An analysis of the epidemiology

and pathophysiology of

Respiratory Syncytial Virus

(RSV)

By Piril Erel

Contents:

1. Importance of Respiratory

Syncytial Virus (RSV)

2. Prevalence of RSV

3. Causes of RSV and Related

Disorders

4. Relationship between RSV

with later onset of Asthma

5. RSV Structure

6. Pathogenesis

7. Non-immunological factors

8. Mechanism of RSV entry

and Replication

9. Genetics of host response to

RSV-bronchiolitis

10. Candidate genes for RSV-

bronchiolitis

11. IL4 and IL4-R

12. IL8

13. IL9

14. CCR5

15. Surfactant protein A and

Surfactant protein B

16. Protective Treatment for all at

risk?

Importance of Respiratory Syncytial Virus

(RSV)

• Most important cause of

bronchiolitis and pneumonia in

infants worldwide

• Severe illness is associated with

asthma later in life.

• 3 million hospitalisations and

approx. 66,000 deaths worldwide

per annum

• Mainly in the autumn and winter

months.

(Bush et al., 2007) (Lambert et al., 2014)

Figure 1: Monthly distribution of positive RSV in a sample of

608 children under the age of one in a specific population

Prevalence of RSV

By age 3 years virtually all children have serological

evidence of RSV infection

High risks predisposing for RSV are associated with

prematurity, congenital heart defects, lung disease or

immune deficiencies

however severe cases of RSV infections are common in

apparently healthy infants

(Lambert et al,. 2014)

Causes of RSV

Age is an important risk factor for

severe disease.

1/100 infants are hospitalised

Of those 0.5 to 1% die from

respiratory failure.

Differences in the immune

response to RSV in the very young

are important in determining the

clinical outcome of this very

common infection

Severe RSV infection is associated

with RSV-asthma, RSV-

bronchiolitis and RSV-pneumonia.

(Lambert et al., 2014)

Relationship between RSV and later onset asthma (Tsukagoshi et al., 2013)

Figure 2: Demonstration of how viral infections can heighten the risk and

prevalence and further the severity of respiratory illnesses such as asthma.

RSV Structure

Retrovirus

RNA has 10 genes encoding 11

proteins.

G protein

responsible for viral attachment to

host cells

F protein

promotes fusion of cells together

known as the syncytial formation.

(McNamara et al, 2002)

Figure 3: Molecular Structure of Human respiratory

syncytial virus

Pathogenesis

Highly contagious

Different strains of RSV therefore

full immunity cannot be achieved

more severe illnesses are

associated with subtype A strain

Incubation period of 2-8 days

After initial symptoms older aged

hosts remain contagious for up to

8 days

3-4 weeks in infants and people with

weakened immune system

(Centers for Disease Control and Prevention

[CDC], 2014)

Figure 4: Electron micrograph of RSV particle binding to

cell membrane protein and beginning the infection process

through syncytial formation

Non-immunological factors

Oedema of the mucosal epithelium

Increased mucus secretion

Formation of mucus plugs

Narrow airway and obstruction from

mucus secretion

Shedding of necrotic airway epithelial

cells

Peribronchial lymphocytic

hyperinflation or collapse of lung

tissue down stream to the block

Similar adverse conditions may be

seen in those individuals who have

asthma and other respiratory

conditions.

(McNamara et al, 2002)

Figure 5: Mild peribronchial infiltrates, lungs are

hyperinflated because of air trapping (air gets in but can not

get out) due to mucous necrotic debris in the airways.

Mechanism of RSV Virus and Replication

Inflammatory response in the lung

Acute RSV-bronchiolitis is characterized by a infiltration of lung tissue

by white blood cells such as neutrophils and lymphocytes which are

markers of inflammation.

(Bush et al., 2007)

Genetics of Host Response to RSV-

bronchiolitis

Single nucleotide polymorphism(SNP) analysis has been used to look

for association of genetic variants with disease

Identification of important variants in candidate genes may help to

explain the mechanisms behind different severities of RSV-bronchiolitis.

A number of published studies have identified genes that predispose to

RSV-bronchiolitis including several that code for proteins important in

controlling:

the immune system

or in lung function.

Candidate Genes for RSV-Bronchiolitis

Genes that predispose to RSV-bronchiolitis include several that code

for proteins important in controlling the immune system and in lung

function for example:

interleukin-4 (IL-4) and the interleukin-4 receptor- chain(IL4R), interleukin-

8 (IL-8), interleukin-9 (IL-9),

C-C chemokine receptor 5 (CCR5),

surfactant protein A and surfactant protein B.

IL4 and IL4R

Pleiotropic cytokine produced by

activated T cells

IL4R gene encodes for the alpha

chain on the receptor protein that

binds to IL4

The gene product affects the

activity of multiple cell types.

Overexpression of IL4 delays viral

clearance and accelerates

inflammation.

(Fischer et al, 1997), (Bukreyev et al, 2005)

Figure 7: Overexpression of IL-4, IL-9 and IL-13 results in

goblet cell hyperplasia further complications of IL-4 expression

found in asthmatic patients

IL-8

Predominant inflammatory marker in RSV-bronchiolitis

Functions as a chemoattractant and elicits neutrophil accumulation at

site of infection

Enhanced IL-8 production in RSV-infected epithelial cells

strong correlation between amount of IL-8 mRNA and disease severity in

RSV-bronchiolitis

Clinical manifestations of RSV-bronchiolitis are determined by local

immunological responses to infections rather than viral character.

(Patel et al., 1998), (Cane, 2007)

IL-9

High concentrations of IL-9 from

neutrophil secretion

found in infants with severe RSV-

bronchiolitis.

IL-9 induces the production of:

proinflammatory cytokines

chemokines

mucus secretion by bronchial

epithelial cells

causing goblet cell hyperplasia.

(Olszewska et al., 2009)

Figure 7: Overexpression of IL-4, IL-9 and IL-13 results in

goblet cell hyperplasia further complications of IL-4 expression

found in asthmatic patients

CCR5

CCR5 is associated with severe

RSV disease, suggesting an

important pathophysiologic role for

these chemokines.

Over expression of CCR5 in RSV

susceptible individuals(Hull et al,. 2003) (Morrison et al,. 2008)

Figure 8: CCR5 surface expression peaks at 36 hours post-

infection before decreasing to background levels by 60

hours

Surfactant protein A and Surfactant

protein B

Key protein regulators in the homeostasis of surfactant in the lungs,

guarding against respiratory pathogens.

Shown to neutralize RSV by binding to the F protein

However,

Decrease in expression of SP-A results in increased severity of RSV

Increase in SP-B leads to susceptibility of RSV infection

(Ghildyal et al., 1999) (Puthouthu et al., 2007)

Protective treatment for all at risk?

Immunoprophylactic antibody palivizumab, is currently offered only to

babies at high risk

Epinephrine has the greatest short-term benefits by reducing the need

of hospital admission, with hypertonic saline and corticosteroids

reducing the length of hospital stay

Preventative treatment for the general population could be

implemented by incorporating genotype assessment as one of the

Guthrie card tests.

(Wang et al., 2011)

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