Steroid Resistance During COPD Exacerbations With Respiratory Failure
Steroid Resistance During COPD Exacerbations With Respiratory Failure
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.
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<AECOPD<AECOPD with respiratory failure. A newly launched team of
 investigators is focused on establishing the presence of steroid resistance, defining the
 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