious Diseases. Elk Grove Village, IL, American Academy of Pediatrics, 2012, pp 533–534. 23. Renaud C, Campbell AP. Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. Curr Opin Infect Dis 2011;24:333–343. 24. Welliver RC, Sun M, Rinaldo D. Defective regulation of immune responses in croup due to parainfluenza virus. Pediatr Res 1985;19:716–720. 25. Sydnor ER, Greer A, Budd AP, et al. An outbreak of human parainfluenza virus 3 infection in an outpatient hematopoietic stem cell transplantation clinic. Am J Infect Control 2012;40:601–605. 26. Nichols WG, Corey L, Gooley T, et al. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood 2001;98:573–578. 27. Tremonti LP, Lin JS, Jackson GG. Neutralizing activity in nasal secretions and serum in resistance of volunteers to parainfluenza virus type 2. J Immunol 1968;101:572–577. 28. Smith CB, Purcell RH, Bellanti JA, Chanock RM. Protective effect of antibody to parainfluenza type 1 virus. N Engl J Med 1966;275:1145–1152. 29. Yanagihara R, McIntosh K. Secretory immunological response in infants and children to parainfluenza virus types 1 and 2. Infect Immun 1980;30:23–28. 30. Glezen WP, Frank AL, Taber LH, Kasel JA. Parainfluenza virus type 3: seasonality and risk of infection and reinfection in young children. J Infect Dis 1984;150: 851–857. 31. Chanock RM, Parrott RH, Johnson KM, et al. Myxoviruses: parainfluenza. Am Rev Respir Dis 1963;88(suppl):52–166. 32. Shek LP, Lee BW. Epidemiology and seasonality of respiratory tract virus infections in the tropics. Paediatr Respir Rev 2003;4:105–111. 33. Liu WK, Liu Q, Chen DH, et al. Epidemiology and clinical presentation of the four human parainfluenza virus types. BMC Infect Dis 2013;13:28.

223

34. Fry AM, Curns AT, Harbour K, et al. Seasonal trends of human parainfluenza viral infections: United States, 1990–2004. Clin Infect Dis 2006;43:1016–1022. 35. Fairchok MP, Martin ET, Kuypers J, Englund JA. A prospective study of parainfluenza virus type 4 infections in children attending daycare. Pediatr Infect Dis J 2011;30:714–716. 36. Frost HM, Robinson CC, Dominguez SR. Epidemiology and clinical presentation of parainfluenza type 4 in children: a 3-year comparative study to parainfluenza types 1–3. J Infect Dis 2014;209:695–702. 37. Lau SK, Li KS, Chau KY, et al. Clinical and molecular epidemiology of human parainfluenza virus 4 infections in Hong Kong: subtype 4B as common as subtype 4A. J Clin Microbiol 2009;47:1549–1552. 38. Lee MS, Mendelman PM, Sangli C, et al. Half-life of human parainfluenza virus type 3 (hPIV3) maternal antibody and cumulative proportion of hPIV3 infection in young infants. J Infect Dis 2001;183:1281–1284. 39. Laurichesse H, Dedman D, Watson JM, Zambon MC. Epidemiological features of parainfluenza virus infections: laboratory surveillance in England and Wales, 1975–1997. Eur J Epidemiol 1999;15:475–484. 40. Ren L, Gonzalez R, Xie Z, et al. Human parainfluenza virus type 4 infection in Chinese children with lower respiratory tract infections: a comparison study. J Clin Virol 2011;51:209–212. 41. Griffin MR, Walker FJ, Iwane MK, et al. Epidemiology of respiratory infections in young children: insights from the new vaccine surveillance network. Pediatr Infect Dis J 2004;23:S188–S192. 42. Abedi GR, Prill MM, Langley GE, et al. Estimates of parainfluenza virus-associated hospitalizations and cost among children aged less than 5 years in the United States, 1998–2010. J Pediatr Infect Dis 2014;1–7. 43. Williams JV, Edwards KM, Weinberg GA, et al. Population-based incidence of human metapneumovirus infection among hospitalized children. J Infect Dis 2010;201:1890–1898. 44. Madhi SA, Klugman KP, and the Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004;10:811–813. 45. Falsey AR, McElhaney JE, Beran J, et al. Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness. J Infect Dis 2014;209:1873–1881. 46. Ansari SA, Springthorpe VS, Sattar SA, et al. Potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus 3 and rhinovirus 14. J Clin Microbiol 1991;29:2115–2159. 47. Brady MT, Evans J, Cuartas J. Survival and disinfection of parainfluenza viruses on environmental surfaces. Am J Infect Control 1990;18:18–23. 48. Lee AV, Bibby DF, Oakervee H, et al. Nosocomial transmission of parainfluenza 3 virus in hematological patients characterized by molecular epidemiology. Transpl Infect Dis 2011;13:433–437. 49. Maziarz RT, Sridharan P, Slater S, et al. Control of an outbreak of human parainfluenza virus 3 in hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 2010;16:192–198. 50. Jalal H, Bibby DF, Bennett J, et al. Molecular investigations of an outbreak of parainfluenza virus type 3 and respiratory syncytial virus infections in a hematology unit. J Clin Microbiol 2007;45:1690–1696. 51. Teo WY, Rajadurai VS, Sriram B. Morbidity of parainfluenza 3 outbreak in preterm infants in a neonatal unit. Ann Acad Med Singapore 2010;39:837–842. 52. Ronchi A, Michelow IC, Chapin KC, et al. Viral respiratory tract infections in the neonatal intensive care unit: the VIRIoN-I study. J Pediatr 2014;165: 690–696. 53. Hodson A, Kasliwal M, Streetly M, et al. A parainfluenza-3 outbreak in a SCT unit: sepsis with multi-organ failure and multiple co-pathogens are associated with increased mortality. Bone Marrow Transplant 2011;46:1545–1550. 54. Wiertsema SP, Chidlow GR, Kirkham LA, et al. High detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media. J Med Virol 2011;83: 2008–2017. 55. Chonmaitree T, Revai K, Grady JJ, et al. Viral upper respiratory tract infection and otitis media complication in young children. Clin Infect Dis 2008;46:815–823. 56. Lau SK, To WK, Tse PW, et al. Human parainfluenza virus 4 outbreak and the role of diagnostic tests. J Clin Microbiol 2005;43:4515–4521. 57. Cherry JD. Clinical practice. Croup. N Engl J Med 2008;358:384–391. 58. Chang ML, Jordan-Villegas A, Evans A, et al. Respiratory viruses identified in an urban children’s hospital emergency department during the 2009 influenza A(H1N1) pandemic. Pediatr Emerg Care 2012;28:990–997. 59. Martin ET, Fairchok MP, Stednick ZJ, et al. Epidemiology of multiple respiratory viruses in childcare attendees. J Infect Dis 2013;207:982–989. 60. Fowlkes A, Giorgi A, Erdman D, et al. Viruses associated with acute respiratory infections and influenza-like illness among outpatients from the Influenza Incidence Surveillance Project, 2010–2011. J Infect Dis 2014;209:1715–1725. 61. Marx A, Torok TJ, Holman RC, et al. Pediatric hospitalizations for croup (laryngotracheobronchitis): biennial increases associated with human parainfluenza virus 1 epidemics. J Infect Dis 1997;176:1423–1427. 62. Segal AO, Crighton EJ, Moineddin R, et al. Croup hospitalizations in Ontario: a 14-year time-series analysis. Pediatrics 2005;116:51–55. 63. Huang CC, Shih SL. Images in clinical medicine: steeple sign of croup. N Engl J Med 2012;367:66. 64. Gurwitz D, Corey M, Levison H. Pulmonary function and bronchial reactivity in children after croup. Am Rev Respir Dis 1980;122:95–99. 65. Mansbach JM, Piedra PA, Teach SJ, et al. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med 2012;166:700–706.

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses 66. Calvo C, Pozo F, Garcia-Garcia ML, et al. Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study. Acta Paediatr 2010;99:883–887. 67. Thomas AO, Lemanske RF Jr, Jackson DJ. Infections and their role in childhood asthma inception. Pediatr Allergy Immunol 2014;25:122–128. 68. Jartti T, Lee WM, Pappas T, et al. Serial viral infections in infants with recurrent respiratory illnesses. Eur Respir J 2008;32:314–320. 69. Nascimento-Carvalho CM, Cardoso MR, Barral A, et al. Seasonal patterns of viral and bacterial infections among children hospitalized with community-acquired pneumonia in a tropical region. Scand J Infect Dis 2010;42:839–844. 70. Mathisen M, Strand TA, Sharma BN, et al. RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal: a cross-sectional study. BMC Med 2009;7:35. 71. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015;372:835–845. 72. Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis 2004;39:681–686. 73. Cilla G, Onate E, Perez-Yarza EG, et al. Viruses in community-acquired pneumonia in children aged less than 3 years old: high rate of viral coinfection. J Med Virol 2008;80:1843–1849. 74. Berkley JA, Munywoki P, Ngama M, et al. Viral etiology of severe pneumonia among Kenyan infants and children. JAMA 2010;303:2051–2057. 75. Madhi SA, Ramasamy N, Petersen K, et al. Severe lower respiratory tract infections associated with human parainfluenza viruses 1–3 in children infected and noninfected with HIV type 1. Eur J Clin Microbiol Infect Dis 2002;21:499–505. 76. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006;85:278–287. 77. Nokso-Koivisto J, Raty R, Blomqvist S, et al. Presence of specific viruses in the middle ear fluids and respiratory secretions of young children with acute otitis media. J Med Virol 2004;72:241–248. 78. Nokso-Koivisto J, Marom T, Chonmaitree T. Importance of viruses in acute otitis media. Curr Opin Pediatr 2015;27:110–115. 79. Ruohola A, Pettigrew MM, Lindholm L, et al. Bacterial and viral interactions within the nasopharynx contribute to the risk of acute otitis media. J Infect 2013;66:247–254. 80. Stockmann C, Ampofo K, Hersh AL, et al. Seasonality of acute otitis media and the role of respiratory viral activity in children. Pediatr Infect Dis J 2013;32:314–319. 81. Alper CM, Winther B, Mandel EM, et al. Rate of concurrent otitis media in upper respiratory tract infections with specific viruses. Arch Otolaryngol Head Neck Surg 2009;135:17–21. 82. Arisoy ES, Demmler GJ, Thakar S, Doerr C. Meningitis due to parainfluenza virus type 3: report of two cases and review. Clin Infect Dis 1993;17:995–997. 83. Romero-Gomez MP, Guereta L, Pareja-Grande J, et al. Myocarditis caused by human parainfluenza virus in an immunocompetent child initially associated with 2009 influenza A (H1N1) virus. J Clin Microbiol 2011;49:2072–2073. 84. Roman G, Phillips CA, Poser CM. Parainfluenza virus type 3: isolation from CSF of a patient with Guillain-Barré syndrome. JAMA 1978;240:1613–1615. 85. Frank JA Jr, Warren RW, Tucker JA, et al. Disseminated parainfluenza infection in a child with severe combined immunodeficiency. Am J Dis Child 1983;137: 1172–1174. 86. Jartti T, Jartti L, Peltola V, et al. Identification of respiratory viruses in asymptomatic subjects: asymptomatic respiratory viral infections. Pediatr Infect Dis J 2008;27:1103–1107. 87. Chonmaitree T, Alvarez-Fernandez P, Jennings K, et al. Symptomatic and asymptomatic respiratory viral infections in the first year of life: association with acute otitis media development. Clin Infect Dis 2015;60:1–9. 88. Lambert SB, Whiley DM, O’Neill NT, et al. Comparing nose-throat swabs and nasopharyngeal aspirates collected from children with symptoms for respiratory virus identification using real-time polymerase chain reaction. Pediatrics 2008;122:e615–e620. 89. Hammitt LL, Kazungu S, Welch S, et al. Added value of an oropharyngeal swab in detection of viruses in children hospitalized with lower respiratory tract infection. J Clin Microbiol 2011;49:2318–2320. 90. Seo S, Xie H, Karron RA, et al. Parainfluenza virus type 3 Ab in allogeneic hematopoietic cell transplant recipients: factors influencing post-transplant Ab titers and associated outcomes. Bone Marrow Transplant 2014;49:1205–1211. 91. Weinberg GA, Erdman DD, Edwards KM, et al. Superiority of reverse-transcription polymerase chain reaction to conventional viral culture in the diagnosis of acute respiratory tract infections in children. J Infect Dis 2004;189:706–710. 92. Selvaraju SB, Selvarangan R. Evaluation of xTAG Respiratory Viral Panel FAST and xTAG Human Parainfluenza Virus Analyte-Specific Reagents for detection of human parainfluenza viruses in respiratory specimens. Diagn Microbiol Infect Dis 2012;72:278–281. 93. Aramburo A, van Schaik S, Louie J, et al. Role of real-time reverse transcription polymerase chain reaction for detection of respiratory viruses in critically ill children with respiratory disease: is it time for a change in algorithm? Pediatr Crit Care Med 2011;12:e160–e165. 94. Kuypers J, Campbell AP, Cent A, et al. Comparison of conventional and molecular detection of respiratory viruses in hematopoietic cell transplant recipients. Transpl Infect Dis 2009;11:298–303. 95. Casiano-Colon AE, Hulbert BB, Mayer TK, et al. Lack of sensitivity of rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults. J Clin Virol 2003;28:169–174.

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96. Terlizzi ME, Massimiliano B, Francesca S, et al. Quantitative RT real time PCR and indirect immunofluorescence for the detection of human parainfluenza virus 1, 2, 3. J Virol Methods 2009;160:172–177. 97. Chakrabarti S, Collingham KE, Holder K, et al. Parainfluenza virus type 3 infections in hematopoetic stem cell transplant recipients: response to ribavirin therapy. Clin Infect Dis 2000;31:1516–1518. 98. Stankova J, Carret AS, Moore D, et al. Long-term therapy with aerosolized ribavirin for parainfluenza 3 virus respiratory tract infection in an infant with severe combined immunodeficiency. Pediatr Transplant 2007;11:209–213. 99. Moss RB, Hansen C, Sanders RL, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis 2012;206:1844–1851. 100. Chen YB, Driscoll JP, McAfee SL, et al. Treatment of parainfluenza 3 infection with DAS181 in a patient after allogeneic stem cell transplantation. Clin Infect Dis 2011;53:e77–e80. 101. Drozd DR, Limaye AP, Moss RB, et al. DAS181 treatment of severe parainfluenza type 3 pneumonia in a lung transplant recipient. Transpl Infect Dis 2013;15:E28–E32. 102. Guzman-Suarez BB, Buckley MW, Gilmore ET, et al. Clinical potential of DAS181 for treatment of parainfluenza-3 infections in transplant recipients. Transpl Infect Dis 2012;14:427–433. 103. Waghmare A, Wagner T, Andrews R, et al. Succesful treatment of parainfluenza virus respiratory tract infection with DAS181 in 4 immunocompromised children. J Pediatr Infect Dis 2014;1–5. 104. Alymova IV, Taylor G, Takimoto T, et al. Efficacy of novel hemagglutininneuraminidase inhibitors BCX 2798 and BCX 2855 against human parainfluenza viruses in vitro and in vivo. Antimicrob Agents Chemother 2004;48:1495–1502. 105. Guillon P, Dirr L, El-Deeb IM, et al. Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin-neuraminidase inhibitors. Nature Commun 2014;5:5268. 106. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. Clin Infect Dis 2014;59(suppl 5):S344–S351. 107. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 2014;14:609–618. 108. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res 2014;110:94–103. 109. Marinez J, Vincent A, Sandin R, Greene J. Interferon alfa-2b as a successful treatment for parainfluenza virus pneumonia in a non-Hodgkin lymphoma patient. Infect Dis Clin Pract 2008;16:187–189. 110. Lee I, Barton TD. Viral respiratory tract infections in transplant patients: epidemiology, recognition and management. Drugs 2007;67:1411–1427. 111. Srinivasan A, Wang C, Yang J, et al. Parainfluenza virus infections in children with hematologic malignancies. Pediatr Infect Dis J 2011;30:855–859. 112. Srinivasan A, Wang C, Yang J, et al. Symptomatic parainfluenza virus infections in children undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1520–1527. 113. Campbell AP, Chien JW, Kuypers J, et al. Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT. J Infect Dis 2010;201:1404–1413. 114. Nichols WG, Erdman DD, Han A, et al. Prolonged outbreak of human parainfluenza virus 3 infection in a stem cell transplant outpatient department: insights from molecular epidemiologic analysis. Biol Blood Marrow Transplant 2004;10:58–64. 115. Elizaga J, Olavarria E, Apperley J, et al. Parainfluenza virus 3 infection after stem cell transplant: relevance to outcome of rapid diagnosis and ribavirin treatment. Clin Infect Dis 2001;32:413–418. 116. Ustun C, Slaby J, Shanley RM, et al. Human parainfluenza virus infection after hematopoietic stem cell transplantation: risk factors, management, mortality, and changes over time. Biol Blood Marrow Transplant 2012;18:1580–1588. 117. Chemaly RF, Hanmod SS, Rathod DB, et al. The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation. Blood 2012;119:2738–2745, quiz 2969. 118. Harvala H, Gaunt E, McIntyre C, et al. Epidemiology and clinical characteristics of parainfluenza virus 3 outbreak in a haemato-oncology unit. J Infect 2012;65:246–254. 119. Kumar D, Husain S, Chen MH, et al. A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients. Transplantation 2010;89:1028–1033. 120. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002;21:559–566. 121. Vilchez RA, Dauber J, McCurry K, et al. Parainfluenza virus infection in adult lung transplant recipients: an emergent clinical syndrome with implications on allograft function. Am J Transplant 2003;3:116–120. 122. Erard V, Chien JW, Kim HW, et al. Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses. J Infect Dis 2006;193:1619–1625. 123. Taylor CE, Osman HK, Turner AJ, et al. Parainfluenza virus and respiratory syncytial virus infection in infants undergoing bone marrow transplantation for severe combined immunodeficiency. Commun Dis Public Health 1998;1:202–203. 124. Dorman SE, Uzel G, Roesler J, et al. Viral infections in interferon-gamma receptor deficiency. J Pediatr 1999;135:640–643. 125. Madhi SA, Schoub B, Simmank K, et al. Increased burden of respiratory viral associated severe lower respiratory tract infections in children infected with human immunodeficiency virus type-1. J Pediatr 2000;137:78–84.

Parainfluenza Viruses 126. King JC Jr, Burke AR, Clemens JD, et al. Respiratory syncytial virus illnesses in human immunodeficiency virus- and noninfected children. Pediatr Infect Dis J 1993;12:733–739. 127. Mendoza Sanchez MC, Ruiz-Contreras J, Vivanco JL, et al. Respiratory virus infections in children with cancer or HIV infection. J Pediatr Hematol Oncol 2006;28:154–159. 128. Sato M, Wright PF. Current status of vaccines for parainfluenza virus infections. Pediatr Infect Dis J 2008;27:S123–S125. 129. Chin J, Magoffin RL, Shearer LA, et al. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol 1969;89:449–463. 130. Durbin AP, Wyatt LS, Siew J, et al. The immunogenicity and efficacy of intranasally or parenterally administered replication-deficient vaccinia-parainfluenza virus type 3 recombinants in rhesus monkeys. Vaccine 1998;16:1324–1330. 131. Slobod KS, Shenep JL, Lujan-Zilbermann J, et al. Safety and immunogenicity of intranasal murine parainfluenza virus type 1 (Sendai virus) in healthy human adults. Vaccine 2004;22:3182–3186. 132. Greenberg DP, Walker RE, Lee MS, et al. A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy. J Infect Dis 2005;191:1116–1122. 133. Lee MS, Greenberg DP, Yeh SH, et al. Antibody responses to bovine parainfluenza virus type 3 (PIV3) vaccination and human PIV3 infection in young infants. J Infect Dis 2001;184:909–913. 134. Gomez M, Mufson MA, Dubovsky F, et al. Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children. Pediatr Infect Dis J 2009;28:655–658. 135. Belshe RB, Newman FK, Tsai TF, et al. Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6–18 months old. J Infect Dis 2004;189:462–470.

223

136. Belshe RB, Newman FK, Anderson EL, et al. Evaluation of combined live, attenuated respiratory syncytial virus and parainfluenza 3 virus vaccines in infants and young children. J Infect Dis 2004;190:2096–2103. 137. Bartlett EJ, Cruz AM, Boonyaratanakornkit J, et al. A novel human parainfluenza virus type 1 (HPIV1) with separated P and C genes is useful for generating C gene mutants for evaluation as live-attenuated virus vaccine candidates. Vaccine 2010;28:767–779. 138. Bernstein DI, Falloon J, Yi T. A randomized, double-blind, placebo-controlled, phase 1/2a study of the safety and immunogenicity of a live, attenuated human parainfluenza virus type 3 vaccine in healthy infants. Vaccine 2011;29: 7042–7048. 139. Bernstein DI, Malkin E, Abughali N, et al. Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children. Pediatr Infect Dis J 2012;31:109–114. 140. Englund JA, Karron RA, Cunningham CK, et al. Safety and infectivity of two doses of live-attenuated recombinant cold-passaged human parainfluenza type 3 virus vaccine rHPIV3cp45 in HPIV3-seronegative young children. Vaccine 2013;31:5706–5712. 141. Nolan SM, Surman SR, Amaro-Carambot E, et al. Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses. Vaccine 2005;23:4765–4774. 142. Karron RA, Thumar B, Schappell E, et al. Evaluation of two chimeric bovinehuman parainfluenza virus type 3 vaccines in infants and young children. Vaccine 2012;30:3975–3981.

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