Innate and Adaptive Immunity in Individuals Experiencing Chronic Obstructive Pulmonary Disease Exacerbations
| Status: | Completed |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 40 - 80 |
| Updated: | 4/21/2016 |
| Start Date: | September 2005 |
| End Date: | September 2010 |
Innate and Adaptive Immunity in COPD Exacerbations: Prospective Cohort Study
The purpose of this study is to determine whether there is a statistical association between
the changes from baseline in the levels of two cytokines interleukin (IL)-17A and IL-6 in
the sputum of patients with chronic obstructive pulmonary disease (COPD) and the severity of
acute exacerbations of COPD (AE-COPD). These sputum cytokine levels are taken as measures of
the adaptive immune response (IL-17A) and the innate immune response (IL-6), respectively.
Sputum will be collected either spontaneously or will be obtained by induction; cytokine
levels will be measured by ELISA. The primary analysis, comparisons of sputum cytokine
levels between clinical states, will be done using random effects modeling.
the changes from baseline in the levels of two cytokines interleukin (IL)-17A and IL-6 in
the sputum of patients with chronic obstructive pulmonary disease (COPD) and the severity of
acute exacerbations of COPD (AE-COPD). These sputum cytokine levels are taken as measures of
the adaptive immune response (IL-17A) and the innate immune response (IL-6), respectively.
Sputum will be collected either spontaneously or will be obtained by induction; cytokine
levels will be measured by ELISA. The primary analysis, comparisons of sputum cytokine
levels between clinical states, will be done using random effects modeling.
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:
A prospective patient cohort will be studied extensively physiologically, functionally, and
immunologically upon enrollment while in the stable state. As part of the study,
participants will be trained in the use of peak flow meters, so that they can record daily
first morning peak expiratory flow rates (PEFR). To confirm the range of fluctuations in
their basal state, participants will be then be followed at three-month intervals for
face-to-face interviews and more limited physiological and functional testing described
below. Participants will also be reminded at each scheduled visit to contact the study
coordinator when they feel that an AE-COPD may be present. If they do contact the study
coordinator, they will be evaluated at one of the study sites within 48 hours.
A diagnosis of AE-COPD will incorporate a modification of the definition used by the COPD
Clinical Research Network (CCRN). The diagnosis will be made in one of two ways: severe
AE-COPD will be defined as a change in respiratory symptoms above the participant's baseline
measurements plus evaluation in the emergency room (ER) or requiring hospitalization; or
mild-to-moderate AE-COPD will be defined as a change in respiratory symptoms above the
participant's baseline measurements and requiring a change in therapy (addition of either
antibiotics, oral steroids, or both), but without evaluation in the ER or hospitalization.
In the latter case, therapy could be changed either at the advice of the patient's own
caregivers or a study physician based on clinical judgment, or could be self-initiated in
the case of participants authorized to do so by their caregiver. A concerted effort will be
made to capture these milder AE-COPD during both winter and non-winter seasons.
Upon enrolling participants, the following will be performed: review of medical history;
review of demographic and smoking history; physical examination, blood and sputum
collection; six-minute walk test; and questionnaires to assess shortness of breath (MMRC and
University of California San Diego SOBQ), sputum production (modified Chronic Bronchitis
Symptom Questionnaire), health status (SF-36 and St. George's Respiratory Questionnaire),
and psychological traits (Hospital Anxiety/Depression Score, Illness Perception
Questionnaire, Coping Index, and an individualized 30-minute clinical interview via
telephone).
Participants will attend study visits every 3 months to review symptoms. During an AE-COPD
(episode of acute bronchitis), sputum and blood will be collected, and a five-symptom
questionnaire will be filled out.
Subjects are reimbursed $25 per scheduled visit and $50 per unscheduled visit (at the time
of perceived exacerbation) to help defray travel expenses.
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:
A prospective patient cohort will be studied extensively physiologically, functionally, and
immunologically upon enrollment while in the stable state. As part of the study,
participants will be trained in the use of peak flow meters, so that they can record daily
first morning peak expiratory flow rates (PEFR). To confirm the range of fluctuations in
their basal state, participants will be then be followed at three-month intervals for
face-to-face interviews and more limited physiological and functional testing described
below. Participants will also be reminded at each scheduled visit to contact the study
coordinator when they feel that an AE-COPD may be present. If they do contact the study
coordinator, they will be evaluated at one of the study sites within 48 hours.
A diagnosis of AE-COPD will incorporate a modification of the definition used by the COPD
Clinical Research Network (CCRN). The diagnosis will be made in one of two ways: severe
AE-COPD will be defined as a change in respiratory symptoms above the participant's baseline
measurements plus evaluation in the emergency room (ER) or requiring hospitalization; or
mild-to-moderate AE-COPD will be defined as a change in respiratory symptoms above the
participant's baseline measurements and requiring a change in therapy (addition of either
antibiotics, oral steroids, or both), but without evaluation in the ER or hospitalization.
In the latter case, therapy could be changed either at the advice of the patient's own
caregivers or a study physician based on clinical judgment, or could be self-initiated in
the case of participants authorized to do so by their caregiver. A concerted effort will be
made to capture these milder AE-COPD during both winter and non-winter seasons.
Upon enrolling participants, the following will be performed: review of medical history;
review of demographic and smoking history; physical examination, blood and sputum
collection; six-minute walk test; and questionnaires to assess shortness of breath (MMRC and
University of California San Diego SOBQ), sputum production (modified Chronic Bronchitis
Symptom Questionnaire), health status (SF-36 and St. George's Respiratory Questionnaire),
and psychological traits (Hospital Anxiety/Depression Score, Illness Perception
Questionnaire, Coping Index, and an individualized 30-minute clinical interview via
telephone).
Participants will attend study visits every 3 months to review symptoms. During an AE-COPD
(episode of acute bronchitis), sputum and blood will be collected, and a five-symptom
questionnaire will be filled out.
Subjects are reimbursed $25 per scheduled visit and $50 per unscheduled visit (at the time
of perceived exacerbation) to help defray travel expenses.
Inclusion criteria:
- Diagnosis of COPD (following American Thoracic Society guidelines) and/or chronic
bronchitis
- Forced Expiratory Volume in 1 second of less than 70% predicted value after
bronchodilator
- Current or former smokers with more than 20 pack-years
- Daily productive cough for 3 months of the year for 2 consecutive years
- At least one AE-COPD requiring medical attention in each year for the previous 3
years
- Willingness to participate in follow-up studies defined in the protocol
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
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