Introduction

Parainfluenza viruses are a group of four distinct respiratory viruses that pose a significant threat, especially to young children and older adults. Classified as HPIV-1, HPIV-2, HPIV-3, and HPIV-4, these viruses are responsible for various respiratory illnesses, from the common cold to more severe conditions like croup, bronchiolitis, and pneumonia.¹ HPIV-1 and HPIV-2 are the primary causes of croup, a condition characterised by a barking cough and difficulty breathing due to swelling around the vocal cords. HPIV-3, on the other hand, is often associated with bronchiolitis and pneumonia. Although less common, HPIV-4 can still cause various respiratory issues. After respiratory syncytial virus (RSV), parainfluenza viruses are the second leading cause of hospitalisation for respiratory illnesses in children under five. They can also pose a significant threat to immunocompromised individuals and the elderly.² 

The common symptoms and short-term effects of parainfluenza virus (HPIV) infection include:

Upper respiratory symptoms³

• Fever
• Runny nose
• Cough
• Sneezing
• Sore throat

Lower respiratory symptoms³

• Croup (barking cough, hoarseness, stridor/noisy breathing)
• Bronchitis (cough, wheezing)
• Bronchiolitis (wheezing, labored breathing)
• Pneumonia (cough, chest pain, breathing difficulties)

Other symptoms¹

• Ear pain
• Irritability
• Decreased appetite
• Vomiting
• Diarrhoea

The symptoms generally appear 2 to 7 days after infection and last for a few days to a week, with some lingering for up to 2 weeks. Healthy adults with human parainfluenza virus (HPIV) infections may experience mild upper respiratory symptoms, while more severe illnesses like pneumonia are more common in young children, older adults, and those with weakened immune systems.¹

Importance of understanding long-term effects

Understanding the long-term effects of parainfluenza virus infections is important for public health and clinical management, as long-term viral shedding, especially in immunocompromised patients, increases the risk of nosocomial (hospital-acquired) transmission and outbreaks. Two distinct genetic clusters of the same respiratory syncytial virus genotype were detected, suggesting nosocomial transmission among patients with long-term shedding.⁴

Epidemiology and transmission

Prevalence and incidence

Human parainfluenza viruses (HPIVs) are globally distributed respiratory pathogens that cause significant morbidity, especially in young children. They account for approximately 7% of all hospitalisations for fever and acute respiratory illness.⁵ HPIVs are serologically and genetically grouped into four species (HPIV-1, HPIV-2, HPIV-3, and HPIV-4) that collectively account for up to 10% of all hospitalisations due to acute respiratory infections.⁶

The highest incidence of HPIV infections is observed in children aged 1-5 months.⁷ While HPIVs can infect individuals of all ages, the majority of detections occur in children aged ≤2 years (36% of cases).⁵ High-risk populations include young children, individuals with chronic respiratory conditions, prematurely born infants, and the immunocompromised.⁶ HPIV-3 tends to infect younger children after the waning of maternal antibodies.⁶

Types of transmission

HPIVs are primarily transmitted through person-to-person contact. They spread via respiratory droplets and close contact with infected individuals or contaminated surfaces.⁸ The viruses can cause both upper and lower respiratory tract infections, with severity varying based on the patient's age and immune status.⁸ HPIV-3 is the most commonly reported type, followed by types 1, 2, and 4. While HPIVs are detected year-round, they show type-specific seasonal variations.⁵

Pathophysiology of parainfluenza infection

Mechanism of infection

The primary target of human parainfluenza viruses (HPIVs) is the respiratory tract's epithelial cells. The fusion (F) protein helps the virus enter the cell more easily, while its hemagglutinin-neuraminidase (HN) protein binds to host cell receptors. The virus replicates its genetic material and creates new viral particles inside the host cell by controlling its machinery.⁹

The body's immune response to HPIV infection involves both innate and adaptive immunity. The innate immune system responds initially with the production of interferons and the activation of natural killer cells. This is followed by the adaptive immune response, which includes the production of virus-specific antibodies and T-cell responses. However, the immune response can also contribute to tissue damage and inflammation in the respiratory tract.⁹

Long-term respiratory effects

Chronic respiratory conditions

Severe HPIV infections, especially those affecting the lower respiratory tract, may significantly affect lung function in the long run. These effects are particularly noticeable in those who have experienced complications such as pneumonia or bronchiolitis.

Development of asthma 

There is an important association between early childhood parainfluenza virus (HPIV) infections and the later onset of asthma. According to research, HPIV infections can alter immune responses and lung function over the long term, especially if they occur during crucial developmental stages. These alterations may contribute to the onset of asthma, especially in genetically predisposed individuals.¹⁰

Chronic obstructive pulmonary disease (COPD) risk

Similar to asthma, early HPIV infections have also been linked to an increased risk of developing chronic obstructive pulmonary disease (COPD) in adulthood.¹⁴,¹⁰ The mechanisms behind this association are not fully understood, but it's believed that repeated viral infections during childhood may cause structural changes in the airways and alter immune responses, potentially setting the stage for COPD development later in life.¹⁰ This is particularly concerning for children who experience recurrent or severe lower respiratory tract infections. The inflammation and damage caused by these infections can lead to structural changes in the lungs, contributing to long-term respiratory problems.¹⁴

Recurrence of respiratory infections

Individuals who have experienced HPIV infections, especially those with chronic lung conditions or compromised immune systems, may be more susceptible to future respiratory infections. This increased vulnerability can be due to the changes in the respiratory epithelium and immune responses following initial HPIV infections.¹ While most people obtain some immunity to HPIVs after their initial infections, infections can occur more than once in a person's lifetime. In healthy individuals, subsequent infections are usually less severe. However, recurring HPIV infections can be more common and severe for some high-risk groups, such as young children, older adults, and immunocompromised individuals.¹

There are concerns for lung transplant recipients, as parainfluenza virus infections have been linked to severe pulmonary dysfunction in both the short and long term. These individuals might have longer recovery times and more severe symptoms, which could affect their overall lung function and quality of life.¹¹

Impact on immunity

Prolonged viral shedding 

Prolonged viral shedding in individuals with parainfluenza, particularly in those with compromised immune systems, is a significant concern of the long-term effects of parainfluenza.⁴. Some patients, especially those with compromised immune systems, may experience long-term shedding of the virus. Studies have shown that viral shedding can occur for several months, even after symptoms have resolved, particularly with HPIV-3.⁴

Immunocompromised patients' prolonged viral shedding duration is likely caused by a weakened immune response that is unable to remove the virus completely. Significant risk factors for extended shedding have been discovered, including the presence of co-infections, prior steroid therapy, and severe leukopenia (low white blood cell count).¹³

After infection, the body creates neutralising antibodies that specifically target the virus's surface proteins. These antibodies play a crucial role in controlling the infection and providing long-term immunity.¹⁵ Immunoglobulin A (IgA) antibodies, which are present in mucosal surfaces, help prevent reinfection. However, IgA responses are typically short-lived, and multiple infections might be necessary for the long-term persistence of mucosal IgA.¹⁶

A study conducted on parainfluenza virus (Sendai virus)-infected aged mice suggested that subclinical infections can affect the immune system in the long run. This included immune system changes that continued long after the primary infection had cleared up.¹⁷ In severe cases, especially those involving lower respiratory tract infections like pneumonia or bronchiolitis, there may be longer-term effects on lung function.¹⁸ Complications like pneumonia can make breathing difficult and may require hospitalisation, particularly in young children, the elderly, and those with compromised immune systems.¹

Summary

Parainfluenza virus infections among patients with lung transplants have been associated with significant short- and long-term pulmonary dysfunction. In these vulnerable populations, HPIV infections can lead to hospitalisation and, in rare cases, respiratory failure. The pathophysiology of severe disease often involves a combination of direct viral damage to the respiratory epithelium and an exaggerated inflammatory response, which can lead to airway obstruction and impaired gas exchange.⁹ Extended viral shed in parainfluenza patients presents serious problems for infection control and patient management, particularly in those with weakened immune systems.¹³ Parainfluenza virus infections can have significant impacts on the immune system, particularly in immunocompromised individuals. The immune response involves both humoral and cellular components, but reinfections are common due to limited long-term immunity.¹⁷