Richard K. Albert

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. Georges Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency.

To evaluate the role of corticosteroids as treatment for acute exacerbations of chronic obstructive pulmonary disease, we conducted a double-blind, randomized, placebo-controlled trial in 44 consecutive patients with chronic bronchitis and severe airflow obstruction. All were hospitalized with acute respiratory insufficiency from acute bronchitis. Patients with asthma, atopy, or pneumonia were excluded. Treatment consisted of intravenous aminophylline, inhaled isoproterenol, antibiotics, and either methylprednisolone, 0.5 mg/kg of body weight, or placebo every 6 h intravenously for 72 h. Bedside spirometry was done before and after bronchodilator inhalation three times daily. The methylprednisolone-treated group had a greater improvement in both prebronchodilator and postbronchodilator forced expiratory volume in 1 second (P less than 0.001). More patients with large improvements in their prebronchodilator or postbronchodilator flow rates, or both (greater than or equal to 40% by 72 h), received methylprednisolone (P less than 0.01). Methylprednisolone improved airflow more than placebo when added to standard therapy in patients with chronic bronchitis and acute respiratory insufficiency.

Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.

Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD

BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs.

The possibility that surface tension may affect the hydrostatic transmural pressure of pulmonary vessels and the development of pulmonary edema was studied in anesthetized, open-chested dogs. Isogravimetric pressure (the static intravascular pressure at which transmural osmotic and hydrostatic pressures are balanced such that net fluid flux is zero and lung weight is constant) was measured in nine animals under three conditions: (a) control, normal surface tension, at an alveolar pressure of 30 cm H2O with the apenic lung at room temperature; (b) after increasing surface tension by cooling and ventilating at a low functional residual capacity, at an alveolar pressure sufficient to produce the same lung volume present during control measurements; and (c) after restoring surface tension by rewarming while holding the lung at a high inflation volume, again at the control lung volume. Lung volumes were established from external dimensions and confirmed +/- 10% by deflation spirometry. The isogravimetric pressure (relative to alveolar pressure) was significantly less with increased surface tension than during either the initial control condition (P less than 0.01), or when the surface tension has been restored (P less than 0.01). Similar changes occurred in each of three additional studies performed with control alveolar pressures of 10 cm H2O. Thus, increased surface tension favors fluid leakage presumably because it increases the microvascular transmural pressure.

Chronic Macrolide Therapy in Inflammatory Airways Diseases

Long-term therapy with the macrolide antibiotic erythromycin was shown to alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since that time, macrolides have been found to have a large number of antiinflammatory properties in addition to being antimicrobials. These observations provided the rationale for many studies performed over the last decade to assess the usefulness of macrolides in other inflammatory airways diseases, such as cystic fibrosis, asthma, COPD, and bronchiolitis obliterans syndrome. This review summarizes the immunomodulatory properties of macrolides and the results of these recent studies demonstrating their potential for being disease-modifying agents.

Role of macrolide therapy in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability worldwide. The Global Burden of Disease study has concluded that COPD will become the third leading cause of death worldwide by 2020, and will increase its ranking of disability-adjusted life years lost from 12th to 5th. Acute exacerbations of COPD (AECOPD) are associated with impaired quality of life and pulmonary function. More frequent or severe AECOPDs have been associated with especially markedly impaired quality of life and a greater longitudinal loss of pulmonary function. COPD and AECOPDs are characterized by an augmented inflammatory response. Macrolide antibiotics are macrocyclical lactones that provide adequate coverage for the most frequently identified pathogens in AECOPD and have been generally included in published guidelines for AECOPD management. In addition, they exert broad-ranging, immunomodulatory effects both in vitro and in vivo, as well as diverse actions that suppress microbial virulence factors. Macrolide antibiotics have been used to successfully treat a number of chronic, inflammatory lung disorders including diffuse panbronchiolitis, asthma, noncystic fibrosis associated bronchiectasis, and cystic fibrosis. Data in COPD patients have been limited and contradictory but the majority hint to a potential clinical and biological effect. Additional, prospective, controlled data are required to define any potential treatment effect, the nature of this effect, and the role of bronchiectasis, baseline colonization, and other cormorbidities.

Predictors of Chronic Obstructive Pulmonary Disease Exacerbation Reduction in Response to Daily Azithromycin Therapy

RATIONALE Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. OBJECTIVES To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. METHODS Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. MEASUREMENTS AND MAIN RESULTS Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71-1.38; P = 0.95). CONCLUSIONS Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).

A structured handoff program for interns.

Purpose To develop, teach, and supervise a structured process for handing off patient care and to evaluate its effect on interns’ knowledge, skills, and attitudes toward handoffs. Method The authors developed a formal process for interns on the medicine ward services to hand off patient care at their teaching hospital. In July 2006, attending physicians began to teach and supervise the process. To evaluate the entire structured handoff program (the process, teaching, and supervision), interns were surveyed on the first day and during the last week of each of their month long rotations. Results From June through December 2006, the authors obtained 137 of 144 surveys (95% response) they had administered to 72 consecutive interns rotating through the hospital. During the first three months of the academic year, first-year interns had little confidence in their ability to hand off patients, make contingency plans, or perform read-backs when they began their rotations, but after exposure to the handoff program, their perceptions of these abilities increased (all P < .05). Eighty-five percent of the interns felt that attending supervision of the handoff process was useful or extremely useful, but only 51% viewed the lecture/small-group session about handoffs as useful. Conclusions The structured handoff program improved the participating interns’ perceptions of their knowledge of the handoff process and their ability to transfer the care of their patients effectively. The formal program for teaching handoffs, that included attendings’ supervision of the process, was well received.

Imitators of the ARDS Implications for Diagnosis and treatment

A cute lung injury (ALI) and ARDS (ALI/ARDS) are defined as follows: (1) an illness having an acute onset, (2) an arterial oxygen tension/inspired oxygen fraction 200 mm Hg (or 300 mm Hg for ALI), (3) the presence of bilateral infiltrates on frontal chest radiographs, and (4) a pulmonary artery occlusion pressure 18 mm Hg if measured, or no clinical evidence of left atrial hypertension when not measured.1,2 There are a group of diffuse, noninfectious parenchymal lung diseases that often present in an acute fashion and fulfill all of the clinical, physiologic, and radiographic criteria for ALI/ARDS. Some of these have distinct BAL characteristics and/or specific histologic findings. It is important to distinguish these from ALI/ARDS because most cases seem to respond to the early initiation of systemic corticosteroid therapy. In addition, studies evaluating novel interventions for ALI/ARDS should not include these patients because their outcomes are dissimilar from ALI/ARDS. This opinion article summarizes what is known about these diffuse noninfectious parenchymal diseases and focuses on the differences in their histologies, BAL findings, prognoses, and treatment responsiveness. We suggest that these conditions should be considered, prompting further diagnostic testing, in every patient thought to have ALI/ARDS ascribed to “pneumonia,” and in those without a well-recognized predisposing factor.