The parainfluenzavirus is a group of viruses within the family Paramyxoviridae, causing a wide spectrum of respiratory infections in humans, ranging from mild upper respiratory tract illnesses such as the common cold to severe lower respiratory tract diseases including croup, bronchiolite, bronchite, and polmonite. These infections predominantly affect vulnerable populations such as children under five years of age, adults over 65, and individuals with compromised sistema immunitario [1]. Human parainfluenza viruses (HPIVs) are classified into four main types—HPIV-1, HPIV-2, HPIV-3, and HPIV-4—each associated with distinct clinical manifestations and seasonal patterns. HPIV-1 and HPIV-2 are primarily linked to croup, while HPIV-3 is a major cause of bronchiolitis and pneumonia in infants, and HPIV-4 typically causes milder respiratory symptoms [2]. The virus spreads through goccioline respiratorie generated by coughing or sneezing and can survive on surfaces, facilitating indirect transmission [3]. Unlike the virus dell'influenza, which belongs to the Orthomyxoviridae family, parainfluenzaviruses have a non-segmented negative-sense RNA genome and lack the high antigenic variability that leads to frequent vaccine updates. Despite their clinical significance, no licensed vaccino currently exists for HPIVs, making prevention reliant on hygiene practices such as handwashing and surface disinfection [4]. Research into novel vaccine platforms, including vaccini a mRNA and viral vectors, shows promise for future prevention strategies [5]. The virus's ability to suppress the host’s risposta all'interferone, a key component of the innate immune system, contributes to its pathogenesis and poses challenges for both natural immunity and vaccine development [6]. Ongoing genomic surveillance through initiatives like RespiVirNet in Italy helps monitor viral evolution and inform public health responses [7].
Virology and Taxonomic Classification
The parainfluenzavirus is a member of the family Paramyxoviridae, a group of enveloped viruses with non-segmented, negative-sense single-stranded RNA genomes [8]. These viruses are responsible for a wide range of respiratory infections in humans, particularly affecting vulnerable populations such as children under five years of age, adults over 65, and individuals with compromised immune system function [1]. Human parainfluenza viruses (HPIVs) are classified into four main types—HPIV-1, HPIV-2, HPIV-3, and HPIV-4—each associated with distinct clinical manifestations and epidemiological patterns. From a taxonomic perspective, HPIVs are further categorized into two primary genera within the Paramyxoviridae family: Respirovirus and Rubulavirus. HPIV-1 and HPIV-3 belong to the genus Respirovirus, while HPIV-2 and HPIV-4 are classified under Rubulavirus [2]. This classification reflects fundamental differences in genomic organization, antigenicity, and pathogenesis among the serotypes. Other notable human pathogens in the Paramyxoviridae family include the measles virus and the mumps virus, highlighting the clinical significance of this viral group [11].
Viral Structure and Genome Organization
The virion of parainfluenzavirus is pleomorphic, typically spherical or filamentous, with a diameter ranging from 150 to 300 nm [12]. It is enveloped, with the lipid bilayer derived from the host cell plasma membrane during the budding process. Embedded in this envelope are two key glycoproteins essential for viral entry: the hemagglutinin-neuraminidase (HN) protein and the fusion (F) protein. The HN glycoprotein mediates viral attachment to host cells by binding to sialic acid receptors on the surface of respiratory epithelial cells, while also possessing neuraminidase activity that facilitates the release of newly formed virions by cleaving sialic acid residues [12]. The F glycoprotein, a trimeric protein, is responsible for the fusion of the viral envelope with the host cell membrane, allowing the viral nucleocapsid to enter the cytoplasm [14]. Beneath the envelope lies the matrix (M) protein, which plays a critical role in coordinating virion assembly and budding [15]. The core of the virus contains the helical nucleocapsid, composed of the RNA genome tightly bound to the nucleoprotein (N), along with the phosphoprotein (P) and the RNA-dependent RNA polymerase (L). This ribonucleoprotein complex protects the genome and serves as the template for both transcription and replication [16].
The HPIV genome is a single-stranded, negative-sense RNA molecule approximately 15,000 to 17,000 nucleotides in length, with HPIV-4 possessing a slightly longer genome than the others [17]. The genetic organization is highly conserved and follows the order: 3′-N-P-M-F-HN-L-5′. Each gene is flanked by conserved transcription start and stop signals, and they are transcribed into individual monocistronic mRNAs in a sequential, polar manner from the 3′ end of the genome [18]. In addition to the six major structural proteins, some serotypes, particularly HPIV-1 and HPIV-2, can produce accessory proteins such as C and D through mechanisms like alternative splicing or the use of alternative reading frames, which may play roles in modulating the host's immune response [19].
Viral Entry and Membrane Fusion Mechanisms
The entry of parainfluenzavirus into host cells occurs exclusively through direct fusion with the plasma membrane, a process that does not involve endocytosis [14]. This process is a highly coordinated interaction between the HN and F glycoproteins. The HN protein first binds to sialic acid receptors on the host cell surface. This binding triggers a conformational change in HN, which in turn activates the F protein [21]. The F protein exists in a metastable prefusion state; upon activation, it undergoes a dramatic structural rearrangement, exposing its hydrophobic fusion peptide. This peptide inserts into the host cell membrane, bringing the viral and cellular membranes into close proximity and ultimately forming a fusion pore through which the nucleocapsid is released into the cytoplasm [22]. The precise nature of the HN-F interaction varies between serotypes, contributing to differences in entry efficiency and tissue tropism. For instance, HPIV-3 shows a high dependence on cell-surface proteases like TMPRSS2 for the cleavage and activation of its F protein, which is a critical step for its fusogenic activity [23].
Replication Cycle and Syncytium Formation
The entire replication cycle of parainfluenzavirus takes place in the host cell's cytoplasm. Following entry, the viral RNA polymerase (L protein, in complex with the P protein) associated with the nucleocapsid performs primary transcription, synthesizing positive-sense mRNAs from the negative-sense genomic RNA [18]. These mRNAs are then translated by host ribosomes into the viral proteins. Once sufficient levels of the N protein are produced, the polymerase switches from transcription to genome replication, producing a full-length positive-sense antigenome, which serves as a template for the synthesis of new negative-sense genomic RNA [25]. The newly synthesized genomic RNA is encapsidated by N protein to form new nucleocapsids. The M protein accumulates beneath the plasma membrane, recruiting the nucleocapsids and the HN and F glycoproteins to specific sites. The virions then assemble and bud from the plasma membrane, acquiring their lipid envelope in the process [12]. A notable feature of HPIV infection is the ability of the overexpression of the F and HN proteins to induce the fusion of infected cells with neighboring uninfected cells, leading to the formation of multinucleated giant cells known as syncytia [25]. This cell-to-cell spread allows the virus to propagate while evading detection by the host's humoral immune system, which targets free virions.
Genomic and Antigenic Differences Among Serotypes
While the overall genomic structure is conserved, significant differences exist among the four HPIV serotypes. The most pronounced differences are found in the genes encoding the HN and F glycoproteins, which are the primary targets of neutralizing antibodies [28]. These proteins exhibit limited cross-reactivity between serotypes, meaning that immunity to one serotype provides little protection against the others [29]. For example, HPIV-3 is known for its rapid replication kinetics and its strong tropism for the lower respiratory tract, which is linked to its efficient use of cell-surface proteases for F protein activation [30]. In contrast, HPIV-1 and HPIV-2 are more commonly associated with upper respiratory tract infections and croup. HPIV-4 is further subdivided into two antigenic subtypes, HPIV-4a and HPIV-4b, which diverged approximately 200 years ago, indicating a relative antigenic stability [31]. The low rate of antigenic variation in HPIVs, compared to the high variability seen in the influenza virus, means that the virus does not undergo frequent antigenic drift or shift, but this stability also complicates vaccine development, as a successful vaccine must be multivalent to cover the major serotypes [32].
Types and Clinical Manifestations
Human parainfluenza viruses (HPIVs) are categorized into four main types—HPIV-1, HPIV-2, HPIV-3, and HPIV-4—each with distinct clinical profiles, tropism for specific regions of the respiratory tract, and seasonal patterns. These viruses belong to the family Paramyxoviridae, sharing structural and genomic features with other members such as the morbillivirus and parotitis viruses, but differing significantly from the virus dell'influenza in both virology and clinical presentation [1]. The clinical manifestations of HPIV infections range from mild upper respiratory tract illnesses resembling the common cold to severe lower respiratory tract diseases, particularly in vulnerable populations such as infants, young children, and individuals with compromised sistema immunitario.
HPIV-1: Primary Cause of Croup
HPIV-1 is the leading cause of croup (laryngotracheobronchitis), a condition characterized by a distinctive barking cough, hoarseness, and inspiratory stridor due to inflammation and swelling of the upper airway, especially the subglottic region [34]. This syndrome predominantly affects children between 6 months and 3 years of age, whose narrower airways are more susceptible to obstruction [35]. HPIV-1 exhibits a characteristic biennial epidemic pattern, with outbreaks typically occurring in the autumn months [35]. The virus is classified within the genus Respirovirus, and its pathogenesis involves a strong tropism for the upper respiratory epithelium [2].
HPIV-2: Secondary Cause of Croup
HPIV-2 is also associated with croup, although it is less common than HPIV-1 as an etiological agent [35]. It can cause both upper and lower respiratory tract infections, including pharyngitis and bronchitis. Like HPIV-1, HPIV-2 circulates primarily in the autumn, often in alternating years with HPIV-1 epidemics [35]. HPIV-2 belongs to the genus Rubulavirus, which also includes the mumps virus, and shares similar mechanisms of cellular entry and replication [40]. Although generally causing less severe disease than HPIV-3, HPIV-2 can still lead to significant respiratory distress in young children.
HPIV-3: Leading Cause of Lower Respiratory Tract Infections
HPIV-3 is the most clinically significant type in terms of lower respiratory tract disease, being a major cause of bronchiolite and polmonite in infants and young children, particularly those under one year of age [41]. It is the second most common viral cause of bronchiolitis after the virus respiratorio sinciziale (VRS), and it is associated with a high rate of hospitalization in this age group [42]. Unlike HPIV-1 and HPIV-2, HPIV-3 tends to circulate in a more endemic pattern, with annual peaks in the spring and early summer [41]. HPIV-3 also belongs to the genus Respirovirus and demonstrates a marked tropism for the lower respiratory tract, including bronchioles and alveoli [19]. Its ability to replicate rapidly and induce a strong pro-inflammatory cytokine response contributes to its high pathogenicity in neonates and immunocompromised individuals.
HPIV-4: Milder and Less Studied Infections
HPIV-4 is the least common and least studied of the four types, generally causing milder upper respiratory tract infections such as the common cold [45]. However, it can also lead to more serious conditions like bronchitis and pneumonia, particularly in immunocompromised individuals or those with underlying chronic diseases [46]. HPIV-4 is further subdivided into two antigenic subtypes, HPIV-4a and HPIV-4b, which diverged approximately 200 years ago, indicating a degree of genetic and antigenic diversity [31]. It belongs to the genus Rubulavirus and has a longer genome compared to the other HPIV types, exceeding 17 kilobases [48]. Its seasonal pattern is less defined, with cases reported throughout the year, and it is often underdiagnosed due to its lower incidence and milder symptoms.
Comparative Clinical Profiles and Risk Populations
The clinical presentation of HPIV infections is heavily influenced by the child's age and immune status. Reinfections are common throughout life, but they are typically milder in healthy adults, often presenting as a common cold [35]. The table below summarizes the key differences among the four HPIV types:
| Sierotipo | Forma clinica predominante | Età a rischio | Stagionalità | Gravità |
|---|---|---|---|---|
| HPIV-1 | Croup | 6 mesi – 3 anni | Autunno (cicli biennali) | Moderata |
| HPIV-2 | Croup, rinite | 6 mesi – 5 anni | Autunno (alternati a HPIV-1) | Leggera-moderata |
| HPIV-3 | Bronchiolite, polmonite | < 1 anno | Primavera/estate (annuale) | Alta (frequente ospedalizzazione) |
| HPIV-4 | Infezioni respiratorie varie | Tutte le età pediatriche | Annuale, meno definita | Generalmente lieve |
Children under five years of age, especially those under one, are at the highest risk for severe disease [1]. Premature infants, those with congenital heart disease, chronic lung disease, or immunodeficiencies are particularly vulnerable to complications from HPIV-3 infection [35]. The lack of a licensed vaccino means that prevention relies on hygiene measures such as handwashing and surface disinfection, and the development of effective antiviral therapies remains a critical unmet need [4].
Transmission and Epidemiology
The transmission and epidemiology of human parainfluenza viruses (HPIVs) are characterized by distinct patterns of spread, seasonal circulation, and population susceptibility. These viruses are highly contagious and primarily affect vulnerable groups such as young children, older adults, and individuals with compromised immune system [1]. Understanding their transmission dynamics and epidemiological behavior is essential for implementing effective public health measures and clinical management strategies.
Modes of Transmission
HPIVs are transmitted predominantly through respiratory droplets generated when an infected individual coughs, sneezes, or speaks [4]. These droplets can be inhaled directly by individuals in close proximity, typically within one meter, facilitating rapid person-to-person spread. In addition to airborne transmission, the virus can also spread via direct contact with respiratory secretions, such as touching contaminated hands or surfaces and then transferring the virus to mucosal surfaces of the eyes, nose, or mouth [3].
The virus is capable of surviving on inanimate surfaces—such as doorknobs, toys, and electronic devices—for several hours, which contributes to indirect transmission in high-touch environments [35]. This persistence on fomites makes settings like daycare centers, schools, and hospitals significant hotspots for outbreaks, particularly among pediatric populations who frequently engage in hand-to-mouth contact [57]. The period of highest contagiosity coincides with the acute phase of illness, and the incubation period ranges from 1 to 7 days, allowing for asymptomatic or presymptomatic spread in some cases [41].
Seasonal and Geographic Patterns
The epidemiological patterns of HPIVs vary significantly by serotype and geographic region, reflecting differences in climate, population density, and host immunity. In temperate climates, such as those in North America and Europe, HPIV infections exhibit a pronounced seasonal trend, with peak activity occurring during the autumn and winter months, generally from October to April [4]. However, the timing and frequency of outbreaks differ among the four main types:
- HPIV-1 is responsible for biennial autumnal epidemics of croup, particularly affecting children between 6 months and 3 years of age [34].
- HPIV-2 also circulates in the autumn, often in alternating years with HPIV-1, and is associated with milder respiratory illness and occasional croup [35].
- HPIV-3 demonstrates a more endemic pattern, with year-round circulation and a distinct peak in spring and early summer [41]. It is a major cause of lower respiratory tract infections such as bronchiolitis and pneumonia in infants [19].
- HPIV-4 has a less defined seasonal pattern and circulates at lower levels throughout the year, often causing mild upper respiratory symptoms [45].
In contrast, in tropical climates, HPIV transmission is less seasonal and more continuous, with outbreaks often linked to periods of high humidity and rainfall [35]. Environmental factors such as temperature, relative humidity, and wind speed influence viral stability and transmission efficiency. Notably, lower humidity levels (20–35%) favor the spread of respiratory droplets and aerosols, while higher humidity (>80%) may inhibit viral diffusion [66].
Population Susceptibility and Risk Factors
Certain populations are at heightened risk for severe HPIV infections. Children under five years of age, especially those under one year, are the most susceptible due to their immature immune systems and smaller airway anatomy, which increases the risk of airway obstruction in conditions like croup and bronchiolitis [1]. Neonates and premature infants are particularly vulnerable, with HPIV-3 being the second most common viral cause of bronchiolitis after the respiratory syncytial virus (RSV) [42].
Adults over 65 and individuals with underlying medical conditions—such as chronic lung disease, heart disease, or immunosuppression due to cancer, organ transplantation, or HIV—are also at increased risk for severe complications [69]. In immunocompromised patients, HPIV infections can lead to prolonged viral shedding (up to 3–4 weeks), higher rates of lower respiratory tract involvement, and increased mortality, with reported rates as high as 20–30% in hematopoietic stem cell transplant recipients [70].
Reinfections with HPIVs are common throughout life, although subsequent infections tend to be milder due to partial immunity acquired from prior exposures [35]. However, the lack of durable and cross-protective immunity between serotypes allows for repeated symptomatic infections, contributing to the ongoing circulation of the virus in communities.
Global Surveillance and Epidemiological Monitoring
Effective surveillance is critical for tracking HPIV circulation, detecting outbreaks, and informing public health responses. In Italy, the RespiVirNet system, coordinated by the Istituto Superiore di Sanità (ISS) in collaboration with the Ministry of Health, monitors the epidemiology of respiratory viruses, including HPIVs, through a network of sentinel physicians, laboratories, and hospitals [7]. This integrated surveillance approach combines clinical data with virological testing, enabling real-time monitoring of acute respiratory infections (ARI) and replacing the older influenza-like illness (ILI) framework with a broader ARI case definition to improve sensitivity [73].
Globally, genomic surveillance has enhanced understanding of HPIV evolution and spread. Phylogenetic analyses have revealed distinct geographic clades and local lineages, such as a newly identified clade D of HPIV-1 circulating exclusively in China, indicating regional viral evolution [74]. Similarly, HPIV-3 lineage C3 has become dominant in multiple countries, highlighting its global dissemination [74]. These data are vital for tracking viral diversity, assessing diagnostic test performance, and guiding vaccine development.
The absence of a licensed vaccine for HPIVs underscores the importance of non-pharmaceutical interventions such as hand hygiene, respiratory etiquette, and environmental disinfection in controlling transmission [4]. In healthcare settings, droplet precautions—including the use of surgical masks, gowns, and gloves—are recommended to prevent nosocomial spread, especially in pediatric and immunocompromised units [41]. Continued investment in surveillance and research is essential to reduce the clinical and economic burden of HPIV infections worldwide.
Immune Response and Pathogenesis
The pathogenesis of human parainfluenzavirus (HPIV) infections is intricately linked to the virus's ability to evade the host's immune defenses, particularly the innate immune system, while efficiently replicating in the respiratory epithelium. The clinical manifestations, ranging from mild upper respiratory tract infections to severe lower respiratory diseases such as croup, bronchiolite, and polmonite, are shaped by the interplay between viral virulence factors and the host's immune response. This complex interaction determines the severity of disease, especially in vulnerable populations like infants, the elderly, and individuals with compromised sistema immunitario [1].
Innate Immune Evasion and Interferon Suppression
The first line of defense against HPIV is the innate immune system, which relies on the rapid production of risposta all'interferone, particularly type I (IFN-α/β) and type II (IFN-γ). These interferons induce a broad antiviral state in neighboring cells by upregulating hundreds of interferon-stimulated genes (ISGs) that inhibit viral replication. However, HPIV has evolved sophisticated mechanisms to counteract this response. The virus produces non-structural accessory proteins, notably the C and V proteins, which act as potent antagonists of the interferon signaling pathway [6]. These proteins interfere with key components of the JAK-STAT signaling cascade, such as MDA5 and STAT1, effectively blocking the expression of antiviral ISGs [80]. This suppression allows HPIV to replicate unchecked in the early stages of infection, facilitating widespread infection of the respiratory tract and contributing to the pathogenesis of severe disease [81].
Adaptive Immune Response: Antibodies and T Cells
The adaptive immune response, which develops over several days, is crucial for viral clearance and the establishment of immunological memory. This response is bifurcated into humoral and cellular immunity.
The humoral response is characterized by the production of neutralizing antibodies, primarily of the IgG and IgA classes. These antibodies target the viral surface glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion (F) protein, which are essential for viral attachment and entry into host cells [82]. By binding to these proteins, neutralizing antibodies prevent the virus from infecting new cells, thereby limiting the spread of infection. The discovery of potent human monoclonal antibodies that can block HPIV3 entry has highlighted the critical role of this mechanism and opened avenues for passive immunotherapy [83].
The cellular immune response, mediated by T lymphocytes, is essential for eliminating infected cells. CD8+ cytotoxic T lymphocytes (CTLs) recognize viral peptides presented by MHC class I molecules on infected cells and induce their apoptosis. CD4+ helper T cells play a regulatory role by producing cytokines like IFN-γ and IL-2, which support the activity of CTLs and promote B cell antibody production. A robust T cell response is particularly important in immunocompromised patients, such as stem cell transplant recipients, where it correlates with better control of HPIV infection [84]. Research into adoptive T cell therapy, using HPIV3-specific T cells, is a promising strategy for treating severe infections in these high-risk groups [85].
Viral Entry, Replication, and Cell-to-Cell Spread
The pathogenesis of HPIV begins with its entry into the respiratory epithelium. The virus uses its HN glycoprotein to bind to sialic acid receptors on the surface of host cells [12]. This binding triggers a conformational change in the F protein, which mediates the fusion of the viral envelope with the host cell membrane, allowing the viral nucleocapsid to enter the cytoplasm [14]. The virus then replicates its non-segmented negative-sense RNA genome entirely within the host cell's cytoplasm using its own RNA-dependent RNA polymerase (L protein) [18].
A key feature of HPIV pathogenesis is its ability to spread directly from cell to cell. The overexpression of the F and HN proteins on the surface of infected cells can induce the formation of multinucleated giant cells, or syncytia, by fusing with adjacent uninfected cells [25]. This cell-to-cell spread allows the virus to propagate efficiently while evading detection by neutralizing antibodies in the extracellular space, a significant mechanism of immune evasion.
Impact of Immune Evasion on Vaccines and Therapeutics
The virus's ability to suppress the interferon response poses a major challenge for both natural immunity and vaccine development. The limited duration and incomplete protection of immunity following natural infection, which allows for frequent reinfections, are partly attributed to this immune evasion [90]. For vaccines, this means that candidates must be carefully designed to overcome this suppression. Live-attenuated vaccine strains with mutations in the P/C gene, which impair the function of the V and C proteins, have shown greater immunogenicity because they induce a stronger interferon response [91]. This highlights the critical importance of understanding immune evasion mechanisms to develop effective vaccines and antiviral therapies that can harness the full power of the host's immune system [35].
Diagnosis and Differential Diagnosis
The diagnosis of parainfluenzavirus infections relies on a combination of clinical evaluation, laboratory testing, and exclusion of other respiratory pathogens. Given the broad spectrum of illness it causes—from mild upper respiratory tract infections to severe lower respiratory diseases such as croup, bronchiolite, and polmonite—accurate identification is essential, particularly in vulnerable populations like children under five, the elderly, and individuals with compromised sistema immunitario. Unlike the virus dell'influenza, which exhibits sudden onset of high fever and systemic symptoms, parainfluenzavirus infections often present with more localized respiratory signs, necessitating careful clinical differentiation [35].
Clinical Diagnosis and Symptom Assessment
Diagnosis often begins with a clinical assessment based on patient history and physical examination. The most common symptoms include fever, sore throat, cough (often dry or barking, especially in croup), nasal congestion, and rhinorrhea [35]. In children, the presentation varies significantly by age and viral subtype. For instance, HPIV-1 and HPIV-2 are primarily associated with croup, characterized by a barking cough, stridor, and hoarseness, typically affecting children between 6 months and 3 years [41]. In contrast, HPIV-3 is more frequently linked to lower respiratory tract infections such as bronchiolitis and pneumonia, especially in infants under one year of age [19].
In adults, symptoms are generally milder and resemble those of the common cold, including cough, low-grade fever, and sore throat [97]. However, in immunocompromised individuals, even mild initial symptoms can progress rapidly to severe respiratory distress, requiring close monitoring [98]. The seasonal patterns of different HPIV types also aid in clinical suspicion: HPIV-1 and HPIV-2 typically circulate in the fall with biennial epidemics, while HPIV-3 peaks in spring and early summer [41].
Laboratory Diagnostic Methods
Definitive diagnosis requires laboratory confirmation, especially in hospitalized patients or during outbreaks. The most sensitive and specific method is reverse transcription polymerase chain reaction (RT-PCR), which can detect and differentiate between HPIV types 1–4 from nasopharyngeal swabs or aspirates [100]. Multiplex PCR panels that simultaneously test for multiple respiratory viruses—including virus respiratorio sinciziale, influenza, and rhinovirus—are increasingly used in clinical settings to improve diagnostic accuracy and guide patient management [101].
Rapid antigen detection tests are available but are less sensitive than PCR, particularly in older children and adults with lower viral loads [2]. Viral culture, though historically used, is slow and less practical for clinical decision-making. Serological testing (measuring antibody titers) is generally not useful for acute diagnosis due to the delay in antibody response and the high prevalence of prior exposure in the population [35].
Differential Diagnosis of Croup and Lower Respiratory Infections
Distinguishing parainfluenzavirus-induced croup from other causes of upper airway obstruction is critical. The differential diagnosis includes several conditions with overlapping symptoms:
- Bacterial tracheitis: Often presents with high fever, purulent secretions, and a more toxic appearance than viral croup. Radiographic findings may show an irregular tracheal narrowing ("hourglass" sign), unlike the uniform subglottic narrowing seen in viral croup [104].
- Epiglottitis: Now rare due to Haemophilus influenzae type b vaccination, it presents with drooling, dysphagia, and a "tripod" posture. It requires immediate airway management and is distinguished by a swollen epiglottis on imaging [105].
- Foreign body aspiration: Typically has a sudden onset without preceding viral symptoms. A history of choking is key, and diagnosis often requires bronchoscopy [106].
- Pertussis (whooping cough): Caused by Bordetella pertussis, it features paroxysmal coughing with an inspiratory "whoop" and post-tussive vomiting, but lacks stridor and hoarseness [107].
- Bronchiolitis: Primarily caused by virus respiratorio sinciziale, it presents with wheezing, tachypnea, and crackles, rather than the barking cough and stridor of croup [108].
- Asthma: May mimic bronchiolitis with wheezing, but typically lacks fever and has a history of atopy or recurrent episodes responsive to bronchodilators [109].
Challenges in Diagnosing Immunocompromised Patients
In immunocompromised individuals, such as those with hematologic malignancies or post-transplant, parainfluenzavirus infections can be more severe and prolonged, with extended viral shedding lasting up to 3–4 weeks [70]. These patients may present atypically, with subtle or delayed symptoms, making early diagnosis challenging. In such cases, routine screening of respiratory specimens using PCR is recommended in high-risk units to detect asymptomatic shedding and prevent nosocomial outbreaks [111].
Moreover, co-infections with other respiratory viruses or bacterial superinfections are common, complicating the clinical picture. For example, studies report co-detection rates of HPIV with other pathogens exceeding 50% in severe pneumonia cases [112]. Therefore, comprehensive respiratory pathogen panels are crucial in this population to guide appropriate therapy and infection control measures.
Role of Genomic Surveillance and Emerging Technologies
Advancements in genomic sequencing have enhanced the ability to track HPIV transmission and evolution. Systems like RespiVirNet in Italy integrate clinical, epidemiological, and virological data to monitor circulating strains in real time [7]. This surveillance helps identify emerging clades—such as a newly reported clade D of HPIV-1 in China—and assess antigenic drift, which could impact diagnostic test performance and vaccine development [74].
Emerging technologies, including next-generation sequencing (NGS) and point-of-care molecular diagnostics, are improving the speed and accuracy of diagnosis. These tools are particularly valuable in hospital settings where rapid identification can inform isolation protocols and reduce transmission [115]. The integration of such systems into routine clinical practice represents a key step toward better management of parainfluenzavirus infections and other respiratory pathogens.
Management and Supportive Care
The management of parainfluenzavirus infections is primarily supportive, as no specific antiviral therapies are currently approved for clinical use [35]. Since these infections are self-limiting in most individuals, treatment focuses on symptom relief, hydration, and monitoring for complications, particularly in vulnerable populations such as infants, young children, and immunocompromised individuals [41]. Supportive care strategies are tailored to the severity and clinical presentation of the illness, ranging from mild upper respiratory symptoms to severe lower respiratory tract disease.
Symptomatic Treatment for Mild Infections
For mild upper respiratory tract infections caused by human parainfluenza viruses (HPIVs), such as common cold-like symptoms, management is largely symptomatic. Recommended measures include rest, adequate fluid intake to prevent dehydration, and the use of over-the-counter medications to alleviate fever and discomfort. Antipyretics such as acetaminophen or ibuprofen are commonly used to manage fever and pain [35]. Nasal saline drops or sprays can help relieve nasal congestion, while humidifiers or steam inhalation may soothe irritated airways and reduce coughing. These non-pharmacological interventions are particularly beneficial in pediatric patients, where airway irritation can exacerbate symptoms [119].
Management of Croup (Laryngotracheobronchitis)
Croup, a hallmark manifestation of HPIV-1 and HPIV-2 infections, requires specific supportive interventions to manage airway inflammation and obstruction. The primary goals are to reduce laryngeal edema and prevent respiratory distress. Corticosteroids, particularly a single dose of oral or intramuscular dexamethasone, are the cornerstone of treatment and have been shown to significantly reduce the need for hospitalization and improve clinical outcomes [120]. In moderate to severe cases with stridor at rest, nebulized epinephrine (adrenaline) may be administered to provide rapid but temporary relief of airway swelling [120]. Patients receiving epinephrine should be observed for several hours due to the risk of symptom rebound after the medication wears off. Humidified air, though historically used, has limited evidence of benefit but may provide subjective comfort.
Supportive Care for Bronchiolitis and Pneumonia
HPIV-3 is a major cause of bronchiolitis and pneumonia, especially in infants and young children. Management of these lower respiratory tract infections centers on respiratory and hydration support. Oxygen therapy is indicated when oxygen saturation falls below 90–92%, and can be delivered via nasal cannula, face mask, or high-flow systems [122]. The use of high-flow nasal cannula has become increasingly common in pediatric settings, as it improves respiratory comfort, reduces work of breathing, and may prevent the need for mechanical ventilation [123]. In severe cases, non-invasive ventilation such as continuous positive airway pressure or invasive mechanical ventilation may be required for respiratory failure [124].
Hydration is critical, as tachypnea and fever can lead to fluid loss. Infants with difficulty feeding due to respiratory distress may require intravenous fluids to maintain adequate hydration [108]. Antibiotics are not indicated unless there is strong evidence of secondary bacterial infection, such as worsening symptoms or radiographic findings suggestive of bacterial pneumonia [126].
Special Considerations for High-Risk Populations
In immunocompromised patients, including those with hematologic malignancies, solid organ transplants, or HIV/AIDS, HPIV infections can progress to severe and prolonged lower respiratory tract disease with high morbidity and mortality [70]. These individuals may shed the virus for weeks, increasing the risk of nosocomial transmission [98]. Supportive care remains the mainstay, but close monitoring in a hospital setting is often necessary. While no antivirals are approved, experimental therapies such as ribavirin or intravenous immunoglobulin have been used off-label in severe cases, though evidence of efficacy is limited [129]. Infection control measures, including droplet precautions and isolation, are essential to prevent outbreaks in healthcare facilities [111].
Monitoring and When to Seek Medical Attention
Most HPIV infections resolve without complications, but caregivers should be vigilant for signs of worsening disease. Medical evaluation is warranted if a child develops high fever unresponsive to medication, increasing respiratory effort (e.g., retractions, grunting), persistent stridor, cyanosis, or lethargy [131]. In adults, particularly the elderly or those with chronic conditions, worsening cough, dyspnea, or signs of pneumonia should prompt clinical assessment. Early recognition and intervention can prevent progression to respiratory failure and reduce hospitalization rates, especially in high-risk groups [35].
Prevention and Public Health Measures
Currently, no licensed vaccino is available for human parainfluenza viruses (HPIVs), making prevention primarily reliant on non-pharmaceutical interventions and public health strategies. The absence of a vaccine underscores the importance of hygiene practices and targeted measures, particularly in protecting vulnerable populations such as children under five, adults over 65, and individuals with compromised sistema immunitario [4]. Effective prevention hinges on interrupting the virus's transmission, which occurs mainly through respiratory droplets and contact with contaminated surfaces.
Hygiene and Infection Control Practices
The cornerstone of preventing parainfluenza virus transmission is rigorous personal and environmental hygiene. The virus spreads efficiently through respiratory droplets released when an infected person coughs, sneezes, or talks, and it can survive on surfaces like doorknobs, toys, and keyboards for several hours [3]. Key preventive measures include:
- Handwashing: Frequent and thorough handwashing with soap and water for at least 20 seconds is one of the most effective ways to prevent spread. This is especially critical after coughing, sneezing, or touching common surfaces [4].
- Alcohol-based hand sanitizers: When soap and water are unavailable, using a hand sanitizer with at least 60% alcohol is recommended to disinfect hands [136].
- Respiratory etiquette: Individuals should cover their mouth and nose with a tissue or their elbow when coughing or sneezing to minimize the dispersion of droplets into the environment [137].
- Surface disinfection: Regular cleaning and disinfection of frequently touched objects and surfaces with products effective against viruses are essential to reduce indirect transmission [136].
These measures are particularly crucial in high-risk settings like asili nido, schools, and healthcare facilities, where close contact facilitates rapid viral spread [57].
Public Health Surveillance and Outbreak Response
Robust public health surveillance is vital for monitoring the circulation of HPIVs and responding to outbreaks, especially in healthcare settings. In Italy, the RespiVirNet system, coordinated by the Istituto Superiore di Sanità (ISS), serves as a national model for integrated surveillance of respiratory viruses, including HPIVs [7]. This network combines data from sentinel physicians, laboratories, and hospitals to provide near real-time information on the prevalence of acute respiratory infections (ARI).
For hospital settings, particularly pediatric units with high patient volume, early detection of HPIV outbreaks is critical. The RespiVirNet protocol recommends active surveillance through systematic collection of nasopharyngeal swabs from pediatric inpatients with acute respiratory symptoms [141]. The use of rapid multiplex PCR tests allows for the simultaneous identification of HPIVs and other respiratory pathogens, enabling prompt diagnosis and implementation of infection control measures [101]. Upon confirmation of an HPIV case, hospitals implement droplet precautions, including patient isolation, use of surgical masks, gowns, and gloves by healthcare workers, and restriction of visitors to prevent nosocomial transmission [41].
Prevention in High-Risk Populations
Children, especially those under two years of age, are the most susceptible to severe HPIV infections like bronchiolitis and pneumonia, with HPIV-3 being a major cause [41]. While specific antiviral prophylaxis is not available, indirect protective measures are recommended for high-risk children, such as premature infants or those with chronic lung or heart disease. These include promoting exclusive breastfeeding for the first six months of life, which provides protective antibodies and strengthens the infant's immune defenses [35]. Additionally, avoiding exposure to tobacco smoke and limiting attendance at crowded childcare facilities during peak HPIV seasons can reduce risk [35].
Although no HPIV vaccine exists, vaccination against other respiratory pathogens is strongly recommended for high-risk individuals. The annual vaccino antinfluenzale stagionale and the vaccinazione contro Streptococcus pneumoniae are crucial to prevent secondary bacterial infections and reduce the overall burden of respiratory illness, which can be particularly severe in immunocompromised patients [147].
Seasonal Patterns and Environmental Factors
The transmission of HPIVs is influenced by seasonal and environmental factors, which inform public health planning. In temperate climates, HPIV-1 and HPIV-2 exhibit a distinct autumn seasonality, with outbreaks occurring every two years, while HPIV-3 tends to circulate more consistently, with peaks in spring and early summer [148]. In contrast, tropical regions see less defined seasonality, with circulation often linked to rainy seasons. Environmental factors such as low relative humidity (20-35%) can increase the stability and transmission of respiratory droplets, whereas maintaining indoor humidity between 40% and 60% may help reduce viral spread [66]. Therefore, public health recommendations often include ensuring adequate ventilation and humidification in indoor environments, especially during high-transmission periods.
Vaccine Development and Therapeutic Research
Despite the significant clinical burden of human parainfluenzavirus (HPIV) infections, particularly in vulnerable populations such as young children and immunocompromised individuals, no licensed vaccine is currently available for any of the four main HPIV types (HPIV-1, HPIV-2, HPIV-3, HPIV-4) [35]. This absence of a preventive tool places a heavy reliance on supportive care and hygiene measures, underscoring the urgent need for effective vaccines and targeted therapies. The challenges in vaccine development are multifaceted, involving immunological, virological, and safety considerations, particularly in the pediatric population most at risk.
Challenges in Vaccine Development
The development of a safe and effective HPIV vaccine faces several major hurdles. One of the primary obstacles is the inability to induce durable and protective immunity following natural infection. Reinfections with HPIV are common throughout life, although subsequent episodes are generally milder, indicating that natural immunity is incomplete and wanes over time [151]. This phenomenon poses a significant challenge for vaccine design, as the goal is to elicit a more robust and longer-lasting immune response than the virus itself.
A critical concern in pediatric vaccine development is the risk of vaccine-associated enhanced disease (VAED), a phenomenon observed with early inactivated HPIV and respiratory syncytial virus (RSV) vaccine candidates. These vaccines, tested in the 1960s, led to more severe disease upon subsequent natural infection, likely due to a skewed, non-protective Th2-biased immune response and inadequate induction of neutralizing antibodies and cytotoxic T cells [152]. This historical precedent necessitates extreme caution in the development of HPIV vaccines, particularly for use in infants.
Furthermore, the virus employs sophisticated immune evasion strategies, most notably the suppression of the host's interferon (IFN) response. HPIV produces accessory proteins, such as the V and C proteins, which inhibit the production and signaling of type I interferons (IFN-α/β). This suppression weakens the innate immune system's first line of defense, allowing the virus to establish infection and replicate more efficiently [6]. This evasion mechanism not only contributes to pathogenesis but also undermines the immunogenicity of potential vaccines, as a robust interferon response is crucial for activating dendritic cells and initiating a strong adaptive immune response [154]. Vaccines that retain this immune-evasive capability may be poorly immunogenic, while those that are over-attenuated may fail to stimulate sufficient immunity.
Promising Vaccine Candidates and Innovative Approaches
Despite these challenges, several promising vaccine candidates are in various stages of preclinical and clinical development, leveraging modern biotechnological platforms.
One of the most advanced and innovative approaches is the use of mRNA vaccine technology. The candidate vaccine mRNA-1653, developed by Moderna, is a bivalent vaccine encoding the fusion (F) protein of both human metapneumovirus (hMPV) and HPIV-3. A Phase 1b clinical trial in children aged 12 to 59 months demonstrated that the vaccine was well-tolerated and induced a significant increase in neutralizing antibody titers against both viruses [5]. This platform offers advantages such as rapid development, the ability to include multiple antigens, and the potential to stimulate both humoral and cellular immunity. However, research also indicates that the type I interferon response can paradoxically limit the efficacy of mRNA vaccines by inhibiting antigen uptake in dendritic cells, highlighting a complex interplay that requires further optimization [156].
Another promising strategy involves viral vector vaccines, particularly those administered intranasally to stimulate mucosal immunity in the respiratory tract. Vectors based on bovine parainfluenza virus type 3 (BPIV3) or human parainfluenza virus type 3 (HPIV3) have been engineered to express antigens from other pathogens, such as the SARS-CoV-2 spike protein, and have shown efficacy in animal models [157]. The parainfluenza virus 5 (PIV5) is another attractive vector candidate because it is non-pathogenic in humans and can induce strong local and systemic immune responses, including neutralizing antibodies and CD8+ T cells, when delivered intranasally [158]. A challenge with this approach is pre-existing immunity to the vector, which could potentially dampen the immune response to the target antigen.
Traditional approaches are also being refined. Live-attenuated vaccines aim to mimic natural infection without causing disease. Clinical trials are ongoing, such as a Phase I study (NCT00641017) for an attenuated HPIV-1 vaccine and another (NCT01254175) for an HPIV-3 vaccine in infants and young children [159][160]. The key to success lies in finding the right balance: the virus must be attenuated enough to be safe but still able to replicate sufficiently to provoke a strong and durable immune response.
Therapeutic Research and Future Directions
In the absence of approved antiviral therapies, treatment for HPIV infections remains supportive care, including hydration, oxygen therapy, and management of symptoms like fever and respiratory distress [41]. The lack of specific treatments is a significant unmet need, especially for severe cases in immunocompromised patients, where HPIV pneumonia can have a mortality rate as high as 20-30% [70].
Research into direct-acting antivirals is in its early stages but focuses on targeting key viral proteins. The hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins, which are essential for viral entry, are prime targets for inhibition [12]. Another highly promising area is the development of monoclonal antibodies (mAbs). Researchers have isolated potent human monoclonal antibodies that can neutralize HPIV-3 by blocking its entry into cells [83]. The success of mAbs like palivizumab and nirsevimab for RSV prevention provides a strong precedent and a potential pathway for similar prophylactic or therapeutic use against HPIV, particularly in high-risk infants [165].
Finally, adoptive T-cell therapy is emerging as a potential treatment for severe HPIV infections in immunocompromised hosts. This approach involves isolating and expanding a patient's own T cells that are specific for HPIV, or using donor cells, and reinfusing them to provide targeted immune control of the virus [85]. This strategy leverages the critical role of T cells in viral clearance and offers a personalized therapeutic option where conventional treatments fail.
Impact on Vulnerable Populations
The parainfluenzavirus poses a disproportionate threat to certain vulnerable populations, including children under five years of age, adults over 65, and individuals with compromised immune system [167]. These groups are at significantly higher risk for severe complications, hospitalization, and long-term morbidity due to the virus's ability to cause lower respiratory tract infections such as bronchiolitis and pneumonia. The impact is further amplified by the absence of a licensed vaccine and specific antiviral therapies, leaving prevention and supportive care as the primary defenses.
Children Under Five Years of Age
Children, particularly those under five, represent the most vulnerable demographic for severe parainfluenzavirus infections. The anatomical immaturity of their airways, combined with an underdeveloped immune response, makes them highly susceptible to complications. The clinical presentation varies significantly by viral subtype and age. HPIV-1 and HPIV-2 are the primary causes of croup (laryngotracheobronchitis), a condition characterized by a distinctive barking cough, stridor, and respiratory distress, most commonly affecting children between 6 months and 3 years of age [120]. This age group is particularly vulnerable because their narrow airways are easily obstructed by the inflammation caused by the virus.
In contrast, HPIV-3 is the most clinically significant subtype for infants and very young children, being the second leading cause of bronchiolitis after the respiratory syncytial virus (RSV) [42]. It is strongly associated with severe lower respiratory tract infections, including bronchiolitis and pneumonia, especially in neonates and infants under one year of age [170]. The impact is profound, with HPIV-3 being responsible for a significant proportion of pediatric hospitalizations and intensive care unit (ICU) admissions for respiratory illness. Premature infants and those with underlying conditions such as congenital heart disease or chronic lung disease (e.g., bronchopulmonary dysplasia) face an even greater risk of severe disease and prolonged recovery. The high rate of hospitalization for HPIV-3 infections underscores its substantial burden on pediatric healthcare systems.
Adults Over 65 and the Elderly
While often considered a pediatric pathogen, parainfluenzavirus also significantly impacts older adults, particularly those over 65. In this population, the virus can cause severe respiratory illness, including pneumonia and exacerbations of pre-existing chronic conditions such as chronic obstructive pulmonary disease (COPD) or heart failure. The increased susceptibility is primarily due to immunosenescence, the age-related decline in immune function, which impairs the body's ability to mount an effective defense against the virus [35]. Reinfections are common throughout life, but in older adults, these reinfections are more likely to result in severe outcomes compared to younger, healthier individuals. The clinical presentation in the elderly may be less specific, sometimes lacking the classic symptoms seen in children, which can lead to delayed diagnosis and treatment.
Immunocompromised Individuals
The impact of parainfluenzavirus is most severe in immunocompromised individuals, where infections can be life-threatening. This high-risk group includes patients undergoing chemotherapy, recipients of hematopoietic stem cell transplantation or solid organ transplantation, individuals with uncontrolled HIV/AIDS, and those on long-term immunosuppressive therapy [69]. In these patients, parainfluenzavirus infections frequently progress from an upper respiratory tract infection to severe lower respiratory tract disease, including pneumonia, with a high risk of respiratory failure. The mortality rate for HPIV pneumonia in hematopoietic stem cell transplant recipients has been reported to be as high as 20-30% [70].
A critical factor contributing to the severity in this population is the prolonged viral shedding. Immunocompromised patients can shed the virus for weeks or even months, far longer than immunocompetent individuals, which not only increases their own risk of complications but also makes them a significant source of nosocomial (hospital-acquired) transmission [174]. This prolonged shedding complicates infection control measures in hospitals and transplant units, requiring strict isolation protocols to prevent outbreaks.
Factors of Risk and Long-Term Consequences
Several factors increase the risk of severe infection in vulnerable populations. For children, these include prematurity, low birth weight, lack of breastfeeding, exposure to tobacco smoke, and attendance at crowded childcare facilities [35]. For all groups, the absence of a specific vaccine is a major gap in public health. The lack of targeted antiviral treatments means management relies on supportive care, such as oxygen therapy and hydration, which may be insufficient for the most severe cases [176]. The economic burden is also significant, with the cost of hospitalization and long-term care for severe respiratory infections placing a strain on healthcare systems [177]. Furthermore, recurrent lower respiratory tract infections in early childhood are associated with an increased risk of developing long-term respiratory problems, such as asthma and chronic lung disease, highlighting the potential for lasting health consequences beyond the acute illness [178].
Global Surveillance and Future Outlook
The global surveillance of human parainfluenza viruses (HPIVs) is essential for tracking viral evolution, identifying emerging strains, and informing public health responses to mitigate the burden of respiratory disease. Despite the absence of a licensed vaccine, coordinated international efforts are enhancing the capacity to monitor HPIV circulation through advanced genomic sequencing and integrated epidemiological networks. These systems enable real-time tracking of viral spread, support early detection of outbreaks, and guide the development of targeted interventions. The future outlook for HPIV control hinges on strengthening surveillance infrastructure, advancing vaccine platforms, and addressing the unique challenges posed by viral immune evasion and antigenic stability.
Genomic Surveillance and Phylogenetic Tracking
Genomic surveillance has revolutionized the understanding of HPIV evolution and global dissemination. High-throughput sequencing technologies allow for comprehensive analysis of viral genomes, revealing patterns of genetic diversity, selection pressures, and transmission dynamics. Studies have shown that HPIV-1 evolves at an estimated rate of 4.97 × 10⁻⁴ mutations per site per year, a relatively stable rate consistent with other negative-sense RNA viruses [179]. This genetic stability facilitates the reconstruction of viral lineages and the tracing of international spread.
Phylogenetic analyses have identified geographically distinct clades, indicating localized evolution and limited global transmission in some cases. For example, a novel clade D of HPIV-1 has been documented exclusively in China, suggesting regional adaptation and circulation [74]. In contrast, HPIV-3 exhibits broader global circulation, with lineage C3 becoming dominant across multiple countries, including China and Argentina [74]. Similarly, research in Argentina has revealed the emergence of new genetic lineages of HPIV-3 between 2009 and 2013, highlighting ongoing viral adaptation within local populations [182].
These insights are critical for diagnosing infections, evaluating the effectiveness of molecular assays, and designing vaccines that target prevalent strains. The World Health Organization (WHO) has recognized the importance of such surveillance by including respiratory viruses like HPIV in its global genomic surveillance strategy for pathogens with pandemic potential [183]. Ongoing monitoring ensures that diagnostic tools remain effective and that vaccine candidates are aligned with circulating variants.
Integrated National Surveillance Systems
National surveillance systems play a pivotal role in detecting and responding to HPIV activity. In Italy, the RespiVirNet program, coordinated by the Istituto Superiore di Sanità (ISS), serves as a model for integrated respiratory virus surveillance [7]. This system combines clinical, epidemiological, and virological data collected from sentinel general practitioners, pediatricians, and hospital laboratories to monitor the circulation of HPIVs alongside other respiratory pathogens such as SARS-CoV-2, respiratory syncytial virus (RSV), and influenza [115]. Since the 2023–2024 season, RespiVirNet has shifted from monitoring influenza-like illness (ILI) to acute respiratory infections (ARI), adopting a broader case definition that improves sensitivity for detecting HPIV-related illnesses such as bronchiolitis and croup [186].
RespiVirNet employs real-time reporting and weekly epidemiological bulletins (e.g., RespiNews) to inform healthcare providers and public health authorities about current viral trends [187]. This rapid dissemination enables hospitals to activate contingency plans, such as increasing staffing or isolating patients, in response to rising HPIV activity. The system also supports early detection of hospital outbreaks, particularly in high-traffic pediatric settings like emergency departments and intensive care units [188].
Hospital Outbreak Detection and Prevention
Effective surveillance in healthcare settings is crucial for preventing nosocomial transmission of HPIV, especially among vulnerable populations such as immunocompromised children and neonates. In pediatric hospitals, active surveillance involves systematic testing of inpatients with acute respiratory symptoms using rapid multiplex PCR assays that can identify HPIV types 1–4, RSV, influenza, and other respiratory viruses [141]. Early identification allows for prompt isolation of infected patients and implementation of droplet precautions, including the use of surgical masks, gowns, and gloves [41].
The integration of syndromic diagnostic approaches—combining clinical evaluation with rapid virological confirmation—enhances the speed and accuracy of outbreak detection [101]. In high-risk units such as pediatric oncology and transplant wards, this strategy is vital for protecting immunocompromised patients who face mortality rates as high as 20–30% if they develop HPIV pneumonia [70]. Prolonged viral shedding, which can last up to 3–4 weeks in immunocompromised individuals, further increases the risk of transmission, underscoring the need for sustained infection control measures [98].
Future Directions in Vaccine and Therapeutic Development
The future outlook for HPIV control is increasingly focused on the development of effective vaccines and antiviral therapies. Although no licensed vaccine currently exists, several promising candidates are in preclinical and clinical development. The mRNA-1653 vaccine, developed by Moderna, encodes the fusion (F) protein of both human metapneumovirus (hMPV) and HPIV3. A Phase 1b trial in children aged 12–59 months demonstrated a significant increase in neutralizing antibodies, indicating strong immunogenicity and paving the way for further evaluation [5]. This mRNA platform offers the advantage of rapid design and scalability, similar to its success with SARS-CoV-2 vaccines.
Viral vector-based vaccines, particularly those administered intranasally, are also showing promise. Candidates using bovine parainfluenza virus type 3 (BPIV3) or parainfluenza virus 5 (PIV5) as vectors have induced robust mucosal and systemic immune responses in animal models, including neutralizing antibodies and CD8+ T cell activation [157]. These mucosal responses are critical for blocking infection at the site of entry. However, pre-existing immunity to the vector may reduce efficacy, necessitating the use of less common viral backbones or multivalent strategies.
Live-attenuated vaccines are another area of active research, with clinical trials underway for HPIV-1 and HPIV-3 (e.g., NCT00641017 and NCT01254175) [160]. Challenges remain in balancing attenuation with immunogenicity, particularly in young infants whose immature immune systems may not mount a strong response. Additionally, the virus’s ability to suppress the interferon response complicates vaccine design, as interferon signaling is essential for activating dendritic cells and initiating adaptive immunity [6]. Mutant strains with impaired interferon antagonism are being explored as safer and more immunogenic vaccine candidates.
Economic and Clinical Burden Driving Innovation
The substantial clinical and economic burden of HPIV infections underscores the urgency of developing preventive and therapeutic tools. In pediatric populations, HPIV-3 is the second leading cause of bronchiolitis after RSV and contributes significantly to hospitalizations, especially in infants under one year of age [42]. In immunocompromised adults, HPIV infections are associated with high morbidity and mortality, yet lack specific antiviral treatments [199]. The absence of targeted therapies means management relies entirely on supportive care, including oxygen therapy, hydration, and mechanical ventilation when necessary.
The economic impact is considerable, with respiratory diseases costing Italy an estimated €45.7 billion annually in healthcare and lost productivity [177]. Globally, the market for HPIV infection treatments was valued at approximately $259 million in 2023, reflecting the unmet need in specialized care settings [201]. These figures highlight the potential return on investment for developing effective vaccines and antivirals.
Future priorities include expanding global surveillance networks, particularly in tropical regions where HPIV circulation is less seasonal and more continuous [35]. Enhanced data collection will improve predictive modeling and inform public health strategies. Moreover, research into passive immunization with monoclonal antibodies—inspired by the success of nirsevimab for RSV—offers a potential short-term solution for protecting high-risk infants [165]. Combined with advances in vaccine technology and a deeper understanding of HPIV immunology, these efforts hold the promise of reducing the global burden of parainfluenza virus infections in the coming decades.