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The article presents a study on the efficacy and safety of the interleukin-5 receptor alpha-directed cytolic monoclonal antibody Benralizumab for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. Topics include the use of placebos to test the efficacy of benralizumab, and the tendency for benralizumab to not be associated with a lower annualized rate of COPD exacerbations than placebo among patients.

Background: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms., Methods: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end., Results: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure., Conclusions: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Background: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV(1)), but data on the variability and determinants of this change in patients who have established disease are scarce., Methods: We analyzed the changes in FEV(1) after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV(1) levels and their changes over time., Results: The mean (±SE) rate of change in FEV(1) was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV(1) of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV(1) that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV(1) was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility., Conclusions: The rate of change in FEV(1) among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema.

Some patients with chronic airflow obstruction experience dyspnea with mild arm exercise but not with more-intense leg exercise. To investigate why these patients have limited endurance during arm exertion, we studied ventilatory responses to exercise with unsupported arms in 12 patients with chronic airflow obstruction (mean [+/- SD] forced expiratory volume in one second, 0.68 +/- 0.28 liters). Unloaded leg cycling was also studied for comparison. In the five patients who had the most severe airflow obstruction, arm exercise was limited by dyspnea after 3.3 +/- 0.7 minutes, and dyssynchronous thoracoabdominal breathing developed. In the other seven patients, arm exercise was limited by the sensation of muscle fatigue after 6.1 +/- 2.0 minutes (P less than 0.05), and dyssynchronous breathing did not occur. None of the 12 patients had dyssynchronous breathing during unloaded leg cycling. Maximal transdiaphragmatic pressure, a measure of diaphragmatic fatigue, declined similarly after arm and leg exercise in both groups. During unsupported arm work, the accessory muscles of inspiration help position the torso and arms. We hypothesize that the extra demand placed on these muscles during arm exertion leads to early fatigue, an increased load on the diaphragm, and dyssynchronous thoracoabdominal inspirations. This sequence may contribute to dyspnea and limited endurance during upper-extremity exercise.

Gram-negative nosocomial pneumonia may result from retrograde colonization of the pharynx from the stomach, and this may be more likely when the gastric pH is relatively high. We studied the rate of nosocomial pneumonia among 130 patients given mechanical ventilation in an intensive care unit who were receiving as prophylaxis for stress ulcer either sucralfate (n = 61), which does not raise gastric pH, or conventional treatment with antacids, histamine type 2 (H2) blockers, or both (n = 69). At the time of randomization to treatment, the two groups were similar in age, underlying diseases, and severity of acute illness. Patients in the sucralfate group had a higher proportion of gastric aspirates with a pH less than or equal to 4 (P less than 0.001) and significantly lower concentrations of gram-negative bacilli (P less than 0.05) in gastric aspirates, pharyngeal swabs, and tracheal aspirates than did patients in the antacid-H2-blocker group. The rate of pneumonia was twice as high in the antacid-H2 group as in the sucralfate group (95 percent confidence interval, 0.89 to 4.58; P = 0.11). Gram-negative bacilli were isolated more frequently from the tracheal aspirates of patients with pneumonia who were receiving antacids or H2 blockers. Mortality rates were 1.6 times higher in the antacid-H2 group than in the sucralfate group (95 percent confidence interval, 0.99 to 2.50; P = 0.07). Although our results fell just short of statistical significance when they were analyzed according to intention to treat, they suggest that agents that elevate gastric pH increase the risk of nosocomial pneumonia in patients receiving ventilation by favoring gastric colonization with gram-negative bacilli. We conclude that in patients receiving mechanical ventilation, the use of a prophylactic agent against stress-ulcer bleeding that preserves the natural gastric acid barrier against bacterial overgrowth may be preferable to antacids and H2 blockers.