Changes in Cytokine Levels During an Acute Exacerbation of Chronic Obstructive Pulmonary Disease

BACKGROUND:

COPD is one of the most pressing healthcare problems facing our nation. AE-COPD is
responsible for the bulk of healthcare costs, and much of the morbidity and decline in
health status among individuals with this common disease. The lack of accepted animal models
of AE-COPD necessitates novel approaches using human samples. Advances in the understanding
of the pathogenesis have been slowed, in part, due to controversy as to how exacerbations
should be defined. The prevailing paradigm has defined AE-COPD as event-based. Such
definitions clearly identify groups of patients with accelerated loss of pulmonary function
and increased mortality. However, limited data show that symptom-based definitions of
AE-COPD also capture episodes inducing significant morbidity and functional decline, and
hence of concern to patients. Fundamental mechanisms are lacking to explain AE-COPD defined
by either means.

Controversy also surrounds triggers of AE-COPD. Bacteria and viruses are involved in some
episodes, but the relative importance of each is intertwined with disputes over the
definition of AE-COPD. Progress at linking specific pathogens to molecular pathogenesis has
been slow, both due to their diversity, and to the high rates of bacterial colonization of
patients with COPD, even in the stable state. Moreover, in many AE-COPD cases, no pathogen
can be identified. Without negating the value of analyzing infections with specific species
of pathogens, it appears that progress in molecular pathogenesis could be accelerated by
focusing on unifying features of the pulmonary immune response during AE-COPD.

DESIGN NARRATIVE:

The research protocol will involve a prospective, observational analysis. Participants will
include acutely ill COPD patients having an AE-COPD who are enrolled during an ER evaluation
or hospitalization at Ann Arbor VA Hospital or the University of Michigan Health Systems ER,
clinic, or wards. All non-study diagnostic testing, decisions to discharge from the ER or
admit to hospital, prescription of medications, and non-study follow-up will be left to the
discretion of the primary caregivers.

Participants who are either being or anticipate being discharged to their usual residence
from the ER will be enrolled while still in the ER. Participants who were discharged to
their usual residence may be contacted by telephone and enrolled up to 24 hours later, if
willing to return to the Medical Center for study initiation. Hospitalized patients will be
enrolled within the first 48 hours. Study physicians and coordinators will be on call to
capture people at presentation, prior to steroids and antibiotics, if possible. However,
clinically indicated treatment will not be delayed to permit enrollment or collection of
research samples. Participants will be questioned about the status of five respiratory
symptoms (dyspnea, cough, sputum production, sputum viscosity, sputum purulence) using a
published Respiratory Symptom score instrument. Each symptom will be scored for severity
using the following three-point scale: 1) Usual level; 2) Somewhat worse than usual; 3) Much
worse than usual. An acute exacerbation of chronic bronchitis (AECB) will be defined
symptomatically as a minor worsening (score of 2) for two or more symptoms, or a major
worsening (score of 3) for one or more symptoms.

A clinical score will be generated using a previously used system (Chest 2000;
118:1557-1565) in which 10 clinical parameters will be assessed (overall feeling of
well-being, dyspnea, cough, sputum production, sputum viscosity, sputum purulence, overall
appearance, respiratory rate, wheezing, and rales); severity of each parameter will be
scored using the same three-point scale. Thus the scores will range from 10 to 30.

The following additional data will be obtained: vital signs (blood pressure, pulse,
temperature, respiratory rate, oxygen saturation level); dyspnea assessment (MMRC &
University of California San Diego SOBQ); estimate of daily sputum production over last 72
hours; sputum color (using a standardized color "paint-chip" scale); changes in medication
usage, with special attention to elicit any history of increased use of potent inhaled
steroids, or patient-initiated use of oral steroids or antibiotics. If there is fever or
focal findings on chest examination, a chest X-ray will be obtained as part of usual
clinical care.

Sputum and blood samples will be collected for measurement of IL-6 and IL-17 levels at time
0 in the ER or hospital, and then 5-7 days, 10-12 days, 33-35 days, and 56-58 days later.
Specimens may be obtained from participants requiring mechanical ventilation during the
first 24 hours of intubation only, and only if they are not suspected to have pneumonia.

Subjects are reimbursed $25 per scheduled return visit following hospital discharge to help
defray travel expenses.

Inclusion criteria:

- Diagnosis of COPD (following American Thoracic Society guidelines) and/or chronic
bronchitis

- ER visit and/or hospitalization with AE-COPD

- Current or former smokers with more than 20 pack-years

- Willingness to participate in follow-up studies defined in the protocol

- Ability to give informed consent

Exclusion criteria:

- Unstable cardiovascular disease

- Other systemic disease in which survival of more than 2 years is unlikely

- Mental incompetence or active psychiatric illness

- Currently taking more than 20 mg/day of Prednisone

- Participation in another experimental protocol within 6 weeks of study entry

- Asthma

- Cystic fibrosis

- Clinically significant bronchiectasis

- Lung cancer

- Other inflammatory or fibrotic lung disease