Overview

A family of Human Parainfluenza Viruses, or HPIVs, is responsible for upper and lower respiratory tract infections in adults, especially young children.¹ Enclosed single-stranded viruses, HPIVs belong to the RNA virus family Paramyoviridae. The four primary HPIV serotypes are HPIV1 - HPIV4, with HPIV4 further divided into two types (HPIV4a and HPIV4b).² These viruses were first identified in the late 1950s when it was found that three distinct viruses recovered from children with lower respiratory illnesses were different from the myxoviruses (influenza viruses) that they closely resembled. In embryonated eggs, this novel respiratory virus family did not grow well and shared few antigenic sites with the influenza virus. A fourth virus that matched these characteristics was discovered in 1959, and a new taxonomic category known as "parainfluenza viruses" was established.³

The virology of parainfluenza

HPIV2 and HPIV4 belong to the genus Rubulavirus, while HPIV1 and HPIV3 are members of the genus Respirovirus. The parainfluenza virus has a pleomorphic shape, with a diameter of 150–200 µm. It contains six essential proteins—phosphoprotein (P), nucleocapsid protein (NP), matrix protein (M), RNA polymerase (L), hemagglutinin-neuraminidase (HN) glycoprotein, and fusion glycoprotein (F)— that are encoded by a single, negative-sense RNA strand, and they are arranged in a conserved order.² The HPIV's structural arrangement is depicted in Figure 1. 

Figure 1: The structure of HPIV³

Mode of transmission

Figure 2 illustrates how the surface proteins known as HN and fusion glycoproteins, respectively, mediate adherence to the sialic acid residues on the exterior of host epithelial cells (HN) and the integration of the envelope of the virus with the host cell membrane (F). By breaking down the sialic acid residue, the HN protein promotes the release of fresh virions from the cell. The primary targets of neutralising antibodies are these two proteins. The interior surface of the envelope is coated with matrix protein. The NP protein coats and binds to the viral RNA, forming a template that the P and L proteins of the RNA-dependent RNA polymerase can use to help with transcription. Other proteins that are not necessary for virus replication and that differ between the four serotypes are also encoded by the P gene.⁵ The virus replicates in the upper respiratory tract and moves to the lower respiratory tract. The infected cells in the small airways trigger inflammation, which is cleared by the immune system. Immunocompromised children (transplant recipients) who contract HPIV infection are at risk for a variety of illnesses, ranging from minor upper respiratory symptoms to life-threatening conditions requiring mechanical ventilation.⁶

Figure 2: Life cycle of HPIV¹⁰

Common HPIV symptoms

The degree of infection is correlated with the location. For example, in the upper respiratory tract, infections cause cold symptoms, laryngeal and tracheal infections leading to croup, bronchiolitis, and distal airway infections that can cause pneumonia,⁷ because of inflammation.⁸ Due to blockage from inflammation of the trachea's subglottic region, hoarseness, coughing, and stridor are the typical symptoms of croup, because this region of the trachea is less extensible than other sections. The increased effort of breathing brought on by the obstruction of airflow can cause fatigue, hypoxia, and in extreme situations, respiratory failure. It also produces the high-pitched inspiratory vibrations known as stridor, however, the disease is usually mild in adults.⁹ The disseminated infection has been linked to several illnesses affecting different organ systems, including rheumatologic, neurologic, and renal diseases, despite HPIV's primary infection of respiratory tissues.²

Incubation period

During an outbreak, understanding a disease’s incubation period - the time between exposure and symptom onset - is crucial for predicting when individuals may become contagious. It provides insights into the pathogen’s growth, replication and toxin production, which helps identify its cause and origin. The incubation period also informs prognosis, treatment timing and infection control, especially when lab testing is unavailable.¹¹ It aids epidemiological studies, guiding policy decisions and evaluating intervention effectiveness. For the HPIV, the incubation period is typically 2-6 days¹² and is influenced by environmental factors like temperature, humidity and pH.⁴

Worldwide, yearly fluctuations in serotype-specific infection rates of the parainfluenza virus vary by region.¹³ Tropical and subtropical regions exhibit minimal annual variation in infection rates and lack the seasonal patterns of infection observed in the northern hemisphere.¹⁴ During epidemic seasons, HPIV1 may be the cause of 50% of croup cases in the US. It normally causes biennial outbreaks in odd-numbered years during autumn.

Every year, there are fall epidemics of HPIV2 infections, and the most common serotype, HPIV3, causes seasonal outbreaks in the spring, usually after influenza epidemics.¹³ Whilst HPIV1 is not prevalent, a secondary, less severe HPIV3 outbreak could happen in the autumn. On the other hand, there have been few reports of a handful of viruses isolated from adults and children, indicating that the epidemiology of HPIV4 infections is still not fully understood.¹⁵ This is because HPIV4 infections frequently cause mild, subclinical illnesses, and the virus is more elusive to identify.

The pathogen's properties, the host's characteristics, and the environment are some of the factors that influence the incubation period, which is impacted by the virus. Symptoms may develop more quickly in more virulent strains. Individuals with compromised immune systems may encounter varying durations of incubation, contingent upon their capacity to generate an immune response, whereby the body's reaction to an infection can be influenced by one's general health and nutritional status. Finally, the incubation period can be influenced by environmental factors like temperature and humidity, which can have an impact on the viability and spread of pathogens.

While HPIV is a well-known source of infection in young adults and immunocompromised patients, HPIV is also becoming acknowledged as a relevant pathogen in other patient populations, such as hospitalised adults, due to the growing application of multiplex molecular testing. Adult hospitalised patients have reported HPIV infection rates ranging from 2% to 11.5%. It has been determined that the most common clinical presentation of HPIV in adults is cold-like symptoms: cough, rhinorrhea, and sore throat, though exacerbations of underlying diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and congestive heart failure, are also common.¹⁷

However, in small children, HPIV infection has a strong correlation with viral pneumonia.¹⁸ The majority of data that is accessible on clinical presentation is from case studies or studies with small population sizes. The majority of patients (70%) will be experiencing upper respiratory tract infection symptoms (URTI) at the time of presentation. The most reliable indicator that a respiratory virus is the cause of an illness and sets it apart from the numerous other infectious agents that affect this population is the appearance of URTI symptoms. Figure 3 below depicts the HPIV progression.

Figure 3: Individuals' progression with HPIV disease

Early detection and prevention

Even though HPIV1 is frequently linked to the clinical syndrome of croup, the majority of other HPIV infection presentations lack distinguishing characteristics that would enable a viral infection to be identified solely based on clinical presentation. Therefore, laboratory testing is required to obtain a specific viral diagnosis, which can be achieved through the host antibody response to infection. The acquisition of a sufficient sample is necessary for the detection of viruses, whether through molecular testing, fluorescent antibody assays, or culture. Combined nose and throat swabs (NTS), Nasopharyngeal swabs (NPS), nasal washes, sputum, and bronchoalveolar lavage (BAL) are among the sample types that are appropriate for testing.¹⁹ There isn't a vaccine approved to prevent parainfluenza at this time. While maintaining good hygiene is always preferable to prevent this illness, particularly in patients with compromised immune systems and children.

Summary

The Paramyxoviridae family of RNA viruses includes human parainfluenza viruses (HPIVs), which cause respiratory tract infections, especially in young children and immunocompromised people. The virus encodes six necessary proteins and has a pleomorphic shape. Viral entry and replication are facilitated by surface proteins that attach to host cells, leading to transmission, mostly in the upper respiratory tract. From minor cold-like symptoms to serious respiratory conditions like cough, bronchiolitis, and pneumonia, HPIV infections can cause a wide range of symptoms. Inflammatory infiltrates are caused by infected cells in the small airways, and humoral and cellular immune responses are involved in both pathogenesis and defence. HPIV normally takes two to six days to incubate, depending on the pathogen's virulence, the host's immune system, and the surrounding circumstances. Seasonal patterns are seen in HPIV infections; HPIV1 causes autumn outbreaks every two years, HPIV2 peaks in the autumn, and HPIV3 causes outbreaks in the spring. Because HPIV4 infections are usually mild and subclinical, little is known about them. Adults with COPD and asthma may experience worsening symptoms from HPIV. Although there is no vaccine, maintaining good hygiene is essential for prevention. Detection requires laboratory testing.