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Elliott Russell, Michael G Ison, Parainfluenza Virus in the Hospitalized Adult, Clinical Infectious Diseases, Volume 65, Issue 9, 1 November 2017, Pages 1570–1576, https://doi.org/10.1093/cid/cix528
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Abstract
Parainfluenza virus (PIV) is a negative-sense single-stranded RNA virus in the Paramyxoviridae family. There are 4 serotypes that follow seasonal patterns with varying rates of infection for each serotype. PIV is an established cause of disease and death in the pediatric and immunocompromised populations, and its impact on the hospitalized adult is becoming more apparent with the increased use of multiplex molecular assays in the clinical setting. The clinical presentation of PIV in hospitalized adults varies widely and includes upper respiratory tract infections, severe lower respiratory tract infections, and exacerbations of underlying disease; 0.2%–11.5% of hospitalized patients with pneumonia have been found to have PIV infection. Currently no licensed treatment is available for PIV infection. Ribavirin has been used, but case studies show no impact on mortality rates. DAS181, an inhaled sialidase, is undergoing clinical development for the treatment of PIV in adults and children.
Although parainfluenza virus (PIV) is a known cause of significant disease and death in pediatric and immunocompromised patients, limited attention has been paid to its impact in other adult populations [1]. From the limited available evidence, PIV infections in adults cause a variety of respiratory illnesses including upper respiratory tract infections, exacerbations of chronic disease, and pneumonias [1, 2]. Compared with pediatric patients, adults infected with PIV have more variable clinical findings and the pathogen is often unsuspected due to the similar clinical presentations as other common respiratory infections [1]. Furthermore, lack of persistent seroprotection facilitates recurrent infections over the course of an individual’s life [3]. This review will focus on PIV in adults, including the virology and epidemiology of the virus, the clinical manifestation of PIV in adult patients, available treatment for those infected, and current research and development concerning a PIV vaccine. Owing to the paucity of data in immunocompetent adults, data from other established patient populations (immunocompromised, pediatric) will be included in the discussion when relevant.
VIROLOGY
PIV is a negative-sense single-stranded RNA virus in the Paramyxoviridae family. There are 4 serotypes (PIV-1, PIV-2, PIV-3, and PIV-4) [4]. PIV-1 and PIV-3 belong to genus Respirovirus, and PIV-2 and PIV-4 to genus Rubulavirus [4]. The virus particle is 150–250 nm in size and is enveloped [4]. This envelope is studded with 2 glycoproteins; one contains hemagglutinin-neuraminidase (HN) protein activity, and the other is involved in the fusion mechanism (F protein) [5]. The HN protein is responsible for attachment of the virus to the host cell via sialic acid–containing molecules on the host cell surface. The neuraminidase activity is important for removing sialic acid residues from the viral and cellular surfaces to allow for budding of the viral progeny [6].
The F protein is synthesized as an inactive precursor, activated, then mediates viral and host cell membrane fusion [7]. The HN and F proteins are exposed on the viral surface and form the antigenic targets for neutralization and protection through host antibodies and may act as targets that can be used for vaccine development, which will be discussed later [7, 8]. Unlike influenza A, no evidence for antigenic shift of the HN protein has been found, but significant nucleotide substitution in the gene encoding the HN protein has been reported and could complicate the production of an effective vaccine [9].
In addition to the HN protein and F protein, the viral genome encodes 4 other proteins: the nucleoprotein (N), phosphoprotein (P), matrix protein (M), and the large polymerase protein (L) [10]. Finally, individual serotypes encode specific proteins; PIV-1 encodes C protein, PIV-2 encodes V protein, and PIV-3 encodes C, D, and V proteins [11]. Although through unrelated mechanisms, the C and V proteins are able to suppress interferon (IFN) regulatory factor, NF-κB, and type 1 IFN pathway signaling in active infection, reducing the cellular response to infection [10, 11].
PATHOGENESIS
PIV pathogenesis of disease is mediated by viral replication and the host immune response to infection, with the relative contribution of each being depending on a number of features, including the host and virus [10]. High levels of viral replication can cause respiratory epithelial changes. Increased epithelial cell turnover and mucin-containing cell hyperplasia have been associated with the increased mucus production observed in individuals infected with PIV [10]. Syncytium formation is not as significant as seen with respiratory syncytial virus because the F protein is concentrated on the apical surface of the epithelial cells, resulting in minimal cell fusion [12]. Second, like many other respiratory viruses, the host immune response, including innate immune system, antibody, and T-cell responses, is a significant contributor to the pathogenesis of PIV infection [11, 13]. Microarray analysis of infected epithelial cells has revealed the involvement of NF-κB, IFN regulatory factor 3, and type 1 IFN in the inflammatory response to PIV infection [10]. IFN-Υ-inducible protein 10 and IFN-inducible T-cell α chemoattractant, which attract activated T-helper 1 cells, have been implicated as the major chemokines released [10, 14].
PIV initially infects the pseudostratified mucociliary airway epithelium of the nose and oropharynx, with subsequent spread to the large and small airways [15]. In addition to the factors previously discussed, the severity of disease has also been found to closely correlate with the location of PIV infection. Mild infections tend to remain limited to the upper respiratory tract, but more severe infections commonly spread to the lower airways, where certain mediators of the immune response have been found to increase increased severity of symptoms in patients with lower respiratory tract infections (LRTIs) [16]. Viremia and infection beyond the respiratory epithelium are rare and are typically encountered in immunocompromised patients [17, 18].
EPIDEMIOLOGY
The prevalence of each serotype attributed to infection varies over time, but most studies have documented PIV-3 as the most common cause of clinically significant infection (Table 1). The 4 serotypes of PIV also show remarkably different seasonal patterns. PIV-1 follows a biennial pattern, marked by a dramatic increase in cases in the months of September to December of odd-numbered years [1]. Outbreaks of PIV-3 infections occur yearly, primarily in the months of April to June. During the absence of endemic PIV-1, PIV-3 shows increased activity, either as a longer spring season or as a second but milder season in the months of November to December [19]. Similar to PIV-3, outbreaks of infection with PIV-2, which are smaller in magnitude, occur annually [19]. PIV-4 is infrequently tested for and isolated, making it difficult to draw conclusions on the seasonality of this serotype [1, 19].
PIV Serotype . | Prevalence, % (No. of Patients) . | ||
---|---|---|---|
Fry et al (2006) [19] (United States, 1990–2004; n = 40630) . | Laurichesse, et al (1999) [20] (England/Wales, 1985–1997; n = 8221) . | Mizuta et al (2012) [21] (Japan, 2002–2011; n = 1033) . | |
PIV-1 | 25.7 (10475) | 17.2 (1417) | 29.5 (305) |
PIV-2 | 12.2 (4927) | 7.5 (619) | 14.9 (154) |
PIV-3 | 51.6 (20962) | 70.8 (5819) | 55.6 (574) |
PIV-4 | 2.3 (954) | 1.1 (88) | NA |
Uncharacterized | 8.2 (3299) | 3.4 (278) | NA |
PIV Serotype . | Prevalence, % (No. of Patients) . | ||
---|---|---|---|
Fry et al (2006) [19] (United States, 1990–2004; n = 40630) . | Laurichesse, et al (1999) [20] (England/Wales, 1985–1997; n = 8221) . | Mizuta et al (2012) [21] (Japan, 2002–2011; n = 1033) . | |
PIV-1 | 25.7 (10475) | 17.2 (1417) | 29.5 (305) |
PIV-2 | 12.2 (4927) | 7.5 (619) | 14.9 (154) |
PIV-3 | 51.6 (20962) | 70.8 (5819) | 55.6 (574) |
PIV-4 | 2.3 (954) | 1.1 (88) | NA |
Uncharacterized | 8.2 (3299) | 3.4 (278) | NA |
Abbreviations: NA, not available; PIV, parainfluenza virus.
PIV Serotype . | Prevalence, % (No. of Patients) . | ||
---|---|---|---|
Fry et al (2006) [19] (United States, 1990–2004; n = 40630) . | Laurichesse, et al (1999) [20] (England/Wales, 1985–1997; n = 8221) . | Mizuta et al (2012) [21] (Japan, 2002–2011; n = 1033) . | |
PIV-1 | 25.7 (10475) | 17.2 (1417) | 29.5 (305) |
PIV-2 | 12.2 (4927) | 7.5 (619) | 14.9 (154) |
PIV-3 | 51.6 (20962) | 70.8 (5819) | 55.6 (574) |
PIV-4 | 2.3 (954) | 1.1 (88) | NA |
Uncharacterized | 8.2 (3299) | 3.4 (278) | NA |
PIV Serotype . | Prevalence, % (No. of Patients) . | ||
---|---|---|---|
Fry et al (2006) [19] (United States, 1990–2004; n = 40630) . | Laurichesse, et al (1999) [20] (England/Wales, 1985–1997; n = 8221) . | Mizuta et al (2012) [21] (Japan, 2002–2011; n = 1033) . | |
PIV-1 | 25.7 (10475) | 17.2 (1417) | 29.5 (305) |
PIV-2 | 12.2 (4927) | 7.5 (619) | 14.9 (154) |
PIV-3 | 51.6 (20962) | 70.8 (5819) | 55.6 (574) |
PIV-4 | 2.3 (954) | 1.1 (88) | NA |
Uncharacterized | 8.2 (3299) | 3.4 (278) | NA |
Abbreviations: NA, not available; PIV, parainfluenza virus.
Among immunocompromised patients, PIV also poses a large infectious burden for hematopoietic stem cell transplant (HSCT) and solid organ transplant recipients, patients with hematologic malignancy (HM), and those with human immunodeficiency virus infection, with the highest mortality rates in patients with HSCT or HM [18, 22]. In multiple studies investigating the incidence of PIV infection in adult and pediatric patients with HM or HSCT, a mean incidence of 4% (range, 0.2%–30%) was identified, with an estimated 3%–7% of patients becoming infected with PIV within 100 days after transplantation [23]. In 28 subpopulations of adult and pediatric patients with HSCT transplants or HM and PIV infections, the incidence of PIV LRTI averaged 37% (range, 0%–74%) [18]. PIV-associated mortality rates are highest in patients with LRTI disease, sepsis with multiorgan failure, and pulmonary copathogens, with an average mortality rate of 27% (range, 0%–62%) [18]. The overall mortality rate is slightly higher in hematopoietic cell transplant recipients (12%) than in patients with HM (8%) [18].
PARAINFLUENZA VIRUS IN HOSPITALIZED ADULTS
Most of the literature on PIV among hospitalized immunocompetent patients is derived from case studies or studies of small sample sizes. From these studies, PIV is the cause of 2%–15% of acute respiratory illnesses in adults and, with respiratory syncytial virus and influenza, among the major pathogens identified in adults hospitalized with acute respiratory conditions [24–27]. Hospitalization for PIV has also been associated with a “low-income” subgroup [27]. Although the subgroup is defined by monetary income, characteristics of this subgroup, compared with the “middle-income” subgroup, were significantly different. The “low-income” subgroup of adults hospitalized with PIV had increased rates of chronic pulmonary disease (asthma, chronic obstructive pulmonary disease), other high-risk conditions (diabetes, hypertension, cardiac disease), crowded living conditions, environmental pollution, and addictive behaviors, and decreased rates of regular disease management leading to increased emergency department visits [27]. Despite its clinical prevalence, few studies have defined presenting symptoms, risk factors, and outcomes of PIV in hospitalized adults.
Clinical Presentation
The clinical presentation of PIV infection in adults is indistinguishable from other that of respiratory illnesses [28]. The most prevalent clinical presentation of PIV in hospitalized adults is coldlike symptoms, including cough, rhinorrhea, and sore throat, although exacerbations of underlying disease, including asthma, chronic obstructive pulmonary disease, and congestive heart failure, is also frequent [3, 29, 30]. The severity of pulmonary disease exacerbations varies from mild to severe [31]. Increasingly, pneumonia is recognized as a common presentation for adults admitted with PIV infection, as discussed in greater detail below [2].
Asymptomatic Infection
In addition to various moderate to severe clinical presentations, mild and asymptomatic PIV infections have been documented in both immunocompetent and immunocompromised patients [1, 32]. This is not surprising, because studies of experimental infection of adults with PIV demonstrated a high rate (75%) of asymptomatic shedding. Furthermore, prolonged asymptomatic shedding of PIV-1 and PIV-3, for a period of >8 months, was found in healthy young adult males [3].
Pneumonia
Pneumonia is a leading cause of hospitalization among US adults, and viruses, including PIV, have been increasingly recognized as a predominant cause of these pneumonias [2]. Parainfluenza has been documented in 0.2%–11.5% of all hospitalized pneumonia cases in adults (Table 2). Of all hospitalized patients infected with PIV, the manifestation of pneumonia was most common (10.5%) in patients >15 years of age [20]. Patients with PIV-associated pneumonia typically present with more wheezing and rhonchi and lower leukocyte counts, and radiology typically demonstrates bilateral involvement [33]. Likewise, the clinical course of illness was different among patients with PIV pneumonia, because they had shorter lengths of hospitalization despite similar duration of supplemental oxygenation, intubation, and intensive care unit admission than patients with bacterial pneumonia [33].
Study . | PIV Serotype . | Prevalence, % (Patients, No./Total) . |
---|---|---|
Marx et al (1999) [33] | PIV-1 | 2.5 (18/721) |
PIV-2 | 0.2 (2/1057) | |
PIV-3 | 3.1 (22/705) | |
Jain et al (2015) [2] | Unspecified | 3.0 (67/2259) |
Fransén et al (1969) [37] | PIV (1–3) | 11.5% (69/598) |
Gaunt et al (2011) [35] | PIV-1 | 0.5 (72/12830) |
PIV-2 | 0.3 (39/11989) | |
PIV-3 | 2.6 (333/12831) | |
Hong et al (2014) [36] | PIV-1 | 0.8 (2/262) |
PIV-3 | 5.7 (15/262) |
Study . | PIV Serotype . | Prevalence, % (Patients, No./Total) . |
---|---|---|
Marx et al (1999) [33] | PIV-1 | 2.5 (18/721) |
PIV-2 | 0.2 (2/1057) | |
PIV-3 | 3.1 (22/705) | |
Jain et al (2015) [2] | Unspecified | 3.0 (67/2259) |
Fransén et al (1969) [37] | PIV (1–3) | 11.5% (69/598) |
Gaunt et al (2011) [35] | PIV-1 | 0.5 (72/12830) |
PIV-2 | 0.3 (39/11989) | |
PIV-3 | 2.6 (333/12831) | |
Hong et al (2014) [36] | PIV-1 | 0.8 (2/262) |
PIV-3 | 5.7 (15/262) |
Abbreviation: PIV, parainfluenza virus.
Study . | PIV Serotype . | Prevalence, % (Patients, No./Total) . |
---|---|---|
Marx et al (1999) [33] | PIV-1 | 2.5 (18/721) |
PIV-2 | 0.2 (2/1057) | |
PIV-3 | 3.1 (22/705) | |
Jain et al (2015) [2] | Unspecified | 3.0 (67/2259) |
Fransén et al (1969) [37] | PIV (1–3) | 11.5% (69/598) |
Gaunt et al (2011) [35] | PIV-1 | 0.5 (72/12830) |
PIV-2 | 0.3 (39/11989) | |
PIV-3 | 2.6 (333/12831) | |
Hong et al (2014) [36] | PIV-1 | 0.8 (2/262) |
PIV-3 | 5.7 (15/262) |
Study . | PIV Serotype . | Prevalence, % (Patients, No./Total) . |
---|---|---|
Marx et al (1999) [33] | PIV-1 | 2.5 (18/721) |
PIV-2 | 0.2 (2/1057) | |
PIV-3 | 3.1 (22/705) | |
Jain et al (2015) [2] | Unspecified | 3.0 (67/2259) |
Fransén et al (1969) [37] | PIV (1–3) | 11.5% (69/598) |
Gaunt et al (2011) [35] | PIV-1 | 0.5 (72/12830) |
PIV-2 | 0.3 (39/11989) | |
PIV-3 | 2.6 (333/12831) | |
Hong et al (2014) [36] | PIV-1 | 0.8 (2/262) |
PIV-3 | 5.7 (15/262) |
Abbreviation: PIV, parainfluenza virus.
However, other studies have shown that outcomes of PIV pneumonia do not differ significantly from outcomes of bacterial or mixed pneumonia [36–39]. Despite the prevalence of PIV as a cause of pneumonia, PIV is typically not among the discharge diagnoses in patients admitted with pneumonia, indicating an underappreciation of PIV as a possible cause [33]. With broader use of molecular diagnostics, data on the outcome of PIV pneumonia may be more clearly appreciated.
Age
Older age is associated with a higher risk of admission to the hospital with PIV infection, particularly among the institutionalized elderly. In a Swedish study, PIV was documented in 11% of community dwelling elderly patients admitted to the hospital for community-acquired pneumonia [34]. The elderly seem to have a higher rate of bacterial pneumonia complicating PIV infections as well as higher mortality rates [40]. In addition, 1 study identified PIV as the most common viral pathogen in patients >65 years of age hospitalized with acute respiratory conditions [27]. The highest mortality rates for PIV have been reported for patients ≥75 years old and nursing home residents [41].
TREATMENT
There currently exists no Food and Drug Administration–approved treatment for PIV infection in adults or children [3]. With the widespread use of multiplex polymerase chain reaction to test patients with respiratory infections, the burden of PIV in adult hospitalized patients has been better understood and is helping to drive development of antiviral therapy.
Ribavirin
It has been shown that ribavirin is active against paramyxoviruses through the depletion of intracellular guanosine triphosphate pools secondary to the inhibition of inosine monophosphate dehydrogenase [42]. This has led to the use of ribavirin in uncontrolled case studies to treat PIV in immunocompromised patients, often with the addition of immunoglobulin therapies. Oral, aerosolized, and intravenous ribavirin have been administered in the management of PIV (Supplementary Table S1), although the efficacy of these interventions has not been studied in prospective or randomized trials. In the 2 largest case series, ribavirin was not associated with significant improvement in viral shedding or mortality rates among patients with PIV-associated pneumonia, compared with no treatment (Table 3) [43, 44].
Study . | Serotype . | Symptoms . | Route of Administration . | Outcome, No. Survived/No. Treated . |
---|---|---|---|---|
Wendt et al (1992) [43] | NA | LRTI/URTI | Aerosolized | 7/9 |
NA | LRTI/URTI | None | 14/18 | |
Elizaga et al (2001) [44] | PIV-3 | URTI | Aerosolized | 8/8 |
PIV-3 | LRTI | Aerosolized | 4/10 | |
NA | LRTI | None | 4/4 | |
Nichols et al (2001) [45] | PIV-3 | LRTI | Aerosolized with or without IVIG | 11/31 (35%) shed virus 21 d after treatment |
PIV-3 | LRTI | None | 8/24 (33%) shed virus 21 d after treatment | |
Dignan et al (2006) [46] | PIV-3 | LRTI | Aerosolized/intravenous | 5/6 |
PIV-3 | LRTI | None | 4/6 | |
PIV-3 | URTI | Aerosolized/intravenous | 2/2 | |
PIV-3 | URTI | None | 8/9 | |
Chemaly et al (2014) [47] | PIV-3 | LRTI/URTI | Aerosolized | 8/9 |
PIV-3 | LRTI/URTI | None | 58/65 | |
Total | … | … | Aerosolized | 34/44 (77.3%) |
None | 88/102 (86.3%) |
Study . | Serotype . | Symptoms . | Route of Administration . | Outcome, No. Survived/No. Treated . |
---|---|---|---|---|
Wendt et al (1992) [43] | NA | LRTI/URTI | Aerosolized | 7/9 |
NA | LRTI/URTI | None | 14/18 | |
Elizaga et al (2001) [44] | PIV-3 | URTI | Aerosolized | 8/8 |
PIV-3 | LRTI | Aerosolized | 4/10 | |
NA | LRTI | None | 4/4 | |
Nichols et al (2001) [45] | PIV-3 | LRTI | Aerosolized with or without IVIG | 11/31 (35%) shed virus 21 d after treatment |
PIV-3 | LRTI | None | 8/24 (33%) shed virus 21 d after treatment | |
Dignan et al (2006) [46] | PIV-3 | LRTI | Aerosolized/intravenous | 5/6 |
PIV-3 | LRTI | None | 4/6 | |
PIV-3 | URTI | Aerosolized/intravenous | 2/2 | |
PIV-3 | URTI | None | 8/9 | |
Chemaly et al (2014) [47] | PIV-3 | LRTI/URTI | Aerosolized | 8/9 |
PIV-3 | LRTI/URTI | None | 58/65 | |
Total | … | … | Aerosolized | 34/44 (77.3%) |
None | 88/102 (86.3%) |
Abbreviations: IVIG, intravenous immunoglobulin; LRTI, lower respiratory tract infection; NA, not available; PIV, parainfluenza virus; URTI, upper respiratory tract infection.
aA literature search was conducted using PubMed. Studies were included if ribavirin was used to treat PIV in immunocompromised patients (compared with no ribavirin). Symptoms, route of administration, and outcome were assessed from available data in the study text. Case studies with no comparison group were excluded and can be found in Supplementary Table S1.
Study . | Serotype . | Symptoms . | Route of Administration . | Outcome, No. Survived/No. Treated . |
---|---|---|---|---|
Wendt et al (1992) [43] | NA | LRTI/URTI | Aerosolized | 7/9 |
NA | LRTI/URTI | None | 14/18 | |
Elizaga et al (2001) [44] | PIV-3 | URTI | Aerosolized | 8/8 |
PIV-3 | LRTI | Aerosolized | 4/10 | |
NA | LRTI | None | 4/4 | |
Nichols et al (2001) [45] | PIV-3 | LRTI | Aerosolized with or without IVIG | 11/31 (35%) shed virus 21 d after treatment |
PIV-3 | LRTI | None | 8/24 (33%) shed virus 21 d after treatment | |
Dignan et al (2006) [46] | PIV-3 | LRTI | Aerosolized/intravenous | 5/6 |
PIV-3 | LRTI | None | 4/6 | |
PIV-3 | URTI | Aerosolized/intravenous | 2/2 | |
PIV-3 | URTI | None | 8/9 | |
Chemaly et al (2014) [47] | PIV-3 | LRTI/URTI | Aerosolized | 8/9 |
PIV-3 | LRTI/URTI | None | 58/65 | |
Total | … | … | Aerosolized | 34/44 (77.3%) |
None | 88/102 (86.3%) |
Study . | Serotype . | Symptoms . | Route of Administration . | Outcome, No. Survived/No. Treated . |
---|---|---|---|---|
Wendt et al (1992) [43] | NA | LRTI/URTI | Aerosolized | 7/9 |
NA | LRTI/URTI | None | 14/18 | |
Elizaga et al (2001) [44] | PIV-3 | URTI | Aerosolized | 8/8 |
PIV-3 | LRTI | Aerosolized | 4/10 | |
NA | LRTI | None | 4/4 | |
Nichols et al (2001) [45] | PIV-3 | LRTI | Aerosolized with or without IVIG | 11/31 (35%) shed virus 21 d after treatment |
PIV-3 | LRTI | None | 8/24 (33%) shed virus 21 d after treatment | |
Dignan et al (2006) [46] | PIV-3 | LRTI | Aerosolized/intravenous | 5/6 |
PIV-3 | LRTI | None | 4/6 | |
PIV-3 | URTI | Aerosolized/intravenous | 2/2 | |
PIV-3 | URTI | None | 8/9 | |
Chemaly et al (2014) [47] | PIV-3 | LRTI/URTI | Aerosolized | 8/9 |
PIV-3 | LRTI/URTI | None | 58/65 | |
Total | … | … | Aerosolized | 34/44 (77.3%) |
None | 88/102 (86.3%) |
Abbreviations: IVIG, intravenous immunoglobulin; LRTI, lower respiratory tract infection; NA, not available; PIV, parainfluenza virus; URTI, upper respiratory tract infection.
aA literature search was conducted using PubMed. Studies were included if ribavirin was used to treat PIV in immunocompromised patients (compared with no ribavirin). Symptoms, route of administration, and outcome were assessed from available data in the study text. Case studies with no comparison group were excluded and can be found in Supplementary Table S1.
DAS181
DAS181 is a novel inhaled host-active antiviral composed of the Actinomyces viscosus sialidase catalytic domain linked to the human amphiregulin glycosaminoglycan-binding sequence [48]. DAS181 selectively cleaves host cell sialic acids, which are required by influenza and PIV for binding of the virus to the host cell [3]. Preclinical studies demonstrated that DAS181 was effective in a murine model of influenza (prevented 100% of fatal disease, prevented 70% of infection) [49]. Subsequently, it was studied in randomized controlled trials in humans with influenza and on a compassionate use basis in treating PIV infections in immunocompromised patients. In these PIV-infected patients, DAS181 resulted in improved pulmonary function and reduced viral loads in most of the patients (Table 4). In the largest study evaluating the use of DAS181, 16 immunocompromised patients with documented PIV infections were treated with DAS181 [56]. All patients with PIV infection alone (13 of 16) had a clinical response, and the 3 nonresponders had coinfections. Three subjects died of PIV infection within 30 days of infection [56]. A randomized, placebo-controlled study of DAS181 in immunocompromised patients with PIV was recently conducted, but results are pending (clinicaltrials.gov NCT01644877).
Series . | Age, y . | Serotype . | Posttreatment Viral Load (Interval, d)b . | Pulmonary Function . | Death (Interval, d)b . | |
---|---|---|---|---|---|---|
Pretreatment . | Posttreatment . | |||||
Chalkias et al (2014) [50] | 64 | PIV-1 | 1.91-Log decrease | Intubated | Extubated | No |
69 | PIV-3 | 1.81-Log decrease | Intubated | Extubated | No | |
Waghmare et al (2015) [51] | 12 | PIV-3 | Negative (48) | … | … | No |
7 mo | PIV-2 | Negative (69) | … | … | No | |
4 | PIV-3 | Negative (4) | … | … | No | |
3 | PIV-3 | Negative (45) | … | … | No | |
Chen et al (2011) [52] | 63 | PIV-3 | Negative (8) | FEV1, 0.76 L; DLCO, 36% | FEV1, 0.91 L; DLCO, 56% | Yes (14) |
Guzmán-Suarez et al (2012) [53] | 55 | PIV-3 | 1-Log decrease (2) | FEV1, 0.93 L; FVC, 1.12 L | FEV1, 1.18 L; FVC, 1.31 L | No |
59 | PIV-3 | Unchanged (2) | FEV1, 1.52 L; FVC, 1.74 L | FEV1, 1.69 L; FVC, 1.98 L | No | |
Dhakal et al (2016) [54] | 74 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | Yes |
35 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | No | |
Drozd et al (2013) [55] | 64 | PIV-3 | Negative (6) | High-flow mask | NC | No |
Salvatore et al (2016) [56] | 53 | PIV-1 | 3.94-Log decrease (10) | 90% on 90% FiO2 (ventilator) | 100% on 55% FiO2 (ventilator) | Yes (21) |
69 | PIV-3 | … | 96% on 50% FiO2 (face mask) | 95% on 4-L NC | No | |
64 | PIV-3 | 1.14-Log decrease (5) | 96% on 35% FiO2 (ventilator) | 97% on 50% FiO2 (ventilator) | No | |
66 | PIV-4 | 1.69-Log decrease (7) | 96% on 3-L NC | 96% on 2-L NC | No | |
67 | PIV-3 | … | 97% on 50% FiO2 (face mask) | 98% on 50% FiO2 (ventilator) | Yes (10) | |
58 | PIV-4 | … | 94% on 3-L NC | 99% on 50% FiO2 (ventilator) | No | |
65 | PIV-3/4 | … | 95% on RA | 99% on RA | No | |
29 | PIV-1 | 3.51-Log decrease (7) | 98% on 3-L NC | 99% on 3-L NC (off oxygen on d 10) | No | |
50 | PIV-1 | 0.19-Log increase (7) | 96% on 3-L NC | 95% on 3-L NC | No | |
65 | PIV-3 | … | 94% on 5-L NC | 96% on 2-L NC | No | |
72 | PIV-3 | … | 90% on RA | 94% on RA | No | |
65 | PIV-3 | … | 97% on RA | 97% on RA | No | |
60 | PIV-3 | 1.60-Log increase (5) | 96% on 6-L NC | 97% on 4-L NC (off oxygen on d 6) | Yes (21) | |
66 | PIV-4 | … | 98% on RA | 99% on RA | No | |
59 | PIV-4 | … | 100% on RA | 100% on RA | No | |
71 | PIV-4 | 2.60-Log decrease (7) | 94% on RA | 95% on RA | No |
Series . | Age, y . | Serotype . | Posttreatment Viral Load (Interval, d)b . | Pulmonary Function . | Death (Interval, d)b . | |
---|---|---|---|---|---|---|
Pretreatment . | Posttreatment . | |||||
Chalkias et al (2014) [50] | 64 | PIV-1 | 1.91-Log decrease | Intubated | Extubated | No |
69 | PIV-3 | 1.81-Log decrease | Intubated | Extubated | No | |
Waghmare et al (2015) [51] | 12 | PIV-3 | Negative (48) | … | … | No |
7 mo | PIV-2 | Negative (69) | … | … | No | |
4 | PIV-3 | Negative (4) | … | … | No | |
3 | PIV-3 | Negative (45) | … | … | No | |
Chen et al (2011) [52] | 63 | PIV-3 | Negative (8) | FEV1, 0.76 L; DLCO, 36% | FEV1, 0.91 L; DLCO, 56% | Yes (14) |
Guzmán-Suarez et al (2012) [53] | 55 | PIV-3 | 1-Log decrease (2) | FEV1, 0.93 L; FVC, 1.12 L | FEV1, 1.18 L; FVC, 1.31 L | No |
59 | PIV-3 | Unchanged (2) | FEV1, 1.52 L; FVC, 1.74 L | FEV1, 1.69 L; FVC, 1.98 L | No | |
Dhakal et al (2016) [54] | 74 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | Yes |
35 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | No | |
Drozd et al (2013) [55] | 64 | PIV-3 | Negative (6) | High-flow mask | NC | No |
Salvatore et al (2016) [56] | 53 | PIV-1 | 3.94-Log decrease (10) | 90% on 90% FiO2 (ventilator) | 100% on 55% FiO2 (ventilator) | Yes (21) |
69 | PIV-3 | … | 96% on 50% FiO2 (face mask) | 95% on 4-L NC | No | |
64 | PIV-3 | 1.14-Log decrease (5) | 96% on 35% FiO2 (ventilator) | 97% on 50% FiO2 (ventilator) | No | |
66 | PIV-4 | 1.69-Log decrease (7) | 96% on 3-L NC | 96% on 2-L NC | No | |
67 | PIV-3 | … | 97% on 50% FiO2 (face mask) | 98% on 50% FiO2 (ventilator) | Yes (10) | |
58 | PIV-4 | … | 94% on 3-L NC | 99% on 50% FiO2 (ventilator) | No | |
65 | PIV-3/4 | … | 95% on RA | 99% on RA | No | |
29 | PIV-1 | 3.51-Log decrease (7) | 98% on 3-L NC | 99% on 3-L NC (off oxygen on d 10) | No | |
50 | PIV-1 | 0.19-Log increase (7) | 96% on 3-L NC | 95% on 3-L NC | No | |
65 | PIV-3 | … | 94% on 5-L NC | 96% on 2-L NC | No | |
72 | PIV-3 | … | 90% on RA | 94% on RA | No | |
65 | PIV-3 | … | 97% on RA | 97% on RA | No | |
60 | PIV-3 | 1.60-Log increase (5) | 96% on 6-L NC | 97% on 4-L NC (off oxygen on d 6) | Yes (21) | |
66 | PIV-4 | … | 98% on RA | 99% on RA | No | |
59 | PIV-4 | … | 100% on RA | 100% on RA | No | |
71 | PIV-4 | 2.60-Log decrease (7) | 94% on RA | 95% on RA | No |
Abbreviations: DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in first second of expiration; FiO2, fraction of inspired oxygen; FVC, forced vital capacity; NC, nasal cannula; PIV, parainfluenza virus; RA, room air.
aA literature search was conducted using PubMed. Studies were included if DAS181 was used to treat PIV in immunocompromised patients. Viral load, pulmonary function, and death or survival was assessed from available data in the study text. No studies were excluded.
bDays after the end of treatment.
Series . | Age, y . | Serotype . | Posttreatment Viral Load (Interval, d)b . | Pulmonary Function . | Death (Interval, d)b . | |
---|---|---|---|---|---|---|
Pretreatment . | Posttreatment . | |||||
Chalkias et al (2014) [50] | 64 | PIV-1 | 1.91-Log decrease | Intubated | Extubated | No |
69 | PIV-3 | 1.81-Log decrease | Intubated | Extubated | No | |
Waghmare et al (2015) [51] | 12 | PIV-3 | Negative (48) | … | … | No |
7 mo | PIV-2 | Negative (69) | … | … | No | |
4 | PIV-3 | Negative (4) | … | … | No | |
3 | PIV-3 | Negative (45) | … | … | No | |
Chen et al (2011) [52] | 63 | PIV-3 | Negative (8) | FEV1, 0.76 L; DLCO, 36% | FEV1, 0.91 L; DLCO, 56% | Yes (14) |
Guzmán-Suarez et al (2012) [53] | 55 | PIV-3 | 1-Log decrease (2) | FEV1, 0.93 L; FVC, 1.12 L | FEV1, 1.18 L; FVC, 1.31 L | No |
59 | PIV-3 | Unchanged (2) | FEV1, 1.52 L; FVC, 1.74 L | FEV1, 1.69 L; FVC, 1.98 L | No | |
Dhakal et al (2016) [54] | 74 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | Yes |
35 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | No | |
Drozd et al (2013) [55] | 64 | PIV-3 | Negative (6) | High-flow mask | NC | No |
Salvatore et al (2016) [56] | 53 | PIV-1 | 3.94-Log decrease (10) | 90% on 90% FiO2 (ventilator) | 100% on 55% FiO2 (ventilator) | Yes (21) |
69 | PIV-3 | … | 96% on 50% FiO2 (face mask) | 95% on 4-L NC | No | |
64 | PIV-3 | 1.14-Log decrease (5) | 96% on 35% FiO2 (ventilator) | 97% on 50% FiO2 (ventilator) | No | |
66 | PIV-4 | 1.69-Log decrease (7) | 96% on 3-L NC | 96% on 2-L NC | No | |
67 | PIV-3 | … | 97% on 50% FiO2 (face mask) | 98% on 50% FiO2 (ventilator) | Yes (10) | |
58 | PIV-4 | … | 94% on 3-L NC | 99% on 50% FiO2 (ventilator) | No | |
65 | PIV-3/4 | … | 95% on RA | 99% on RA | No | |
29 | PIV-1 | 3.51-Log decrease (7) | 98% on 3-L NC | 99% on 3-L NC (off oxygen on d 10) | No | |
50 | PIV-1 | 0.19-Log increase (7) | 96% on 3-L NC | 95% on 3-L NC | No | |
65 | PIV-3 | … | 94% on 5-L NC | 96% on 2-L NC | No | |
72 | PIV-3 | … | 90% on RA | 94% on RA | No | |
65 | PIV-3 | … | 97% on RA | 97% on RA | No | |
60 | PIV-3 | 1.60-Log increase (5) | 96% on 6-L NC | 97% on 4-L NC (off oxygen on d 6) | Yes (21) | |
66 | PIV-4 | … | 98% on RA | 99% on RA | No | |
59 | PIV-4 | … | 100% on RA | 100% on RA | No | |
71 | PIV-4 | 2.60-Log decrease (7) | 94% on RA | 95% on RA | No |
Series . | Age, y . | Serotype . | Posttreatment Viral Load (Interval, d)b . | Pulmonary Function . | Death (Interval, d)b . | |
---|---|---|---|---|---|---|
Pretreatment . | Posttreatment . | |||||
Chalkias et al (2014) [50] | 64 | PIV-1 | 1.91-Log decrease | Intubated | Extubated | No |
69 | PIV-3 | 1.81-Log decrease | Intubated | Extubated | No | |
Waghmare et al (2015) [51] | 12 | PIV-3 | Negative (48) | … | … | No |
7 mo | PIV-2 | Negative (69) | … | … | No | |
4 | PIV-3 | Negative (4) | … | … | No | |
3 | PIV-3 | Negative (45) | … | … | No | |
Chen et al (2011) [52] | 63 | PIV-3 | Negative (8) | FEV1, 0.76 L; DLCO, 36% | FEV1, 0.91 L; DLCO, 56% | Yes (14) |
Guzmán-Suarez et al (2012) [53] | 55 | PIV-3 | 1-Log decrease (2) | FEV1, 0.93 L; FVC, 1.12 L | FEV1, 1.18 L; FVC, 1.31 L | No |
59 | PIV-3 | Unchanged (2) | FEV1, 1.52 L; FVC, 1.74 L | FEV1, 1.69 L; FVC, 1.98 L | No | |
Dhakal et al (2016) [54] | 74 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | Yes |
35 | PIV-3 | … | Intubated | Intubated with improved oxygen requirements | No | |
Drozd et al (2013) [55] | 64 | PIV-3 | Negative (6) | High-flow mask | NC | No |
Salvatore et al (2016) [56] | 53 | PIV-1 | 3.94-Log decrease (10) | 90% on 90% FiO2 (ventilator) | 100% on 55% FiO2 (ventilator) | Yes (21) |
69 | PIV-3 | … | 96% on 50% FiO2 (face mask) | 95% on 4-L NC | No | |
64 | PIV-3 | 1.14-Log decrease (5) | 96% on 35% FiO2 (ventilator) | 97% on 50% FiO2 (ventilator) | No | |
66 | PIV-4 | 1.69-Log decrease (7) | 96% on 3-L NC | 96% on 2-L NC | No | |
67 | PIV-3 | … | 97% on 50% FiO2 (face mask) | 98% on 50% FiO2 (ventilator) | Yes (10) | |
58 | PIV-4 | … | 94% on 3-L NC | 99% on 50% FiO2 (ventilator) | No | |
65 | PIV-3/4 | … | 95% on RA | 99% on RA | No | |
29 | PIV-1 | 3.51-Log decrease (7) | 98% on 3-L NC | 99% on 3-L NC (off oxygen on d 10) | No | |
50 | PIV-1 | 0.19-Log increase (7) | 96% on 3-L NC | 95% on 3-L NC | No | |
65 | PIV-3 | … | 94% on 5-L NC | 96% on 2-L NC | No | |
72 | PIV-3 | … | 90% on RA | 94% on RA | No | |
65 | PIV-3 | … | 97% on RA | 97% on RA | No | |
60 | PIV-3 | 1.60-Log increase (5) | 96% on 6-L NC | 97% on 4-L NC (off oxygen on d 6) | Yes (21) | |
66 | PIV-4 | … | 98% on RA | 99% on RA | No | |
59 | PIV-4 | … | 100% on RA | 100% on RA | No | |
71 | PIV-4 | 2.60-Log decrease (7) | 94% on RA | 95% on RA | No |
Abbreviations: DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in first second of expiration; FiO2, fraction of inspired oxygen; FVC, forced vital capacity; NC, nasal cannula; PIV, parainfluenza virus; RA, room air.
aA literature search was conducted using PubMed. Studies were included if DAS181 was used to treat PIV in immunocompromised patients. Viral load, pulmonary function, and death or survival was assessed from available data in the study text. No studies were excluded.
bDays after the end of treatment.
Other Available Therapies
Intravenous immunoglobulin has been proved effective in animal models but lacks evidence to support its use in humans [3, 45]. Two PIV HN inhibitors (BCX 2798 and BCX 2855) have been studied in mouse models but has not yet advanced to clinical studies [3]. A trypanocidal drug that has historically been used in the treatment of sleeping sickness has been shown as an inhibitor of HN that works synergistically with the anti-influenza drug zanamivir and demonstrates in vitro activity against PIV but has yet to be explored in a human model [57].
VACCINE
Given the significant burden of PIV infections and the lack of a licensed PIV vaccination, a significant opportunity exists for the development of a vaccine and a subsequent impact on PIV-associated morbidity and mortality rates in children and adults. Since the 1960s, efforts to develop a PIV vaccine have been underway.
Several live attenuated vaccines active against PIV have been generated with positive results. HPIV3cp45 was developed from cold passage of PIV-3 and has been found to be well tolerated, safe, and immunogenic in children 6–18 months old, but it requires further investigation in infants <6 months old [58]. Vaccines using bovine PIV-3 (BPIV-3), a virus closely related to human PIV-3, have been developed that are safe and immunogenic but show insufficient antibody titers to human PIV-3, owing to the antigenic differences between BPIV-3 and human PIV-3 [58]. Current work is focused on using recombinant BPIV-3 that expresses antigens found in human PIV-3 [58]. Although human studies are early, there is significant interest in PIV vaccines. Even if used predominantly in children, a vaccine may have positive effects on disease in adults, as has been shown with influenza [59]. Although these preliminary studies show promising results, no licensed vaccine exists for PIV, further substantiating the need for more studies on vaccine development and efficacy.
CONCLUSIONS
PIV is a significant contributor to hospitalization in adults but has historically not been well recognized by clinicians. Most infections in adults result in mild and self-limited upper respiratory tract infections, but more serious infections involving the lower respiratory tract, including pneumonia and exacerbation of underlying lung disease affect a significant number of adults. With wider availability of multiplexed molecular diagnostics, the recognition of the scope of PIV has grown. Novel PIV-active antivirals and vaccines are in clinical development and will increase the attention paid to this important cause of disease and death in adults. Given the paucity of data, contemporary studies on the presentation, incidence, and clinical impact of PIV among hospitalized adults are needed. Such studies can also help define appropriate end points to facilitate the licensure of new PIV-active agents.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Financial support. This work was supported by the Infectious Disease Society of America’s Medical Scholars Program (E. R.).
Potential conflicts of interest. M.G.I. has received research support, paid to Northwestern University, from Beckman Coulter, Chimerix, Gilead and Janssen; is a paid consultant to Celltrion, Chimerix, Farmark, Genentech/Roche, Toyama/MediVector, Seqirus, and Shionogi; and is a paid member of a data and safety monitoring board for studies sponsored by GlaxoSmithKlein and Shionogi. E. R. reports no potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
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