Steroid Resistance During COPD Exacerbations With Respiratory Failure
| Status: | Recruiting |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, Chronic Obstructive Pulmonary Disease, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 40 - 89 |
| Updated: | 1/17/2019 |
| Start Date: | July 21, 2017 |
| End Date: | January 2020 |
| Contact: | Jonathan Zakrajsek |
| Email: | jonathan.zakrajsek@ucdenver.edu |
| Phone: | 303-724-6066 |
Targeting Steroid Resistance During Acute Exacerbations of Chronic Obstructive Pulmonary Disease With Respiratory Failure - The AECOPD Resistance Study
Chronic obstructive pulmonary disease (COPD) is a lung disease caused by cigarette smoke that
affects millions of people. In the United States, COPD is the 3rd leading cause of death
making it one of our most important public health problems. Some people with COPD get disease
flares that are called acute exacerbations of COPD - or AECOPDs for short. When people get an
AECOPD they experience increased shortness of breath, wheezing and cough; symptoms that often
require urgent or emergent treatment by healthcare providers. In the most severe,
life-threatening situations, people with AECOPDs are put on a ventilator in the emergency
department and admitted to the intensive care unit. Most AECOPDs can be treated with low
doses of medications called steroids. This is good because high doses of steroids can cause
unwanted side effects. Unfortunately, recent studies suggest that the sickest people, those
admitted to the intensive care unit needing ventilator support, need higher doses of steroids
because they may have resistance to these important medications. The investigators are
studying steroid resistance during very severe AECOPDs so that we can eventually develop
better and safer therapies for these vulnerable people.
affects millions of people. In the United States, COPD is the 3rd leading cause of death
making it one of our most important public health problems. Some people with COPD get disease
flares that are called acute exacerbations of COPD - or AECOPDs for short. When people get an
AECOPD they experience increased shortness of breath, wheezing and cough; symptoms that often
require urgent or emergent treatment by healthcare providers. In the most severe,
life-threatening situations, people with AECOPDs are put on a ventilator in the emergency
department and admitted to the intensive care unit. Most AECOPDs can be treated with low
doses of medications called steroids. This is good because high doses of steroids can cause
unwanted side effects. Unfortunately, recent studies suggest that the sickest people, those
admitted to the intensive care unit needing ventilator support, need higher doses of steroids
because they may have resistance to these important medications. The investigators are
studying steroid resistance during very severe AECOPDs so that we can eventually develop
better and safer therapies for these vulnerable people.
Chronic obstructive pulmonary disease (COPD) is a cigarette smoke-induced disease of the
lungs that affects millions of people in the United States and worldwide. COPD is the 3rd
leading cause of death, making it one our most important public health problems. Perhaps most
importantly, COPD confines many people to their homes, tethers them to oxygen lines, and
destroys their independence. Like many diseases of chronic inflammation, the course of COPD
is marred by intermittent disease flares that need more intensive treatment. In COPD, disease
flares are called acute exacerbations of COPD (AECOPDs). AECOPDs are characterized by
increased shortness of breath, wheezing or cough that leads to urgent, and sometimes
emergent, treatment with inhaled bronchodilators, antibiotics and steroids. AECOPDs can be
devastating to many because they worsen quality of life and lung function, frequently lead to
hospitalization, and increase the risk of death. For instance, the death rate can reach
25-30% when COPD patients are admitted to the intensive care unit with respiratory failure
(i.e. needing ventilator support). Accordingly, our research is focused on improving outcomes
in the sickest patients admitted to the hospital with an AECOPD.
Oral or intravenous steroids (glucocorticoids) have been the mainstay of treatment for over
40 years, but virtually no research has been done to determine the optimal therapy for the
sickest patients who are admitted to the intensive care unit. Results from the few clinical
studies suggest that steroid resistance is increased in these critically-ill patients and
that many physicians under- or over-dose steroids. For example, patients hospitalized with an
AECOPD (without respiratory failure) are effectively treated with steroids (such as
prednisone) dosed as low as 40mg/day. In contrast, two recent clinical studies showed that
~80mg/day of prednisone was ineffective for AECOPD patients hospitalized with respiratory
failure (those who require ventilatory support), while in a second study ~160mg/day of
methylprednisolone improved outcomes. The investigators recent epidemiologic study showed
that 66% of patients admitted with an AECOPD and respiratory failure between 2003-2008 were
treated with >240mg/day of methylprednisolone, a dose that increases steroid-related side
effects. The investigators hypothesize that there is a stepwise increase in steroid
resistance with COPD
cause(s), devising new treatments to combat this problem and optimizing therapy for these
vulnerable patients.
Steroids suppress inflammation by inducing anti-inflammatory genes, such as the
dual-specificity phosphatase (DUSP) family - including DUSP1. DUSP1 inhibits inflammatory
cytokines by removing phosphates from p38 and c-Jun N-terminal kinase (JNK) mitogen-activated
protein kinases, which turns them off. Preliminary data show that DUSP1 is decreased in
alveolar macrophages from COPD patients, suggesting the central hypothesis that steroid
resistance is increased in AECOPDs with respiratory failure due to impaired
glucocorticoid-mediated induction of DUSP1. To address this hypothesis, the investigators
will inject 23 AECOPD patients with respiratory failure and 23 matched stable COPD subjects
with 60mg of methylprednisolone to: 1) determine the presence of corticosteroid resistance in
AECOPDs, 2) determine the role of DUSP1, and 3) examine alternative mechanisms driving
steroid resistance. The goal of The AECOPD Resistance Study is to identify targets associated
with steroid resistance in AECOPDs with respiratory failure to pave the way for new
treatments based upon novel mechanisms.
lungs that affects millions of people in the United States and worldwide. COPD is the 3rd
leading cause of death, making it one our most important public health problems. Perhaps most
importantly, COPD confines many people to their homes, tethers them to oxygen lines, and
destroys their independence. Like many diseases of chronic inflammation, the course of COPD
is marred by intermittent disease flares that need more intensive treatment. In COPD, disease
flares are called acute exacerbations of COPD (AECOPDs). AECOPDs are characterized by
increased shortness of breath, wheezing or cough that leads to urgent, and sometimes
emergent, treatment with inhaled bronchodilators, antibiotics and steroids. AECOPDs can be
devastating to many because they worsen quality of life and lung function, frequently lead to
hospitalization, and increase the risk of death. For instance, the death rate can reach
25-30% when COPD patients are admitted to the intensive care unit with respiratory failure
(i.e. needing ventilator support). Accordingly, our research is focused on improving outcomes
in the sickest patients admitted to the hospital with an AECOPD.
Oral or intravenous steroids (glucocorticoids) have been the mainstay of treatment for over
40 years, but virtually no research has been done to determine the optimal therapy for the
sickest patients who are admitted to the intensive care unit. Results from the few clinical
studies suggest that steroid resistance is increased in these critically-ill patients and
that many physicians under- or over-dose steroids. For example, patients hospitalized with an
AECOPD (without respiratory failure) are effectively treated with steroids (such as
prednisone) dosed as low as 40mg/day. In contrast, two recent clinical studies showed that
~80mg/day of prednisone was ineffective for AECOPD patients hospitalized with respiratory
failure (those who require ventilatory support), while in a second study ~160mg/day of
methylprednisolone improved outcomes. The investigators recent epidemiologic study showed
that 66% of patients admitted with an AECOPD and respiratory failure between 2003-2008 were
treated with >240mg/day of methylprednisolone, a dose that increases steroid-related side
effects. The investigators hypothesize that there is a stepwise increase in steroid
resistance with COPD
cause(s), devising new treatments to combat this problem and optimizing therapy for these
vulnerable patients.
Steroids suppress inflammation by inducing anti-inflammatory genes, such as the
dual-specificity phosphatase (DUSP) family - including DUSP1. DUSP1 inhibits inflammatory
cytokines by removing phosphates from p38 and c-Jun N-terminal kinase (JNK) mitogen-activated
protein kinases, which turns them off. Preliminary data show that DUSP1 is decreased in
alveolar macrophages from COPD patients, suggesting the central hypothesis that steroid
resistance is increased in AECOPDs with respiratory failure due to impaired
glucocorticoid-mediated induction of DUSP1. To address this hypothesis, the investigators
will inject 23 AECOPD patients with respiratory failure and 23 matched stable COPD subjects
with 60mg of methylprednisolone to: 1) determine the presence of corticosteroid resistance in
AECOPDs, 2) determine the role of DUSP1, and 3) examine alternative mechanisms driving
steroid resistance. The goal of The AECOPD Resistance Study is to identify targets associated
with steroid resistance in AECOPDs with respiratory failure to pave the way for new
treatments based upon novel mechanisms.
Inclusion Criteria for AECOPD with Ventilatory Failure Cohort:
- Emergency Department (ED) or ICU physician diagnosis of an acute exacerbation of COPD
- Age ≥ 40 years of age
- Need for ventilator support in the ED or ICU during the first 24 hours
Inclusion Criteria for Stable COPD Cohort:
- Physician diagnosis of COPD
- Age ≥ 40 years of age
- Frequency matched to AECOPD subjects for:
- Age (± 10 year increments)
- Current/Former smoking status (former smoker = no smoking for ≥ 1 month)
- Lung function (FEV1% predicted by ± 10% increments)
Exclusion Criteria for AECOPD with Ventilatory Failure Cohort:
- Systemic steroid use ≤ 30 days prior to return visit
- Infection requiring antibiotics ≤ 1 month prior to return visit
- Hemoglobin < 8.0 g/dl
- Acute pulmonary embolism
- Diabetes
- History of immunodeficiency, interstitial lung disease, neuromuscular disorder or
heart failure with respiratory exacerbation
- Tracheostomy
- Drugs that induce cytochrome P450 3A enzyme activity (e.g. barbiturates, phenytoin or
carbamazepine) or drugs that inhibit cytochrome P450 3A activity (e.g. ketoconazole
and chronic macrolide antibiotics)
- Age ≥ 90 year of age
- Known pregnancy
- Nursing mothers
- Prisoners
Exclusion Criteria for Stable COPD Cohort:
- Systemic steroid use ≤ 30 days prior to return visit
- Infection requiring antibiotics ≤ 1 month prior to return visit
- Hemoglobin < 8.0 g/dl
- Acute pulmonary embolism
- Diabetes
- History of immunodeficiency, interstitial lung disease, neuromuscular disorder or
heart failure with respiratory exacerbation
- Tracheostomy
- Drugs that induce cytochrome P450 3A enzyme activity (e.g. barbiturates, phenytoin or
carbamazepine) or drugs that inhibit cytochrome P450 3A activity (e.g. ketoconazole
and chronic macrolide antibiotics)
- Age ≥ 90 year of age
- Known pregnancy
- Nursing mothers
- Prisoners
We found this trial at
1
site
13001 E. 17th Pl
Aurora, Colorado 80045
Aurora, Colorado 80045
303-724-5000
Phone: 303-724-6068
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