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Parainfluenza viruses (PIV) belong to the Paramyxoviridae family and have single-stranded enveloped negative-sense RNA genomes. The classification of human PIV includes four main serotypes: The HPIV family consists of four serotypes which go from HPIV1 through HPIV4 and HPIV4 further separates into two distinct subtypes named HPIV4a and HPIV4b. These serotypes exhibit distinct taxonomic classifications: Human parainfluenza viruses HPIV1 and HPIV3 belong to the Respirovirus genus while HPIV2 and HPIV4 belong to the Rubulavirus genus.
Figure 1. HPIV virion and genome organization
(Source: Schmidt AC, et al. 2011)
Their genome consists of a single negative-sense RNA strand encoding six key proteins: The virus genome codes for six essential proteins: nucleoprotein, phosphoprotein, RNA polymerase, matrix protein, fusion protein, and hemagglutinin-neuraminidase protein. The parainfluenza virus utilizes HN and F as essential surface proteins. The HN protein binds the virus to host epithelial cell surface sialic acid residues to enable viral attachment. Through mediating membrane fusion between the viral envelope and host cell membrane the F protein enables the viral genome to enter the cell. HN protein helps detach new virus particles from the host cell by cleaving sialic acid residues. These two proteins are the main targets of neutralizing antibodies in the immune response. The viral envelope gains structural support through the lining of its interior by the M protein. The nucleocapsid complex formed by the NP binding to viral RNA functions as a template for the RNA-dependent RNA polymerase which consists of P and L proteins to facilitate viral RNA replication and transcription. The P protein contributes to the polymerase complex and produces accessory proteins that differ between serotypes and manage virus-host interactions. HPIV1 and HPIV3 produce short C proteins in their genetic code but HPIV2 produces a V protein which together they inhibit host immune functions by blocking type I interferon activity to help the virus avoid immune detection.
Table 1. Characterization of HPIV common structural proteins
| Localisation | Protein | Function |
| Associated with vRNA (nucleocapsid formation) | L | RNA-dependent RNA polymerase |
| P | Phosphoprotein subunit of the RNA-dependent RNA polymerase | |
| N | Nucleocapsid protein | |
| Surface glycoproteins | HN | Haemagglutinin-neuraminidase, found on the lipid envelope of hPIV and infected cells, functions in virus-host cell attachment via sialic acid receptors |
| F | Fusion protein that allows the viral nucleocapsid to enter and infect a host cell; required for membrane fusion between host cells (syncytial formation) | |
| M | Matrix protein with a role in attaching nucleocapsids to areas of the infected cell membrane, generating the viral envelope; may be involved in viral budding |
(Source: Pawełczyk M, et al. 2017)
Scientists first isolated HPIV from children with laryngotracheitis in 1955 and called it the "croup-associated virus." Research demonstrates that HPIV leads to upper respiratory tract infections across all age groups and lower respiratory tract infections in children under five years old as well as older adults or immunocompromised people which highlights its bimodal age distribution. The virus transmits between humans through direct contact and by large respiratory droplets.
HPIV infections have a global distribution, with infection rates of different serotypes varying seasonally and influenced by geographic regions. The Northern Hemisphere experiences regular seasonal patterns which stand in contrast to the weaker seasonal distinctions found in tropical and subtropical areas. HPIV-1 and HPIV-2 produce outbreaks during autumn and winter while HPIV-3 reaches peak infection rates in spring and summer after influenza epidemics. Limited epidemiological evidence exists for HPIV-4 because its infections tend to produce mild or asymptomatic symptoms while virus detection proves challenging and reporting remains scarce.
Breastfeeding protects infants from severe HPIV infections and pneumococcal vaccines reduce their risk additionally. Patients who have compromised immune systems experience increased severe pneumonia risk post-infection if they suffer from hematologic malignancies or have undergone hematopoietic stem cell or solid organ transplantation. Socioeconomic factors such as poor nutrition and living conditions in crowded spaces combined with vitamin A deficiency and environmental smoke exposure cause infection risks to climb.
The HPIV-3 serotype stands out as the primary cause of symptomatic infections while HPIV-1 comes next in frequency. The burden of disease and hospitalization rates for children affected by HPIV-1 show notable increases during epidemic periods. Research indicates that HPIV-1 leads to numerous adult hospital admissions every year while being a frequent factor in nursing home outbreaks and deadly pneumonia cases that involve bacterial co-infections. The majority of children encounter HPIV-3 infections during their first year with half becoming infected by their first birthday and 92% by the time they reach three years old. The first infections with HPIV-1 and HPIV-2 develop later in childhood and occur between the ages of 2 to 6 years.
The development of HPIV disease results from complex interactions between the virus and its host. HPIV targets and multiplies in ciliated epithelial cells located in both upper and lower parts of the respiratory system. The virus first infects the nasal cavity and oropharynx before moving to the lower respiratory tract where viral replication reaches its peak between 2 and 5 days after infection begins. The clinical presentation of HPIV infection depends on which body site is affected. The symptoms of upper respiratory tract infections generally resemble those of a common cold. Croup and bronchiolitis emerge from infections of the larynx and trachea and viral replication in distal airways advances to pneumonia.
An infection in the small airway epithelium triggers local inflammatory cell infiltration while the immune response from the host becomes a critical factor in disease development. The infection destroys ciliated epithelial cells which triggers excessive mucus production together with inflammatory cytokine release of IL-6 and TNF-α leading to blocked airways and decreased blood oxygen levels. Inflammation causes the subglottic region of the larynx to narrow which produces the primary symptoms of croup including hoarseness, cough and inspiratory stridor. The surrounding cricoid cartilage limits its elasticity which results in airway blockage creating a high-pitched inspiratory noise known as stridor. Airflow obstruction raises breathing effort and can trigger fatigue along with hypoxia and respiratory failure in severe situations. Adults who suffer from HPIV infection face mild symptoms while asthma patients develop worsened symptoms due to the viral infection causing airway hyperresponsiveness through pro-inflammatory cytokine and chemokine release.
Different serotypes show significant differences in tissue tropism: HPIV-1 and HPIV-2 target the larynx and trachea for infection while HPIV-3 shows preference for distal bronchi and alveoli infection HPIV-4 appears less frequently and causes milder symptoms like cough and runny nose but some research indicates it can also lead to severe lower respiratory tract infections.
Table 2. Kinetics of replication, cytokine release and clinical manifestations of infections with HPIV serotypes 1–3
| Serotype | Locus of replication | Kinetics of replication | Released cytokine upon infection | Clinical manifestations | Remarks |
| HPIV-1 | Upper respiratory tract | Replicates to high titres and does not induce cytokine secretion until late in infection | RANTES IP-10 I-TAC | Upper respiratory tract illnesses, croup | Undetected for several days post infection |
| HPIV-2 | Upper respiratory tract | Replicates less efficiently than hPIV-1 but induces an early cytokine peak | IFN-α IL-6 MCP-1 RANTES IP-10 I-TAC | Upper respiratory tract illnesses, croup | Less able to inhibit an early immune response |
| HPIV-3 | Lower respiratory tract | Replicates to high titres but induces a slower increase in cytokine secretion | IFN-α IL-6 MCP-1 RANTES IP-10 I-TAC | Bronchiolitis, pneumonia | Induces a steadily increasing inflammatory response over several days |
(Source: Pawełczyk M, et al. 2017)
The host defense system against HPIV includes both humoral immunity and cellular immunity components. Serum antibodies that target the viral surface glycoproteins F and HN exhibit neutralizing capabilities while providing protective benefits. The body creates mucosal secretory IgA upon natural infection to neutralize the virus and decrease disease severity. Neutralizing antibodies exhibit specificity for a particular serotype and display limited protective capabilities across different HPIV serotypes 1 to 4. T cell epitopes on HN, P, and NP proteins play an essential role in cytotoxic T lymphocyte responses which facilitate viral clearance. Total protection of the lower respiratory tract in children develops through repeated infections and reaches full effectiveness when neutralizing antibodies work with cellular immunity to establish long-term immunity. Incomplete immunity to HPIV permits reinfection by various serotypes to happen during an individual's lifetime.
No antiviral medication has been proven effective for HPIV infections thus treatment remains limited to supportive care for symptoms. Medical professionals administer oxygen therapy along with bronchodilators and corticosteroids to treat severe respiratory distress. Corticosteroids serve as the primary treatment for croup and show effectiveness in patients with varying severity levels. In critically ill children, corticosteroid administration reduces intubation rates by fivefold. For milder cases, corticosteroids shorten emergency department stays, reduce follow-up visits, and improve sleep quality. Heliox (a helium-oxygen mixture) has been proposed for croup management but is not routinely recommended due to challenges in administration and lack of proven superiority over conventional therapies.
Currently, there is no approved vaccine for the prevention of HPIV infection. Antibodies targeting the two viral surface glycoproteins-the F protein and HN-have virus-neutralizing effects. Both serum and nasal secretory antibodies against these proteins protect the host from HPIV infection and reduce disease severity. Therefore, vaccines that enhance serum and/or mucosal antibody responses may be beneficial, but successful vaccine development faces multiple challenges.
The HN protein from HPIV demonstrates greater stability than its counterpart in influenza A virus. Antigenic variations in the HPIV HN protein have developed over time which created differences in both serological and genetic aspects when compared to early isolates. The antigenic drift creates challenges for vaccine development because vaccines need to protect against changing viral strains. The limited and temporary cross-protection between HPIV serotypes requires the creation of multivalent vaccines.
Most vaccine research currently focuses on HPIV-3, the main serotype causing severe disease and pneumonia in infants and the elderly. Subunit vaccines are generally avoided in HPIV vaccine development. Current strategies include cold-adapted live-attenuated vaccines, bovine parainfluenza virus vaccines, and recombinant bovine/human parainfluenza virus vaccines. Because RSV and HPIV-3 affect similar age groups, recombinant vaccines expressing both RSV and HPIV proteins are being explored. Several candidate vaccines have already entered Phase I/II clinical trials in children.
References
| Target | Cat. No. | Product Name | Size | Species | Application | Detection Sample | |
| PIV | DEIA369 | Parainfluenza 1/2/3 IgG ELISA Kit | 96T | Human | Quantitative | Serum, plasma | Inquiry |
| DEIA370 | Parainfluenza Virus IgA ELISA Kit | 96T | Human | Quantitative | Serum, plasma | Inquiry | |
| DEIA371 | Parainfluenza 1/2/3 IgM ELISA Kit | 96T | Human | Quantitative | Serum, plasma | Inquiry | |
| DEIA1857 | Parainfluenza virus Antibody IgA ELISA Kit | 96T | Human | Qualitative | Serum, citrate plasma | Inquiry | |
| DEIA1948 | Parainfluenza 1/2/3 IgG ELISA Kit | 96T | Human | Qualitative | Human Serum or Plasma (citrate, heparin) | Inquiry | |
| DEIA1949 | Parainfluenza 1/2/3 IgM ELISA Kit | 96T | Human | Quantitative | Serum, plasma | Inquiry | |
| DEIA1950 | Parainfluenza 1/2/3 IgA ELISA Kit | 96T | Human | Qualitative | Human Serum or Plasma (citrate, heparin) | Inquiry | |
| DEIA1949NS | Human anti-parainfluenza virus(PIV) antibody(IgM) ELISA Kit | 96T | Human | Quantitative | Serum | Inquiry |
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