Association of Inhaled Corticosteroids with Incident Pneumonia and Mortality in COPD Patients; Systematic Review and Meta-Analysis

Background: Inhaled corticosteroids are commonly prescribed for patients with severe COPD. They have been associated with increased risk of pneumonia but not with increased pneumonia-associated or overall mortality. Methods: To further examine the effects of inhaled corticosteroids on pneumonia incidence, and mortality in COPD patients, we searched for potentially relevant articles in PubMed, Medline, CENTRAL, EMBASE, Scopus, Web of Science and manufacturers' web clinical trial registries from 1994 to February 4, 2014. Additionally, we checked the included and excluded studies' bibliographies. We subsequently performed systematic review and meta-analysis of included randomized controlled trials and observational studies on the topic. Results: We identified 38 studies: 29 randomized controlled trials and nine observational studies. The estimated unadjusted risk of pneumonia was increased in randomized trials: RR 1.61; 95% CI 1.35–1.93, p < 0.001; as well as in observational studies: OR 1.89; 95% CI 1.39–2.58, p < 0·001. Six randomized trials and seven observational studies were useful in estimating unadjusted risk of pneumonia ­case-fatality: RR 0.91; 95% CI 0.52–1.59, p = 0.74; and OR 0.72; 95% CI 0.59–0.88, p = 0.001, respectively. Twenty-nine randomized trials and six observational studies allowed estimation of unadjusted risk of overall mortality: RR 0.95; 95% CI 0.85–1.05, p = 0.31; and OR 0.79; 95% CI 0.65–0.97, p = 0.02, respectively. Conclusions: Despite a substantial and significant increase in unadjusted risk of pneumonia associated with inhaled corticosteroid use, pneumonia fatality and overall mortality were found not to be increased in randomized controlled trials and were decreased in observational studies.     

Association of Inhaled Corticosteroids With All-Cause Mortality Risk in Patients With COPD: A Meta-analysis of 60 Randomized Controlled Trials

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Association of Comorbidities With Postoperative In-Hospital Mortality: A Retrospective Cohort Study

The purpose of this article is to evaluate the American Society of Anesthesiologists Physical Status (ASA PS) and the Charlson comorbidity index (CCI) for the prediction of postoperative mortality.The ASA PS has been suggested to be equally good as the CCI in predicting postoperative outcome. However, these scores have never been compared in a broad surgical population.We conducted a retrospective cohort study in a German tertiary care university hospital. Predictive accuracy was compared using the area under the receiver-operating characteristic curves (AUROC). In a post hoc approach, a regression model was fitted and cross-validated to estimate the association of comorbidities and intraoperative factors with mortality. This model was used to improve prediction by recalibrating the CCI for surgical patients (sCCIs) and constructing a new surgical mortality score (SMS).The data of 182,886 patients with surgical interventions were analyzed. The CCI was superior to the ASA PS in predicting postoperative mortality (AUROC_CCI 0.865 vs AUROC_ASAPS 0.833, P < 0.001). Predictive quality further improved after recalibration of the sCCI and construction of the new SMS (AUROC_SMS 0.928 vs AUROC_sCCI 0.896, P < 0.001). The SMS predicted postoperative mortality especially well in patients never admitted to an intensive care unit.The newly constructed SMS provides a good estimate of patient''s risk of death after surgery. It is capable of identifying those patients at especially high risk and may help reduce postoperative mortality.     

Effects of Extra-Fine Inhaled and Oral Corticosteroids on Alveolar Nitric Oxide in COPD

Purpose

Alveolar nitric oxide (CA_NO) has been suggested as a surrogate marker of distal airway inflammation in COPD. Coarse particle-inhaled corticosteroids (ICS) have been shown not to suppress CA_NO. We evaluated whether extra-fine particle size ICS (HFA-BDP) or systemic oral corticosteroids could suppress CA_NO in COPD.

Methods

Chronic obstructive pulmonary disease (COPD) patients with a FEV1/FVC ratio <0.7, FEV1 <80% predicted with CA_NO?>?2?ppb underwent a double-blind randomized, controlled, crossover trial with an open-label systemic steroid comparator. After a 2?week steroid washout period, participants were randomized to 3?weeks of 100 mcg of HFA-BDP twice daily and then 3?weeks of 400?mcg of HFA-BDP twice daily, or matched placebos with subsequent crossover. All patients then received 1?week open-label, 25?mg/day of prednisolone. Exhaled nitric oxide, plasma cortisol, and lung function were recorded. CA_NO was corrected for axial diffusion.

Results

In 16 participants, there were no significant differences seen with either dose of HFA-BDP compared with placebo. Oral prednisolone significantly reduced FE_NO and J’aw_NO but not CA_NO. Plasma cortisol was significantly suppressed by oral prednisolone only.

Conclusions

Whilst CA_NO remains a biomarker of interest in COPD, it is not suppressed by systemic or extra-fine particle ICS. CA_NO is not a useful marker for monitoring response of small airway disease to therapies in COPD. The study was approved by the local Committee on Medical Research Ethics and registered on ClinicalTrials.Gov (NCT 00921921).     

Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients With Chronic Obstructive Pulmonary Disease: A Nationwide Cohort Study

The association of inhaled corticosteroids (ICS) and pneumonia in patients with chronic obstructive pulmonary disease (COPD) is still controversial.From the National Health Insurance Database of Taiwan, COPD cases with history of acute exacerbation (AE) were identified (COPD cohort). Time-dependent Cox regression analysis was applied to investigate the risk factors for pneumonia with COPD severity controlled by surrogate variables. Among the COPD cohort, those who continuously used ICS for more than 360 days without interruption were selected (ICS cohort). The incidence rate of pneumonia during ICS use was compared with those before ICS use and after ICS discontinuation by using pair t test.A total of 6034 and 842 cases were identified as the COPD and ICS cohorts, respectively. In the COPD cohort, recent ICS use was independently associated with pneumonia (hazard ratio: 1.06 [1.02–1.11] for per 80 mg of budesonide). Other independent risk factors included age, male, diabetes mellitus, malignancy, low income, baseline pneumonia event, and recent use of oral corticosteroids and aminophylline. In the ICS cohort, while AE rate gradually decreased, the incidence rate of pneumonia significantly increased after ICS use (from 0.10 to 0.21 event/person-year, P = 0.001).This study demonstrates the association between ICS use and pneumonia in patients with COPD and history of AE. ICS should be judiciously used in indicated COPD patients.     

Presentation and Mortality of Cryptococcal Infection Varies by Predisposing Illness: A Retrospective Cohort Study

BackgroundCryptococcal epidemiology is changing in the modern antiretroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by immune status in the antiretroviral therapy era.MethodsWe conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality.ResultsWe identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with human immunodeficiency virus (HIV), 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV nontransplant (NHNT). Age analysis showed that people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (P < .001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (P = .003 and P = .001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, P < .001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared with transplant (66%) or NHNT (73%) (P < .001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, interquartile range [IQR] ± 9 days) and NHNT patients (median 2 days, IQR ± 7 days) as compared with people living with HIV (median 1 day, IQR ± 2 days) (P = .003). NHNT patients had a higher risk of 90-day mortality (hazard ratio 3.3; 95% confidence interval, 1.9-5.8) as compared with people living with HIV.ConclusionsThe majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher level of clinical suspicion than it currently receives.     

Bronchodilators in COPD: Impact of ��-agonists and anticholinergics on severe exacerbations and mortality

This review summarizes the long-term clinical outcomes associated with β-agonist and anticholinergic bronchodilator use in patients with chronic obstructive pulmonary disease (COPD). Pooled data from randomized placebo-controlled trials of at least three months duration were used to evaluate the risk for COPD hospitalizations, respiratory mortality, and total mortality. The results show that anticholinergic use is associated with a 30% reduction in COPD hospitalizations, a 70% reduction in respiratory mortality, and without a significant effect on total mortality. In contrast, β-agonist use had no effect on COPD hospitalizations and was associated with a two-fold increased risk for respiratory death compared with placebo. When the two bronchodilators were directly compared with each other, β-agonists were associated with a two-fold increased risk for COPD hospitalization and a five-fold increased risk for total mortality compared with anticholinergics. When β-agonists were added to either anticholinergic use or inhaled corticosteroid use alone, there was no significant improvement in any long-term clinical outcome. These results indicate that anticholinergics should be the bronchodilator of choice in COPD, while β-agonists may be associated with poorer disease control.     

A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia

Background

Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible.

Methods

We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance.

Results

A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p?=?0.002 and p?=?0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p?<?0.006).

Conclusion

Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

     

Impact of Prior Healthcare-Associated Exposure on Clinical and Molecular Characterization of Methicillin-Susceptible Staphylococcus aureus Bacteremia: Results From a Retrospective Cohort Study

By virtue of medical advances and an aging society, people have increased opportunities for healthcare exposure. Little is known about the impact of healthcare exposure on the clinical features and molecular typing of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We classified the onset of MSSA bacteremia into 3 mutually exclusive categories according to the Centers for Disease Control definition, and conducted a retrospective cohort study to investigate the differences among patients with community-associated (CA), healthcare-associated community onset (HACO), and hospital onset (HO) MSSA bacteremia at a medical center from January 1, 2002 through December 31, 2011. Antibiotic susceptibilities and multilocus sequence typing of MSSA isolates were also determined.A total of 290 patients with MSSA bacteremia, including of 165 (56.9%), 91 (31.4%), and 34 (11.7%) of HACO, HO, and CA, respectively, were studied. ST188 (29.3%) was the most common sequence type regardless of classification. Patients with HACO bacteremia were significantly older, had more solid tumors, higher Charlson scores, and more catheter-related bloodstream infections than those with CA bacteremia. The proportions of osteoarticular infections among patients with both HACO and CA bacteremia were higher than that of patients with HO bacteremia. By univariate analysis, patients with HO bacteremia had significantly higher in-hospital mortality compared to those with CA or HACO bacteremia (31.9% vs 18.8% and 20.4%). Multivariate analysis showed that Charlson score (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.10–1.52), septic shock (OR, 5.28; 95% CI, 2.37–11.78), liver cirrhosis (OR, 3.57; 95% CI, 1.14–11.24), receipt of β-lactams other than oxacillin and cefazolin as definitive therapy (OR, 9.27; 95% CI, 4.25–20.23), and higher oxacillin minimum inhibitory concentration (MIC) (≥0.5 mg/L) (OR, 2.35; 95% CI, 1.05–5.25) of the causative pathogen were independently associated with in-hospital mortality.In conclusion, patients with HACO bacteremia had different host factors compared with those with CA bacteremia. Infection foci varied with different onset settings. Overall, ST188 was the most predominant sequence type. Onset settings were not independently associated with outcomes.     

U-Shaped Relationship of Sodium-to-chloride Ratio on admission and Mortality in Elderly Patients with Heart Failure: A Retrospective Cohort Study

Serum sodium and chloride have clinical significance in the prognosis of heart failure. Little is known regarding the prognostic value of sodium-to-chloride (Na/Cl) ratio in patients with heart failure. This study sought to investigate the association between Na/Cl ratio on admission and mortality risk of elderly patients with acute heart failure in a retrospective cohort. We included 1819 patients (aged over 60) from the Zigong Heart Failure Study. Patients were grouped according to Na/Cl ratio and followed up for all-cause mortality at 3 months. Restricted cubic spline, cox proportional hazard regression and Kaplan-Meier curve were used to examine the correlation between serum Na/Cl ratio on admission and mortality risk. Restricted cubic spline analysis suggested a U-shaped association between Na/Cl ratio on admission and 3 months mortality risk (P nonlinearity <0.001), with the nadir of risk at 1.34. After adjustment for multivariate, patients with Na/Cl ratio <1.3 or ≥ 1.4 had hazard ratios for mortality of 3.58 (95% CI, 1.63-7.84) and 2.66 (95% CI, 1.23-5.72) compared with those with Na/Cl ratio of 1.3-1.4. The cumulative hazard of mortality estimates significantly differed across Na/Cl ratio groups (log-rank P<0.001). Subgroup analysis showed there were no interactions with absent or present of hyponatremia and hypochloremia (P for interaction all >0.05). Both low and high Na/Cl ratios were associated with an increased mortality risk in elderly patients with acute heart failure. Further studies need to verify these 2 biochemical phenotypes and develop corresponding treatment strategies.     

Risk Factors of Local Oropharyngeal and Laryngeal Adverse Effects from Use of Single Inhaled Corticosteroids and Long-Acting Beta-Agonists

Background: Single inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) are clinically effective and safe. However, if local oropharyngeal and laryngeal adverse effects (LOLAE) appear, adherence to the use of ICS is impaired. To minimize the development of adverse effects, it is essential to identify the underlying risk factors.Methods: The study included 481 asthmatic patients who were prescribed ICS/LABA for the first time in their life between January and September of 2010. Patients ranged in age from 14 to 86 years old and consisted of 281 never smokers and 200 smokers. All data were collected retrospectively by respirologists.Results: Seventy-three out of 481 patients suffered from one or more adverse effects, with 54 of these exhibiting LOLAE. Patients with LOLAE (51.4 ± 16.2 yrs) were significantly older than those without LOLAE (43.7 ± 15.9 yrs) (p = 0.0011) and were also prescribed a significantly higher dose of ICS. The pack-years of patients with LOLAE (2.1 ± 4.9) were significantly lowerthan those without LOLAE (6.0 ± 13.0) (p = 0.0087). The type of administered ICS was also significantly associated with a risk of developing LOLAE.Conclusions: Our survey indicated that a greater age, a higher dose of ICS, and the type of ICS were potential risk factors of LOLAE. The identified factors should be considered in a clinical setting in order to prevent the development of LOLAE and provide optimal treatment to patients.