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1.  Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans 
COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD.
We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW).
Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms).
Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.
PMCID: PMC4329763
COPD; Comorbidities; Race
2.  A score to predict short-term risk of COPD exacerbations (SCOPEX) 
There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.
Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.
The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).
SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.
PMCID: PMC4315304
chronic obstructive pulmonary disease; exacerbation; model; predictor; inhaled corticosteroids; bronchodilators
3.  Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol 
In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted.
A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George’s Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations.
Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, −0.005 (−0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (−0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (−0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network.
When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD.
PMCID: PMC4124050  PMID: 25114521
COPD; olodaterol; indacaterol; meta-analysis; systematic review; LABA
4.  Implications of the GOLD 2011 Disease Severity Classification in the COPDGene Cohort 
The 2011 Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) consensus report uses symptoms, exacerbation history and FEV1% to define four categories: A, low symptoms/low risk; B, high symptoms/low risk; C, low symptoms/high risk; and D, high symptoms/high risk where risk refers to exacerbations, hospitalization and death. Our objective was to determine (1) the influence of symptom instrument on category membership and (2) prospective exacerbation risk by category.
4,484 COPD subjects from COPDGene were analyzed. All subjects had smoking history ≥ 10 pack-years and FEV1/FVC<0·7. Categories were defined using the modified Medical Research Council Dyspnea [mMRC] (0–1 versus ≥ 2) and the Saint George’s Respiratory Questionnaire [SGRQ] (≥25 versus <25 as a surrogate for the COPD Assessment Test ≥ 10 versus <10) in addition to COPD exacerbations in the prior year (<2 versus ≥ 2), and FEV1% predicted (≥50 versus <50).
Category assignment using mMRC versus SGRQ were similar but not identical. Using the mMRC, category assignments were 34% A, 21% B, 8% C and 38% D and for SGRQ were 29% A, 25% B, 5% C and 41% D (kappa=0·77). Significant heterogeneity in exacerbation rates (exacerbations/person-year) were seen particularly within the D group, depending on the risk factor that determined category assignment (lung function (0·89), prior exacerbation history (1·34) or both (1·86), p<0·001.
The GOLD classification emphasizes the importance of symptoms and exacerbation risk in assessing COPD severity. The choice of symptom measure influences category assignment. The relative number of subjects with low symptoms and high risk for exacerbations (category C) is low. Differences in exacerbation rates for subjects in the highest risk category D were seen depending on whether risk was based on lung function, exacerbation history or both.
PMCID: PMC4105297  PMID: 24321803
5.  The authors reply 
Critical care medicine  2013;41(2):e16-e17.
PMCID: PMC4068404  PMID: 23353969
6.  Long-term prognosis in community-acquired pneumonia 
Purpose of review
Pneumonia is considered the leading infectious diseases cause of death and the seventh leading cause of death overall in the US. There is significant interest in understanding the relationship between community-acquired pneumonia (CAP) and mortality.
Recent findings
Most clinical studies examining patients with CAP have used an arbitrary in-hospital or 30-day mortality as a short-term mortality clinical end point. However, long-term mortality (arbitrary >3 months) factors, incidence, prediction, and implications on patient care are important issues that require further evaluation in patients with CAP. This review focuses on the most recent literature assessing the importance and the frequency of long-term associated outcomes in patients with CAP, the risk factors, and possible implications for future strategies. Multiple risk factors that include age, sex, comorbid conditions, type of pneumonia, and severity of illness are associated with higher long-term mortality. In addition, several biomarkers were demonstrated to be independently associated with long-term mortality.
Despite advances in the understanding of long-term mortality among CAP patients, there is still a high unacceptable long-term mortality. Public health programs should address this important gap, considering the high level of complexity factors in patients with CAP.
PMCID: PMC4066634  PMID: 23426328
biomarkers; community-acquired pneumonia; outcome
7.  Effects of Inhaled Corticosteroids on Pneumonia Severity and Antimicrobial Resistance 
Respiratory care  2013;58(9):1489-1494.
Limited information is available regarding the impact of prior use of inhaled corticosteroids (ICS) in patients subsequently developing community-acquired pneumonia (CAP). We assessed the effects of prior ICS use on severity of illness and microbiology in CAP hospitalized patients.
A retrospective cohort study of subjects with CAP (by the International Classification of Diseases, 9th Revision, Clinical Modification) was conducted over a 4-year period at 2 tertiary teaching hospitals. Subjects were considered to be ICS users if they received ICS prior to admission. Primary outcomes were severity of illness and microbiology at admission.
Data were abstracted on 664 subjects: 89 prior ICS users (13.4%) and 575 non-users (86.6%). Prior ICS users had higher severity of illness at admission: mean ± SD Pneumonia Severity Index 100.8 ± 31.4 vs 68.8 ± 33.4, P = .001, and CURB-65 (confusion, urea nitrogen, respiratory rate, blood pressure, > 65 years of age) score 1.56 ± 1.02 vs 1.19 ± 1.02, P = .002. Prior ICS use was independently associated with antimicrobial-resistant pathogens: 11.2% vs 5.9%, odds ratio 2.6, 95% CI 1.1– 6.1, P = .04.
Prior ICS use was associated with higher severity of illness at admission and higher incidence of antimicrobial-resistant pathogens in CAP hospitalized patients.
PMCID: PMC4066635  PMID: 23345471
drug resistance; inhaled corticosteroids; pneumonia; severity of illness index
8.  Comparison of two guideline-concordant antimicrobial combinations in elderly patients hospitalized with severe community-acquired pneumonia 
Critical care medicine  2012;40(8):2310-2314.
Two of the guideline-concordant therapies for severe community-acquired pneumonia are either a beta-lactam and fluoroquinolone or beta-lactam and macrolide. However it is unclear if there is a benefit for one vs. the other for elderly patients with severe community-acquired pneumonia.
A retrospective population-based cohort study of patients with community-acquired pneumonia.
Patients admitted to an intensive care unit of any Department of Veterans Affairs hospital during 5-yr period.
We included only those patients >65 yrs of age admitted to the intensive care unit with community-acquired pneumonia who received either beta-lactam + fluoroquinolone or beta-lactam + macrolide antibiotic therapy for pneumonia.
Not applicable.
We used multilevel regression models to examine the effect of beta-lactam + fluoroquinolone vs. beta-lactam + macrolide on each of the outcomes after adjusting for potential confounders using propensity scores.
Main Results
The cohort consisted of 1,989 patients: 98.5% male and a mean age of 74 yrs. For treatment, 44% of subjects received beta-lactam + fluoroquinolone and 56% received beta-lactam + macrolide. Unadjusted 30-day mortality was 27% for beta-lactam + fluoroquinolone and 24% for beta-lactam + macrolide (p = .11). In the multilevel models, the use of beta-lactam + fluoroquinolone was not significantly associated with 30-day mortality (odds ratio 1.05, 95% confidence interval 0.85–1.30). However, the use of beta-lactam + fluoroquinolone was significantly associated with increased mean length of stay (incidence rate ratio 1.30, 95% confidence interval 1.27–1.33).
We found no significant difference for 30-day mortality but did demonstrate an association with increase in length of stay associated with the use of beta-lactam + fluoroquinolone. Randomized controlled trials are needed to determine the most effective antibiotics regimes for patients with severe pneumonia.
PMCID: PMC4066649  PMID: 22622401
antimicrobial therapy; length of stay; mortality; pneumonia
9.  Prior cardiovascular disease increases long-term mortality in COPD patients with pneumonia 
There is controversy regarding the impact of chronic obstructive pulmonary disease (COPD) in clinical outcomes in elderly patients with pneumonia. Comorbidities such as cardiovascular disease have been reported to play an important role in patients with acute exacerbations of COPD. However, limited data are available regarding the impact of cardiovascular disease in elderly COPD patients who require hospitalisation for pneumonia.
We examined a cohort of subjects with pneumonia and pre-existing COPD. Prior cardiovascular disease was defined as history of myocardial infarction, congestive heart failure, cardiac arrhythmia, unstable angina or stroke. Outcomes examined included 30-day, 90-day, 6-month and 1-year mortality.
We included 17 140 elderly COPD patients who were hospitalised for pneumonia. Prior cardiovascular disease was present in 10 240 (59.7%) patients. Prior cardiovascular disease was independently associated with 90-day mortality (21.3% versus 19.4%; hazard ratio (HR) 1.29, 95% CI 1.02–1.17), 6-month mortality (29.0% versus 26.1%; HR 1.28, 95% CI 1.07–1.50) and 12-month mortality (39.2% versus 34.5%; HR 1.33, 95% CI 1.15–1.54) when compared to no prior cardiovascular disease. The temporal differential effect between groups increases from 1.0% at 30 days to 4.7% at 1 year.
Prior cardiovascular disease is associated with increased long-term mortality in elderly COPD patients with pneumonia. Differences in mortality rates increased over time.
PMCID: PMC4066656  PMID: 23598950
10.  Improving the 2007 IDSA/ATS severe Community-Acquired Pneumonia criteria to predict ICU admission 
Journal of critical care  2012;28(3):284-290.
To improve 2007 IDSA/ATS severity criteria to predict ICU admission in patients hospitalized with pneumonia.
A composite score that included the 2007 IDSA/ATS criteria for severe pneumonia and additional significant variables identified by recent publications was tested in patients hospitalized with CAP.
Among 787 patients hospitalized with CAP, 156 (19.8%) required admission to the ICU. We identified one major criterion (arterial pH <7.30), and four minor criteria (tachycardia >125 bpm, arterial pH 7.30–7.34, sodium <130 mEq/L and glucose >250 mg/dl) to be associated with ICU admission. Adding arterial pH <7.30 to the two 2007 IDSA/ATS major criteria increased sensitivity from 61.5% to 71.8% and AUC from 0.80 to 0.86. Adding in sequence the four minor criteria to the 2007 IDSA/ATS minor criteria, increased sensitivity from 41.7% to 53.8%, and AUC from 0.65 to 0.69. In the new composite score, combining 1 of 3 major criteria with 3 of 12 minor criteria showed a sensitivity of 92.9% and an AUC of 0.88.
The addition of arterial pH <7.30 to the 2007 IDSA/ATS major criteria improves sensitivity and AUC to identify patients who will require ICU care.
PMCID: PMC3626746  PMID: 23265290
Community-acquired pneumonia; ICU admission; arterial acidosis; severity scores
11.  The Association of Cardioprotective Medications with Pneumonia-Related Outcomes 
PLoS ONE  2014;9(1):e85797.
Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes.
Materials and Methods
We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events.
Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63–0.77), ACE inhibitors (OR 0.82, 95% CI 0.74–0.91), and ARBs (OR 0.58, 95% CI 0.44–0.77). However, none of the medications were significantly associated with decreased cardiovascular events.
While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects.
PMCID: PMC3904855  PMID: 24489672
12.  Non-invasive mechanical ventilation and mortality in elderly immunocompromised patients hospitalized with pneumonia: a retrospective cohort study 
Mortality after pneumonia in immunocompromised patients is higher than for immunocompetent patients. The use of non-invasive mechanical ventilation for patients with severe pneumonia may provide beneficial outcomes while circumventing potential complications associated with invasive mechanical ventilation. The aim of our study was to determine if the use of non-invasive mechanical ventilation in elderly immunocompromised patients with pneumonia is associated with higher all-cause mortality.
In this retrospective cohort study, data were obtained from the Department of Veterans Affairs administrative databases. We included veterans age ≥65 years who were immunocompromised and hospitalized due to pneumonia. Multilevel logistic regression analysis was used to determine the relationship between the use of invasive versus non-invasive mechanical ventilation and 30-day and 90-day mortality.
Of 1,946 patients in our cohort, 717 received non-invasive mechanical ventilation and 1,229 received invasive mechanical ventilation. There was no significant association between all-cause 30-day mortality and non-invasive versus invasive mechanical ventilation in our adjusted model (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.66-1.10). However, those patients who received non-invasive mechanical ventilation had decreased 90-day mortality (OR 0.66, 95% CI 0.52-0.84). Additionally, receipt of guideline-concordant antibiotics in our immunocompromised cohort was significantly associated with decreased odds of 30-day mortality (OR 0.31, 95% CI 0.24-0.39) and 90-day mortality (OR 0.41, 95% CI 0.31-0.53).
Our findings suggest that physicians should consider the use of non-invasive mechanical ventilation, when appropriate, for elderly immunocompromised patients hospitalized with pneumonia.
PMCID: PMC3914374  PMID: 24468062
Mechanical ventilation; Mortality; Immunocompromised; Pneumonia
13.  Pneumonia: An Arrhythmogenic Disease? 
The American journal of medicine  2012;126(1):43-48.
Recent studies suggest that there is an increase in cardiovascular disease after pneumonia, however there is little information on cardiac arrhythmias after pneumonia. The aims of this study were to assess the incidence of, and examine risk factors for, cardiac arrhythmias after hospitalization for pneumonia.
We conducted a national cohort study using Department of Veterans Affairs (VA) administrative data including patients ≥65 years hospitalized with pneumonia in fiscal years 2002–2007, receiving antibiotics within 48 hours of admission, who did not have a prior diagnosis of a cardiac arrhythmia, and having at least one year of VA care. We included only the first pneumonia-related hospitalization, and follow-up was for the 90 days after admission. Cardiac arrhythmias included atrial fibrillation, ventricular tachycardia/fibrillation, cardiac arrest, and symptomatic bradycardia. We used a multilevel regression model, adjusting for hospital of admission, to examine risk factors for cardiac arrhythmias.
We identified 32,689 patients who met the inclusion criteria. Of these, 3,919 (12%) had a new diagnosis of cardiac arrhythmia within 90-days of admission. Variables significantly associated with increased risk of cardiac arrhythmia included increasing age, history of congestive heart failure, and a need for mechanical ventilation or vasopressors. Beta-blocker use was associated with a decreased incidence of events.
An important number of patients have new cardiac arrhythmia during and post-hospitalization for pneumonia. Additional research is needed to determine if use of cardioprotective medications will improve outcomes for patients hospitalized with pneumonia. At risk patients hospitalized with pneumonia should be monitored for cardiac arrhythmias during the hospitalization.
PMCID: PMC3615552  PMID: 23177550
Clinical pulmonary medicine  2013;20(1):10.1097/CPM.0b013e31827a2a60.
Community-acquired pneumonia (CAP) is the leading infectious cause of death in developed countries. Several studies have shown that the risk of pneumonia is increased in patients with Chronic Obstructive Pulmonary Disease (COPD) who are receiving chronic inhaled corticosteroids (ICS). The impact of ICS On pneumonia prognosis is controversial. Recent studies have shown that COPD patients with prior ICS use have less mortality after developing CAP as compared with patients with COPD without prior ICS use. This review discusses the association of ICS and the risk of CAP and its association with clinical outcomes in patients with COPD and pneumonia.
PMCID: PMC3828120  PMID: 24244086
15.  Population-Based Study of Statins, Angiotensin II Receptor Blockers, and Angiotensin-Converting Enzyme Inhibitors on Pneumonia-Related Outcomes 
This study suggests that for older patients hospitalized with pneumonia, use prior to hospitalization of statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers may be potentially beneficial. In addition, continuing these medications during hospitalization may also be potentially beneficial for patients with pneumonia.
Background. Studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors might be beneficial for the treatment of infections. Our purpose was to examine the association of statin, ACE inhibitor, and angiotensin II receptor blocker (ARB) use with pneumonia-related outcomes.
Methods. We conducted a retrospective cohort study using Department of Veterans Affairs data of patients aged ≥65 years hospitalized with pneumonia. We performed propensity-score matching for 3 medication classes simultaneously.
Results. Of 50 119 potentially eligible patients, we matched 11 498 cases with 11 498 controls. Mortality at 30 days was 13%; 34% used statins, 30% ACE inhibitors, and 4% ARBs. In adjusted models, prior statin use was associated with decreased mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], .68–.82) and mechanical ventilation (OR, 0.81; 95% CI, .70–.94), and inpatient use with decreased mortality (OR, 0.68; 95% CI, .59–.78) and mechanical ventilation (OR, 0.68; 95% CI, .60–.90). Prior (OR, 0.88; 95% CI, .80–.97) and inpatient (OR, 0.58; 95% CI, .48–.69) ACE inhibitor use was associated with decreased mortality. Prior (OR, 0.73; 95% CI, .58–.92) and inpatient ARB use (OR, 0.47; 95% CI, .30–.72) was only associated with decreased mortality. Use of all 3 medications was associated with reduced length of stay.
Conclusions. Statins, and to a lesser extent ACE inhibitors and ARBs, are associated with improved pneumonia-related outcomes. Prospective cohort and randomized controlled trials are needed to examine potential mechanisms of action and whether acute initiation at the time of presentation with these infections is beneficial.
PMCID: PMC3491858  PMID: 22918991
16.  Shortness of Breath with Daily Activities questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease 
BMJ Open  2013;3(10):e003048.
To test the reliability, validity and responsiveness of the 13-item Shortness of Breath with Daily Activities (SOBDA) questionnaire, and determine the threshold for response and minimal important difference (MID).
6 week, randomised, double-blind, placebo-controlled study.
40 centres in the USA between 29 October 2009 and 1 July 2010.
Primary and secondary outcome measures
547 patients with chronic obstructive pulmonary disease (COPD) were enrolled and 418 entered the 2-week run-in period. Data from the run-in period were collected to test internal consistency, test–retest reliability, convergent validity and known-groups validity of the SOBDA. Three hundred and sixty six patients were randomised 2:2:1 to fluticasone propionate/salmeterol 250/50 µg, salmeterol 50 µg or placebo, twice daily. Results from the SOBDA questionnaire, Patient Global Assessment of Change Question, modified Medical Research Council Dyspnoea Scale (mMRC), Clinician Global Impression of Dysponea Severity (CGI-S), Clinician Global Impression of Change Question and Chronic Respiratory Disease Questionnaire self-administered standardised version (CRQ-SAS) were evaluated; spirometry and safety parameters were measured. Study endpoints were selected to investigate the cross-sectional and longitudinal validity of the SOBDA questionnaire in relation to the clinical criteria.
Internal consistency of the SOBDA questionnaire (Cronbach α) was 0.89. Test–retest reliability (intraclass correlation) was 0.94. The SOBDA weekly scores correlated with the patient-reported and clinician-reported mMRC, CGI-S and CRQ-SAS dyspnoea domain scores (0.29, 0.24, 0.24 and –0.68, respectively). The SOBDA weekly scores differentiated between the responders and the non-responders as rated by the patients and the clinicians. Anchor-based and supportive distribution-based analyses produced a range of the potential values for the threshold for the responders and MID.
The 13-item SOBDA questionnaire is reliable, valid and responsive to change in patients with COPD. On using anchor-based methods, the proposed responder threshold shows a −0.1 to −0.2 score change. A specific threshold value will be identified as more data are generated from future clinical trials.
Trial registration
NCT00984659; GlaxoSmithKline study number: ASQ112989.
PMCID: PMC3808824  PMID: 24154513
17.  Factors associated with change in exacerbation frequency in COPD 
Respiratory Research  2013;14(1):79.
Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined.
1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2.
Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE.
No parameter clearly predicts an imminent change in exacerbation frequency category.
Trial registration
SCO104960, identifier NCT00292552
PMCID: PMC3733814  PMID: 23899210
COPD; Exacerbations; Exacerbation frequency; Exacerbation phenotype
18.  The Tiotropium Safety and Performance in Respimat® Trial (TIOSPIR®), a large scale, randomized, controlled, parallel-group trial-design and rationale 
Respiratory Research  2013;14(1):40.
Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.
The TIOSPIR® trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists.
To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2–3 years.
TIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.
PMCID: PMC3621103  PMID: 23547660
Tiotropium; COPD; Respimat® Soft Mist™ Inhaler; HandiHaler®
19.  Acute Kidney Injury in Patients with Acute Lung Injury: Impact of Fluid Accumulation on Classification of Acute Kidney Injury and Associated Outcomes 
Critical care medicine  2011;39(12):2665-2671.
It has been suggested that fluid accumulation may delay recognition of acute kidney injury (AKI). We sought to determine the impact of fluid balance on the incidence of non-dialysis requiring AKI in patients with acute lung injury and to describe associated outcomes, including mortality.
Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative versus liberal fluid management and of management guided by a central venous versus pulmonary artery catheter.
Setting and Patients
1000 patients at ARDS Network hospitals.
Measurements and Main Results
The incidence of AKI, defined as an absolute rise in creatinine of ≥ 0.3 mg/dL or a relative change of > 50% over 48 hours, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of AKI before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57 versus 51%, p = 0.04). After adjustment for fluid balance, the incidence of AKI was greater in those managed with the liberal fluid protocol (66 versus 58%, p = 0.007). Patients who met AKI criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet AKI criteria both before and after adjustment for fluid balance (31 versus 12%, p < 0.001) and those who had AKI before but not after adjustment for fluid balance (31 versus 11%, p = 0.005). The mortality of those patients meeting AKI criteria after but not before adjustment for fluid balance was similar to patients with AKI both before and after adjustment for fluid balance (31% versus 38%, p = 0.18).
Fluid management influences serum creatinine and therefore the diagnosis of AKI using creatinine-based definitions. Patients with “unrecognized” AKI that is identified after adjusting for positive fluid balance have high mortality rates, and patients who have AKI before but not after adjusting for fluid balance have low mortality rates. Future studies of AKI should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.
PMCID: PMC3220741  PMID: 21785346
Acute kidney injury; acute lung injury; acute respiratory distress syndrome; fluid balance; creatinine; mortality
20.  Observational Study of Inhaled Corticosteroids on Outcomes for COPD Patients with Pneumonia 
Rationale: Treatment with inhaled corticosteroids (ICS) for those with chronic obstructive pulmonary disease (COPD) has been shown to be associated with an increased incidence of pneumonia. However, it is unclear if this is associated with increased mortality.
Objectives: The aim of this study was to examine the effects of prior use of ICS on clinical outcomes for patients with COPD hospitalized with pneumonia.
Methods: We conducted a retrospective cohort study using the national administrative databases of the Department of Veterans Affairs. Eligible patients had a preexisting diagnosis of COPD, had a discharge diagnosis of pneumonia, and received treatment with one or more appropriate pulmonary medications before hospitalization. Outcomes included mortality, use of invasive mechanical ventilation, and vasopressor use.
Measurements and Main Results: There were 15,768 patients (8,271 with use of ICS and 7,497 with no use of ICS) with COPD who were hospitalized for pneumonia. There was also a significant difference for 90-day mortality (ICS 17.3% vs. no ICS 22.8%; P < 0.001). Multilevel regression analyses demonstrated that prior receipt of ICS was associated with decreased mortality at 30 days (odds ratio [OR] 0.80; 95% confidence interval [CI], 0.72–0.89) and 90 days (OR 0.78; 95% CI, 0.72–0.85), and decreased use of mechanical ventilation (OR 0.83; 95% CI, 0.72–0.94). There was no significant association between receipt of ICS and vasopressor use (OR 0.88; 95% CI, 0.74–1.04).
Conclusions: For patients with COPD, prior use of ICS is independently associated with decreased risk of short-term mortality and use of mechanical ventilation after hospitalization for pneumonia.
PMCID: PMC3175534  PMID: 21512168
inhaled corticosteroids; pneumonia; chronic obstructive pulmonary disease; mortality
22.  Changing needs of community-acquired pneumonia 
Journal of Antimicrobial Chemotherapy  2011;66(Suppl 3):iii3-iii9.
Community-acquired pneumonia (CAP) is a serious condition associated with significant morbidity and potential long-term mortality. Although the majority of patients with CAP are treated as outpatients, the greatest proportion of pneumonia-related mortality and healthcare expenditure occurs among the patients who are hospitalized. There has been considerable interest in determining risk factors and severity criteria assessments to assist with site-of-care decisions. For both inpatients and outpatients, the most common pathogens associated with CAP include Streptococcus pneumoniae, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis. Atypical pathogens, Gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA) and viruses are also recognized aetiological agents of CAP. Despite the availability of antimicrobial therapies, the recent emergence of drug-resistant pneumococcal and staphylococcal isolates has limited the effectiveness of currently available agents. Because early and rapid initiation of empirical antimicrobial treatment is critical for achieving a favourable outcome in CAP, newer agents with activity against drug-resistant strains of S. pneumoniae and MRSA are needed for the management of patients with CAP.
PMCID: PMC3143426  PMID: 21482567
antimicrobial therapy; PSI/CURB-65 score; clinical outcomes
23.  Incidence of Cardiovascular Events Following Hospital Admission for Pneumonia 
The American journal of medicine  2011;124(3):244-251.
Several studies have suggested an increased risk of cardiovascular events, primarily acute myocardial infarction, around the time of hospital admission for pneumonia. Therefore we examined cardiovascular events, including myocardial infarction, congestive heart failure, unstable angina, stroke, and serious cardiac arrhythmias, within 90 days after hospitalization for pneumonia.
Using data from the administrative databases of the Department of Veterans Affairs, we examined a cohort of subjects hospitalized with pneumonia between October 2001 and September 2007. Subjects were at least 65 years of age. We examined the incidence of myocardial infarction, congestive heart failure, cardiac arrhythmias, unstable angina, and stroke by ICD-9 codes excluding those with a diagnosis prior to the admission for pneumonia.
The cohort comprised 50,119 subjects with a mean age of 77.5 years (SD 6.7 years), and 98% of the cohort was male. The 90-day incidence of cardiovascular events was 1.5% for myocardial infarction, 10.2% for congestive heart failure, 9.5% for arrhythmia, 0.8% for unstable angina, and 0.2% for stroke. The majority of events occurred during the hospitalization for pneumonia.
A clinically important number of subjects in this cohort suffered a cardiovascular event within 90 days of hospital admission, suggesting that such events may have an important role in post-pneumonia mortality. Additional research is needed to determine whether interventions may reduce the number of cardiovascular events after pneumonia.
PMCID: PMC3061467  PMID: 21396508
pneumonia; cardiovascular disease; congestive heart failure; cardiac arrhythmia; myocardial infarction
24.  Clinical evaluation of the role of ceftaroline in the management of community acquired bacterial pneumonia 
Ceftaroline fosamil (ceftaroline) was recently approved for the treatment of community- acquired pneumonia (CAP) and complicated skin infections. This newly developed cephalosporin possesses a broad spectrum of activity against gram-positive and gram-negative bacteria. Most importantly, ceftaroline demonstrates potent in vitro antimicrobial activity against multi-drug resistant Streptococcus pneumoniae and methicillin-resistant strains of Staphylococcus aureus. In two Phase III, double-blinded, randomized, prospective trials (FOCUS 1 and FOCUS 2), ceftaroline was shown to be non-inferior to ceftriaxone for the treatment of CAP in hospitalized patients. Ceftaroline exhibits low resistance rates and a safety profile similar to that of other cephalosporins. In this review, we will evaluate the pharmacological characteristics, safety, antimicrobial properties, and efficacy of ceftaroline and its applications in the treatment of CAP.
PMCID: PMC3278208  PMID: 22355258
s. pneumoniae; s. aureus; cephalosporins; pneumonia; ceftaroline; community acquired pneumonia
25.  A novel study design for antibiotic trials in acute exacerbations of COPD: MAESTRAL methodology 
Antibiotics, along with oral corticosteroids, are standard treatments for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The ultimate aims of treatment are to minimize the impact of the current exacerbation, and by ensuring complete resolution, reduce the risk of relapse. In the absence of superiority studies of antibiotics in AECOPD, evidence of the relative efficacy of different drugs is lacking, and so it is difficult for physicians to select the most effective antibiotic. This paper describes the protocol and rationale for MAESTRAL (moxifloxacin in AECBs [acute exacerbation of chronic bronchitis] trial; NCT00656747), one of the first antibiotic comparator trials designed to show superiority of one antibiotic over another in AECOPD. It is a prospective, multinational, multicenter, randomized, double-blind controlled study of moxifloxacin (400 mg PO [ per os] once daily for 5 days) vs amoxicillin/clavulanic acid (875/125 mg PO twice daily for 7 days) in outpatients with COPD and chronic bronchitis suffering from an exacerbation. MAESTRAL uses an innovative primary endpoint of clinical failure: the requirement for additional or alternate treatment for the exacerbation at 8 weeks after the end of antibiotic therapy, powered for superiority. Patients enrolled are those at high-risk of treatment failure, and all are experiencing an Anthonisen type I exacerbation. Patients are stratified according to oral corticosteroid use to control their effect across antibiotic treatment arms. Secondary endpoints include quality of life, symptom assessments and health care resource use.
PMCID: PMC3133509  PMID: 21760724
AECOPD; moxifloxacin; amoxicillin/clavulanic acid; clinical trial design; exacerbation; antibiotic

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