Context Recent studies of inhaled corticosteroid (ICS) therapy for managing stable chronic obstructive pulmonary disease (COPD) have yielded conflicting results regarding survival and risk of adverse events. Objective To systematically review and quantitatively synthesize the effects of ICS therapy on mortality and adverse events in patients with stable COPD. Data Sources Search of MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and PsychInfo through February 9, 2008. Study Selection Eligible studies were double-blind, randomized controlled trials comparing ICS therapy for 6 or more months with nonsteroid inhaled therapy in patients with COPD. Data Extraction Two authors independently abstracted data including study characteristics, all-cause mortality, pneumonia, and bone fractures. The I2 statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model (when I2≥50%) or a fixed-effects model (when I2<50%). For the primary outcome of all-cause mortality at 1 year, our meta-analysis was powered to detect a 1.0% absolute difference in mortality, assuming a 2-sided α of .05 and power of 0.80. Results Eleven eligible randomized controlled trials (14 426 participants) were included. In trials with mortality data, no difference was observed in 1-year all-cause mortality (128 deaths among 4636 patients in the treatment group and 148 deaths among 4597 patients in the control group; relative risk [RR], 0.86; 95% confidence interval [CI], 0.68–1.09; P=.20; I2=0%). In the trials with data on pneumonia, ICS therapy was associated with a significantly higher incidence of pneumonia (777 cases among 5405 patients in the treatment group and 561 cases among 5371 patients in the control group; RR, 1.34; 95% CI, 1.03–1.75; P=.03; I2=72%). Subgroup analyses indicated an increased risk of pneumonia in the following subgroups: highest ICS dose (RR, 1.46; 95% CI, 1.10–1.92; P=.008; I2=78%), shorter duration of ICS use (RR, 2.12; 95% CI, 1.47–3.05; P<.001; I2=0%), lowest baseline forced expiratory volume in the first second of expiration (RR, 1.90; 95% CI, 1.26–2.85; P=.002; I2=0%), and combined ICS and bronchodilator therapy (RR, 1.57; 95% CI, 1.35–1.82; P<.001; I2=24%). Conclusions Among patients with COPD, ICS therapy does not affect 1-year all-cause mortality. ICS therapy is associated with a higher risk of pneumonia. Future studies should determine whether specific subsets of patients with COPD benefit from ICS therapy.

BackgroundProton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults.MethodsWe conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy.ResultsSystematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31).DiscussionOutpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD, however, is a heterogeneous collection of diseases with differing causes, pathogenic mechanisms, and physiological effects. Therefore a comprehensive approach to COPD prevention will need to address the complexity of COPD. Advances in the understanding of the natural history of COPD and the development of strategies to assess COPD in its early stages make prevention a reasonable, if ambitious, goal.

We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection.DOI: http://dx.doi.org/10.7554/eLife.18447.001

The health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review. The potential benefits of electronic cigarettes to an individual smoker should be weighed against potential harm to the population of increased social acceptability of smoking and use of nicotine, the latter of which has addictive power and untoward effects. As a precaution, electronic nicotine delivery devices should be restricted or banned until more information about their safety is available. If they are allowed, they should be closely regulated as medicines or tobacco products.

Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States with a significant economic burden related to hospital admissions for exacerbations. One of the primary treatment modalities for COPD is medications delivered through breath-actuated dry powdered inhalers (DPIs). For users to successfully receive inhaled medication, they must inhale with enough flow to overcome the internal resistance of the device, leading to deaggregation of the medication powder. Peak inspiratory flow rate (PIFR) is the maximal flow rate obtained during an inspiratory maneuver. PIFR measurement can be impacted by the internal resistance of the device, which varies with device design. Many devices require a PIFR >60 L/min for adequate medication dispersal, while others appear to have adequate drug deaggregation with a PIFR >30 L/min. Studies have shown PIFRs are reduced among females and decrease with age, without a clear correlation between forced expiratory volume in 1 second and PIFR. PIFR can be reduced at the time of COPD exacerbation. Recent data suggest that reduced PIFR may be associated with worse COPD-related symptom burden, increased odds of COPD-related hospital readmissions, and improved responsiveness to nebulized therapy. This review article aims to examine the physiology and clinical correlations of PIFR, as well as review published studies related to PIFR with DPIs used to treat COPD.

Background: Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Methods: The multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel found varying quality and availability of evidence and made the following judgments: 1 ) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia, 2 ) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia, 3 ) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia, 4 ) a conditional recommendation for ambulatory liquid-oxygen use in patients who are mobile outside the home and require >3 L/min of continuous-flow oxygen during exertion (very-low-quality evidence), and 5 ) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (best-practice statement). Conclusions: These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.