The role of innate immunity in the pathogenesis of acute respiratory syncytial virus lower respiratory tract infection:
Repeated measurements of nasopharyngeal type 1 interferon levels in RSV infections

Respirator Syncytial Virus (RSV) lower respiratory tract infection (LRTI) is
the most common cause of pediatric hospitalisation during the winter season.
During the first year of life, 0.5-1% of Dutch children is admitted for RSV
infection. Risk factors for RSV bronchiolitis hospitalisation are prematurity
(with or without chronic pulmonary disease), neonatal status and congenital
heart disease. However, most patients have no identifiable risk factor. Recent
literature shows that the elderly population is also at risk for RSV LRTI
hospitalisation.

The role of the immune response during RSV infection and during recuperation of
serious illness is largely unknown. It is speculated that inadequate viral
clearance during the neonatal period is the result of a premature immune
system. Indeed, healthy babies show an increase of interferon (IFN) gamma
production during the first 12 months of life. Studies also show that a
decrease in adaptive immune response during RSV bronchiolitis is associated
with an increase in disease severity and that there is a positive correlation
between disease severity and viral titers.

Apart from immature T-cel immunity, innate immune responses, such as Toll-like
receptor systems and Type 1 interferons, are also suboptimal at birth.
TLR4-CD14 complex-mediated tumor necrosis factor (TNF) alpha is largely absent
at birth. TLR4 is considered the putative receptor for RSV. Type 1 interferons
have a direct anti-viral effect, but also play a role in activation of antigen
presenting cells, natural killer (NK) cells and T-cells. Epithelial and
plasmoid dendritic cells produce interferon after infection with RSV. However,
RSV inhibits TNF-alpha mediated interferon production. Inhibition of interefron
production could be an important mechanism by which RSV attempts to evade the
immune system. So far, the role of Type 1 interferons during RSV LRTI has not
been studied in humans.

To obtain insight in the role of the innate immune response, especially Type 1
interferons, in the pathogenesis of RSV LRTI. New techniques are used to
unravel the local (nasopharyngeal) immunological milieu during viral LRTI. The
hypothesis is that nasopharyngeal Type 1 interferon concentration is associated
with severity of disease during RSV LRTI in children and the elderly.

Outpatient children (RSV + en RSV -):
Nasopharyngeal aspirate during the outpatient visits.

Hospitalised, non-intubated children (RSV + en RSV -):
Nasopharyngeal aspirate after admittance and 3 times a week, and during
outpatient visits, 2 max.

Intubated children (RSV + en RSV -):
Nasopharyngeal aspirate and noseswab after intubation and 3 times a week until
extubation. 2 1/2 ml of blood 3 times a week, during regular laboratory
work-up, until extubation. For subgroup of children discharged to the pediatric
ward of WKZ nasopharyngeal aspirate at ward 3 times a week, and at home once a
week for 2 weeks after discharge.

Hospitalised elderly (RSV +):
Nasopharyngeal aspirate after admittance and 3 times a week until discharge.

Hospitalised elderly (RSV -):
Nasopharyngeal aspirate only after admittance.

na