Respiratory Syncytial Virus (RSV) Pathophysiology

RSV is the leading cause of hospitalization in infants younger than 12 months.²* Therefore, understanding the etiology and pathophysiology of RSV in infants is crucial for developing effective treatments and preventive strategies.

RSV pathology is characterized by infection of respiratory epithelial cells, which triggers a variety of immune and inflammatory events. These early host immune responses to RSV are critical determinants of the progression of the disease and whether it develops into RSV bronchiolitis pathophysiology.³

*Based on leading primary diagnosis (RSV bronchiolitis, Oct 2015-Dec 2019, rank 1: 165,930 cases).²

Mechanism of RSV infection

RSV is an enveloped RNA virus. Two main subtypes are involved in most outbreaks: A and B.¹

Once spread via respiratory droplets, the RSV mechanism of infection begins with replication of the virus in the nasopharynx, where it rapidly spreads into the respiratory tract and targets apical ciliated epithelial cells.⁶

From there, the virus binds to cellular receptors, fuses with the host cell membrane, and inserts its nucleocapsid into the host cell to begin intracellular replication.⁶

Two important glycoproteins are involved in this RSV mechanism of action: the attachment glycoprotein (G) and the fusion glycoprotein (F), which mediate viral cell entry.⁷ The latter is highly conserved among both RSV strains and is the target of preventive interventions.⁸

Along with mediating cell entry, glycoprotein F triggers the merging of adjacent cells, giving rise to large multinucleated structures called syncytia, which cause epithelial lesions in the upper respiratory tract.^7,9,10 Progression to the lower respiratory tract is common.³

From here, the process of viral shedding begins with the release of infectious virions into surrounding healthy cells or the environment to facilitate RSV transmission.^9,11

For some infants, the initial RSV infection will progress into RSV bronchiolitis.⁶

RSV immune response

In response to RSV infection, many elements of host immunity are activated to protect infants.

This RSV immune response includes the production of virus-neutralizing antibodies, such as IgG, IgM, and IgA as well as T-cell activation.^8,12

However, with more than half its proteins having an immunomodulatory effect, RSV has a variety of mechanisms to overcome this RSV immune response.¹³

NS1 and NS2 are major viral proteins that have evolved multiple ways to supress type I IFN production and signaling.¹³

The resulting effect of both viral cytotoxicity and host cell cytotoxicity causes the death of the respiratory epithelial cells, which are sloughed and may be aspirated, carrying RSV to lower respiratory tract cells, where small airway obstruction and plugging by mucus and other resulting infectious debris occurs.⁶

Clinical manifestations of RSV

Following the incubation period of RSV, symptoms normally appear in infants within a few days⁸ and will initially present as an upper respiratory tract infection, including coughing, nasal congestion, rhinorrhea, and fever.^8,14 Parents may also notice irritability and poor feeding.⁸

If the infection travels deeper into the lower respiratory tract, RSV can manifest as bronchiolitis, with symptoms including wheezing, tachypnea, accessory muscle use, and prolonged expiration.⁶

Across the RSV pathway, from infection to clinical presentation, transmission of RSV is possible through viral shedding.⁸

Factors influencing RSV pathophysiology

Every infant is at risk of RSV.^15,16

Others factors influencing RSV pathophysiology include:

• Age of the patient⁶
• Underlying medical conditions⁸
• The patient's primary infection with RSV⁶

RSV bronchiolitis pathophysiology

RSV is the most common viral cause of severe respiratory illness in children younger than 5 years and the major cause of bronchiolitis in infants.^18,21,22 The pathophysiology of RSV bronchiolitis involves inflammation of the distal bronchial airways, which ultimately leads to distal airway obstruction.^3,10

Although the exact mechanism of RSV bronchiolitis pathophysiology is unclear, it’s thought that viral cytotoxicity causes necrosis of the epithelial cells, with subsequent sloughing and mucus production plugging the bronchioles and leading to lung hyperinflation and atelectasis.²¹ These factors may work in combination with peribronchiolar inflammatory infiltration and submucosal edema—all of which contribute to distal airway obstruction.^12,18

RSV progresses to bronchiolitis in some infants largely because of an immature immune system and lack of functionally RSV-protective maternal transplacental antibodies. Therefore, this immaturity, combined with the smaller physical dimensions of their airways, provides a logical explanation of why infants are more likely to develop severe distal airway disease during respiratory virus infection than older children or adults.¹⁸

Multinucleated cells and syncytial giant cells are another feature of RSV infection that are also likely to contribute to the small airway obstruction seen in RSV bronchiolitis.¹⁸ 

As the airway becomes obstructed, gas exchange is compromised, resulting in hypoxemia and potentially the need for supportive respiratory therapy, such as ventilation.³ Ultimately, 2 to 3 out of every 100 infants with RSV infection may need to be hospitalized.²³

Abbreviations

IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IFN, interferon.