Mark D. Eisner

Lebrikizumab Treatment in Adults with Asthma

BACKGROUND Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. METHODS We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. RESULTS At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). CONCLUSIONS Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).

An Official American Thoracic Society Public Policy Statement: Novel Risk Factors and the Global Burden of Chronic Obstructive Pulmonary Disease

RATIONALE Although cigarette smoking is the most important cause of chronic obstructive pulmonary disease (COPD), a substantial proportion of COPD cases cannot be explained by smoking alone. OBJECTIVES To evaluate the risk factors for COPD besides personal cigarette smoking. METHODS We constituted an ad hoc subcommittee of the American Thoracic Society Environmental and Occupational Health Assembly. An international group of members was invited, based on their scientific expertise in a specific risk factor for COPD. For each risk factor area, the committee reviewed the literature, summarized the evidence, and developed conclusions about the likelihood of it causing COPD. All conclusions were based on unanimous consensus. MEASUREMENTS AND MAIN RESULTS The population-attributable fraction for smoking as a cause of COPD ranged from 9.7 to 97.9%, but was less than 80% in most studies, indicating a substantial burden of disease attributable to nonsmoking risk factors. On the basis of our review, we concluded that specific genetic syndromes and occupational exposures were causally related to the development of COPD. Traffic and other outdoor pollution, secondhand smoke, biomass smoke, and dietary factors are associated with COPD, but sufficient criteria for causation were not met. Chronic asthma and tuberculosis are associated with irreversible loss of lung function, but there remains uncertainty about whether there are important phenotypic differences compared with COPD as it is typically encountered in clinical settings. CONCLUSIONS In public health terms, a substantive burden of COPD is attributable to risk factors other than smoking. To prevent COPD-related disability and mortality, efforts must focus on prevention and cessation of exposure to smoking and these other, less well-recognized risk factors.

Recent Trends in Acute Lung Injury Mortality: 1996-2005

Objective:Studies from single centers have suggested that mortality from acute lung injury (ALI) has declined over time. However, recent trends in ALI mortality from centers across the United States are unknown. We sought to determine whether recent advances in the treatment of ALI and related critical illnesses have resulted in decreased mortality from ALI. Design:Retrospective cohort study of patients enrolled in the Acute Respiratory Distress Syndrome (ARDS) Network randomized controlled trials. Setting:Adult intensive care units participating in the ARDS Network trials. Patients:2,451 mechanically ventilated patients with ALI enrolled in the ARDS Network randomized controlled trials between 1996 and 2005. Measurements and Main Results:Crude mortality was 35% in 1996–1997 and declined during each subsequent time period to a low of 26% in 2004–2005 (test for trend p < 0.0005). After adjusting for demographic and clinical covariates, including receipt of lower tidal volume ventilation and severity of illness, the temporal trend persisted (test for trend p = 0.002). When analyzed by individual causes of lung injury, there were not any statistically significant temporal trends in 60-day mortality for the most common causes of lung injury (pneumonia, sepsis, aspiration, and trauma). Conclusions:Over the past decade, there seems to be a clear temporal improvement in survival among patients with ALI treated at ARDS Network centers. Our findings strongly suggest that other advancements in critical care, aside from lower tidal volume ventilation, accounted for this improvement in mortality.

The occupational burden of chronic obstructive pulmonary disease

Although chronic obstructive pulmonary disease (COPD) is attributed predominantly to tobacco smoke, occupational exposures are also suspected risk factors for COPD. Estimating the proportion of COPD attributable to occupation is thus an important public health need. A randomly selected sample of 2,061 US residents aged 55–75 yrs completed telephone interviews covering respiratory health, general health status and occupational history. Occupational exposure during the longest-held job was determined by self-reported exposure to vapours, gas, dust or fumes and through a job exposure matrix. COPD was defined by self-reported physicians diagnosis. After adjusting for smoking status and demography, the odds ratio for COPD related to self-reported occupational exposure was 2.0 (95% confidence interval (CI) 1.6–2.5), resulting in an adjusted population attributable risk (PAR) of 20% (95% CI 13–27%). The adjusted odds ratio based on the job exposure matrix was 1.6 (95% CI 1.1–2.5) for high and 1.4 (95% CI 1.1–1.9) for intermediate probability of occupational dust exposure; the associated PAR was 9% (95% CI 3–15%). A narrower definition of COPD, excluding chronic bronchitis, was associated with a PAR based on reported occupational exposure of 31% (95% CI 19–41%). Past occupational exposures significantly increased the likelihood of chronic obstructive pulmonary disease, independent of the effects of smoking. Given that one in five cases of chronic obstructive pulmonary disease may be attributable to occupational exposures, clinicians and health policy-makers should address this potential avenue of chronic obstructive pulmonary disease causation and its prevention.

Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING 193 investigational sites in the United States and 4 sites in Canada. PATIENTS 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE Genentech and Novartis Pharmaceuticals.

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury

Objectives: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. Design, setting and participants: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. Measurements and main results: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). Conclusions: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease.

BackgroundExposure to environmental tobacco smoke (ETS), which contains potent respiratory irritants, may lead to chronic airway inflammation and obstruction. Although ETS exposure appears to cause asthma in children and adults, its role in causing COPD has received limited attention in epidemiologic studies.MethodsUsing data from a population-based sample of 2,113 U.S. adults aged 55 to 75 years, we examined the association between lifetime ETS exposure and the risk of developing COPD.Participants were recruited from all 48 contiguous U.S. states by random digit dialing. Lifetime ETS exposure was ascertained by structured telephone interview. We used a standard epidemiologic approach to define COPD based on a self-reported physician diagnosis of chronic bronchitis, emphysema, or COPD.ResultsHigher cumulative lifetime home and work exposure were associated with a greater risk of COPD. The highest quartile of lifetime home ETS exposure was associated with a greater risk of COPD, controlling for age, sex, race, personal smoking history, educational attainment, marital status, and occupational exposure to vapors, gas, dusts, or fumes during the longest held job (OR 1.55; 95% CI 1.09 to 2.21). The highest quartile of lifetime workplace ETS exposure was also related to a greater risk of COPD (OR 1.36; 95% CI 1.002 to 1.84). The population attributable fraction was 11% for the highest quartile of home ETS exposure and 7% for work exposure.ConclusionETS exposure may be an important cause of COPD. Consequently, public policies aimed at preventing public smoking may reduce the burden of COPD-related death and disability, both by reducing direct smoking and ETS exposure.

Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury

Background: Because injury to the alveolar epithelial barrier is a characteristic feature of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), plasma surfactant protein levels may have prognostic value. To test this hypothesis plasma surfactant proteins A and D (SP-A and SP-D) levels were measured in patients with ALI or ARDS enrolled in the NHLBI sponsored multicentre ARDS Network randomised controlled trial of a 6 ml/kg v 12 ml/kg tidal volume strategy. Methods: Data from 565 participants in the clinical trial were used. Plasma levels of SP-A and SP-D were measured at baseline and on day 3 after the start of the mechanical ventilation protocol. The longitudinal impact of baseline plasma surfactant protein levels on clinical outcomes was examined by multivariate analysis, controlling for mechanical ventilation group, APACHE III score, and other clinical covariates. The effect of 6 ml/kg tidal volume ventilation on plasma SP-A and SP-D levels was evaluated using analysis of covariance. Results: Baseline plasma SP-A levels were not related to any clinical outcome. In contrast, higher baseline plasma SP-D levels were associated with a greater risk of death (OR 1.21 per 100 ng/ml increment; 95% CI 1.08 to 1.35), fewer ventilator-free days (mean decrease −0.88 days; p=0.001), and fewer organ failure-free days (mean decrease −1.06 days; p<0.0001). The 6 ml/kg tidal volume strategy had no effect on the rise in plasma SP-A levels (p=0.91) but attenuated the rise in plasma SP-D levels (p=0.0006). Conclusions: Early in the course of ALI/ARDS an increased level of plasma SP-D is associated with a worse clinical outcome. The 6 ml/kg tidal volume strategy attenuated the rise of SP-D early in the clinical course. Taken together, these observations indicate that plasma SP-D, a product of alveolar type II cells, is a valuable biomarker in ALI/ARDS.

The work impact of asthma and rhinitis: Findings from a population-based survey

Asthma and rhinitis are common chronic conditions that affect adults of working age. Little is known about their relative impacts on work loss and decreased productivity. Using random digit telephone dialing, we carried out a population-survey of adults in Northern California aged 18-50 years. We interviewed 125 persons with asthma (with or without concomitant rhinitis) and 175 persons with rhinitis alone. Study eligibility was based on subject report of a physicians diagnosis of asthma and/or a rhinitis-related condition. Any adult labor force participation since condition onset was lower among those with asthma (88%) than among those with rhinitis alone (97%) (P = 0.002). In contrast, among those still employed, decreased job effectiveness was more frequently reported in the rhinitis group (43 of 121; 36%) compared to those with asthma (14 of 72; 19%) (P = 0.02). Condition-attributed lost work was common in both groups, with more than 20% reporting one or more complete or partial work days lost in the 4 weeks previous to interview. Taking into account age, gender, race, and smoking status, those with asthma were more likely to have no labor force participation after diagnosis (OR = 3.0; 95% CI 1.1-7.7) and less likely to report decreased job effectiveness among those remaining employed (OR = 0.4; 95% CI 0.2-0.9). Excluding subjects from the rhinitis group most likely to have unreported asthma based on past medication use had little impact on these associations. Both asthma and rhinitis negatively affect work productivity. Those with asthma are less likely to be employed at all, while among those remaining on the job, rhinitis is a more potent cause of decreased work effectiveness. The economic impact of asthma and rhinitis and related conditions may be under-appreciated.

Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

RATIONALE Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.