RESCUE STUDY: BURDEN OF RSV
An Observational Study to Assess Respiratory Syncytial Virus (RSV)-associated Illness in Adults With Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a leading cause of death
worldwide and its morbidity and mortality are still rising. The WHO predicts
that COPD will become the fourth leading cause of death worldwide by 2030

COPD is defined by the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) as a preventable and treatable disease with some significant
extra-pulmonary effects that may contribute to the severity in individual
patients. Its pulmonary component is characterized by airflow limitation that
is not fully reversible. The airflow limitation is usually progressive and
associated with an abnormal inflammatory response of the lungs to noxious
particles or gases. The main pathologic features of COPD include tissue
remodelling in the small airways (fibrosis and smooth muscle hypertrophy) and
tissue destruction in the lung leading to emphysema. The first signs of COPD
are often chronic cough, increased sputum production, and dyspnea. The presence
and severity of COPD is generally documented by a decrease in FEV1 compared to
the predicted FEV1 and a decreased FEV1/FVC ratio that is not or only little
reversible by an inhaled bronchodilator. In addition, air trapping is present
in a considerable proportion of COPD patients, as reflected by an increased
RV%TLC. This trapped air, i.e. hyperinflation, contributes to the dyspnea
intensity that is experienced by COPD patients.

Exacerbations are regarded as important events for COPD prognosis, since an
increased frequency of these episodes may hasten disease progression by
accelerated decline in lung function and increased mortality rates,
particularly if these require a hospital admission. The mechanisms by which
exacerbations lead to progressive loss of lung function are not yet unknown.
However, it is likely due to effects of acute inflammation and associated lung
tissue damage. Of interest, the Cosmic study showed that symptoms persist for
several weeks after an exacerbation, suggesting that underlying pathophysiology
is not resolved with a two-week course of oral corticosteroids or antibiotics.
It may thus be of importance to attack the ongoing inflammation with
appropriate treatment at the appropriate location in the lungs.

Viruses that are commonly associated with acute exacerbations in COPD patients
include influenza viruses, picornaviruses, coronaviruses, and paramyxoviruses.
Most of the published studies to date have involved small study populations,
and the percentage of illnesses caused by RSV in persons with COPD ranges
widely from 0% to 17.4%. Though the percentage of illnesses caused by RSV shows
a wide range, RSV has been nevertheless recognized as an important cause of
COPD exacerbations

Human respiratory syncytial virus (RSV) causes severe disease in the very
young, elderly and in high-risk groups. It has been estimated that RSV was
associated with 34 million cases of acute lower respiratory tract infection
(ALRI), 3.4 million ALRI hospitalisations and 55,000 to 199,000 deaths in
children <5 years in 2005. These estimates are based on limited data and there
is a substantial gap in knowledge (on morbidity and associated healthcare and
social costs) across Europe. RSV infection in childhood is associated with
subsequent wheezing and asthma. These long-term sequelae pose a substantial
additional burden on the healthcare system. In addition, RSV is a significant
cause of ALRI morbidity in elderly and COPD patients. Most published data on
RSV disease burden in the elderly are from the United States and from hospital
settings. The knowledge gaps have an impact on Europe*s ability to make
evidence-based decisions nationally about novel vaccines and therapeutics.
There is a parallel need to assemble clinical resources to identify correlates
of severe RSV disease for clinical management, classification of disease
severity in clinical trials and identification of biomarkers for severe disease.

COPD has been traditionally considered a self-inflicted disease induced by
tobacco smoking. In healthy subjects, lung function declines physiologically
with age. By contrast, the traditional pathophysiological paradigm of COPD
proposed by Fletcher and Peto in the late seventies states that, COPD develops
in the so called *susceptible* individuals because smoking enhances the
physiological decline of lung function through life [18]. Recent research,
however, has challenged this traditional paradigm by showing that an enhanced
decline of lung function occurs only in half of the COPD patients whereas the
other half develop COPD because of poor lung function development early in
life. Potential causes of poor lung development are multiple and include
genetic and epigenetic factors, associated with environmental exposures such
as, poor diet, repeated lung infections in infancy, passive smoking and/or
prematurity. It is likely that the driving biological mechanisms vary between
these conditions, thereby making COPD the common clinical endpoint of diverse
molecular pathologies. In any case, this new concept has fundamental
implications for the understanding of COPD, since it allows a novel
stratification of patients based on their lung function trajectories that may
be highly relevant for their individualized management. It provides the
opportunity to treat or even prevent COPD with tailored interventions,
targeting specific molecular networks operating in (innate and acquired)
immunity, inflammation and remodelling. This study will aim to identify
patients who are more susceptible to viral exacerbations with the potential to
develop further treatments to prevent RSV exacerbations.

The primary objective of this prospective observational study is to determine
the incidence of RSV disease and document resource utilization in patients with
COPD. In addition, we will assess if and how the occurrence of an RSV virus
infection affects the long-term outcome of COPD as reflected by rate of lung
function decline, course of symptoms, and rate of COPD exacerbations during the
follow-up of this study.

As a secondary objective, we will investigate whether it is possible to predict
the long-term outcome of COPD, occurrence of COPD exacerbations and
susceptibility to respiratory viral infections including RSV. To this end, we
will analyse clinical data as well as GWAS in blood and genome-wide gene
expression in brushed nasal epithelium.

This is a prospective, observational study conducted across three consecutive
RSV seasons to determine the incidence of RSV disease and document the incident
rate of ALRI*s and COPD exacerbations in patients with COPD. Clinically stable
subjects with COPD (i.e. Global Initiative for Chronic Obstructive Lung Disease
[GOLD] Stage I-IV will be enrolled and followed for three years. At baseline,
subjects will be more extensively characterized with a full medical history,
lung function, blood for transcriptomics, nasal mucosal sampling, body
plethysmography, multiple breath nitrogen washout (MBNW), blood and sputum cell
differential, HRCT, and particles in exhaled air (PExA). Subjects will have
twice yearly scheduled visits to obtain blood, nasopharyngeal swab, sputum, and
clinical data and perform a spirometry. One visit will be scheduled before the
RSV season (in the months between May and October), and one visit will be
scheduled during the RSV season (between October and April). In addition,
unscheduled visits to collect blood, nasopharyngeal swab, sputum, and clinical
data will be conducted in cases where a subject experiences an increase in
symptoms consistent with a COPD exacerbation. Participants will be seen within
7 days of symptom onset.

Burden and risk associated with participation:
Nasal swab collections have the potential to irritate the intranasal cavity and
lead to acute epistaxis; however, the risks associated with discomforts from
such events are minimal. Additional risks include obtaining blood that may
sometimes cause pain at the site where the blood is drawn, bruising, performing
spirometry may cause mild chest tightening and coughing. There are no other
risks to subjects in this study above that from the usual treatment of their
disease.